JPH01232967A - Implant bone piece substitute composition having biodegradability and bone forming property - Google Patents

Abstract

PURPOSE: To make a bone graft unnecessary to be taken from an iliac crest or a rib, by composing a composition body of a microtissue integrated with a macrotissue, a polymer of the macrotissue, or a drug or a treatment drug active to an organism carried in a border area of the microtissue and the macrotissue. CONSTITUTION: This composing body is in a form of a macrotissue consisting of a biodegradable polymer such as a polymer of lactic acid partially 'included and with gap parts at random positions, and with random sizes and random shapes mutually connected and communicated and further communicated with the outside of the main body' and facilitates the treatment of a morphologically defective part. Furthermore, this composition body is in a form of microstructure, which consists of a biodegradable chemotactic basic substance, for instance, glycoprotein, known as glucosaminoglycan or fibronectine, in random positions, with random sizes and random shapes and mutually connected and having void parts to communicate with all outer positions to make treatment of a morphologically defect part be easier.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a bone graft substitute composition, and more particularly, it is a biodegradable bone graft substitute composition for general orthopedic surgery, throat and maxillofacial surgery. The present invention relates to a bone graft substitute composition used as a bone graft substitute composition material and as a research material for bone new formation, osteogenesis, cell differentiation, and cell induction by biochemical action.

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

■ "M. Jalco, Calcium Phosphate Ceramic as a Hard Tissue Filler", Clinical Orthopedics,
No. 157 (June 1981), pp. 260-278.

■ J, J, Tarareiter, S, F, Fulpert, "Use of porous ceramics as fixtures in load-bearing internal orthopedic applications," Journal Biomedical Materials Research Symposium, vol.
Volume 1) (1972), pp. 161-229
page.

■ L. Sprinnell et al., "Effect of poly(glycol monomethacrylate) gel structure on calcium deposition of transplanted tissue," Calcification Tissue Research, No. 13 (1973), pp. 63-73.

■ T. D. Triskel et al., “Development of ceramic and ceramic composite materials for use in maxillofacial surgery”;
Journal Biomedical Materials Research Symposium, Volume 2 (Part 1) (1972)
, pp. 91-115.

■ J. H. Brecke et al., “Effect of polylactic acid mesh on the development of localized osteitis,” Oral Surgery.
1 Vol. 56, pp. 240-245 (September 1983)
.

■ J. H. Brekke et al., "Surgical trauma and the effect of polylactic acid cubes and cervical grains on the development of alveolar osteitis in mandibular third molar extraction trauma," Journal Canadian Dental Association (in press).

■ B, P, Raj, “Embryological role of hyaluronic acid compounds”, Connective Tissue Research (1)
(982), Vol. 10, pp. 93-100.

■ G. Abatangiello et al., “Lifetime Histological Observation of Hyaluronic Acid-Rich Trauma Healing,” Journal.
Surgery Research, Vol. 35 (1983), pp. 410-416.

■ E. Canalis et al., “Stimulation of DNA and synthesis of collagen by autologous growth factors in the calvaria of reared fetal rats,” Science, Vol. 210 (No. 28)
, pp. 1021-1023 (1980).

@ M, R, Urist et al., “Human bone morphogenetic protein (hBMP) J,” Proceedings Society of Experimental Biological Medicine, Vol.
Vol. 73, pp. 194-199 (1983).

■ M. R. West et al., “β-tricalcium phosphate supply system for bone morphogenetic proteins,” Clinical Orthopedics, Vol. 187 (July-August 1984),
Pages 277-280.

■ U.S. Pat. No. 4,186,448, ``Compositions and Methods for Treating and Healing Newly Formed Bone Void''.

[Purpose of the invention] The present invention has been made with the following objectives in mind.

■ To provide a biodegradable structure (with incompletely interconnected interstices) carrying chemotactic substrates in the form of fibrous velor.

■ Generating an electronegative environment by maintaining an interface 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 the biodegradable bone graft substitute composition, an endogenous current generated by the interaction between the hyaluronic acid liquid phase and the polylactic acid solid phase and due to the inherent electronegativity of hyaluronic acid is activated. Creating the biophysical conditions and environment in which the associated synergistic effects occur.

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

■ To provide a composition with a unique juxtaposition of polylactic acid, hyaluronic acid, and chemical osteogenic/osteogenic agents.

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

■Providing a composition in which either or both of the solid-shaped part and the part having an empty pore cell network structure are made of a biodegradable polymer, and a chemotactic basic substance is proximate to the polymer. to do.

[Means for Accomplishing the Objects] To achieve the above-mentioned objects, the present invention comprises three compositional elements proximal to each other in combination to promote healing of tissue voids in bone, cartilage, and soft tissues. A biodegradable composition comprising a macro-tissue made of a biodegradable organic polymer and filling the voids of the affected tissue with compositional, structural and strength integrity, and chemotactic composition. by a microstructure consisting of a macrostructure and integrated with the macrostructure in a space inside and/or around the macrostructure, a polymer of the macrostructure and/or a matrix of the microstructure, or It is characterized by comprising at least one biologically active drug and/or healing drug carried in the boundary region between the macro- and micro-tissues.

Furthermore, the present invention provides that the macrostructure is formed from a biodegradable polymer that is either a polymer of a single organic acid belonging to oxyacids or a copolymer of two or more organic acids. Features.

Furthermore, the invention is characterized in that the macro-tissue is formed from mobile basic substances derived from the group of organic compounds known as glycoproteins or from the group of organic compounds known as glycosaminoglycans.

Furthermore, the present invention provides biologically active agents and/or
Alternatively, the therapeutic agent is injected into the polymer of the macro-tissue so that it is present on the exposed surfaces of the cavity partitions of the macro-tissue and in the material surrounded by these partitions.

On the other hand, the present invention involves attaching a drug and/or therapeutic agent active to living organisms to the surface of a polymer in a macro-tissue, and also attaching the drug and/or therapeutic agent to the surface of a polymer in a macro-tissue, and exclusively to the surface of a cavity partition wall (when these partition walls are not present in the central part of the macro-tissue). It is characterized by being made to exist above.

The present invention is characterized in that a drug active and/or therapeutic for a living body is injected into the substance of the macro tissue.

Furthermore, the present invention is characterized in that it contains a biologically active and/or therapeutic agent confined within the voids within the microstructure.

Furthermore, the present invention is characterized by the inclusion of a biologically active and/or therapeutic agent trapped at the interface between the macro-tissue septum or its material and the micro-tissue septum or its material.

Furthermore, the present invention provides compositions that can be used as drugs, biological modifiers,
It is characterized by being used as a carrier for proteins, antigens, and adducts.

Furthermore, the present invention is characterized in that the composition is a body for ossification.

Furthermore, the present invention is characterized in that the composition is a cartilage substitute.

Furthermore, the present invention is characterized in that the composition is a soft tissue substitute.

[Embodiments Congenital malformations, diseases of bone tissue and/or bone marrow tissue,
Bone graft substitute compositions for treating bone defects, defects, voids and tissue discontinuities in mammals caused by trauma (including accidents and/or surgery) and functional atrophy are described in detail below.

The present invention provides a composition molded from four materials, each contributing to the specific requirements needed for new bone formation. Viewed as a whole, the functions of each component of the composition are integrated into a single body member. That is, when the body member is implanted into a bone defect, the body member becomes tissue and structurally integrated and begins to induce bone formation.
While serving to stimulate the bone formation and maintain the body's bone formation process, the implanted body tissue simultaneously biodegrades the body member. Finally, due to the function of the composition of the present invention, healthy and viable bone tissue is formed in places where no bone existed before, while at the same time, the composition itself is completely hydrolyzed and converted into living tissue. Completely metabolized.

The body member of the composition is comprised of four disparate elements.

The presence of each of these elements contributes to the essential function of the composition according to the invention, so that the essential conditions for the fracture formation process are established. These functions are as follows.

■ Structural Complementarity The macrostructure of the composition according to the present invention compensates for the strength, organization and structural deficiencies in bone defects, and at the same time, during the dynamic biological processes of healing of the affected area and bone formation. It functions to support the tissue and secure the surface area of the tissue.

■ Chemotaxis Aspiration of mesenchymal cells at various stages of maturation from adjacent healthy tissue and from collateral vessels lining the affected space.

■ Electronegative Field Creation and maintenance of an electronegative environment in the affected area of healing bone by means of electrodynamics and electrochemistry.

■ Induction of bone formation The use of chemical agents to generate basic genetic changes that cause primitive mesenchymal cells (perivascular cells) to differentiate into mature bone-forming cells (osteoblasts) during the subsequent maturation process. .

■ Stimulation of the biosynthetic process of cells already induced to mature as bone-forming osteoblasts.

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

``Components and biological functions of the main body member of the composition j Biodegradable polymeric macrostructure The macrostructure constituting the main body member of the composition is the so-called,
"Enclosed randomly sized, randomly located, randomly shaped voids are interconnected and in communication with each other and with the generally metallic exterior of the body" (U.S. Pat. No. 4,186). (Quoted from No. 448) It is made into an integral porous member and is made of a biocompatible and biodegradable polymer.

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 an oxyacid (also called hydroxy acid, hereinafter referred to as oxyacid) group. Other compounds belonging to this group (e.g. glycolic acid, malic acid and alpha
-hydroxybutyric acid) can also be polymerized to biodegradable polymers suitable for use as macrostructures according to the invention. Furthermore, organic compounds that are intermediates of oxyacids such as fumaric acid can also be polymerized and used in the same manner.

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

Biodegradable Macro-Tissues The macro-tissues of the present invention perform three important functions required for bone formation. These functions are as follows.

■ Restoration of strength, composition and tissue reinforcement to the healing bone void; ■ Formation, growth and development of new unmineralized and mineralized connective tissue with bioacceptable properties; (1) To act as a carrier for the other components of the composition according to the invention, which have no strength and textural reinforcing properties.

Biodegradation of oxyacid polymers is initiated by the process of hydrolysis. When the polymer absorbs water at body temperature, it is first hydrolyzed to a dimer of lactic acid (ie, lactide). This lactic acid dimer is further hydrolyzed into free lactic acid, which is then taken up by nearby cells and undergoes the Cleves cycle (1 (reb')).
It is metabolized to energy (in the form of adenosine triphosphate), water, and carbon dioxide via 5 cycles).

Biodegradable Polymer Microstructure On the other hand, the microstructure, which together with the aforementioned macrostructure constitutes the main body member of the composition, consists of chemotactic basic substances. for example,
Glycoproteins such as collagen and fibronectin are suitable chemotactic substrates for the microtissues of the present invention. In addition, glycosaminoglycans and hyaluronic acid are also suitable. In this case, hyaluronic acid is a chemotactic basis substance worth choosing. This is because hyaluronic acid can be obtained in large quantities by commercial means and has several desirable properties in addition to chemotaxis.

The hyaluronic acid is the main component of mammalian connective tissue (both unmineralized and calcified connective tissue). Hyaluronic acid used in the present invention can be synthesized, for example, by a known process using bacteria. After purification, hyaluronic acid is processed into velour, consisting of hyaluronic acid fibrils interspersed with microscopic sized voids.

In such hyaluronic acid velor, all the voids are in communication with each other.

Therefore, a microstructure consisting of a chemotactic basic substance such as hyaluronic acid velor is injected into the interstices of the macro (polylactic acid) structure of the main body member of the composition. In the final form of the composition, the velor of the chemotactic base material completely occludes all interstices of the polylactic acid macrostructure of the body member of the composition.

Velor, a chemotactic substance (hyaluronic acid), performs several biochemical and biomechanical functions essential for bone trauma healing and bone formation. There are mainly five functions, and they are as follows.

■ Blood flow suction Hyaluronic acid has extremely high water absorption. It can absorb 500 to 1000 times its own weight in water. This hyaluronic acid thus attracts water-based body fluids, such as blood, plasma and serum. This property of hyaluronic acid helps to attract blood flow to the entire area of the affected bone cavity and to form a viable blood clot throughout the area of the affected bone cavity.

■ Chemotaxis for the migration and aggregation of mesenchymal cells Hyaluronic acid is an important substrate for the migration, proliferation and aggregation of germ cells and trauma-resistant mesenchymal cells due to its water-absorbing properties and properties that bind specific cells to each other. It is. That is, the presence of this hyaluronic acid promotes the migration of undifferentiated mesenchymal cells from their place of origin around healthy tissue, and also promotes blood circulation in side branches of blood vessels throughout the entire area of the affected bone cavity.

■ Carrier for osteoinductive/osteogenic substances Hyaluronic acid is a carrier for osteogenic/osteogenic substances, for example bone morphogenetic proteins (BMPs) and bone-derived growth factors (
It can easily combine with osteoinductive/osteogenic substances such as BDGF).

■ Creation and maintenance of an electronegative environment Hyaluronic acid is a highly electronegative chemical substance. Its presence by chemical means in a new wound makes the wound environment electronegative. When saturated with blood (containing 80% water), hyaluronic acid velor becomes an electrically negatively charged, highly viscous gel or plasma. Whenever a slight tissue deformation occurs in the body member of the composition, an electrokinetic phenomenon occurs in the interface 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 highly electronegative chemical property of hyaluronic acid, but can also occur independently of this.

■ Aggregation of connective tissue matrix with each other Hyaluronic acid is a nucleoprotein of glycosaminoglycan and proteoglycan aggregates. It further binds to proteoglycans through specific receptors (particularly collagen, fibronectin and osteonectin) and to the pericellular matrix of undifferentiated mesenchymal cells and mature connective tissue.

Because of this extensive binding to cells and pericellular matrix components, hyaluronic acid can be said to be the most effective agent for the growth, development and maintenance of unmineralized and mineralized connective tissue.

Hyaluronic acid is hydrolyzed by the enzyme hyaluronidase. This enzyme is produced in the lysosomes of cells grown within a hyaluronic acid polymer matrix.

Osteogenic/Osteogenic Substances Within the growth phase of bone tissue, there are substances that serve to differentiate primitive mesenchymal cells into bone-forming cells (osteoblasts) or to stimulate the activity of mesenchymal cells. exist. These substances are present not only in bone tissue during all normal growth stages, but also in bone grafts obtained from living organisms of the same species, allogeneic, allogeneic, and xenogeneic.

To date, at least two such substances have been identified, isolated, purified and partially characterized.

One of these is bone-derived growth factor (BDGF).
), and the other is bone morphogenetic protein (hereinafter referred to as B
MP). Cartilage or bone development cells before differentiation are target cells of BDGF. BDGF is a substance that includes baratalin and autotalin, and increases the activity of active deoxyribonucleic acid (DNA) chains, possibly by releasing the controls or constraints that normally keep these genes in check. Promote the activity of the gene and the rate of its replication. BMPs target mesenchymal cells that are at a primitive stage and have little or no differentiation. Mesenchymal cells are known as perivascular parasites.

BMPs initiate the activity of DNA chains within these mesenchymal cells, resulting in the development of bone tissue that follows an overall embryonic course.

Immediately before implanting the composition according to the present invention into the bone cavity of the affected area, one or both of these BDGFSBMPs are injected into the microstructure made of hyaluronic acid constituting the composition.

This allows these substances to be evenly distributed throughout the composition and, therefore, evenly distributed throughout the affected bone voids.

When pericytes migrating on microstructures made of hyaluronic acid come into contact with BDGF (which is bound to the hyaluronic acid microstructures), osteogenic zones are formed. Similarly, bone formation is accelerated where differentiated cartilage or osteogenic cells come into contact with BMPs within the hyaluronic acid microstructure.

FIG. 1 is a cross-sectional view of the macrostructure of a composition according to the invention consisting of interconnected voids of random shape, random location and random size. The incomplete partition walls of these voids are formed from a biodegradable polymer. In the case of the composition, the polymer is polylactic acid. Note that in FIGS. 1 and 2, nothing is injected into the empty space IItaB with random dimensions, random shapes, and random positions.

FIG. 2 is an enlarged view of FIG. 1, showing more clearly the shape of the interconnecting voids in the structural polymer.

FIG. 3 shows the macro-tissue shown in FIG. 1 in which the voids of the macro-tissue are filled with velor of chemotactic basic substances such as glycosaminoglycans or glycoproteins (particularly hyaluronic acid or fibronectin). FIG. The thick solid line represents the biodegradable lactic acid polymer, while the dotted area represents the chemotactic base material (i.e., hyaluronic acid) velor.

FIG. 4 is an enlarged view of FIG. 3, showing the relationship between the macrostructure of a composition composed of a polymer of lactic acid and the microstructure of the composition composed of a filamentous network structure of chemotactic basic substances. is shown even more clearly. Velor, a basic chemotactic substance, covers the entire surface of the structural polymer of macro tissues with a dense network of its constituent glycosaminoglycans or glycoprotein fibrils. The chemotactic substrate velor also occludes the entire void area between the polymeric septa with its component glycosaminoglycan or glycoprotein fibril network. The fibril network of the chemotactic basic substance velor that coats the surface of the structural polymer is the same as and continuous with the fibril network of the chemotactic basic substance velor that blocks the voids inside the structural polymer. ing.

FIG. 5 is a cross-sectional view of the composition shown in FIGS. 3 and 4. FIG. In this case, the composition is infused with a solution of biologically active agents known as bone morphogenetic proteins, ie, osteoinductive agents. This solution is dispersed throughout the composition, enveloping the entire fibrils of the chemotactic substrate velor and covering 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 osteoinducing drug solution and its distribution throughout the pot body.

Compositions according to the invention facilitate healing of structural voids in bone. This composition is formed from macro-tissues formed from biodegradable elements and chemotactic base materials while correcting compositional and structural/strength imperfections in the affected bone voids and a microstructure integrated with the macrostructure throughout the interior of the void;
It contains a biologically active drug and/or therapeutic agent carried in a macro-tissue component, a micro-tissue component, or a boundary region between a macro-tissue and a micro-tissue.

The composition also facilitates the healing of structural voids in bone and may be a polymer of a single organic acid (lactic acid) or a copolymer of two or more organic acids. a macro-tissue consisting of biodegradable polymers, a micro-tissue consisting of chemotactic basic substances (specifically, glycosaminoglycans and/or glycoproteins or a combination of these substances), and bone morphogenesis. It contains biologically and/or therapeutically active osteogenic substances known as biogenic proteins and bone-derived growth factors.

Furthermore, the composition is characterized in that the macrostructure consisting of a biodegradable polymer, such as a polymer of lactic acid, is partially "encapsulated" and that voids of random locations, random sizes, and random shapes are interconnected. 4.186.448 to facilitate healing of structural defects in the bone. Additionally, this composition may include, for example:
The microstructure, which consists of biodegradable chemotactic substrates such as glycosaminoglycans known as hyaluronic acid or glycoproteins known as fibronectin, is similarly randomly located, randomly sized and randomly located. The shape is connected to each other and has a gap that communicates with all the external surface areas of the chemotactic substance, thereby facilitating the healing of the structural defect in the bone.

Furthermore, this composition fills the interstices where filamentous network structures made of chemotactic substances are interconnected and promotes healing of structural defects in bone.

Different forms of compositional elements appear in different forms.

That is, as a chemotactic basic substance polymer consisting of velour, a chemotactic basic substance, in which empty voids are arranged in a network pattern, or as a solid form of a chemotactic basic substance.

The therapeutically and/or biologically active agent is carried by the structural polymer. Therapeutically and/or biologically active agents are also carried by chemotactic substrates. The therapeutically and/or biologically active agent is trapped and carried in the interface area between the chemotactic substrate and the structural polymer.

Manufacture and Use of the Composition The physiological effects of the composition described above create a number of focal points for osteogenic progression in the final implanted composition.

In this case, these bone-forming centers coalesce as they grow;
It becomes new, larger bone tissue. At the same time, cells involved in the osteogenic process metabolize free lactic acid, which is constantly produced by hydrolysis of macrostructures made of lactic acid polymers.

In addition, the same cells produce the enzyme hyaluronase,
These enzymes hydrolyze the hyaluronic acid that forms the microstructure of the composition. Additionally, osteogenic/osteogenic agents injected into the composition are metabolized by the cells surrounding these agents.

Finally, the macrostructure consisting of lactic acid polymer and the microstructure consisting of hyaluronic acid polymer are hydrolyzed, and further, various mesenchymal cells that constitute the seed lineage of osteoblasts, or
Metabolized by scavenger cells such as macrophages or, in some cases, giant cells of external origin. The bone voids, which were initially filled by the constituent elements of the composition, are sequentially filled with new bone that grows from a large number of osteogenic mesenchymal cells initiated in the microcomposition of hyaluronic acid by osteogenic/osteogenic agents. Occupy.

The composition can be used in the same manner as bone grafts obtained from other living organisms of the same or different species. It is not simply wetted with sterile saline, blood, or plasma, as was the case with previous Bractis, immediately before insertion into the bone cavity to be implanted.
The composite macro- and micro-tissue composition contains an osteoinductive and/or osteogenic agent (bone morphogenetic protein and/or bone-derived growth factor) in a sterile solution;
Inject plasma or serum dissolved.

The macrostructure of the composition is fixed to the surrounding healthy bone using various flanges, rods, bars and other auxiliary devices, including wires, screws (which are also made of lactic acid polymers) and PLA staples. and using sutures.

The macrostructure is formed by vacuum foaming using standard freeze-drying techniques. The microstructure is formed by injecting an alcohol gel solution of hyaluronic acid into the voids of the macrostructure and then freeze-drying the alcohol gel solution of hyaluronic acid.

The bone permeability/osteogenic agent is a composite of a macrostructure consisting of a polymer of lactic acid and a microstructure consisting of a polymer of hyaluronic acid, just before the composition is inserted into the bone cavity to be treated. injected into. This is done by the operating 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 countless voids at random locations, random shapes, and random sizes, and all of these voids are partitioned by incomplete partition walls. These incomplete voids communicate with each other in effect, each communicating with the front of its adjacent void, and forming an unobstructed path of communication with every point on the surface of the hyaluronic acid moiety in the composition. It turns out.

Since the absorbability of hyaluronic acid is utilized, a sterile solution of a biologically active drug (in this case, bone morphogenetic protein and/or bone-derived growth factor) is evenly distributed over the main body member, and the drug itself is is attached to the hyaluronic acid velor, cells that have invaded this composition are attracted to and kept in contact with this material by the chemotaxis of the hyaluronic acid.

Hyaluronic acid is a highly electronegative substance.

It has been clinically proven that an electrically negative environment in the affected area is favorable for bone formation. Due to its electronegativity and its uniformity in degree, the widespread presence of hyaluronic acid in the form of open-cell velor throughout the wound volume creates an electronegative affected area environment, and subsequently hyaluronic acid The environment continues until the acid is biodegraded to below the critical minimum mass.

Chemotactic basic substances include, for example, hyaluronic acid and fibronectin. Biodegradable polymers include polymers of oxyacid (other examples include polylactic acid,
polyglycolic acid or polysulfone).

[Effects of the Invention] As described above, the macrostructure constituting the main body member of the composition according to the present invention has [encapsulated random dimensions, random positions, and random shapes, and is interconnected with each other]. "Many voids that communicate with each other and communicate with the outside" (
(quoted from U.S. Pat. No. 4,186,448). Although polylactic acid was used in this embodiment to form the macrostructure, other organic compounds belonging to the oxyacid group can also be used. The macrostructure according to the present invention exhibits three main functions during bone formation. These include: ■ strength, composition, and complementation of structural deficiencies; ■ surface structure suitable for the formation, growth, and development of new connective tissue, either unmineralized or mineralized, that is acceptable to the organism and has strength. (2) The ability to support other components constituting the composition of the present invention that do not have flexibility in terms of strength or structure.

The microstructure of the body member consists of a chemotactic substance, namely hyaluronic acid. Hyaluronic acid in the form of velour, which has a large number of interconnected voids similar to the macrostructure on a microscopic scale, is injected into the interstices of the macrostructure (polylactic acid) of the main body member as the microstructure. The functions of hyaluronic acid microstructure are as follows.

■ attraction of blood throughout the composition, ■ chemotaxis for migration and aggregation of mesenchymal cells, ■ ability to carry osteogenic agents, ■ generation and maintenance of an electronegative diseased environment, ■ other connective tissues. Agglomerating the substrates together.

Also, bone morphogenetic protein (BMP) as an osteoinductive agent
has the ability to induce the differentiation of primitive mesenchymal cells into osteogenic cells. Another bone-inducing agent, bone-derived growth factor (BDGF), stimulates the activity of more mature mesenchymal cells to form a new skeletal floor.

Significant advantages and features of the composition according to the invention include the following. ■ Eliminating the need to harvest bone grafts from the iliac crest or ribs for transplantation purposes.

■ Perform the function of fixing itself in the bone cavity where the graft is to be transplanted.

■ function as a carrier for biologically active agents (i.e., chemotactic substances), ■ osteoinductive/
Functioning as a carrier for osteogenic drugs as well as other therapeutic substances (eg, antibiotics).

■ By themselves creating an electrically negative environment that contributes to bone formation.

■ Fully biodegradable, eliminating the need for a second surgery to remove the composition.

Although the present invention has been described above with reference to preferred embodiments, the present invention is not limited to these embodiments.
Of course, various improvements and changes in design are possible without departing from the gist of the present invention.

[Brief explanation of the drawing]

FIG. 1 is a cross-sectional view of a macrostructure according to the present invention including interconnected voids of random shape, random location, and random size; FIG. 2 is an enlarged cross-sectional view of FIG. 1; FIG. 3 is a macrostructure. Figure 4 is an enlarged cross-sectional view of Figure 3. Figure 5 is a cross-sectional view of Figures 3 and 4. FIG. 6 is an enlarged sectional view of FIG. 5. FIG, 4 FIG, 5 FIG, 6

Claims (12)

[Claims] (1) A biodegradable composition consisting of three compositional elements in close proximity to each other and a biodegradable composition for promoting healing of tissue voids in bones, cartilage, and soft tissues, and a biodegradable organic a macrostructure made of a polymer and filling the voids of the affected tissue with compositional, structural, and strength integrity;
A microstructure consisting of a chemotactic substrate and integrated with the macrostructure in the space inside and/or around the macrostructure, and a polymer of the macrostructure and/or a matrix of the microstructure, or at least one biologically active drug and/or carried in the boundary area between the macro-tissue and the micro-tissue;
or a bone graft substitute composition comprising a healing agent. (2) In the composition according to claim 1, the macrostructure is a biodegradable polymer that is either a polymer of a single organic acid belonging to oxyacids or a copolymer of two or more organic acids. A bone graft substitute composition characterized in that it is formed by coalescence. (3) A composition according to claim 1, wherein the macrostructure is formed from a mobile basic substance derived from the group of organic compounds known as glycoproteins or from the group of organic compounds known as glycosaminoglycans. A bone graft substitute composition characterized by the following. (4) In the composition according to claim 1, a biologically active drug and/or therapeutic agent is injected into the polymer of the macro-tissue, and the exposed surface of the partition wall of the cavity of the macro-tissue and the area surrounded by the partition wall are A bone graft substitute composition characterized in that it is present in a substance. (5) In the composition according to claim 1, the biologically active drug and/or therapeutic agent is attached to the surface of the polymer of the macro-tissue, and is exclusively applied to the cavity partitions (these partitions are located in the central part of the macro-tissue). 1. A bone graft substitute composition, characterized in that it is present on the surface of a bone graft (if not present). (6) A bone graft substitute composition according to claim 1, characterized in that the composition is obtained by injecting a drug active and/or therapeutic to a living body into the substance of the macro tissue. (7) A bone graft substitute composition according to claim 1, characterized in that it contains a biologically active and/or therapeutic agent confined within the voids within the microstructure. (8) The composition according to claim 1, comprising a biologically active and/or therapeutic agent confined at the interface between the macro-tissue partition wall or its material and the micro-tissue partition wall or its material. A bone graft substitute composition characterized by the following. (9) The composition according to claim 1, wherein the composition is a drug,
A bone graft substitute composition characterized in that it is used as a carrier for biological modifiers, proteins, antigens, and adducts. (10) The bone graft substitute composition according to claim 1, wherein the composition is a bone substitute. (11) The bone graft substitute composition according to claim 1, wherein the composition is a cartilage substitute. (12) The bone graft substitute composition according to claim 1, wherein the composition is a soft tissue substitute.