JP2820415B2 - Biodegradable and osteogenic graft bone graft substitute composition - Google Patents

Description

The present invention relates to a graft substitute composition, and more particularly, to a graft substitute composition.
In general orthopedic surgery, throat and maxillofacial surgery, as a biodegradable graft bone substitute composition material,
The present invention relates to a graft bone substitute composition used as a research material for bone neogenesis, bone formation, cell differentiation, and cell induction by biochemical action.

[Background of the Invention] The following documents have been published as technical documents relating to the graft bone substitute composition according to the present invention.

"M. Jarco, Calcium Phosphate Ceramic as a Hard Tissue Replacement Material", Clinical Orthopedics, No.
No. 157 (June 1981), pp. 260-278.

JJ Klawiter, SF Fulbert, "Use of Porous Ceramics as a Fixture in Load-Bearing Internal Orthopedic Applications," Journal of Biomedical Materials Research Symposium, Volume 2 (Part 1) (19)
72), pp. 161-229.

L. Sprinel et al., "Effects of Poly (glycol monomethacrylate) Gel Structure on Calcium Deposition in Transplanted Tissues", Calcification Tissue Research, 13 (1973), pp. 63-73.

TD Doriskel et al., "Development of Ceramics and Ceramic Composites Used for Maxillofacial Surgery", Journal Biomedical Materials Research Symposium, Volume 2 (Part 1) (1972), pp. 91-115
page.

JH Brecke et al., "Effect of Polylactic Acid Mesh on the Development of Localized Osteitis", Oral Surgery, No. 56
Vol. 240-245 (September 1983).

JH Brecke et al., "Surgical trauma and the effect of polylactic acid cubes and granules on the development of alveolar osteomyelitis in lower third molar extraction trauma", Journal Canadian,
Dental Association (publishing).

BP Toure, “Evolutionary Role of Hyaluronic Acid Compounds”, Connective Tissue Research (1982
Year), Volume 10, pages 93-100.

G. Abatandiello et al., "Healing of hyaluronic acid-rich trauma-histological observation", Journal Surgery Research, Vol. 35 (1983), pp. 410-4
16 pages.

E. Canaris et al., "Stimulation of DNA and Collagen Synthesis by Autologous Growth Factors in Calvaria of Domestic Fetal Rats," Science, 210, (28), 102.
Pages 1 to 1023 (1980).

MR Urist et al., "Human bone morphogenic protein (hBM
P) ", Proceeding Society Experimental Biological Medicine, Vol. 173, 194
Pp. 199 (1983).

MR West et al., “Β-Tricalcium Phosphate Supply System for Bone Morphogenetic Protein”, Clinical Orthopedics, Vol. 187 (July-August 1984), pp. 277-280.
page.

U.S. Patent No. 4,186,448, "Compositions and methods for treating and healing newly formed bone voids."

[Object of the Invention] The present invention has been made for the following points.

To provide a biodegradable structure (having imperfectly interconnected gaps) carrying a chemotactic basal substance in the form of a fibrous velor.

To generate an electronegative environment by maintaining the boundary region between the liquid phase of hyaluronic acid and the solid phase of polylactic acid, or by the electronegative chemical properties of hyaluronic acid itself.

When an external electrical signal is applied to a biodegradable bone graft substitute composition, there is an endogenous current generated by the interaction between the hyaluronic acid liquid phase and the polylactic acid solid phase, and by the inherent electronegativity of hyaluronic acid. Creating biophysical conditions and environments in which synergy occurs.

To provide a granule form which is a granule filled with hyaluronic acid, osteogenic protein and / or bone-derived growth factor, respectively.

To provide a composition having a unique side-by-side arrangement of polylactic acid, hyaluronic acid and a chemical osteoinductive / osteogenic agent.

To provide a composition in which the unique arrangement of bone-derived growth factor components enhances the osteoinductive effects of external potentials and electromagnetic fields.

Either one or both of the solid-shaped part and the part having an empty void cell network structure are made of a biodegradable polymer, and a composition is provided in which the chemotactic basic substance is located proximal to the polymer. thing.

[Means for Achieving the Object] To achieve the above object, the present invention provides a host (host:
An open-ended void (op) in an organized composition for use as a surgical implant to the host, wherein the composition promotes the recovery of structural defects in the host bone and other tissues.
a biodegradable polymer in the form of a porous macro (gross) structure having en voids) and a mobile material having a large surface area per unit weight and located in the open voids. Provide a composite.

The composition may have at least one solution of an agent that is active and therapeutic for the living body,
In such a case, the solution promotes the growth of the tissue injected into at least a part of the open space in the open space.

The biodegradable polymer can be selected from homopolymers of α-hydroxy acids, copolymers of at least two α-hydroxy acids or mixtures thereof.

The mobile material may comprise a material having a negative potential with respect to the host tissue.

 The runnable material may have a tibia form.

The runnable material can be selected from glycoaminopolysaccharides, glycoproteins, lamins or type V collagen.

The agent may be osteoinductive or osteogenic.

The open voids are interconnected, have a random shape and size, and may be randomly distributed.

The drug is, for example, a bone morphogenic protein or an osteoinductive growth hormone.

 The runnable material may close the open void.

The runnable material can cover the biodegradable polymer at least partially and adhesively.

 The traveling material is, for example, hyaluronic acid.

The present invention also relates to a method of forming a composition for treating structural tissue defects, comprising: (a) a porous macromolecule comprising a biodegradable polymer so as to take the form of a porous macrostructure having open porosity; Forming a structure; and (b) forming a porous microstructure in the open voids of the macrostructure so that the microstructure is retained by the macrostructure to form a composite of the microstructure and the macrostructure; C.) Introducing a substance selected from an active agent or a therapeutic agent into the complex.

The drug may be introduced into the complex before inserting the complex into a structural defect.

The agent may be osteoinductive or osteogenic.

The open voids are interconnected, have a random shape and size, and may be randomly distributed.

In addition, the traveling basic substance, the traveling substrate and the traveling material are used as synonyms, and the traveling basic substance,
I also agree with a migratory substrate.

Embodiments Congenital malformations, diseases of bone and / or bone marrow tissue, trauma (including accidents and / or surgery), and bone deficiencies, defects, voids and tissue discontinuities caused by functional atrophy in mammals. The graft bone substitute composition for treatment is described in detail below.

The present invention provides an integrally molded composition from four materials, each of which contributes to the specific requirements needed for new bone formation. Overall, the function of each component of the composition is integrated into a single body member. That is, when the body member is implanted into a bone defect, the body member begins to induce bone formation as a tissue and structural unity,
The implanted body tissue simultaneously biodegrades the body member while stimulating its bone formation and maintaining the bone formation process of the living body. Eventually, the function of the composition according to the present invention results in the formation of healthy and viable bone tissue in places where no bone was previously present, while at the same time the composition itself is completely hydrolyzed into living tissue It is completely metabolized.

The body member of the composition is composed of four different elements. The presence of each of these elements contributes to the essential function of the composition according to the invention, and as a result sets the essential conditions for the process of bone neoplasia. These functions are as follows.

Structural complementarity The macrostructure of the composition according to the invention complements the strength, organizational and structural deficiencies in the bone defect,
During the dynamic biological processes in healing and bone formation of the affected area,
Performs the function of supporting the tissue and securing the surface area of the tissue.

Running base material A base material that has the property of aspirating mesenchymal cells at various stages of maturation from adjacent healthy tissue and from the blood vessel subbranch covering the affected space.

Electronegative field By means of electrokinetic and electrochemical applications,
The development and maintenance of an electronegative environment in the affected area of the healing bone.

Induction of osteogenesis The generation of basic genetic changes by chemical agents that cause primitive mesenchymal cells (perivascular cells) to differentiate into mature osteogenic cells (osteoblasts) during the subsequent maturation process.

Bone formation Stimulation of the biosynthetic process of cells already induced to mature as osteoblasts.

The components that make up the body member of the tissue body and their osteogenic functions will be described first generally and then in detail.

"Components and Biological Functions of Body Member of Composition" Biodegradable macroscopic macrostructure The macrostructure constituting the body member of the composition is a so-called "enclosed random size, random position" ,
Randomly shaped voids interconnect and communicate with each other, and also communicate with substantially the entire exterior of the body "(quoted from U.S. Pat. No. 4,186,448) adjusted to an integral porous member, In addition, it is made of a biodegradable polymer that is compatible with the living body.

The raw material currently used to form this macrostructure is a polymer of lactic acid (polylactic acid). This is a specific example of a biodegradable polymer. Lactic acid is one of the organic compounds classified as a group of oxyacids (also referred to as hydroxyacids, hereinafter referred to as oxyacids). Other compounds belonging to this group (eg, glycolic acid, malic acid and α-hydroxybutyric acid) can also be polymerized into biodegradable polymers suitable for use as macro-tissues according to the present invention. Further, for example, an organic compound which is an intermediate of an oxyacid such as fumaric acid can be polymerized and used in the same manner.

The macrotissue thus exhibits a network-like morphology composed of polymers of organic acids (oxyacids) and consisting of interconnected open small pores, and is essentially a replica of the iliac crest spongy. And has physical properties (strength) greater than those of the iliac crest of humans (mammals). And, for at least 90 days after transplantation of the macro tissue according to the present invention,
Maintains physical properties at least equal to the trabecular bone of human iliac crest bone.

Biodegradable Macro Tissue The macro tissue according to the present invention performs three important functions required for bone formation. These functions are as follows.

Restoration of strength, composition and tissue reinforcement to the healing bone cavity, suitable for the formation, growth and development of new connective tissue that has bioacceptable properties and is uncalcified and calcified To provide a surface structure that is stable in terms of strength, and to act as a carrier for other components of the composition according to the present invention that do not have strength and systematic reinforcing power.

Biodegradation of the oxyacid polymer is initiated by the process of hydrolysis. When the polymer absorbs water at body temperature, the polymer is first hydrolyzed to a dimer of lactic acid (ie, lactide). This dimer of lactic acid is further hydrolyzed to a simple substance of free lactic acid, and this lactic acid is then taken up by nearby cells and taken up by Kreb's cycling (Kreb's cycling).
e) via energy (in the form of adenosine triphosphate),
It is metabolized to water and carbon dioxide.

Biodegradable polymer microstructure On the other hand, the microstructure constituting the main body of the composition together with the macrostructure described above is composed of a chemotactic basic substance. For example, glycoproteins such as collagen and fibronectin are suitable chemotactic substrates for the microstructure of the present invention.
In addition, glycosaminoglycans and hyaluronic acid are also suitable. In this case, hyaluronic acid is a valuable chemotactic base substance of choice. This hyaluronic acid is available in bulk quantities from commercial routes and has some desirable properties in addition to chemotaxis.

The hyaluronic acid is a major component of mammalian connective tissue (uncalcified and calcified connective tissue).
The hyaluronic acid used in the present invention can be synthesized, for example, by a known process using bacteria.
After purification, hyaluronic acid is processed to velours consisting of hyaluronic acid fibrils with microscopically sized voids. In such a hyaluronic acid velor, all the voids are in communication with each other.

Therefore, a microstructure composed of a chemotactic basic substance such as velor hyaluronate is injected into the gaps between the macro (polylactic acid) tissues of the main body member of the composition. In the final form of the composition, the chemoattractant base material velours completely occlude all gaps in the polylactide macrotissue of the body member of the composition.

The chemotactic basic substance (hyaluronic acid) velor performs several biochemical and biomechanical functions essential for bone wound healing and bone formation. There are mainly five of these functions,
They are as follows.

Suction of blood flow Hyaluronic acid has extremely high water absorption. It can absorb 500 to 1000 times its own weight of water. Thus, this hyaluronic acid aspirates water-based bodily fluids such as, for example, blood, plasma and serum.
This property of hyaluronic acid serves to attract blood flow to the entire area of the affected bone cavity and to form a viable clot over the entire area of the bone cavity.

Chemotaxis for mesenchymal cell migration and aggregation Hyaluronic acid is an important substrate for the migration, proliferation and aggregation of germinal and wound-healing mesenchymal cells due to its water absorption and the ability to bind specific cells to each other . In other words, the presence of this hyaluronic acid promotes the migration of undifferentiated mesenchymal cells from the position of occurrence around the healthy tissue, and also promotes the blood circulation of the vascular sub-branch over the entire region of the affected bone cavity.

Carriers for osteoinductive / osteogenic substances Hyaluronic acid is chemically bound and physically entrapped, for example, osteoinducible / bone, such as bone morphogenic protein (BMP) and bone derived growth factor (BDGF). It can be easily combined with a forming substance.

Generation and maintenance of an electronegative environment Hyaluronic acid is a highly electronegative chemical. Its presence by chemical means in a new wound makes the wound environment electrically negative. When saturated with blood (containing 80% water), hyaluronate velor becomes an electrically negatively charged viscous gel or plasma. Whenever slight tissue deformation occurs in the body member of the composition, an electrokinetic phenomenon always occurs in the boundary region between the hyaluronic acid plasma and the lactic acid polymer constituting the body member of the composition. This electrokinetic phenomenon is secondary to the negative charge associated with the chemical property of hyaluronic acid being highly electronegative, but can also occur independently of this.

Aggregation of connective tissue substrates with one another Hyaluronic acid is the nuclear protein of glycosaminoglycans and proteoglycan aggregates. It binds to proteoglycans via specific receptors (particularly collagen, fibronectin and osteonectin), as well as to the pericellular matrix of undifferentiated mesenchymal cells and mature connective tissue.

Because of this extensive binding to cells as well as matrix components around cells, hyaluronic acid can be said to be the most effective agent for the growth, development and maintenance of uncalcified and calcified connective tissue.

Hyaluronic acid is hydrolyzed by the enzyme hyaluronidase. This enzyme is produced in the lysosome of cells grown in a hyaluronic acid polymer substrate.

Osteoinductive / osteogenic substances Within the growth phase of bone tissue, substances that differentiate primitive mesenchymal cells into osteogenic cells (osteoblasts) or stimulate the activity of mesenchymal cells Exists. These substances are present not only in all normal growing bone tissue, but also in transplanted bone grafts obtained from generally allogeneic or allogeneic and allogeneic organisms.

Heretofore, at least two such substances have been identified, isolated, purified and partially characterized. One of these is bone-derived growth factor (BDGF).
The other is bone morphogenetic protein (BM)
P). The cartilage or bone pre-developed cells before differentiation are the target cells for BDGF. BDGF is a substance containing paracrine and autocrine that increases the activity of the chain of active deoxyribonucleic acid (DNA) and possibly releases the control or restriction that normally keeps these genes in a checked state. Promotes the activity of the gene and the rate of its replication. BMPs target mesenchymal cells that are less or less differentiated at most or no primitive stages. Mesenchymal cells are known as parasites around blood vessels. BMP initiates the activity of the DNA chain in these mesenchymal cells, resulting in the development of bone tissue that follows an overall embryonic course.

Immediately before transplanting the composition according to the present invention into the bone cavity of the affected part, one or both of these BDGF and BMP are injected into the micro-tissue composed of hyaluronic acid constituting the composition. This allows these substances to be distributed evenly throughout the composition and therefore evenly distributed throughout the bone cavity of the affected area.

When perivascular cells migrating on microstructures of hyaluronic acid come into contact with BDGF (which is bound to the hyaluronic acid microstructure), osteogenic sites are formed. Similarly, bone formation is accelerated where more differentiated cartilage or bone pre-formed cells come into contact with BMPs in the hyaluronic acid micro-tissue.

FIG. 1 is a cross-sectional view of a macrostructure of a composition according to the present invention, which has a random shape, a random position, and a random size and is composed of interconnected voids. These imperfect partition walls are formed of a biodegradable polymer. In the case of the composition, the polymer is polylactic acid. In FIGS. 1 and 2,
Nothing is injected into the voids with random dimensions, random shapes and random locations.

FIG. 2 is an enlarged view of FIG. 1 and more clearly shows the shape of the interconnected voids of the structural polymer.

FIG. 3 shows the macro-tissue shown in FIG. 1 in which the voids of the macro-tissue are filled with a velor of a chemotactic basic substance such as glycosaminoglycan or glycoprotein (particularly hyaluronic acid or fibronectin). FIG. The thick solid line indicates the biodegradable lactic acid polymer, while the halftone dots indicate the velor of the chemotactic basic substance (ie, hyaluronic acid).

FIG. 4 is an enlarged view of FIG. 3, showing the relationship between the macrostructure of the composition composed of a polymer of lactic acid and the microstructure of the structure composed of a filamentous network structure of a chemotactic basic substance. Is shown more clearly. The chemotactic basic substance, velor, covers the entire surface of the macromolecular structural polymer with a dense network of glycosaminoglycans or glycoprotein fibrils. The chemoattractant velor also blocks the entire void area between the polymer septum with a network of its constituent glycosaminoglycans or glycoprotein fibrils. The mesh of the velor fibrils of the chemotactic base material covering the surface of the structural polymer is the same as and continuous with the mesh of the fibrils of the chemotactic base material velor closing the voids inside the structural polymer. ing.

FIG. 5 is a cross-sectional view of the composition shown in FIGS. 3 and 4. In this case, the composition is infused with a drug that is active against the body, known as a bone morphogenic protein, ie, a solution of an osteoinductive drug. This solution is dispersed throughout the composition and envelops the entire fibrils of the chemotactic base material, velor, and coats the entire surface of the structural polymer of the composition.

FIG. 6 is an enlarged view of FIG. 5, showing more clearly the injection of the active osteoinductive drug solution and the dispersion of the solution throughout the composition body.

The composition according to the invention facilitates the healing of structural voids in bone. The composition is formed from a macrotissue formed from biodegradable elements and a chemotactic basal material, while filling in the compositional and structural / strength imperfections in the bone cavity of the affected area. A microstructure integrated with the macrostructure in the entire interior of the gap, and a bioactive agent and / or therapeutic agent carried on the macrostructure component or the microstructure component or in the boundary region between the macrostructure and the microstructure. Including.

The composition also facilitates the healing of structural voids in bone, and either a polymer of a single organic acid (lactic acid) or a copolymer of two or more organic acids. Macro-tissue consisting of a biodegradable polymer, micro-tissue consisting of a chemotactic basic substance (specifically, glycosaminoglycan and / or glycoprotein or a combination of these substances), and bone morphogenesis And / or a healingly active osteogenic substance known as a sexual protein and as a bone-derived growth factor.

Further, the composition has a macrostructure composed of a biodegradable polymer such as a polymer of lactic acid partially embraced and voids having random positions, random sizes and random shapes are mutually reciprocal. (See US Pat. No. 4,186,448) to facilitate healing of bone structural defects. In addition, the composition may also comprise a microstructure of biodegradable chemotactic biomass, such as, for example, glycosaminoglycans known as hyaluronic acid, or glycoproteins known as fibronectin, which are similarly random. A form having a gap which is connected to each other in a position, a random size and a random shape, and which are all connected to each other, and which are connected to all external surfaces of the chemotactic base material, so that a bone structural defect can be easily healed. To

In addition, this composition fills the interstices of the interconnected fibrous network of chemotactic base material and promotes the healing of bone structural defects.

Different forms of compositional elements may appear in different forms. In other words, as a polymer of a chemotactic basic substance consisting of a velor of a chemotactic basic substance in which empty voids are arranged in a network,
Alternatively, as a solid form of a chemotactic basic substance.

Healing and / or biologically active agents are carried by the structural polymer. The healing and / or biologically active agent is also carried by the chemotactic basis.
The therapeutically and / or biologically active agent is confined and carried in the interface between the chemotactic base material and the structural polymer.

Production and use of the composition By the physiological action of the composition described above,
In the final implanted composition, a number of parts that are central to the progression of bone formation are generated. In this case, these bone formation centers coalesce as they grow, resulting in larger new bone tissue. At the same time, cells involved in the osteogenesis process metabolize free lactic acid which is constantly generated by the hydrolysis of macro tissues composed of lactic acid polymers. In addition, the same cells produce enzymes, hyaluronase, which hydrolyze the hyaluronic acid that forms the microstructure of the composition. Also, osteoinductive / osteogenic drugs injected into the composition are metabolized by cells surrounding these drugs.

Finally, the macrostructure composed of the lactic acid polymer and the microstructure composed of the hyaluronic acid polymer are hydrolyzed, and further, various mesenchymal cells constituting the osteoblastic cell lineage, or scavenger cells such as macrophages. Or, in some cases, metabolized by giant cells from outside. The bone cavity, which was initially filled by the compositional components of the composition, is engendered by osteoinductive / osteogenic agents, in turn, with new bones grown from a large number of osteogenic mesenchymal cells that started in the microcomposition of hyaluronic acid. Occupy.

The composition can be used in the same manner as a bone graft obtained from another living body of the same or different kind. Immediately prior to insertion into the implanted bone cavity, as in previous practice, rather than simply wetting with sterile saline, blood, or plasma, the macro- and micro-tissue composites have an osteoinductive and / or Alternatively, an osteogenic drug (bone morphogenic protein and / or bone-derived growth factor) dissolved in a sterile solution, plasma or serum is injected.

The macrostructure of the composition is secured to the surrounding healthy bone using various flanges, rods, bars, and other aids, with wires, screws (which also consist of a polymer of lactic acid) and PLA staples And sutures.

The macrostructure is formed by a vacuum foaming method applying a standard freeze-drying technique. After injecting the alcohol gel solution of hyaluronic acid into the voids of the macrostructure,
It is formed by freeze-drying the alcohol gel solution of the hyaluronic acid.

The osteoinductive / osteogenic agent is combined with a macro-tissue composed of a polymer of lactic acid and a micro-tissue composed of a polymer of hyaluronic acid immediately before the composition is inserted into the bone cavity to be treated. Injected. This is done by the surgeon or his assistant. The void network structure in the hyaluronic acid polymer as a microstructure is composed of hyaluronic acid having a fibrous velor morphology. This velor is characterized by having a myriad of voids of random positions, random shapes and random sizes, all of which are separated by imperfect partitions. These imperfect cavities communicate effectively with each other, each communicating with the front of its adjacent cavities, and forming an unimpeded path communicating with any point on the surface of the hyaluronic acid portion of the composition. Will be.

Drugs that are active on living organisms (in this case, bone morphogenic proteins and / or
Or a bone-derived growth factor) spread evenly throughout the composition, and since the drug itself adheres to the hyaluronate velor, cells that have invaded the composition will have a greater potential for hyaluronan chemotaxis. And is kept in contact with the material.

Hyaluronic acid is a substance with a high electronegativity. It has been clinically proven that an electronegative environment in the affected area is suitable for bone formation. Due to its electronegativity and its degree of equality, the widespread presence of hyaluronic acid in the form of open-cell velours throughout the wound volume creates an electronegative diseased environment, followed by hyaluronan. The environment continues until the acid is biodegraded below the minimum critical mass.

Chemotaxis basal substances include, for example, hyaluronic acid and fibronectin. Examples of the biodegradable polymer include a xylic acid polymer (other examples include polylactic acid, polyglycolic acid, and polysulfone).

[Effects of the Invention] As described above, the macrostructure constituting the main body member of the composition according to the present invention has “enclosed random dimensions, random positions and random shapes, and is interconnected with each other. Many voids that communicate and communicate with the outside ”
(Cited from U.S. Pat. No. 4,186,448) consisting of a biologically acceptable biodegradable polymer molded as an integral porous member. In this embodiment, polylactic acid is used to form a macrostructure, but other organic compounds belonging to the oxyacid group can also be used. The macro-tissue according to the present invention performs three main functions in bone formation. Surface structure suitable for the formation, growth and development of new, uncalcified or calcified connective tissue that is acceptable to the body and stable in strength And a function of supporting other components constituting the composition of the present invention which have no strength or structural adaptability.

The microstructure of the body member consists of a chemotactic basic substance, ie, hyaluronic acid. Velor-shaped hyaluronic acid having a large number of interconnected voids similar to the macro-tissue on a microscopic scale is injected into the gap of the macro-tissue (polylactic acid) of the main body member as the micro-tissue. The function of the hyaluronic acid microstructure is as follows.

 Aspiration of blood throughout the composition, chemotaxis for mesenchymal cell migration and aggregation, ability to carry osteoinductive agents, generation and maintenance of an electronegative diseased environment, aggregation of other connective tissue substrates with each other thing.

Also, bone morphogenetic protein (BMP) as an osteoinductive agent
Has the ability to induce primitive mesenchymal cells to differentiate into osteogenic cells. Bone-derived growth factor (BDGF) as another osteoinductive material stimulates the activity of more mature mesenchymal cells to form new bone composition.

Significant advantages and features of the compositions according to the invention include the following. The elimination of the need to collect graft bone from the iliac crest or ribs for transplantation purposes.

Performing the function of fixing itself in the bone cavity to be implanted.

To function as a carrier for drugs that are active on the living body (ie, the chemotactic base substance); and to function as a carrier for osteoinductive / osteogenic drugs and other therapeutic substances (eg, antibiotics).

To form an electronegative environment that contributes to bone formation by itself.

Completely biodegraded, eliminating the need for a second surgery to remove the composition.

As described above, the present invention has been described with reference to the preferred embodiments. However, the present invention is not limited to these embodiments, and various improvements and design changes can be made without departing from the gist of the present invention. Of course.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view of a macrostructure according to the present invention including interconnecting voids having random shapes, random positions and random dimensions, FIG. 2 is an enlarged cross-sectional view of FIG. 1, and FIG. 4 is an enlarged sectional view of FIG. 3, FIG. 5 is an enlarged sectional view of FIG. 3, and FIG. 5 is a sectional view of FIG. 3 and FIG. FIG. 6 is an enlarged sectional view of FIG.

Continuation of front page (58) Field surveyed (Int. Cl. ⁶ , DB name) A61L 27/00

Claims (27)

(57) [Claims] Claims: 1. An organized composition for use as a surgical implant on a host, the composition for promoting the recovery of structural defects in bone and other tissues of the host. Open voids formed of biodegradable polymers
And a porous macrostructure having a large surface area per unit weight and having a porous microstructure located in the open space. 2. A composition according to claim 1, wherein the porous microstructure is formed of a mobile basic material. 3. The method according to claim 1, wherein the solution has at least one solution of an agent which is active and useful for a living body, and wherein the solution is injected into at least a part of the open space in the open space. The compound according to claim 1 or 2, which is a solution for promoting the growth of. 4. A composite according to claim 1, wherein the biodegradable polymer is selected from homopolymers of α-hydroxy acids, copolymers of at least two α-hydroxy acids or mixtures thereof. 5. The composition according to claim 2, wherein said migratory basic substance comprises a material having a negative potential with respect to a host tissue. 6. The composite according to claim 2, wherein said traveling basic substance has a form of fibrous velour. 7. The composition according to claim 2, wherein said basic substance for traveling is selected from glycoaminopolysaccharide, glycoprotein, lamin or type V collagen. 8. The composition according to claim 3, wherein said drug is osteoinductive or osteogenic. 9. A composition according to claim 1 wherein the open cavities are interconnected, have a random shape and size, and are randomly dispersed. 10. The composition according to claim 3, wherein the drug is a bone morphogenetic protein or an osteoinductive growth hormone. 11. The compound according to claim 2, wherein said mobile basic substance closes said open space. 12. A composition according to any of claims 2 to 11, wherein said mobile base material covers said biodegradable polymer at least partially and adhesively. 13. The composition according to claim 2, wherein the traveling basic substance is hyaluronic acid. 14. A biodegradable therapeutic implant composition for treating a tissue defect made from the composition of claim 1-13 formed prior to implantation. 15. The assembly according to claim 14, wherein said tissue defect is bone loss or destruction. 16. A method for forming a composition for treating structural defects, comprising: a) a porous macrostructure comprising a biodegradable polymer so as to take the form of a porous macrostructure having open porosity. B) forming a porous microstructure in the open pores of the macrostructure so that the microstructure is retained by the macrostructure to form a composite of the microstructure and the macrostructure; c) the composite Introducing into the body a substance selected from an active agent or a therapeutic agent. 17. Before inserting the complex into a structural defect,
17. The method of claim 16, wherein said agent is introduced into said complex. 18. The method according to claim 16, wherein the drug has osteoinductive or osteogenic properties. 19. The method of claim 16, wherein the open cavities are interconnected, have a random shape and size, and are randomly dispersed. 20. A method of forming a composition for treating structural tissue defects, comprising: a) a porous macrostructure comprising a biodegradable polymer so as to take the form of a porous macrostructure having open porosity. And b) forming a porous microstructure in the open voids of the macrostructure so that the microstructure is retained by the macrostructure to form a composite of the microstructure and the macrostructure. 21. The method according to claim 16, wherein the porous microstructure is formed by a mobile base material. 22. A surgical implant composition for promoting the healing of bone, cartilage and soft tissue of a host, wherein the biodegradable polymer comprises communicating open voids or open cells. A porous macrostructure having the strength required for the objective implantation, and a porous microstructure widely located in the voids of the porous macrostructure or in and / or around the cells. An implant composition for promoting recovery of a structural defect comprising a porous macrostructure and a porous microstructure contained therein. 23. A surgical implant composition for promoting the healing of bone, cartilage and soft tissue of a host, wherein the composition comprises (1) a biodegradable polymer,
(2) a mobile basic substance, wherein the (1) biodegradable polymer is composed of communicating open pores or open cells and has a strength necessary for surgical implantation. A macroscopic structure, wherein the (2) mobile basic material is widely located in the voids or cells inside and / or around the porous macrostructure, and (2) the mobile basic material itself An implant composition for promoting recovery of a structural tissue defect, comprising a porous macrostructure and a porous microstructure contained therein, comprising a communicating porous microstructure. 24. A surgical implant composition for promoting healing of bone, cartilage and soft tissue of a host, wherein the composition component of the composition is (1) a biodegradable polymer,
(2) mobile basic substances, (3) bioactive agents and / or
Alternatively, the biodegradable polymer comprises three constituent elements of a healing agent, and the (1) biodegradable polymer has a porous macrostructure composed of communicating open pores or open cells and having a strength required for surgical implantation. And (2) the porous microstructure in which the mobile basic material is widely located in the voids or cells inside and / or around the cells of the porous macrostructure, and (2) the mobile basic material itself communicates. A porous macrostructure and a porous microstructure contained therein, wherein the (3) drug and / or healing agent is contained in the porous microstructure. An implant composition for promoting recovery of a damaged structural tissue. 25. A surgical implant composition for promoting the healing of bone, cartilage and soft tissue of a host, wherein the composition comprises (1) a biodegradable polymer,
(2) mobile basic substances, (3) bioactive agents and / or
Alternatively, the biodegradable polymer comprises three constituent elements of a healing agent, and the (1) biodegradable polymer has a porous macrostructure composed of communicating open pores or open cells and having a strength required for surgical implantation. And (2) the porous microstructure in which the mobile basic material is widely located in the voids or cells inside and / or around the cells of the porous macrostructure, and (2) the mobile basic material itself communicates. And (3) the porosity remaining without being covered with the pores or cells of the porous microstructure and / or the (2) transportable base material. Macroscopic voids or cells and / or at least a part of the voids or cells formed between the biodegradable polymer (1) and the traveling basic substance (2). An implant composition for promoting recovery of a structural tissue defect composed of a porous macrostructure and a porous microstructure contained therein. 26. A surgical implant composition for promoting the healing of bone, cartilage and soft tissue of a host, wherein the composition comprises a α-hydroxy acid homopolymer and an α-hydroxy acid copolymer. A biodegradable polymer (1) comprising one or more compounds selected from the group consisting of polymers and mixtures thereof; and a group consisting of glycoproteins such as collagen and fibronectin, hyaluronic acid and glycoaminopolysaccharides. Runnable basic substance consisting of one or more selected compounds (2)
And three components of an osteoinductive or osteogenic agent and / or a healing agent (3), wherein the biodegradable polymer comprises open cells or open cells communicating with each other. The mobile basic substance (2) is located widely in a space or inside and / or around a cell of the macro structure, and has a porous macrostructure having a strength required for the mobile base. The substance (2) itself is provided with a porous microstructure in communication therewith, and the drug and / or the healing agent is used as a solution in the voids or cells of the porous microstructure and / or the mobile basic substance (2). And / or voids or cells formed between the biodegradable polymer (1) and the mobile basic substance (2), which remain without being covered with the porous macrostructure. An implant composition for promoting the recovery of a structural defect comprising a porous microstructure and a porous microstructure contained therein, which is injected into at least a part of the implant composition. 27. A surgical implant composition for promoting the healing of bone, cartilage and soft tissue of a host according to claim 22, 23, 24, 25 or 26, comprising a porous macrostructure and a porous macrostructure. An implant composition for promoting recovery of a structural tissue defect organized such that voids or cells with a contained porous microstructure are in communication with each other and throughout the cell.