Devices for treating defects in the tissue of a living being

The present invention generally relates to medical devices and treatment methods, and in particular to devices and methods for treating defects in living tissues.

To better treat us aging humans, doctors are looking for new and better products and methods that will provide rapid cure for musculoskeletal injuries and degenerative diseases by strengthening the mechanisms of the human body itself. Treatment of these deficiencies has traditionally relied on the inherent self-healing ability of this type of tissue. In many cases, the body cannot repair such defects in a reasonable amount of time, even if it can be repaired. Advances in biomaterials have enabled devices that facilitate wound healing of both bone and soft tissue defects and injuries. Such devices have been used for tissue regeneration as a tissue (eg, bone) graft skeleton for use in trauma and spine, as well as for delivery of drugs and growth factors.

Bone and soft tissue repair is needed to treat various medical (eg, surgical) conditions. For example, when hard tissue such as bone is damaged as a result of illness or injury, it is often necessary to provide implants or grafts to strengthen the damaged bone during the healing process to further prevent damage and stimulate repair. .. Such implants can take many forms (eg, plugs, putties, rods, pegs, wedges, screws, plates, etc.) and are placed within the tissue. Generally, such implants can be rigid, soft, deformable or fluid, and can be made in a variety of shapes and sizes. In the case of rigid implants (eg bone screws), the injured part is usually in preparation for applying the implant by forming a depression, passage or other form (eg, pre-plugged hole) in it. , The conditions are set in advance. For conveniently used non-rigid structural restoration materials (eg putty and glue), they must be able to form a variety of complex shapes to fit the contours of the restoration site. Precisely constructed implants that substantially fill the injured site improve natural bone and tissue integration and reduce recovery time. For example, when repairing a bone defect, close contact between the natural bone and the bone substitute is often desired to transmit the load in order to promote bone remodeling and regeneration, which results in the graft. Is taken up by the host bone.

Current bone graft materials include autologous grafts (use of patient bone), allogeneic grafts (use of corpse bone), and various other artificial or synthetic bone replacement materials. Autologous grafts are usually composed of cancellous bone and / or cortical bone. Cancellous bone grafts exhibit essentially minimal structural integrity. Bone strength increases as the implant takes up surrounding cells and new bone is deposited. In the case of cortical bone, the graft initially exhibits some structural strength, but as it is taken up by the host bone, the non-growth bone is removed by reabsorption, resulting in a significant decrease in the strength of the graft. It ends up. There is a limit to the amount of bone that can be collected from an autologous graft because the use of autologous grafts can lead to severe distress in the patient and other complications at the site of collection. Allogeneic grafts are similar to autologous grafts in that they are composed of cancellous bone and / or cortical bone, and generally larger quantities and sizes are available. Disadvantages of allografts include limited supply of materials and the potential for transmission of the disease. Due to the shortcomings of existing products, there is a need for better devices and methods for treating defects in living tissues.

Collagen is the most abundant protein in the body. Collagen's unique chemistry makes it an ideal material for structural and hemostatic applications in both clinical and diagnostic environments. Collagen, like all other proteins, is composed of peptides or amino acids that are covalently linked via amide bonds. The amino acid sequence, or primary structure, outlines the three-dimensional structure of the protein, which determines the function and properties of the molecule. Collagen is composed of three peptide chains linked in a triple helix arrangement. These triple helices combine to form fibrils, which ultimately create connective tissue and other structural elements.

Collagen has been used in a number of applications in the art. For example, one use is for hemostatic devices to stop bleeding, which are described, for example, in US Pat. Nos. 5,310,407 (Casal) and 4,890,612 (Kensey). However, neither of them teaches the use of natural insoluble fibrous collagen. In U.S. Pat. No. 5,425,769, Snyders, Jr. is biocompatible and biocompatible, consisting of reduced fibrillar collagen in a calcium sulfate dihydrate matrix and having the same physical and chemical properties as bone. It discloses a bone substitute having reabsorption. The proportions of calcium sulphate and collagen are adjusted for each application, and this bone substitute is in It is formed in situ to form a solid layer. Similarly, US Pat. No. 5,425,770 (Piez et al.) Is made from calcium phosphate particulate inorganics such as hydroxyapatite or tricalcium phosphate containing atelopeptide reduced fibrous collagen for conductive bone repair. The composition is disclosed. U.S. Pat. No. 5,904,718 (Jefferies) describes methods and inventions involving dechlorinated bone particles and collagen. Examples of medical implants utilizing reduced fibrous collagen include US Pat. Nos. 4,642,117 (Nguyen et al.), 4,795,467 (Piez et al.) And 5,997,896 (Carr et al.). All of the above 718, 769 and 770 patents require the use of reduced fibrous collagen.

U.S. Pat. Nos. 4,563,350 and 4,888,366 each describe the use of freeze-dried, preformed, bone-inducing factor collagen carriers in bone repair. When used as preformed solid implants, these carriers are generally composed of ceramic materials held together by collagen. Similarly, US Pat. No. 4,776,890 describes a non-crosslinked collagen / inorganic implant that can be moistened prior to implantation and molded into the desired shape. In the patent, cross-linking is described as undesirable because it has an inhibitory effect on internally grown bone. U.S. Pat. Nos. 4,795,467, 5,035,715 and 5,110,604 describe porous collagen-containing implants for bone repair and / or wound healing. U.S. Pat. No. 4,948,540 (Nigam) describes certain fibrous natural collagens used as hemostatic bandages. These references do not teach or propose solutions to the universal problems of high porosity and excessive elasticity of collagen-containing implant materials for bone defect repair.

Devices made from compressed collagen matrix include those from Robinson et al. (Cardiovasc Intervent Radiol 1990; 13: 36-39), which were made from Gelfoam (Parmacia & Upjohn, Kalamazoo, Michigan). It describes the repair of a biopsy tract defect in the lung using a compressed collagen plug. Armstrong et al. (Arch Dermatol 1986; 122: 546-549) describe the repair of skin wounds in biopsy using a compressed collagen plug made from Helistat (Integra Life Sciences). All of these references teach the use of collagen, but none of them teach the use of the multilayer composition of the invention, and the function of these devices is to stop bleeding from puncture. It is not for regenerating tissue.

Therefore, there is still a need for a defect filling material that is collagen-based, has improved mechanical stability, has sufficient density, and is well suited for medical or surgical use.

U.S. Pat. No. 6,110,484 (Sierra) describes implants that are formed in situ and contain a biodegradable porosifying agent. However, the embodiment is a pre-formed solid plug, and since the porosity is not rapidly induced after transplantation, a bone-inducible structure is not formed. Therefore, there is a demand for implants that are rapidly porousd after implantation.

Various embodiments of these devices include polysaccharides in their components. Polysaccharides are key components of the extracellular matrix component of bone and related tissues because of their hydrophilicity and important structural aspects. When incorporated into medical implants, polysaccharides also impart hydrophilicity, assist in controlling the wound healing response associated with the implant, and even improve cell connectivity. Combinations of polysaccharides and collagen are described in US Pat. Nos. 4,614,794 (Easton et al.) And 5,972,385 (liu et al.). The 794 patent is limited to production by the hydrolysis process and must be crosslinked in the equipment of the 385 patent. Therefore, there is a demand for polysaccharides that are not limited to production from the hydrolysis process and do not require cross-linking.

Dechlorinated bone alone can be effective in repairing bone defects, but since bone is a natural substance, there are many inconsistencies. Approaches for harvesting these inorganic components include bone degreasing, grinding, calcining, and calcining or overheating. However, the resulting natural bone-inorganic mixture is chemically and physically variable. In addition, allogeneic bone from corpses is carefully harvested under strict conditions and properly stored in tissue banks to prevent possible immune complications or transmission of possible viral or bacterial pathogens. There must be. Sterilization of dechlorinated bone by methods such as gamma irradiation can change the physicochemical properties that are important for bone induction. Irradiation of dechlorinated bone powder prior to transplantation has been shown to reduce the bone formation response by approximately 20%. Therefore, the use of natural bone as an implant is so difficult that there is still a demand for synthetic bone replacement materials.

U.S. Pat. No. 5,425,769 (Snyders, Jr. et al.) Incorporates calcium phosphate granules in a binding matrix such as roasted soap or in soluble or reduced fibrous collagen to handle calcium phosphate implants and bones. It is taught that many attempts have been made to improve the forming ability. This will improve the workability of the implant and promote internal growth of the bone due to partial reabsorption of the implant. Disadvantages of this complex include the inability of the malleable collagen matrix to take a solid state in vivo and the resistance of the solidified plaster matrix to molding. This is overcome by the present invention, which is uniquely formulated with soluble natural fibrous collagen that remains strong after transplantation without the need for ceramic additives, although it is still somewhat compliant. I'm thinking of a usable improvement for.

In US Pat. No. 4,394,370, Jefferies describes implants made from reduced collagen and mineral-depleted bone or other bone morphogenic proteins that cause bone formation when implanted in bone. This collagen may be chemically crosslinked. The physical properties of these corpus cavernosum are not specified in this disclosure, but reports dealing with similar collagen cavernosa have shown that these materials are very weak and are quickly reabsorbed (wet tear strength (wet tear strength). It has been shown that there is no wet tear strength) and it is reabsorbed in 1 to 2 weeks).

In addition, in US Pat. No. 4,430,760, Smestad describes implants consisting of dechlorinated bone or dentin in a container made of fibers such as collagen or microporous membranes. The pores of the implant are sized to selectively allow bone cells and interfilled cells to pass through and not through particulate dechlorided bone or dentin. The problem with this patent is that it cannot be used where it is loaded. Therefore, there is a need for implants that maintain structural or mechanical integrity after implantation.

In US Pat. No. 4,440,750, Glowacki et al. Describe water-dispersible reduced collagen mixed with dechlorinated bone powder used to induce bone formation. The use of this implant material is limited because it has little physical strength and mechanical properties. In addition, over time, the dechlorinated bone particles suspended in the aqueous collagen sol-gel begin to settle due to gravity, resulting in the formation of non-uniform or stratified graft material. On the other hand, since the present invention provides strength and does not utilize sol-gel processing, it is possible to avoid sedimentation of any gel component or unintended non-uniformity. In addition, US Pat. No. 4,485,097 (Bell) describes a material composed of hydrated collagen lattice, fibroblasts, and dechlorinated bone powder. Since this material exists in the form of a hydrated collagen gel, its physical strength, or mechanical integrity, is extremely low. Therefore, this material cannot overcome the above-mentioned drawbacks in the art.

In US Pat. No. 4,623,553, Ries et al. Describe how to produce a bone replacement material consisting of collagen and hydroxyapatite and partially crosslinked with a suitable crosslinker such as glutaraldehyde or formaldehyde. The order in which these substances are added is such that the cross-linking agent is added to the water-dispersed collagen prior to the addition of the hydroxyapatite or calcium phosphate particulate material. The resulting dispersion is mixed and lyophilized. In the above 553 patent, none of the known bone formation-inducing factors such as dechlorinated bone matrix or extracted bone protein are described as constituents. Similarly, in U.S. Pat. Nos. 4,865,602 and 5,035,715 (Smestad et al.), A living body composed of atelopeptide fibrillar reduced collagen and an inorganic component which may be calcium phosphate, hydroxyapatite, or tricalcium phosphate. It describes how to make a compatible bone implant. In order for the implant to exhibit the desired handleability and mechanical properties for the implant, the implant has been sterilized with sufficient irradiation with gamma rays to cause collagen cross-linking. The above 602, 715 and 553 patents differ from the present invention in that they require cross-linking that is suspected of adversely affecting internal growth, and the above 602 and 705 patents are reduced. It contains a type collagen matrix.

In US Pat. No. 5,071,436, Huc et al. Disclose a new bone replacement biomaterial that is a combination of collagen, hydroxyapatite, and glycosaminoglycans that exists in the form of the corpus cavernosum. The concentration of glycosaminoglycan is preferably 1 to 2% per liter of 1% collagen gel. The concentrations of hydroxyapatite and collagen are preferably approximately equal, which is more than 6 times the concentration of the glycosaminoglycan component.

In US Pat. No. 5,320,844, Liu et al. Describe a composite material for hard tissue replacement that is similar in nature to natural bone. The homogeneous complex obtained by this synthesis contains a collagen component and a calcium phosphate-containing component precipitated from a liquid medium.

In US Pat. No. 5,711,957, Patat et al. Disclose an implant made from a porous calcium carbonate-based material as an outer wall that supports growth factors. The authors also do not need collagen when the outer wall is the only area that contains growth factors in the 957 patent above, but the implant is intended to be used as a bone-forming implant. And it teaches why they think it is unfavorable.

In US Pat. No. 5,904,718, Jefferies describes a chemically cross-linked matrix of dechlorinated bone particles or collagen that may or may not contain drugs or inorganic additives. In the above 718 patent, it is disclosed that it is possible to give mechanical strength to the composition by cross-linking. Further, in the above 718 patent, it is disclosed that a drug or an inorganic substance can be bound to an organic matrix by cross-linking. Embodiments of the invention do not rely on cross-linking for its strength, nor do they rely on cross-linking for binding to drugs or other therapeutic agents. This is an important feature of the present invention, as it has been shown by others that cross-linking inhibits tissue growth.

The fabrication and application of microspheres is known and examples such as the following are included by reference herein. U.S. Pat. No. 3,887,699 describes a solid biodegradable polymer spheroidal implant that incorporates a drug that is continuously released as the polymer spontaneously degrades in the human body. Many different methods have been developed for constructing this type of controlled emission system. A uniform matrix of polymers provides a simple and efficient structure for controlled release of drugs using microspheres, but many advanced therapeutic agent inclusion and release methods have been developed. U.S. Pat. No. 4,637,905 (Gardner) discloses a method of encapsulating a therapeutic agent inside a biodegradable polymer microsphere. U.S. Pat. No. 4,652,441 (Okada et al.) Discloses a method for using water-in-oil emulsions for long-term release of water-soluble drugs. The patent describes a wide variety of drugs that can be delivered via long-term release microcapsules, as well as polymeric materials and drug-retaining substances. It is believed that the system of the present invention can have beneficial effects on heart tissue by incorporating any of the drugs described in this patent. U.S. Pat. No. 5,718,921 (Mathiowitz et al.) Discloses a method for constructing a multilayer microsphere that can release two different drugs at a controlled rate or one drug at two different rates. U.S. Pat. No. 5,912,017 (Mathiowitz et al.) Also states that organic solvents are used to form bilayer microspheres by melting two different polymers and then combining them with the desired material and cooling. Is disclosed. Microspheres are not limited to water-soluble therapeutic agents only. See, for example, US Pat. No. 5,288,502 (McGinity et al.), Which discloses multi-layer microspheres capable of incorporating water-soluble and water-insoluble drugs.

The present invention includes various aspects. For example, systems and methods for treating tissues in vivo are provided. The present invention substantially comprises a synthetic tissue replacement material and a system and method for placing the implant. The main advantages and features of the various embodiments of the present invention include, but are not limited to, the following features.

(1) An object of the present invention is to provide an implant that is generally made from one or more biocompatible materials that function as a scaffold for the internal growth of tissue. Examples of materials include polymers (eg, polyester, collagen, polysaccharides), ceramics, and metals.

(2) An object of the present invention is to provide an implant capable of containing a material that maintains a required level of physical integrity after implantation.

(3) An object of the present invention is to provide an implant in which at least a part, if not all, is reabsorbed after being transplanted and no longer needed.

(4) An object of the present invention is to provide an implant that helps restore the mechanical, constructive, and structural capacity of a tissue defect being treated, that is, a bone void.

(5) An object of the present invention is to provide an implant containing a storage place for substances that support the internal growth of cells (for example, calcium salts, collagen, cytokines, drugs, etc.).

(6) An object of the present invention may provide a biologically acceptable and mechanically stable surface structure suitable for neoplasia, growth and development of new connective tissue (eg, non-calcified and calcified). To provide implants.

(7) An object of the present invention is to provide an implant capable of functioning as a carrier for other components of the present invention (eg, insoluble collagen, drugs, biologics, cells, etc.) having no mechanical and structural capabilities. It is in.

(8) An object of the present invention is as a carrier for other components of the present invention (for example, drugs, biologics, cells, radioisotopes, platelet-rich plasma, etc.) that advantageously treat the living body to be transplanted. The purpose is to provide functional implants.

(9) An object of the present invention is to provide an implant that provides a bone conduction matrix that provides a scaffold for internal growth of bone when used in bone applications and other applications described herein. is there.

(10) An object of the present invention is to provide an implant capable of incorporating a bone-inducing factor for providing a chemical substance that induces bone regeneration and repair.

(11) An object of the present invention is to provide an implant capable of incorporating osteogenic progenitor cells, which provide the basic structure of bone regeneration by its ability to differentiate into osteoblasts and osteoclasts.

(12) An object of the present invention is to provide an implant capable of providing a level of structural integrity suitable for the load applied by itself to a defect and surrounding tissue.

(13) An object of the present invention is to provide an implant capable of providing a biocompatible alternative for utilizing autologous bone (eg, bone from the iliac crest or rib) or other tissue for transplantation. There is.

(14) An object of the present invention is to provide an implant capable of creating an environment that promotes tissue regeneration (for example, bone formation) within its own authority.

(15) An object of the present invention is for biologically active agents (ie, chemotactic substances) or other osteoconductive / osteogenic agents, as well as other therapeutic substances (ie, antibiotics). To provide an implant that can function as a carrier.

(16) An object of the present invention is to provide an implant that reabsorbs or decomposes (at least partially) in several steps to internally grow new tissue and eliminates the need for a second operation to remove the implant. To do.

(17) An object of the present invention is to provide an implant that can impart structural integrity to an implant by utilizing natural fibrous collagen and that functions as an ideal substrate for tissue regeneration.

To this end, a preferred embodiment of the treatment system comprises a delivery device and an implant. The implant may comprise one or more biocompatible materials for introduction into the bone or other tissue to be treated. The delivery device is configured to introduce the implant into or near the target tissue so that the implant directly enters the target tissue at the entry position.

A preferred embodiment of the present invention comprises an implant comprising a tissue (eg, bone, cartilage, soft tissue, etc.) alternative material, and a method and system for placing the implant. Generally, the implants of the present invention are generally made from one or more biocompatible materials (eg, polymers, metals, ceramics) that act to heal wounds and act as the backbone of tissue internal growth. This implant contains a reservoir of substances that support the internal growth of cells (eg, calcium salts, collagen, cytokines, drugs, etc.) and functions to favorably treat the implant site in vivo. Can function as a carrier for the constituents of (see, eg, Tables 2-7 and the accompanying discussions, etc.). Some embodiments of the invention also incorporate cells or other biological components that are fundamental components in tissue regeneration.

Many substances can be used to construct the implants of our invention, or parts thereof. Biocompatible polymers (eg, collagen, chitosan, alginate, polylactide glycolide, polyurethane, polyethylene) are preferred for use in the present invention. Collagen, specifically natural fibrous collagen, is a preferred component of this implant, as described below. In addition, biocompatible reabsorptive synthetic polymers such as those listed in Table 1 may be used, but are not limited thereto. However, virtually any biodegradable and / or biocompatible material can be used in the present invention.

In the art, there are roughly three types of collagen that are generally useful as medical implant materials. These include collagen-based implants composed of soluble collagen, reduced collagen fibers or naturally insoluble collagen fibers.

First, "soluble collagen" refers to individual tropocollagen molecules that are soluble in the environment of an acidic aqueous solution. Tropocollagen can be regarded as a monomer unit of collagen fibers, and its triple helix structure is well known.

Second, "reduced collagen" is a collagen fiber segment that is substantially depolymerized into individual triple helix molecules, exposed to solution, and then assembled into a fibril-like shape. Therefore, the degree of polymerization of reduced collagen is between soluble fibrous collagen and natural insoluble fibrous collagen. In general, the drawback of reduced collagen is its mechanical strength, and its in vivo survival rate is inferior to that of natural (that is, natural) insoluble fibrous collagen.

Third, as used herein, "naturally insoluble collagen" means collagen that is insoluble in an alkaline aqueous solution or any inorganic salt solution without chemical denaturation, eg, hide, split. And other mammal or worm husks are included. For example, "natural insoluble collagen" can be produced from the dermis, the middle layer of hide in animals (eg, bovine, pig) located between grains and muscle tissue.

The term "bioabsorbable" is frequently used in this embodiment, as well as in the specification and claims. About the exact meaning and function of bioabsorbable materials (eg polymers) and how much they are "reabsorptive", "absorbent", "bioreabsorbable", "biodegradable" and "bioerosible" There is a debate among those skilled in the art as to whether it is different from. All of these materials are considered in this disclosure and all of them are combined as bioreabsorptive materials. That is, any alternative disclosed herein will include everything else.

Table 1: Examples of additional biodegradable polymers used to build the matrix of the invention Aliphatic polyester cellulose Kitchen collagen Glycolide copolymer Lactide copolymer Elastin Fibrin Glycolide / l-lactide copolymer (PGA / PLLA) Glycolide / trimethylene carbonate copolymer (PGA / TMC) Hydrogel Lactide / tetramethylglycolide copolymer Lactide / trimethylene carbonate copolymer Lactide / ε-caprolactone copolymer Lactide / σ-valerolactone copolymer L-lactide / dl-lactide copolymer Methyl Methacrylate-N-Vinylpyrrolidone Copolymer Denatured protein Nylon-2 PHBA / γ-hydroxyvalerate copolymer PLA / polyethylene oxide copolymer PLA / Polyethylene Oxide (PELA) Poly (amino acid) Poly (trimethylene carbonate) Polyhydroxy Fatty Acid Polymer (PHA) Poly (alkylene oxalate) Poly (butylene diglycolate) Poly (hydroxybutyrate) (PHB) Poly (n-vinylpyrrolidone) Poly (orthoester) Polyalkyl 2-cyanoacrylate Polyanhydride Polycyanoacrylic acid Polydepsipeptide Polydihydropyran Poly-dl-lactide (PDLLA) Polyester amide Oxalic acid polyester Polyglycolide (PGA) Polyimino carbonate Polylactic acid (PLA) Poly-1-lactide (PLA) Polyorthoester Poly-p-dioxanone (PDO) Polypeptide Polyphosphazene Polysaccharide Polyurethane (PU) Polyvinyl alcohol (PVA) Poly-β-hydroxypropionic acid (PHPA) Poly-β-hydroxybutyrate (PBA) Poly-σ-Valero Lactone Poly-β-carboxylic acid Poly-β-malic acid (PMLA) Poly-ε-caprolactone (PCL) Pseudo poly (amino acid) Starch Trimethylene carbonate (TMC) Tyrosine-based polymer

As described above, one of the preferred constituent materials of the apparatus is collagen, more specifically natural fibrous collagen. In one embodiment of the present invention, collagen is combined in two or more shapes to produce a unique composite material having multifaceted properties. Mechanically stable and well-shaped collagen-based implants are made by lyophilizing a special collagen suspension of natural insoluble collagen suspended in a soluble collagen slurry of favorable viscosity. .. In a preferred embodiment, the ratio of soluble fibrous collagen to insoluble fibrous collagen is kept in the range of approximately 1:20 to 10: 1 and the resulting product is approximately 5 to 95% of its original volume. It is compressed to. However, other constituent ratios and compression levels are available depending on the desired result. The material can be treated by any physical cross-linking technique known in the art (eg, thermal dehydration, gamma-ray irradiation, ethylene oxide or UV irradiation). Chemical cross-linking agents can use chemical cross-linking methods as long as the residual elements can interfere with the healing process but the addition does not have a detrimental effect. Implants made in this way are highly absorbent (ie, absorb 5 to 20 times their weight in isotonic saline) and are therefore carriers of other agents (drugs, biologics, cells, etc.). Very useful as. The implant can then be coated or impregnated with various other substances, or combined with these to improve mechanical properties or curability.

Since the collagen suspension in a preferred embodiment of the invention contains both soluble and insoluble collagen, the soluble and insoluble collagen fibers are first prepared separately and then combined. The soluble and naturally insoluble collagen fibers (natural collagen fibers) according to the present invention are preferably derived from bovine hide, but other collagen sources (eg bovine tendon, porcine tissue, recombinant DNA technology, fermentation, etc.). It can also be prepared from.

In order to create a polyphasic implant, for example, soluble fibrous collagen can be lyophilized and then optionally crosslinked to obtain a mechanically stable and porous collagen structure. The compression of the collagen sheet reduces the porosity of the structure and effectively increases the density of the implant. When transplanted, soluble collagen breaks down faster than natural fibrous collagen. Thus, soluble collagen behaves like a slow-acting "porous" agent, and its plug becomes more porous after transplantation. Substantial density of implant material changes, perhaps within the first 2-3 days after transplantation to receive optimal cell penetration. For example, plugs thus further facilitate cell penetration and binding to the remaining fibrous collagen backbone. This is important for the development of bone regeneration.

In yet another embodiment, a portion of the implant of the present invention can also be formed from a synthetic polymeric material (eg, PTFE, polylactic acid / glycolic acid, etc.). U.S. Pat. No. 5,683,459 (Brekke), assigned to the same business entity as the present invention and incorporated by reference herein, describes methods and devices for the treatment of bone defects using devices made from polymers. Has been done.

The devices of the invention (eg, implants, delivery systems) may include or deliver, for example, one or more biologically active agents or pharmaceuticals (ie, therapeutic agents) disclosed in Table 2, but are limited thereto. It is not something that will be done.

Table 2: Examples of biologics, pharmaceuticals and other active ingredients that can be delivered by the present invention. Adenovirus with or without genetic material Angioplasty Angiotensin converting enzyme inhibitor (ACE inhibitor) Angiotensin II antagonist Anti-angioplasty Antiarrhythmic drug Antibacterial drug Antibiotics erythromycin penicillin Anticoagulant Heparin Anti-growth factor Anti-inflammatory drug Dexamethasone aspirin Hydrocortisone Antioxidants Antiplatelet drug Forskolin Antiproliferative drug Anti-rejection drug Rapamycin Anti-restenosis drug Antisense Antithrombotic drug Argatroban Hirudin GPIIb / IIIa inhibitor Antiviral drug Arteriosclerosis Acid Fibroblast Growth Factor (aFGF) Angio Jenin Angiotropin Basic fibroblast growth factor (bFGF) Bone morphogenetic protein (BMP) Epidermal Growth Factor (EGF) Fibrin Granulocyte macrophage colony stimulating factor (GM-CSF) Hepatocyte growth factor (HGF) HIF-1 Insulin growth factor (IGF-1) Interleukin-8 (IL-8) MAC-1 Nicotinamide Platelet-derived endothelial cell growth factor (PD-ECGF) Platelet-Derived Growth Factor (PDGF) Transforming Growth Factors α and β (TGF-α, TGF-β) Tumor necrosis factor α (TNF-α) Vascular Endothelial Growth Factor (VEGF) Vascular Permeability Factor (VPF) Bacteria Beta blocker Blood coagulation factor Bone morphogenetic protein (BMP) Calcium channel blocker Carcinogen cell Bone marrow cells Blood cells Stem cells Umbilical cord cells Fat cells Bone cells Chondrocytes Chemotherapeutic agents (eg, ceramide, taxol, cisplatin) Cholesterol lowering drug Chondroitin Collagen inhibitor Colony stimulating factor Kumajin Cytokine prostaglandins Dentin Etretinate Genetic material Glucosamine Glycosaminoglycan GPIIb / IIIa inhibitor L-703,081 Granulocyte colony stimulating factor (GM-CSF) Growth factor antagonist or inhibitor Growth factors Acid Fibroblast Growth Factor (aFGF) Self-derived growth factors Basic fibroblast growth factor (bFGF) Bone morphogenetic proteins (BMPs) Pig-derived growth factors Cartilage-derived growth factor (CDF) Epithelial cell growth factor (ECGF) Epidermal Growth Factor (EGF) Fibroblast Growth Factor (FGF) Hepatocyte growth factor (HGF) Insulin-like growth factor (eg, IGF-I) Nerve Growth Factor (NGF) Platelet-derived endothelial cell growth factor (PD-ECGF) Platelet-Derived Growth Factor (PDGF) Recombinant NGF (rhNGF) Recombinant growth factor Tissue-derived cytokines Tissue necrosis factor (TNF) Transforming Growth Factor α (TGF-α) Transforming Growth Factor β (TGF-β) Tissue necrosis factor α (TNF-α) Vascular Endothelial Growth Factor (VEGF) Vascular Permeability Factor (UPF) Growth hormone Heparin Sulfate Proteoglycan HMC-CoA Reductase Inhibitor (Statin) hormone Ellis lopoietin immoxidal Immunosuppressive drug Inflammatory transmitter Insulin Interleukin Interleukin-8 (IL-8) Interlukin Fat reducing drug Lipoprotein Low molecular weight heparin lymphocytes Ricin MAC-1 Morphogen Nitric oxide (NO) nucleotide peptide PR39 protein Prostaglandin Proteoglycan Pearl Can Radioactive material Iodine-125 Iodine-131 Iridium-192 Palladium-103 Radiopharmaceutical Secondary transmitter Ceramide Somatomedin Statins steroid Sulfonyl Thrombin Thrombin inhibitor Thrombolytic drug Chikrid Tyrosine kinase inhibitor ST638 AG-17 Vasodilator histamine Forskolin Nitroglycerin vitamin E C yeast

Regardless of when these therapeutic agents are embedded or incorporated, they can take solid particulates, solution gels, or other deliverable forms. The use of gelled carriers may allow these materials to be contained for some adjustment period after wetting. In addition, additives may be incorporated into the macrostructure during or after production. Such incorporation may be made by injecting into a gel or solid material, or by blending or mixing the additive into a macro or microstructured material by a method known to those of skill in the art. Other methods of incorporating additives, biologics and other therapeutic agents into macrostructures or microstructures in one or more areas of the device are carried out by the method using microspheres.

As used herein, the term "microsphere" refers to a small additive that is approximately an order of magnitude smaller (at an approximate maximum relative size) than an implant. This term does not refer to a particular shape. That is, it is believed that a perfect sphere cannot be easily produced. In the present invention, an elongated sphere having an uneven shape is considered.

Microspheres can be made from a variety of materials such as polymers, silicon and metals. Biodegradable polymers are ideal for making microspheres (see, for example, the materials listed in Tables 2 and 3). Release of agents from bioreabsorptive microparticles depends on diffusion via microsphere polymers, polymer degradation, and microsphere structure. Most biocompatible polymers may be applicable to the present invention, but preferred materials exhibit in vivo degradation. It will be appreciated by those skilled in the art that other mechanisms such as hydrolysis, enzymatic degradation, and whole or surface erosion may be involved in implant degradation. These mechanisms can influence the host reaction alone or jointly by determining the amount and properties of degradation products released from the implant. Generally, in synthetic medical polymers such as polyester, polyamide and polyurethane The main mechanism involved in vivo degradation is thought to be hydrolysis, which breaks ester bonds and breaks chains. In extracellular fluid of living tissue, water is susceptible to hydrolytic chemical bonds, so that a water-absorbing polymer (that is, a polymer that sucks up a large amount of water) is susceptible to hydrolysis or total erosion. Some variables, such as crystallinity, molecular weight, additives, polymer surface morphology and environmental conditions, can affect the mechanism of polymer degradation and kinetics. Thus, the performance of the invention is modifiable to the extent that each of these properties can be tuned or altered.

In embodiments where the implant material for delivery of the therapeutic agent is homogeneous (ie, a single or complex of homogeneous dissimilar components), the device delivers the therapeutic agent over the entire degradation period of the device or over a period of time. Continue to release. In embodiments that incorporate microspheres, the therapeutic agent is released at a preferred rate, independent of the matrix reabsorption or degradation rate. In some applications, a sudden or delayed release of the active agent may be required. The device can also be designed so that two or more agents are delivered at different intervals and doses, and this time-stepped delivery does not include non-delivery pauses (ie, no therapeutic agent). Part) is possible, so that incompatible therapeutic agents can be delivered alternately. The rate of delivery can be influenced by the amount of therapeutic substance relative to the amount of reabsorption structure, or the rate of reabsorption of the structure.

Time-stepped delivery can be achieved via microspheres in many different ways. The concentration of the therapeutic agent may vary in the radial direction, i.e., there may be areas where there is little therapeutic agent or areas where there is no therapeutic agent at all. In addition, the therapeutic agent can be varied radially so that one therapeutic agent is delivered before the second therapeutic agent, thereby making the incompatible therapeutic agent a sphere of the same type. Can be delivered during the same transplant procedure using. Also, the composition of the spheres can be different between the spheres. That is, one sphere population may contain one agent and the rest may contain one or more other agents. These different spheres can each have different delivery rates. Finally, as in the previous example, different delivery rates but the same agent may be used, which allows for a sudden administration following a moderately maintained administration.

As will be described in more detail later, the acting substance may be any substance such as a therapeutic agent or an enzyme. The active substance is preferably a protein such as a degrading enzyme, a cytokine or a cytokine inhibitor, and more preferably a growth factor. As will be appreciated by those skilled in the art, combinations of agents may be used, and these agents, whether synthetic or natural, may be derived from a variety of sources, and recombinant methods may be used in their production. May be included. The amount of bioactive substance in the implant can be adjusted to achieve the desired administration. Preferably, the implant material contains approximately 0.01 ng to 300 mg of active substance per milliliter of the implant material. The device can contain higher or lower amounts, depending on the intended use of the device and the required activity level of the agent selected. The agent can be encapsulated within the implant by many techniques known to those of skill in the art.

The term "therapeutic agent" is used in various cases herein. Regardless of these various uses (often in combination with other substances (eg, drugs, biologics, agents, bioactive agents, etc.)), therapeutic agents are meant to exclude them. Rather, they are included, and vice versa. This usage herein is intended to describe possible treatment forms in more detail and does not limit the definition of terms. In addition, "bioactive agents" may be relatively inactive, but can provoke a response by occupying space or causing tissue strain or exfoliation.

In yet other embodiments, the implant may incorporate microparticles (eg, microspheres) that diffuse throughout its structure to deliver the therapeutic agent. As is known in the art, it is well known that microspheres are used for long-term controlled release of drugs or other beneficial substances. This is a highly developed technique used in many applications, and such microspheres are available from a variety of sources (eg Polymicrospheres, Indianapolis, Indiana). Microsphere structures typically consist of (a) a continuous drug layer (microcapsules) surrounded by a continuous barrier membrane or outer shell, and (b) a large number of domains in which the drug layer is uniformly scattered within the microspheres. The drug is dissolved or molecularly diffused into a shell structure that is subdivided into (c) a polymer matrix in which the drug is uniformly diffused throughout, and (d) a carrier material in which microspheres are adjusted. It consists of a structure that is present, or (e) a homogeneous solid. In the most common method of delivering a drug and other therapeutic agent using microspheres, these agents are uniformly included in the polymer matrix, but in the present embodiment, the therapeutic agent is delivered in chronological order. It is considered that the spheres are arranged so as to be non-uniform in the radial direction.

In the present invention, cellular additives can also be incorporated. Cellular material can be delivered with or independently of drug delivery. The cellular material may be present inside the implant, outside the implant, or may be included within the implant in a porous structure, laminate or other such embodiment. Cellular material may be added to the implant just before it is inserted into the body, or days or weeks before implantation so that more mature cells are placed when the device is implanted. May be grown on the implant. When cells are infused into an implant days or weeks prior to transplantation, the implant simulates an in vivo environment (eg, an environment in which blood or a substitute blood medium circulates at the appropriate pressure and temperature). Placed in an in vitro environment, cells can adapt to the intravascular environment. Implants inoculated with cells may be incubated under physiological conditions in this in vitro environment for several days prior to implantation into the body. Cell inoculation methods for various types of cells have been developed. Examples of cellular materials that can be inoculated into implants are listed in Table 3 below.

Table 3: Cellular materials deliverable by the present invention Fat cells Blood cells Bone marrow Cells with modified receptors or binding sites Endothelial cells Epithelial cells Fibroblasts Genetically modified cells Glycoprotein Growth factors Lipid Liposomes Macrophages Mesenchymal stem cells Progenitor cells Red blood cells Skeletal muscle cells Smooth muscle cells Stem cells Vesicle

It is also believed that sources of cytokines or growth factors (eg, platelet-rich plasma, bone marrow cells, etc.) can be delivered by the apparatus of the invention, whether synthetic, autologous, or heterologous. (For example, incorporation into an implant or delivery by a delivery system). For example, one of the first growth factors to initiate the cascade that triggers bone regeneration is known to be platelet-derived growth factor (PDGF) and transforming growth factor β (TGF-β). Each of these growth factors is obtained by degranulating platelets at the wound, defect or trauma site. It is believed that the increase of such platelets at the wound or trauma site may increase the healing rate and increase the proliferation required for bone regeneration.

The application of platelet-rich plasma (PRP) or other autologous blood components is one way to deliver high concentrations of autologous platelets. PRP is easily prepared by extracting a small amount of a patient's blood, further treating it, and separating and concentrating the patient's platelet-derived growth factor, for example, by concentration gradient centrifugation. In other preparation methods, water is removed from the soft layer and a filtration system is utilized to concentrate platelets and fibrinogen. It is believed that application of PRP or other self-growth factors to the wound site with the present invention increases the amount of PDGF and TGF-β available to activate the healing process. PRP can be prepared for treatment with a small amount of blood drawn by a doctor or nurse prior to surgery. Usually, 40 ml to 100 ml of blood is drawn before surgery and placed in a PRP preparation unit. SmartPREP (Harvest Technologies, Norwell, Mass.), And UltraConcentrator (Interpore) Cross, Irvine, Lifonia) has been shown to be an efficient device for producing PRP for use in surgery, clinic transplantation, and periodontal tissue.

Once the PRP is prepared, other additives (eg, activators, growth factors, drugs, chemicals, bone, etc.) can be added to the plasma. For example, the activator can be used to gel the PRP material prior to application to the implant device or delivery to the surgical site. Such activators include 5 ml of 10% calcium chloride supplemented with 5000 units of topical bovine thrombin (GenTrac, Middleton, Wisconsin). Depending on the fluidity of the PRP, the type and amount of activator can be adjusted. For example, in order to inject a PRP gel sample into the implant material of the present invention, PRP is contained in a larger proportion in the component ratio so that PRP can pass and penetrate through the porous implant material more efficiently. It is also believed that implant materials (eg, cylinders or other biomaterial implants) can be inserted into PRP preparation units (eg, centrifuges, concentrating units). Such a method allows for direct enrichment of platelets, at least directly on or in the implant. For example, one PRP device includes a centrifuge to separate blood components. The biomaterial implant can be positioned in the centrifuge so that the desired blood component is guided into the implant material during processing.

The benefits of applying autologous growth factors such as PRP will be doubled. First, the large amounts of fibrin and fibronectin components of PRP provide structural parts that allow progenitor cells to migrate and bone to grow, thus enhancing cell adhesion and inducing bone induction. Second, the action of PDGF and TGF-β formed as platelet degranulation is amplified. Addition of externally delivered high concentrations of PDGF and TGF-β promotes amplification of the cascade, which increases cell number and later expresses more growth factors. Such benefits can contribute to the healing process and can lead to faster and more effective tissue regeneration. This may be due to levels of fibrin, PDGF, TGF-β, as well as other unidentified growth factors or proteins.

Other autologous materials can also be incorporated into and / or used with the invention (eg, autologous bone marrow cells (BMC)). Bone marrow cells include bone marrow progenitor cells capable of bone formation and bone repair. Bone marrow can be harvested and dispersed into a single cell suspension. The cells can then be concentrated (eg, by filtration, centrifugation) or ready to use. The resulting mixture can be diluted and implanted at the wound site, incorporated into the implant material, or delivered by the delivery system of the invention.

The use of growth factors such as PRP, or progenitor cells from BMC, is generally a risk factor that reduces the success of bone grafting and bone integration, such as teethless, patients with severe atrophic maxilla, and patients with osteoporosis. Especially useful. Combining growth factors and progenitor cells with an absorptive delivery system can significantly alter the outcome we expect for induced tissue regeneration.

There are many other materials that can be used to build implants or parts thereof. Table 4 below lists some of the possible materials that can be used as fillers or main components. This list is not complete and is only presented as a non-limiting example of some of the materials that can be used in the present invention.

Table 4: Examples of suitable materials for fillers or main components of the invention Alginate calcium Calcium phosphate Calcium sulphate ceramic Chitosan Cyanoacrylate collagen Dacron Desalted bone Elastin Fibrin gelatin Glass Money hyaluronic acid Hydrogel Hydroxyapatite Hydroxyethyl methacrylate hyaluronic acid Liposomes Mesenchymal cells Nitinol Osteoblasts Redox cellulose Phosphate glass Polyethylene glycol polyester Polysaccharide Polyvinyl alcohol Platelets, blood cells Radiopacifiers salt silicon silk Steel (eg stainless steel) Synthetic polymer Thrombin Titanium

In addition to pure polymeric materials, additives may be combined with polymers to improve their mechanical, biological or reabsorption properties. Examples of additives may include plasticizers that make the polymer more elastic by altering the mechanical performance of the polymer, or make the polymer more plastically deformed. Other additives may be nanoparticles that can alter the reabsorption property of the polymer and increase its strength. Additives can be incorporated into polymers by standard dissolution formulations, solvent mixing, or other processes known in the art. Tables 5 and 6 show examples of plasticizers and nanoparticles, but are not limited to these.

Table 5: Polymeric plasticizers that may be useful in the present invention 1,2-Cyclohexadione Acetoxytriethyl citrate Acetylated coconut oil (EPZ) Acetyl Tri-n-Butyl Citrate Acetyl Tri-n-Hexyl Citrate Acetyltriethyl citrate Adipate ester Benzoic acid-2-hydroxyacetate Bis-2-methoxyethyl phthalate Calcium stearylate Camphor Caprolactone Citric acid ester Dibutyl phthalate Diethyl phthalate Dioctyl adipate Epoxy soybean oil Ethyl benzoate Ethyl, butyl, and hexyl esters of acetylated citric acid Lactic acid oligomer terminated with an ethyl group Glycerol Glyceryl triacetate Glycolide Hexamethylbenzene Lactide Flaxseed oil Lipid Liposomes N-butyltri-n-hexyl citrate oil Phthalic ester Polyurethane Stearyl acid Tributyl citrate Triethyl citrate

Table 6: Nanoparticles silica Clay metal Aluminum oxide ceramic polymer Metal oxide

When implanting material into living tissue (eg, for the treatment of wounds and defects), it is generally important that the implant is physically and chemically compatible with the host tissue. As used herein, "integration matching" refers to the process of varying the strength of an implant such that the strength obtained is consistent with or close to the strength of the organic host tissue. "Porosity matching" is a process of changing the pore structure (eg, size, shape and / or number) within an implant so that the resulting porosity matches or approximates the porosity of the organic host tissue. Say that. "Compression rate matching" refers to the process of matching the compressibility of an implant (elastic modulus and / or coefficient of restitution, etc.) so that the compressibility of the implant matches or approximately approximates the compressibility of the organic host tissue. "Structural matching" refers to any process used to create a structure that resembles a host tissue (eg, fibrous or other heterogeneous). "Weight matching" refers to the process of changing the molecular weight of the implant matrix so that the resulting molecular weight matches or approximately approximates the structure / molecular weight of the organic host tissue. These "matching" processes are called "biological matching" separately, together, or in any combination, and "biological matching" implants are created by using this biomatching process.

Some of the biomatched implants of one embodiment of the invention can be formed from ceramic materials such as calcium phosphate, calcium carbonate and calcium sulfate or other derivatives. Examples of products constructed from these materials include Osteoset (Trademark) from Wright Medical Technology, ProFusion (Trademark) from BioGeneration (Arlington, TEX), and Stimulan from Encore (Arlington, TEX). Includes Trademarks) (Austin, Texas), Norian's SRS (Cupertino, CA) and Interpore Cross's ProOsten (Irbin, CA).

There are many ceramics that are biocompatible and degradable. In the body, the bone itself is a natural inorganic reservoir. The major inorganic component of bone is hydroxyapatite, which is a form of calcium oxide. Other calcium phosphate salts in bone include monotite, blush stone, calcium pyrophosphate, tricalcium phosphate, octacalcium phosphate and non-crystalline calcium phosphate. In addition, bone contains calcium carbonate. Hydroxyapatite and tricalcium phosphate are the most widely studied calcium phosphates, each with a ratio of calcium to phosphate between 1.5 and 1.67. Calcium phosphate, Ca₁₀(PO₄)₆(OH)₂Is known as a physiologically acceptable biomaterial useful as a hard tissue prosthesis. Another calcium mineral used as a bone substitute is calcium sulphate. Most calcium-based biomaterials can be molded under high pressure, providing integrity and strength. The pores can help assist the host matrix during bone induction, and the pores can be formed in the formed calcium phosphate by compressing the calcium phosphate powder containing naphthalene and then removing naphthalene by leaching or sublimation.

Hydroexchange and hydrogen peroxide decomposition of marine coral structures (ie, calcium carbonate for calcium phosphate) are other techniques for producing pore-filled structures. The high-density shape of calcium phosphate implants has mechanical properties equal to or better than natural bone, but usually does not have its porous shape. Specific or other processing steps known to those of skill in the art, such as these, are used to adjust the physical and mechanical properties of the resulting implant.

In addition to drugs and biologics, a coating may be added to the implant to improve the performance of the device. The coating can increase lubricity to improve insertability, increase thrombus formation to promote hemostatic and platelet deposition, or provide other benefits to the implant. The coating can also be used as a mechanical barrier to protect the underlying cellular material, which can be incorporated onto the implant material to work with aspects of the agent delivery of the invention. Table 7 lists examples of possible coating materials.

In addition, one embodiment of the invention may comprise a calcium salt and a natural collagen matrix. This can be achieved by first preparing a special collagen suspension of naturally insoluble collagen fibers suspended in a soluble collagen slurry of preferred viscosity, in which insoluble fibers of soluble fibrous collagen. The ratio to quality collagen is kept in the range of approximately 1:20 to 10: 1. A calcium salt such as calcium sulfate is added to this slurry. It is desirable to add sufficient calcium salts to this slurry to ensure that the final product has a preferred weight ratio, i.e., a calcium salt between approximately 10% and 90%. The final product can be made in many ways. In one of these methods, the solution is completely homogenized and then poured into a mold of the desired shape and thickness, i.e. a large sheet, which is known in the art to be sufficient for such applications. It is known that there are other technologies that have been used. This product is lyophilized as described above. Materials thus produced can also be subjected to any cross-linking treatment (chemical treatment, thermal dehydration treatment, gamma irradiation treatment, ethylene oxide treatment or UV irradiation treatment), as will be understood by those skilled in the art upon examination of this disclosure. May be processed with.

Table 7: Examples of materials used for coating of the present invention albumin Alkyl methacrylate Glycosaminoglycan Heparin hyaluronic acid Absorbent polymer Integrin Parilen Phosphorylcholine Phospholipids Polyacrylamide Polyanhydride Polyethylene acetate Polyethylene glycol Polyethylene oxide Polypeptide Polyurethane Polyvinyl alcohol Polyvinylpyrrolidone Silane silicon

The implants of the present invention are placed in tissue for improved healing, i.e. stimulation. Also, by combining these implants with other surgical devices such as sutures, screws, pins and rods, the tissue repair effect can be significantly improved (eg, acting as a second tissue attachment site). ).

The present invention can be used to repair, i.e., treat wounds in various tissues. Tissues are usually described as agglomerates of allogeneic specialized cells that are integrated to perform a particular function. The structure and material of the implant can be manipulated (integration matching) so that it is very close to the mechanical properties (eg, stiffness, compressibility) consistent with the surrounding tissue. Implant materials can be designed to match the mechanical properties of bone, cartilage, tendons, skin, ligaments, arteries, etc. As a non-limiting example, the device is available for the treatment, i.e., healing of bone defects. Bone is a unique connective tissue with a hard extracellular collagen matrix impregnated with inorganic, predominantly hydroxyapatite. Generally, there are two types of bone tissue. That is, as will be described later, it is cortex and spongy.

There are many other tissues that can be repaired using implants or parts thereof. Table 8 below lists some of the possible tissues and procedures for which the present invention can be used. This list is not complete and is only presented as an example of some of the tissues and treatments that can be used in the present invention.

Table 8: Examples of tissues and treatments that may benefit from the present invention Bone Bone tissue collection Spinal fusion Spine fixation / fusion Osteotomy Bone biopsy Maxillofacial reconstruction Long bone fusion Compression fracture Reconstruction / replacement of the crotch joint Reconstruction / replacement of the knee joint Reconstruction of the hand Reconstruction of the foot Reconstruction of the ankle joint Reconstruction of wrist joint Reconstruction of the elbow joint Shoulder reconstruction cartilage Autologous osteochondral transplantation Meniscus Tooth bone Alveolar ridge augmentation plasty Third molar extraction tendon Ligaments Skin Local wound Burn treatment Biological tissue examination muscle Dura lung liver Pancreas Bold kidney Nervous artery Bypass surgery Cardiac catheterization heart Heart valve replacement method

In a time-stepped delivery embodiment, the implant may be constructed to provide delivery tailored to each active ingredient. As a result of the delivery of the following in no particular order, both the presence of the implant and the delivery of the selected agent have been made to lead to the recovery of patients with tissue defects. That is, (1) a cell proliferative base, (2) a drug or biologic capable of functioning as a signaling molecule capable of activating proliferation or pathway differentiation, (3) a nutrient source for proliferation and cell growth. Drugs or organisms that can act as reservoirs, and (4) give therapeutic agents that prevent harmful tissue responses to implants or reduce infections and / or treat underlying diseases or conditions. It is a formulation.

Next, with reference to the figure, FIG. 1 illustrates one of the preferred embodiments of the tissue defect treatment system 10 of the present invention. As shown in FIG. 1, the tissue defect treatment system 10 generally comprises a sheath 12, a mass of implant material 14, and an applicator 16. The treatment system is suitable for incisions, laparoscopy, arthroscopy, endoscopy and other known surgical procedures for treating various injuries or diseases.

The sheath 12 generally includes a tubular housing 18 defining the lumen 19, a hub 20 located at the proximal end of the housing 18, and a discharge port 13 at the distal end. The hub 20 is provided at its proximal end with a flange 21 designed to act as a knob. The treatment system 10 may be hard or soft, depending on the application. The sheath 12 or applicator 16 may be lubricated to reduce friction or otherwise facilitate the placement of the implant material. It is also desirable to provide a tubular enclosure 18 made of a transparent material such as Lexan so that the implant material 14 can be seen through the tubular enclosure 18. In general, the tubular enclosure 18 is preferably from a somewhat soft and flexible biocompatible material (eg, gamma-ray sterilable material) that has a sufficiently small outer diameter, such as 5-10 mm, and is suitable for surgical procedures. It is an elongated member constructed, and is preferably made of a durable plastic material such as Teflon, polyethylene or polyurethane, or a metal.

If required for an arthroscopic procedure, the outer diameter and cross-sectional shape of the housing 18 should allow gliding through the laparoscopic cannula (eg, mantle needle) passage or incision with minimal clearance. To be elected. In a preferred embodiment, the sheath is circular in its cross section and has an outer diameter in the range of approximately 3-10 mm. In general, these dimensions are suitable for existing laparoscopy or endoscopy cannulas. However, actual dimensions will vary depending on the procedure and circumstances, as will be readily appreciated by those skilled in the art.

The applicator 16 basically comprises an elongated cylindrical rod-shaped plunger 22 having a thumb plate 24 and a distal end 15 located at its proximal end. The plunger 16 is generally made of a flexible biocompatible material suitable for use in surgical procedures (eg, gamma-ray sterilizable material), preferably composed of a plastic material such as polypropylene, polycarbonate or polyethylene. Will be done. The outer diameter of the plunger 22 has a cross section and a configuration that allows sliding through the cavity 19 of the tubular housing 18 with the smallest gap, so that the implant 14 can be pushed forward, that is, pushed out within the discharge port 13. Choose to make it possible.

To achieve movement of the extruder from retracted position to extended position, the tubular housing 18 includes a collar having a flanged protrusion 21 provided to be grasped by the user's finger of the device 10. In addition, the proximal end of the applicator 16 includes an expansion cap 24 provided to engage the user's thumb. Therefore, in carrying out the release of the implant 14, the user of the device 10 only needs to grasp the protrusion 21 with his / her finger while applying pressure to the cap 24 with his / her thumb. This action pushes the extruder downward to the extension position, releasing the implant 14. In this way, the applicator 16 is provided so as to be moved from the retracted position as shown in FIG. 1 to the extended position as shown in FIG. 8, and in FIG. 8, the distal end 15 thereof is a tubular housing. Located near the outlet 13 of 18 (eg, the plunger so that the distal end of the plunger 22 is aligned with the distal end of the sheath 12 when the thumb plate 24 abuts the knob 21 of the hub 20). 22 lengths are selected). In a preferred embodiment, the plunger 22 is made of a solid plastic material that engages with the implant 14 and has a blunt distal end for extrusion through the sheath 12.

Implant 14 is preferably preloaded into the delivery system prior to insertion of the delivery system into the patient's body. For solid or rigid implant materials (eg, those that do not easily fluidize), the size of the implant 14 is that the implant sheaths unless the fit between the implant and the inner surface of the tubular housing 18 is propelled by the plunger 22. Therefore, it should not fall unintentionally. If necessary, loose or tight fitting can be achieved by adjusting the size of the implant or the inner diameter of the sheath 12.

Alternatively, many methods can be used to hold the implant within the sheath 12 until the device is properly placed. For example, the distal tip 13 of the sheath 12 can be modified to provide a valve-like property (eg, a duckbill valve) that holds the implant in the delivery system until it is propelled by the plunger 22. The deformable tip can be made from an elastomer such as polyisobutane (ie rubber) or a plastic such as polyethylene. Detachable caps, dented distal tips, or other retaining means can be used, as well as other techniques known to those of skill in the art.

As shown in FIG. 2A, the embodiment of implant 14 is formed from a high density polymer (eg, collagen) foam reinforced with long natural collagen fibers. The implant is compressed prior to loading into the delivery system to have a high rate of expansion (from wet to dry) and good mechanical wet strength. For improved healing properties, the implant may contain particles of a calcium derivative such as calcium sulfate or hydroxyapatite throughout the implant, but is not limited thereto. Implant openings allow permeation of body fluids and cells into the implant during the healing process, that is, promote the healing process. The devices of this embodiment and other embodiments can be constructed from a variety of polymers, as described above. Generally, the overall structure of the device is composed of a biologically acceptable biodegradable polymer that is arranged as one or more porous bodies with interconnected voids. In some cases, it may be desirable for each void to communicate with most of the other voids. Depending on the application, the voids or holes may be of uniform or random size, position and shape. For example, interconnected, open cell network implants reproduce the structure of human cancellous bone at the iliac crest and, if made from the appropriate material (eg, polymer), human (mammary) iliac bone. It has a physical property (strength) value that exceeds that of iliac cancellous bone.

Implant 14E, the diametrically inflated implant 14 after being released from the sheath and reacting with body fluids, is shown in FIG. 2B. In a preferred embodiment, the implant 14 is a slightly inflatable member that can be compactly contracted or compressed to fit within the tubular housing 18, but is suitable for filling and treating wounds or defects in tissue. It changes shape (eg, swells) (eg, when released from a tubular housing, when it comes into contact with body fluids, when it becomes the same as body temperature, etc.).

As described below, the implant is compressible to any extent that allows for good fit with the delivery system and tissue wounds. Compression can also increase the effective density and mass of the implant and can help control reabsorption time and post-treatment strength (integration matching). In some cases, it may be preferable to provide an uncompressed implant. If the solid implant is uncompressed, a retaining cap or retaining band can be used to retain the implant 14 within the tubular enclosure 18 until delivery time.

As mentioned above, the implant material 14 may be composed of a wide variety of biocompatible materials, preferably bioreabsorptive materials (eg, polymers, collagen), and preferably incorporates natural fibrous collagen. .. The implant material may be in any shape suitable for delivery by the healing system. For example, it may be in the form of a loose fibrous material (eg, cotton or wool material), sponge, glue or flowable shape, folded membrane, woven or non-woven sheet, compressed / melted granules or pellets. As mentioned earlier, implants are preferably formed from bioreabsorptive (eg, biodegradable) materials. These features allow the implant to remain in place until the tissue later reabsorbs it. Therefore, it is not necessary to remove the implant after it has finished its purpose.

Implant 14 may be composed of any biocompatible material, but natural fibrous collagen is considered to be very suitable as at least one of the implant components. The physical shape of the implant 14 can vary widely, and the shape chosen by the physician depends on the situation. In alternative embodiments, the implant 14 can consist of a combination of one or more materials (eg, collagen, synthetic polymers and ceramics). The implant 14 can include a sea level portion and a loose fibrous portion, which is located at the most distal end of the sheath 12. Alternatively, the implant 14 may include a soft portion surrounding a harder structural portion. The following will be understood. That is, in this arrangement, a soft material (eg, collagen, polymer foam) for close contact with the wound site is first provided, and this soft material is a stiffer material (eg, for example) to apply pressure over the entire bleeding site. , Synthetic polymer pins) Reinforced with a backing (sponge), the pressure is the same as (eg, pressure matched) or somewhat higher than the static pressure normally found at the site. A plurality of implant devices may be connected, or may be structurally separated and independent. Other combinations and their advantages will be immediately apparent to those skilled in the art.

In a preferred embodiment, at least a portion of the implant is porous. The size of the hole can vary depending on the process of manufacturing the implant 14. In this way, the perforation rate may exceed 50% of the volume measurement area of each structural part / material. In addition, the hole size may be in the range of 25-1000um. However, it should be understood that the density of the holes as well as the size of the holes can be varied outside these ranges depending on the particular manufacturing process selected. It is also desirable that the implant has a non-perforated portion. It is preferred that the implant 14 be manufactured so that it has a porosity (eg, porosity-matched or structure-matched) that roughly matches the structure of the tissue surrounding the site where the implant 14 is located. Thus, various sizes and numbers of holes can be included by adjusting the material and / or method of manufacture of the implant 14 according to the particular application desired. It is believed that the porosity of the implant can change over time. For example, implants can be made from porous reabsorbable polymer macrostructures (US Pat. No. 4,186,448, Brekke), where the pores of the macrostructure decompose faster than the porous macrostructure. It is filled with microstructured materials. After transplantation, the macrostructure is degraded or reabsorbed, leaving a greater effective perforation rate. In addition, the implant 14 has structural and mechanical properties (rigidity and compressibility, structurally matched, integrated, respectively, that closely match the structural and / or mechanical properties of the tissue surrounding the site where the implant 14 is located. It can be manufactured to have a match (matched or compressibility matched, etc.).

Tissue implants 14 can include materials that can have different porosity and / or mechanical properties. Therefore, this implant is particularly applicable for placement in junctions adjacent to tissue regions with different porosity and / or mechanical properties. Correspondingly, the structure and material of the implant 14 is porous (biological matching) that closely matches the properties of the tissue junction after implantation, as described and discussed elsewhere herein. , And can be modified to have mechanical properties such as rigidity and compressibility.

It should be noted that at this junction, the implant can have any suitable shape as long as it can be effectively placed at the wound site, and it must be a cylindrical implant 14 as shown in FIG. 2A. There is no. An alternative embodiment of the implant 40 having a generally cylindrical body 44 and a large cylindrical head 42 is shown in FIG. 2C. This cylindrical head can be made from the same material as the implant body 44, or from an alternative material. For example, the head 44 can be constructed from a further rapid reabsorption material such as soluble collagen. This head facilitates hemostasis at the wound site and then is rapidly reabsorbed, leaving a columnar body 44 that is reabsorbed over time at the wound site, providing a structural matrix for tissue regeneration. Can be done. The head 42 or body 40 of the implant 40 can also include selected biologics or agents, such as thrombin, which assists in achieving hemostasis. The head 42 of the device 40 can also be used to limit the depth of the location where the device is implanted. The head 42 can be used as an impact surface for driving the implant into the tissue defect site, just like the head of a nail. In this application, the head is made of a suitable elastic material and is removable after implantation of the device 14.

Yet another embodiment of the implant, ie the implant 46 constructed in a generally conical shape, is shown in FIG. 2D. Implant 46 has a tapered tip 47 and a widened bottom 48. The tapered nature of this implant may allow for better press-fitting into the defect site. This implant may be suitable for non-cylindrical (eg, tapered) defect sites.

Next, with reference to FIG. 2E, an alternative embodiment of the implant device 14 is shown and is indicated by reference numeral 54. As can be seen, the implant 54 basically has a generally elongated structure, which is formed from a sheet or film 53 that is wound around a core axis (not shown) to form a tube. preferable. Similar sheets can be laminated to form this structure to create the final implant device. Tubular members 54 also have various configurations (eg, powders, fibers, pellets, spheres, etc.) that can be rolled up or laminated from a variety of different materials described herein (eg, ECM, collagen, polymers, polysaccharides, etc.). ) Can be formed. For example, by using multiple sheets of different materials, different degradation rates (eg, multi-step), different porosity suitable for internal growth tissues, and agents or biologics (eg, thrombogenic drugs, etc.) It allows the implant to be designed to have a gradual release of (growth factor). The implant 54 is also believed to have a longitudinally extending central passage 55 that accommodates a guide pin or other guide element (not shown) that can be used to orient the implant to the desired implantation site. .. This guide element can be removed or left in place. The pin may also extend beyond the distal portion of the implant and serve to stabilize or secure the implant within the defect site.

Next, with reference to FIG. 2F, a further alternative embodiment of the implant device 14 is shown and is indicated by reference numeral 56. As can be seen, the implant 56 basically has a generally elongated circular structure, which is preferably formed from an outer tubular material 57 and an inner core material 58. In essence, the implant is made of rod or rod-like material, in which a longitudinal passage is formed in which at least other material extending through a portion of the rod or rod is placed. There is. To minimize post-placement bleeding, the tube 57 may consist of a hemostatic material. The tube 57 may also be configured to be reabsorbed more rapidly as the surrounding tissue regenerates at its outer periphery. The inner core 58 is then reabsorbed more slowly, providing a long-term structural basis for tissue regeneration. It is also possible that the implant 59 may include an open central passage extending longitudinally that accommodates a guide pin or other guide element (not shown) that can be used to orient the implant to the desired implantation site. ..

With reference to FIG. 2G, the alternative implant 50 substantially comprises a synthetic or composite structure formed from a first structure / material 51 and a second structure / material 52. Although the synthetic structure embodiment of FIG. 2G is shown with two different components, this implant is made by combining any number of different components to achieve the desired result. It may be. With respect to FIG. 2G, the first structure / material 51 and the second structure / material 52 are preferably made of biocompatible materials. The first structure / material 51 is linked to the second structure / material 52, where the structure / material 14 is a different material, therapeutic agent (eg, drug, biologic) or property (eg, drug, biologic) than the material 12. For example, it includes a body having mechanical properties, porosity, wettability). Both materials 51 and 52 may include a therapeutic agent mixed within the pores or structure of the material. Implant 50 may be particularly useful for placement in any physiological system that has junctions between different types of tissue. Implant 50's combined heterogeneous structures / materials 51 and 52 can be implanted in any area that joins two different types of tissue (ie, bone, cartilage, tendons, skin, ligaments, cementum, etc.). By connecting the structures / materials to each other and implanting this conjugate into the tissue junction, the carrier / implant 10 ensures that the tissue junction remains bonded during the healing process, which is a rapid healing. Can help promote. Since it is considered that blood vessels are newly formed in a part of the tissue defect site to facilitate bleeding, the embodiment of the synthetic structure in FIG. 2G is a portion composed of a hemostatic material (for example, collagen) that assists hemostasis. May be designed to have. These materials may be manufactured adjacent to each other during the manufacturing process (eg, lyophilization) or may be bonded later (eg, thermal welding, solvent welding, mechanical coupling, etc.).

Now refer to Figure 2H, which is a circle with one or more ridges, or barbs 60, that function to secure the implant in the tissue and prevent the device from coming off, or coming off, after installation. An alternative implant 59 with substantially a columnar structure is depicted. This ridge or barb 60 is formed on the outer surface of the implant 59. Preferably, the barb is a circular ridge that extends around the body. The sharpness, or angle, of the barb 60 can be adjusted depending on the implant material and application. The side of the perforation in bone or other tissue is grabbed by the trailing edge of the barb. A flat, tapered tip is formed at the distal end of the implant 59 body. The posterior end of the implant 59 body is located at the end opposite the distal end of the body. Like others, this embodiment can also be sutured, glazed, glued, and otherwise fixed in place after transplantation.

The embodiment of implant 61 shown in FIG. 3 is a "fluid" implant made of a fluid material such as collagen paste, cyanoacrylate (glue / adhesive), thrombin lou, hydrogel, growth factor gelatin, but fluid. Sexual materials These are not limited. The fluid material can be stored in a tube (not shown) and dispensed into the tissue defect site by a needle-like instrument such as a syringe (not shown). The fluid material, like epoxy or silicone caulking material, can be designed to cure after transplantation so that it is not pushed out of the puncture during tissue movement or flexion. This material can also be photopolymerized, such as FocalSeal (Focal, Lexington, Mass.). As mentioned above, this implant can contain drugs or other agents. It is possible to make the fluid material porous by incorporating citric acid or other "foaming" agents that form pores in the implant during and / or after placement. That is, by mixing the foaming agent immediately before implant injection, foaming mainly occurs after transplantation, and by cooling the implant material, the foaming reaction is delayed until the implant is warmed to body temperature. The implant can also be formed by pouring two or more materials (eg, two-component epoxy resin) together into the defect so that the material conjugate fits the defect properly and heals the wound. Is.

The implant 14 of the present invention is suitable for introduction into a wound, defect or cut in various living tissues or organs (eg, bone, muscle, artery, dura mater, lung, liver, bile sac, etc.). For purposes of explanation, the use of this device in the treatment of bone defects, especially long bone defects, will be described. Long bones (arm and leg bones) and bank bones have many common anatomical and biological structures. FIG. 4 shows the human femur 63, tibia 62 and fibula 64.

FIG. 5 is a cross-sectional view of the femur 63. All long bones (eg, the femur) are composed of an outer shell structure of dense and tough tissue, which encloses a low density or hollow interior. This structure maximizes strength and minimizes weight so that the bone is given structural support and mobility without compromising organ mobility. It is important to note that bone is a living tissue that contains living cells that must receive oxygen and nutrients from the blood system to survive. Macroscopically, there are two main types of bone tissue. That is, there are dense bone, that is, cortical bone, and cancellous bone, that is, cancellous bone. FIG. 5 shows the positions of these types of bones in the femur, which will be described later. Dense bone, or cortical bone, is a high-density substance with a specific gravity of approximately 2. The spongy bone tissue, also called trabecular bone, is a sponge-like open cell network of calcareous collagen fibers. The fibers of cancellous bone act like a bridge or building girder, providing a lightweight support mechanism for the forces exerted on the bone structure.

As shown in Figure 5, long bones (arm, finger, leg and toe bones) have a solid bone structure at each end, a hollow trunk known as the diaphysis, capped at the epiphysis. Have. The diaphysis is composed of a thick columnar cortex 72, that is, dense bone surrounded by the outer layer of the periosteum 70 and the inner layer of the endosteal tissue (endosteum) 74, which is the intima of the periosteum. Generally, the surface of the periosteum is very smooth. Like the periosteum 70, the endosteal tissue layer 74 is composed of a fibrous leather-like structure that assists in the angiogenesis of bone tissue and is rich in osteoblasts, which are osteoblast progenitor cells. This is a rough-faced tissue that resembles cancellous bone.

The cancellous bone is also present in the epiphyseal and metaphyseal regions of the long bone, and is within the cortical bone because it is composed of short struts, which are bone substances called trabecular bones. This connected cancellous bone gives the cancellous bone a spongy appearance. This is often referred to as cancellous bone. There are no blood vessels in the trabecular bones, but there are blood vessels right next to the tissue, which zigzags through the wide space between the individual trabecular bones. Cancellous bone has a vast surface area, as indicated by its cancellous appearance.

There is no bone tissue inside the trunk of the long bone. However, this cavity, the medullary canal 76, contains the red bone marrow that produces blood cells in the fetal and infants. As the need for excessive blood cell production disappears, so does the need for bone marrow for red blood cell production. Red bone marrow is eventually replaced by adipose tissue, often referred to as yellow bone marrow.

The epiphysis comprises a thin layer of cortical bone (on the connecting surface of the joint), the articular cartilage 80 that surrounds the lattice structure of the bone fibers that make up the cancellous bone 78. The periosteum 70 overlying the diaphysis extends over the cortical bone region 77 of the epiphysis 78 and contacts the articular cartilage 80.

Cartilage resembles bone tissue in many respects. Like bone, cartilage consists of a reticular structure of fibers in which chondrocytes are encapsulated. Unlike bone tissue, the fibers are not calcified, but contain chondroitin sulfate, a gel-like substrate. In addition, hyaluronic acid is present in the intracellular space. It is a viscous substance that facilitates the passage of nutrients from blood vessels to cells in the matrix. The irregular arrangement of collagen or elastic fibers in cartilage results in surface traits and compressive strength.

Chondrocytes occupy only about 5% of tissue volume and are not in direct contact with each other. The rest is occupied by extracellular matrix and interstitial fluid. Since cartilage tissue lacks blood vessels, lymphatic vessels, and neural structures, chondrocytes must rely on the diffusion of nutrients rather than the supply of blood vessels for the substances they need to survive. In human anatomy, there are three types of chondrocytes: glass cartilage, fibrocartilage and elastic cartilage. The most common chondrocytes in surgical applications are the glass cartilage that forms the articular surface of the bone and the fibrocartilage that forms the disc within the articular structure.

The surface cells of cancellous bone 78 contain red bone marrow. Flat and non-uniform bones such as vertebrae have a structure similar to the epiphysis of long bones. The outer layer of thin cortical bone, the articular cartilage in the articular formation of bone, encloses cancellous bone tissue. The resulting structure is similar to foam injection molded parts used in the construction of electronic devices and is suitable for withstanding mechanical stresses on the device due to the solid outer shell of the plastic supported by the inner core of the foam. Lightweight construction is provided. Similar to cancellous bone at the epiphysis of long bones, the space within the cancellous bone fiber matrix in flat and heterogeneous bone is occupied by red marrow.

There are numerous injuries or surgical procedures that require cartilage to be damaged or repaired. In some cases, bone is removed from one part of the body, the site of collection, and transferred to another part of the body to repair the wound or treat the patient (eg, cartilage repair, spinal fixation). Depending on the procedure performed, the implants of the present invention may be suitable for the original tissue defect and may also be beneficial for the treatment of the collection site. One such surgical procedure that creates a collection site is Arthrex's (Naples, Florida) Osteochondral Autograft Transfer System for the treatment of full-thickness defects in the femoral condyle in the knee joint. OATS). This procedure uses a series of thin-walled excision tubes to remove a plug of autologous bone capped with fresh glass cartilage and transfer it to the site of injury. These osteochondral core implants are then press-fitted into one or more sockets made in the condyle defect.

The OATS procedure may be arthroscopic or open, depending on the surgeon's preference, the location and extent of the condyle defect, and the site of collection. The preferred donor site is the lateral epicondyle of the femur just above the demarcation groove. This region has a convex flexion on its articular surface similar to the convex flexion of the central weight-bearing region of both femoral condyles.

Donor sockets are usually left open after such tissue harvesting procedures.

FIG. 6 is an enlarged view of the femoral tibial joint 82 shown in FIG. Tissue defects 84, 85 and 86 have been shown. Defects 84 and 85 extend through the articular cartilage layer 80 and reach the cancellous bone. A tissue defect 86 extending within the cancellous bone (see 78 of the femur 63 in Figure 5) is shown.

Next, the application of the present invention to tissue defects will be described. According to the procedure of the present invention, and as shown in FIG. 7, the surgeon positions the distal end of the sheath 13 at the defect site 32 of the tissue 30. As shown in FIG. 7, the sheath tip 13 can be sized to abut on the outside of the wound site, or the sheath tip can be sized to fit inside the wound site ( Not shown). Once the treatment system 10 is properly positioned, the surgeon applies pressure to the thumb plate 24 of the applicator 16. As the plunger 22 slides in the sheath 12, the plunger pushes the implant material 14 out of the sheath. Note that the length of the proximal end of the plunger extending from the proximal end of the sheath 12 is "L" so that the surgeon can accurately determine when the device 14 is just completely contained within the distal end of the sheath 12. May be adjusted to the exact length of the implant device 14. The instructional marking 11 allows the surgeon to measure how far the implant has advanced into the tissue defect site. As shown in FIG. 8, when the thumb plate 24 of the applicator 16 abuts on the hub 20, the doctor said that the implant 14 was completely pushed out of the lumen 19 and that the distal end of the plunger 22 was sheathed. Recognize that it is almost aligned with the distal ends of the twelve. On the other hand, a transparent or translucent material can be used for the sheath 12 to allow the physician to directly see the implant placement. When the advancing implant 14 engages the tissue defect site, the physician feels resistance to the thumb plate 24. The physician may then maintain axial pressure to press the implant 14 against the defect site. If the defect site is bleeding, the implant 14 may be mechanically pressed against the bleeding site to achieve rapid hemostasis. As soon as the implant material (eg, collagen) begins to interact with the bleeding site, it begins to be replaced by self-sustaining hemostasis, and soon no mechanical pressure is needed. Implant once as shown in Figure 8 If 14 is properly placed, system 10 may be removed from the defect site. As mentioned above, implant 14E can expand to fill the defect site.

In some cases, it may be necessary to adjust the length of the implant 14. Multiple implants may be inserted if the implant material is too short to properly fill the defect site. As shown in Figure 9, if the implant is too long (eg, part of the implant extends from the wound site), use a suitable trimming tool 212 (eg, scalpel, scissors) for the unwanted part 210 of the implant. Can be removed. It is also conceivable that the delivery system 10 may incorporate a blade, knife or other tool at its distal end (not shown) to reshape the implant.

In some cases, it may be necessary to modify the defective site to remove non-growing tissue, otherwise adjust the size of the defective site. Figure 10 shows a drilling tool that can be used both to remove a freshly collected tissue plug for use at the defect site and to reshape the defect site to allow better fit of the tissue implant. 110 is drawn. The drilling tool 110 generally has a columnar distal portion 140 and a distal tip 130, both made of hardened stainless steel. The distal portion 140 may have an instruction marking 132 that helps measure the depth of the tool to the wound site during the drilling process. The body of the drilling tool 138 has a proximal segment and may also have a notched portion 136 and a proximal surface 134 to provide the surgeon with a good grasping surface. The drilling tool also includes a drilling sleeve 142 consisting of an elongated thin wall tube 143 with a columnar knob 144 at its proximal end. The drilling tool 110 and drilling sleeve 142 are assembled and driven, ie inserted into the wound site, as shown in FIG. Using this tool, the uneven wound site 146 can be shaped into a more regularly shaped wound site 148 by removing the bone portion 150 from the wound site.

It is expected that many sizes of drilling tools 110 will be available to accommodate the various tissue defect shapes that may be encountered. Tissue defects can be examined arthroscopically or directly, and their size can also be measured. A suitable drilling tool / delivery system 110 can be selected (eg, the diameter of the distal drilling tool tip 140 is 5, 6, 7, 8, 9, 10 mm). These drilling tools can be color coded to match their size with the diameter of the defect site and also with the size of the implant and the delivery system. Then, using a sturdy mallet, the coring tool 110 can be driven into the bone 152 to the desired depth (eg, 15 mm) and the core material 150 can be removed. With proper use, as shown in FIG. 9, this tool can be used to turn the unevenly shaped defect site 146 into a more regularly shaped implant site 148.

By removing the core tool inner sleeve 142 from the core tool body 138, it is possible to obtain an unobstructed delivery passage for the implant material into the shaped wound site 148. The removed tissue, or bone 150, is an autologous substance that can contain active growth factors or other beneficial components and is therefore used for further shaping (eg, stacking) for insertion into this or other wound site. Or, by incorporating it into the implant 14, it can be useful for stimulating healing.

As shown in FIG. 13, the drilling tool can also be used as a delivery device. In this alternative embodiment, the implant material can be loaded into the delivery system while the delivery system (eg, drilling tool 110) is pre-positioned at or within the defect site. Therefore, as shown in FIG. 11, after the drilling tool 110 is inserted so that the outlet 130 (as shown in FIG. 10) is within the wound site, the extruder 154 is extended, i.e. as described above. The central passage 156 can be pushed downwards, so that its distal end 155 pushes the implant 14 towards the outlet 130. After the implant is pushed to the end of the central passage 156 by the extruder 154, the tubular body 138 itself is removed from the wound 148 and completely moves out of the patient's body. This action leaves the implant 14 in the wound.

It will be immediately clear from the above description that more than one implant device 14 can be used. If doctors decide to use more than one plug for tissue defect treatment systems 10 and 110, they / they remove the plunger 22 and insert the implant 14 (of the same or different material) into the lumen 19 All you have to do is insert it at the proximal end and then reinsert the plunger 22 behind it. Alternatively, the entire system 10 may be removed and replaced with a pre-loaded, ready-to-use second system. Therefore, the second, third and the like implants 14 may be delivered and applied to the defect site or a plurality of defect sites during the procedure. Other methods of loading multiple implants 14 into the patient's body using an alternative delivery treatment system 162 are shown in FIGS. 14-16. FIG. 14 shows that the tissue defect treatment system 162 includes roughly a sheath 12 and a mass of implant material 14.

It is further conceivable that multiple implants with different components can be delivered to the same site or other nearby sites. The various components include delivery of various therapeutic agents or biomatching of varying degrees or types (eg, porous centers or deep regions / implants following hard surface components), which include: It can be selected on the basis of any number of grounds, not limited.

The sheath 12 generally includes a tubular housing 18 defining the lumen 19 and a hub 20 located at the proximal end of the housing 18. Generally, the tubular housing 18 has a window 158 for inserting the implant device 14 formed in a part of the tube wall. The size of the window is chosen to accommodate implants 14 of various sizes. The system uses an applicator similar to Applicator 16 in FIG. 1 (not shown in its entirety). The applicator basically comprises an elongated cylindrical and rod-shaped plunger 22 having a thumb plate (not shown) and a distal end 15 located at its proximal end. To load the implant 14 into the device, plan until the distal end 15 is close to the window 158 of the tubular enclosure 18 and the indicator mark 250 on the plunger 22 is visible as shown in FIG. Pull up the jar 22. The plunger 22 is then pushed forward and the implant 14 is transferred through the sheath 18 to the target site. As shown in FIG. 14, another plug 14B may be loaded and placed in the window 158 and then oriented to the same or other defect site. This system may have special advantages during endoscopic procedures where the physician does not want to remove the delivery system from the patient to deliver additional plugs, eg plugs of different component 14C. According to System 162, the sheath 12 remains in the patient so that additional implants can be loaded into the device.

It may be possible to automate or semi-automate the loading of one or more implants by attaching a cartridge or magazine of implants similar to those used to deliver surgical shavings to the delivery system 10. .. The cartridge can be designed to connect to the window 158, or the cartridge can be designed to connect directly to the distal end of the applicator 16 as shown in FIGS. 17-19. The treatment system 200 shown in FIG. 17 is similar to the treatment system 10 in FIG. 1 except that it can be used with the implant transport cartridges 202 and 204 shown in FIGS. 18-21. The cartridge is essentially a thin-walled cylindrical tubular structure designed to house the implant device. Cartridges can be made from injection molded polymers such as thin-walled stainless steel or polycarbonate. Cartridges 202 and 204 are sized to hold implants of various outer diameters and lengths. As an example, the cartridge 202 can accommodate a large diameter implant 206 and the cartridge 204 can accommodate a small diameter implant 208. The cartridge is designed to connect to the distal end 216 of the treatment system 200. Proximal segments of cartridges 202 and 204 have connections 218A and 218B that connect to the distal end 216 of the treatment system. Connections are made by taper fits, threads, plug-in pin connections, recessed connection rings, or other means known to those of skill in the art. The desired implant size and length and associated cartridges are selected by the surgeon and attached to the treatment system. The distal ends of cartridges 220A and 220B are positioned at the desired site and the thumb plate 24 is pushed down to push the distal end 15 of the applicator 16 into contact with implants 206 and 208, resulting in , Implant ejected from cartridge sleeves 202 and 204 Will be done. Once the implant has been ejected, the empty cartridge sleeves 202 and 204 can be removed and replaced with other cartridges.

The design of the treatment system 200 allows one delivery system to be used to deliver one or more similar or different sized implants.

In addition, these embodiments can be used to deliver multiple fluid implants, in which the indicated marking 250 can be used to measure the amount of each implant. Similarly, the drilling tool 110 can be used to remove material to a certain depth indicated by core depth indication 154, i.e. to the measured depth. The amount of implant material 14 required to fill the void or defect can be calculated, i.e., calculated by associating the drilling instruction marking 145 with the plunger marking 250. As mentioned above, this association can be made by using the drilling tool 110 separately from the system 10 or by feeding the plunger mechanism 22 through the core tool body 138 (ie, as mentioned above, the two devices. You can do it, whether you are using it or both steps are done with a single tool).

FIG. 22 shows a 100x scanning electron microscope image of the bone replacement material embodiment. This implant is composed of Kensey Nash P1076, a bovine hide-derived collagen material that is a combination of natural collagen fibers and soluble collagen. The holes that make up the macrostructure of this implant are 100-200 um in diameter.

FIG. 23 shows a 100x scanning electron microscope image of the bone replacement material. The component of this implant is Kensey Nash P1076, a bovine hide-derived collagen material that is a combination of natural collagen fibers and soluble collagen. Blended in collagen at 25% by weight is medical grade calcium sulphate, shown as small columnar particles throughout the porous macrostructure.

FIG. 24 shows a 100x scanning electron microscope image of the bone replacement material embodiment. This implant is composed of Kensey Nash P1076, a bovine hide-derived collagen material that is a combination of natural collagen fibers and soluble collagen. The implant is approximately 233% crushed and the hole size is reduced from 20um to 50um. This gives a biomatched state, more specifically a porosity-matched or compression-matched state.

As mentioned above, this implant can be used to deliver a variety of agents (eg, drugs, biologics, etc.) into the patient's body. The agent elution 164 from implant 14A is shown in Figure 25. In this embodiment, the implant can be configured to provide immediate or time-stepped delivery of one or more active components. The presence of implants and delivery of selected agents can (1) act as signaling molecules in which the agent or biologic activates growth and differentiation pathways, (2) the agent proliferates and proliferates cells. Patients with tissue defects through at least one of several methods, such as which can act as a reservoir of nutrients for growth, (3) the agent can prevent a harmful tissue response to the implant, etc. It is designed to lead to recovery.

In a preferred embodiment shown in FIG. 25, the agent delivery implant material 14A continuously and smoothly releases the active agent 164 over the entire degradation period of the device, or over a period of which. In another preferred embodiment, the agent is released for the duration of the device remaining in the tissue. In some applications, it may be necessary to suddenly release the active agent more than once. The device can be designed to deliver two or more agents at different, i.e., stepwise intervals and doses. Implant 14A is also placed so that the agent is retained within the boundaries of the device (eg, without releasing the agent into surrounding tissues) and affects only cells migrating within the porous structure of the device. It is also possible that it can be designed.

As a non-limiting example, implant 14A is capable of incorporating microparticles within its structural skeleton. These particles are degraded after in vivo transplantation and are proteins, genetics, peptides, pharmacologically active substances, vitamins, sedatives, steroids, hypnotics, antibiotics, chemotherapeutic agents, prostaglandins and It can be used for delivery of any kind of molecular compound such as radiopharmaceuticals. The delivery system of the present invention comprises the above substances and other substances such as proteins, peptides, nucleotides, carbohydrates, monosaccharides, steroids, pharmaceuticals, cells, genes, antithrombotic agents, antimetabolites, growth factor inhibitors, growth promoters. , Anticoagulants, anti-thread-dividing agents, antibiotics, thrombolytic agents, anti-inflammatory steroids, monoclonal antibodies, etc. are suitable for delivery, but the substances are not limited thereto. Microspheres can be made from a variety of materials such as polymers, silicon and metals. Biodegradable polymers are ideal for use in the production of microspheres. Material properties such as crystallinity, molecular weight, additives, polymer surface morphology and environmental conditions can affect the mechanism of polymer degradation and kinetics. Thus, the performance of the invention is modifiable to the extent that each of these properties can be tuned or altered.

After the implant of the invention has been placed in the anatomy, some of the devices are degraded or reabsorbed as new cells and tissues move into the implant. FIG. 26 depicts a long-term tissue defect site and implant. Implant 171 is shown early immediately after implantation, implant 172 is shown after some time, implant 173 is shown after a while, and the implant is almost complete. A fourth time point implant 174 is shown that has been reabsorbed and replaced with fresh tissue 170.

FIG. 27 shows an enlarged view of a portion of yet another embodiment of the implant device 230, which is a series of spherical structures that combine with each other to form the macrostructure or skeleton of the implant device 230. It is composed of beads 232. Beads 232 can be made from calcium alginate, polylactic acid, gelatin, or other suitable biomaterials described herein or known to those of skill in the art. In certain embodiments, natural collagen fibers 234 and filler 236 may also be incorporated. Fillers can be made from more soluble collagen, such as Semed S from Kensey Nash, Exton, PA, or other biological material known to those of skill in the art.

FIG. 28 shows yet another embodiment of the implant material, the implant 240, which includes the anchoring part 244. This fixing component can be used to hold the implant 240 at the defect site during defect treatment.

FIG. 29 shows an embodiment of an agent delivery system (eg, a syringe) in which the implant 14 is actively loaded with an agent (eg, bone marrow cells, growth factors, antibiotics, etc.). In this embodiment, the agent 262 is infused and loaded into the implant 14 prior to placement in the delivery system and thus prior to in vivo implantation. The delivery system 260 comprises a syringe-like body 270 containing the agent 262. The agent plunger 264 is pushed in the direction of the arrow to dispense the agent through the distal outlet opening 268 of the system 260. Depending on the application, a preset amount of the agent can be applied to the implant or surrounding tissue. Markings (not shown) can be used to measure the amount of substance applied. It is also conceivable that the agent can be added to the implant while it is stored in the delivery system, or it can be added after it has been placed in the living tissue.

FIG. 30 is a partial cross-sectional side view of a portion of a delivery system to which yet another embodiment of the implant of the present invention is applied. This segmented delivery system 280 is suitable for delivery of implants 282 composed of multiple segments (eg, granules, chips, fibers, etc.). These implants may be more suitable for filling non-uniform, i.e., uneven tissue defects 286 in living tissue 30. This syringe-like delivery system uses a syringe-like housing 270 to hold a material and a plunger 264 that ejects the material through a distal opening in the syringe body. The compartmentalized implants can be fluidized or otherwise distributed to fill the void. The implant material can be any of the materials described above, or a combination of materials, as described herein.

It will be appreciated that many other embodiments and modifications will be apparent to those skilled in the art, and that the above description of preferred embodiments is only an example. This is not intended to limit the scope of the invention as defined in the appended claims. Without further elaboration, the above matters fully explain our invention, so others adopt the same in various service environments by applying their current or future knowledge. Can be done.

<figref num="1">A plan of the tissue treatment system 10 of the invention, partially cut out to show a cross section of the components of the tissue treatment system of the invention, including a sheath, an applicator plunger, and a loaded implant placed within the sheath. The figure is shown.</figref><figref num="2A">It is a perspective view of one Embodiment of the implant of this invention.</figref><figref num="2B">It is a perspective view of the alternative embodiment of the implant of this invention.</figref><figref num="2C">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="2D">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="2E">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="2F">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="2G">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="2H">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="3">It is a perspective view of the alternative embodiment of an implant.</figref><figref num="4">It is one perspective view of various tissues suitable for treatment by the treatment apparatus of this invention.</figref><figref num="5">It is sectional drawing of the structure of FIG. 4 shown partially and enlarged.</figref><figref num="6">It is an enlarged detailed perspective view of a part of the tissue shown in FIG.</figref><figref num="7">A plan view of the tissue treatment system of the present invention delivering an implant into a living tissue, partially cut out to show a cross section of a component, is shown.</figref><figref num="8">Shown is a plan view of a tissue treatment system of the invention that has been partially cut out to show a cross section of a component and has been removed from the tissue after delivery of the implant into the living tissue.</figref><figref num="9">A cross-sectional view of the treated tissue, including the implant, and tools for aligning the contour of the implant are shown.</figref><figref num="10">It is a side elevation view of the alternative treatment and delivery system 110 of the present invention.</figref><figref num="11">A side elevation view of the tissue treatment system 110 of the present invention, which shapes a living tissue, is shown.</figref><figref num="12">A side elevation view of the tissue treatment system 110 of the present invention showing a state in which a tissue core is removed from a living body is shown.</figref><figref num="13">Shown is a side elevation view of the tissue treatment system 110 of the present invention, partially shown in cross section, delivering an implant into a living tissue.</figref><figref num="14">FIG. 6 is a partial cross-sectional side view of a portion of an embodiment of the treatment system of the present invention showing a state before the implant material is loaded into the system.</figref><figref num="15">FIG. 5 is a partial cross-sectional side view of a portion of an embodiment of the treatment system of the present invention showing a state in which the implant is loaded into the system.</figref><figref num="16">FIG. 6 is a partial cross-sectional side view of a portion of an embodiment of the treatment system of the present invention showing a state in which an implant is loaded into the system and pushed through the system.</figref><figref num="17">FIG. 5 is a plan view of yet another embodiment of the tissue treatment system 200 of the invention, partially cut out to show a cross section of the components of the tissue treatment system of the invention, including a sheath, an applicator plunger.</figref><figref num="18">It is a top view of the tissue treatment system 200 shown in FIG. 17 assembled to the implant transport device 202.</figref><figref num="19">FIG. 5 is a plan view of the tissue treatment system 200 shown in FIG. 17, assembled into yet another embodiment of the implant transport device 204.</figref><figref num="20">It is a side sectional view of the implant transport device shown in FIGS. 18 and 19.</figref><figref num="21">It is a perspective view of the implant transport device shown in FIGS. 18 to 20.</figref><figref num="22">It shows a 100x scanning electron micrograph of the bone replacement material, and the component of this implant is Kensey Nash P1076, a collagen material derived from bovine hide, which is a combination of natural collagen fibers and soluble collagen. The holes that make up the macrostructure have a diameter of 100 to 200 um.</figref><figref num="23">It shows a 100x scanning electron micrograph of a bone replacement material, and the component of this implant is Kensey Nash P1076, a collagen material derived from bovine hide, which is a combination of natural collagen fibers and soluble collagen, and is contained in collagen. In 25% by weight, medical grade calcium sulphate is shown as small columnar particles throughout the porous macrostructure.</figref><figref num="24">Showing 100x scanning electron micrographs of bone replacement material, this implant is composed of Kensey Nash P1076, a bovine hide-derived collagen material that is a combination of natural collagen fibers and soluble collagen. Approximately 233% crushed, which reduces the hole size from 20um to 50um.</figref><figref num="25">FIG. 6 is a cross-sectional view of a tissue comprising an embodiment of an implant of the present invention that releases an agent to treat a local tissue.</figref><figref num="26">FIG. 6 is a cross-sectional view of a tissue comprising one embodiment of the implant of the present invention, showing the gradual reabsorption of the implant and the regeneration of the tissue.</figref><figref num="27">It is an enlarged sectional view of one Embodiment of the implant material of this invention.</figref><figref num="28">It is a perspective view of the alternative embodiment of the implant 240 of this invention.</figref><figref num="29">FIG. 5 is a partial cross-sectional side view of an embodiment of an agent delivery system in which an agent is added to an implant.</figref><figref num="30">FIG. 5 is a partial cross-sectional side view of a portion of a delivery system to which yet another embodiment of the implant of the present invention is applied.</figref>