TW420604B - An absorbable calcium phosphate biomedical compound material particle and it's manufacturing procedure - Google Patents

Abstract

This invention is an absorbable calcium phosphate biomedical compound material particle and it's manufacturing procedure. The manufacturing procedure controls the collagen with full time to form a cellulose structure with a well dispersed calcium phosphate ceramics powder. The biomedical compound material which is easy absorbed by human body and similar to the composition structure of bone can generate the new bone. Patient do not need second operation in clinic.

Description

420604 V. Description of the invention (1)-[Scope of application of the invention] The present invention relates to a biomedical composite material particle and its manufacturing process, especially a group of calcium phosphate biomedical composite material used in orthopedic surgery. [Related technology of the invention] Bone defect caused by X external force or lesion resection is a major problem in orthopedics and other surgical operations. 'Although autograft bone contains bone-forming proteins and several types of living bone cells, it can add vaginous bone. Tissue healing is the best choice for bone transplantation. However, since the autQgenous bone graft must be obtained by surgery in the patient itself, it is easy to cause postoperative infection of the patient and the amount is small. UUogenous bone graft) may cause viral infection (such as acquired immunodeficiency syndrome), and poor healing is its disadvantage. Therefore, in order to promote the healing of bone defects and avoid the potential problems of autograft or allograft, the development of synthetic bone graft substitutes (bone graft substitutes) is indispensable. At present, synthetic bone defect filling materials cannot be decomposed and absorbed in the human body, and have poor operability or plasticity, which is inconvenient for clinical application. Therefore, it is necessary to develop human absorbable 'handling and plasticity (01 〇1 (1 &};) 111 ^) Excellent bone defect filling material to meet the needs of skull face plastic surgery, dental or orthopedic bone defect filling and bone regeneration needs. The conventional commercial product coilagraft is composed of a composite material formed of bioceramics and collagen ’, but the weight ratio of the collagen to the ceramic material and the bone group disclosed therein

42〇6〇 5. Description of the invention (2)---- --- Many. Although many studies have shown that Collagraft has a particularly good bone regeneration capacity when implanted in animals, the ceramic component contains 60% of biodegradable hydroxyapatite, which can cause new bone formation in the body and integrate bone tissue Sexual limitations are its main disadvantage. In addition, the techniques disclosed in U.S. Patent Nos. 5,658,593 and 5,424,084 are methods for making such collagen microparticles. The network structure of collagen is thin and the main form of the outer stroma, so collagen U particles with a netlike structure are more similar to the tissue β, but previously known patented technology disclosed However, it has not been proposed that the collagen particles formed by the collagen particles have a reticular fibrous structure, and the technology of how to form a reticular fibrous structure in collagen has not been disclosed. In addition, "complex materials formed by collagen and ceramic powder are currently known" in which the proportion of victorin is much lower than the proportion of victorin in bone tissue. [Summary and purpose of the invention] In view of this, the main purpose of the present invention is to solve the above-mentioned conventional synthetic bone defect filling material which cannot be decomposed and absorbed in the human body, and has poor operability or plasticity, which is inconvenient for clinical application The problem is to provide an absorbable calcium phosphate biomedical composite particle and its manufacturing process. The present invention utilizes the soluble osteo-conduct i ve of collagen which has the characteristics of reconstructed into a network fiber structure, combined with calcium scaly-based ceramic powder, such as hydrogen-apatite-based apatite ( hydroxy 1 apatite), so that the calcium phosphate ceramic powder can be uniformly dispersed in the recombinant collagen network fiber structure. Significant in bone tissue

420604 V. Description of the invention (3) In the microstructure, 'bioapatite' (bio_apatite) is nucleated on osteoconductive organic fibers, and in the present invention, it is formed by calcium phosphate ceramic powder and collagen-protein network fiber structure. The microstructure of composite particles is similar to that of bone tissue. In addition, the novel resorbable calcium carbonate-based composite material particles for bone filling regeneration produced by the present invention can achieve a weight ratio of collagen to ceramic powder of 3 5: 6 5 and this ratio is related to bone tissue. Similar, and the ceramic powder has a particle size of 5 μm each, so it has the characteristics of being absorbed by the human body, and its composition and composition are similar to those of bone tissue, without the need for secondary surgery, it is not only manipulable and plastic, but also adequate Utilize the regeneration function of bone tissue to achieve rapid and effective bone regeneration effect. Another object of the present invention is to make the developed absorbable hyaluronic acid I-based (calcium phosphate-based) biomedical composite material, which can be used alone or in combination with bone marrow of the patient, Or apply the concept of tissue engineering to use absorbable linoleic acid-based biomedical composites as scaffolds for implanted cells (seecjed cells) and carriers for growth factors In order to fully apply the natural regeneration function of bone tissue to achieve a more rapid and effective bone regeneration function, the bone defect can be repaired and regenerated more quickly. Another object of the present invention is to provide a manufacturing technology of absorbable calcium phosphate biomedical composite particles. According to the above purpose of the present invention, the process for providing the absorbable calcium phosphate biomedical composite particles includes at least the following steps: After the collagen and the hydroxyl ash are mixed uniformly, they are dropped into the oil phase.

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V. Description of the invention (4) The collagen / hydroxyapatite mixture is made to the right g I in the oil phase. Recombination to form the network fiber structure particles' and then cross-linking for eight hours to the required absorbable formula Calcium phosphate biomedical composite particles. " and separation · Detailed information and technology related to the present invention 1 will be described in conjunction with the drawings, such as [the description of the preferred embodiment] The absorbable calcium phosphate-based biomedical composite material of the present invention_, The process includes: leather Degreasing treatment, collagen extraction, purification of particles, and preparation of absorbable calcium phosphate-based biomedical composite particles. Please refer to FIG. 1, which is a process flow chart of the absorbable pterosin acid biomedical composite particles according to the present invention. The first step is the treatment of fat from cowhide (10); then the extraction of collagen (20 ); And then obtaining collagen purification (30); and preparation of absorbable calcium phosphate-based biomedical composite particles (40) and other steps. Now, the preparation steps of the whole absorbable calcium phosphate-based biomedical composite particles are described in a preferred embodiment as follows. First, in the degreasing treatment step of the cowhide, a cowhide that has been removed from a living body is provided and placed. —70. 〇 Freeze and store in a refrigerator, and then perform hair removal with a razor under 4 ° C, then rinse with 4 ° C, 0.02M phosphate-based (PBS) buffer solution. The cowhide was cut into a size of about 5 mm, and then 'placed in an aerosol-like methanol solution of equal volume ratio and then degreased'. After the solution was pale yellow, the new chloroform methanol solution was replaced until the solution became transparent. The degreased cowhide fragments were placed in 100% methanol to remove residual aeroform. The cowhide fragments were then placed in a 50% methanol solution ’followed by 0.15 M sodium gaseous solution, 50 mW [hydroxymethylaminomethane buffer

420604 V. Description of the invention (5) Solution (Tris buffer), pH 7.4 solution.

In the extraction step of vicin protein, the washed degreased cowhide was placed in a 0.5 M acetic acid solution, and 5 mg / ml pepsin was added to the solution, and stirred with a homomixer. After standing for about 20 hours, 'the upper clear solution was collected after centrifugation at high speed for about 1 hour, and sodium gaseous solution was added to make the sodium chloride concentration in the solution to 2, 5M. After standing for about 20 hours, the precipitate was collected by high speed centrifugation' Mix the precipitate with 50 mM hydroxymethylaminomethane buffer solution (pH = 7_ 2-7. 4), and leave it to stand for about 20 hours', then collect the upper clear solution by high-speed centrifugation, and IM vaporized sodium, pH = 7. 2-7. 4, 50mM hydroxymethylaminofane buffer solution was dialyzed to the system equilibrium at pH = 7-2 ~ 7.4. Add sodium gaseous solution to the solution so that the sodium chloride concentration in the solution is 1.8M. Stir off evenly with a homomixer and leave to stand for an hour. At high speed. Collect the upper layer e: ¾. Then add sodium gasification to the solution, so that the concentration of 2.5 in the solution reaches 2.5 M ′ and collect the precipitate by high-speed centrifugation. At this time, Sa 2 ::: 1 ^ 1 ^^ collagen was obtained. Add the precipitate to an appropriate amount of 0.5M acetonol, and stir with a homogenizer. In the step of purifying the original protein Φ, therefore, / / 〒 'Pour the well-mixed precipitate into the dialysis bag, and push the 0.5 M acetic acid solution > swimming > ^, ^ ^ into the dialysis' Save the glands until the collagen solution in the dialysis bag is transparent. This collagen solution is placed at -20 ° C in the preparation step of acid two, in which-oxystone biomedical composite material; prepared; = acid salt, etc. Take 5ml of collagen (f R y mg ml) with nitrogen and 80mg of hydroxide scale gray

V. Description of the invention (6) After the stones are mixed uniformly at 4 ° C, the mixed solution is placed in a syringe of a flat-head stainless steel needle, and then extruded into a ball drop by a syringe pump. The ball is dropped into the olive oil (or other non-biotoxic oil) at 37 ° C, and continuously stirred with an agitator for 1 hour, so that the collagen / hydroxyapatite mixture has sufficient time to re-

I forms a network structure. Slowly add 2.5% by weight of cross-linking agent in olive oil. The cross-linking agent can be glutaraldehyde, genipin, or carbodiimide, so that the collagen has been reconstituted. / Hydroxyapatite spheres are cross-linked in the cross-linking agent. The size of the cross-linked particles ranges from 50 / zin to 5 nm. Aspirate the oil phase, add an acidic buffer solution and centrifuge again to separate the remaining oil phase. The washed collagen granules containing hydroxide ash were freeze-dried and stored at -20. [Effects of the invention] (1) The calcium phosphate-based biomedical composite particles produced by the present invention, the fresh phosphate-based ceramic powders provided therein all have a particle size of $ 5 to m, compared with the previous US patent compilation of 5, 658,593 and 5,424,084, which are directly absorbable 'and this collagen has the property of recombination to form a reticular fibrous structure similar to bone tissue' and use this property to make fine calcium phosphate ceramic powder 'Like hydroxylapatite (hydroxylapatite)' is evenly distributed in the collagen network fiber structure. (2) The calcium phosphate-based biomedical composite material produced by the present invention

Page 9 420604 V. Description of the invention (7)-To achieve rapid and effective bone regeneration. (3) In addition to being used alone, the calcium phosphate-based biomedical composite particles produced by the present invention can also be used with the patient's own bone marrow (bone marrow) or by applying the concept of tissue engineering. Absorbable calcium phosphate-based biomedical composites are used as scaffolds for implanted cells and carriers for growth factors in order to fully utilize the natural regeneration function of bone tissue to achieve The more rapid and effective bone regeneration function enables the bone defects to be repaired and regenerated more quickly. (4) The calcium phosphate-based biomedical composite particles produced by the present invention can achieve a weight ratio of collagen to ceramic powder of 35:65, and this ratio is similar to bone tissue. C5) The calcium phosphate-based biomedical composite particles produced by the present invention, wherein the weight ratio of collagen to ceramic powder can be made according to different clinical needs to produce composite materials ranging from 1: 0: 90 to 1: 0: 0 Particles. (6) The calcium phosphate-based biomedical composite particles produced by the present invention can be embedded with osteoporos is a drug or hormone to treat osteoporosis, osteolysis, or can be embedded. Related Chinese medicine is used to treat orthopedic diseases such as fractures. (7) The calcium phosphate-based biomedical composite particles produced by the present invention can be applied in the following fields: orthopedics, dental applicati, cranio-and maxillofacial cosmetic surgery Defect repair

Page 10 42〇e〇4 V. Description of the invention (8) Supplement; bone fracture materials for orthopedic fractures; scaffolds for tissue engineering products; spinal fusion;

I osteo-porosis; carriers of biological agents, such as: embedding and releasing anti-osteoporotic hormones or agents, anti-infection or anti-inflammatory antibiotics, angio-regeneration (angio- genesis) growth factors, growth factors for bone regeneration, such as: bone growth factors (BMPs), transforming growth factor (TGF-Beta); traditional Chinese medicine for the treatment of orthopedic diseases. As above, however, it is not inseparable from the present invention, therefore, the present invention shall prevail. Although the present invention is disclosed in the foregoing preferred embodiments to limit the present invention, anyone skilled in the art can, within the spirit and scope, make a few changes and retouches. The scope of protection is defined by the scope of the attached patent

^ 20〇 Q4 Brief Description of Drawings [Illustration of Drawings] Figure 1 is a flow chart for the production of the absorbable calcium phosphate biomedical composite particles according to the present invention. [Illustration of Symbols] 10 ........ Degreasing treatment of cowhide 20 ........ Extraction of collagen 30 ........ Purification of collagen 40 ... ..... Preparation of Absorbable Calcium Phosphate Biomedical Composite Particles

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Claims (1)

420604 VI. Application for Patent Scope 1. A process for producing absorbable calcium phosphate biomedical composite particles, including at least the following steps: Mixing collagen and calcium phosphate ceramic powder into a mixed solution: Drop the mixed solution into an oil dropwise In the phase, the mixed solution is recombined to form reticulated fibrous structure particles; a cross-linking agent is injected into the oil phase to cross-link the particles; and the particles are separated from the selling phase. 2. The manufacturing process of the absorbable phosphate phosphate biomedical composite particles as described in item 1 of the scope of the patent application, which further includes a stirring means to fully stir the mixed solution during the recombination of the mixed solution. 3. The process of producing absorbable calcium phosphate biomedical composite materials and particles as described in item 1 of the scope of the patent application, wherein the particles 0 are separated by the following steps: The oil phase is sucked out of the mixed solution in the phase Injecting a buffer solution; and centrifuging to separate the remaining oil phase so that the particles are separated out. 4. Biomedical reinstatement of absorbable calcium phosphate as described in item 3 of the scope of patent application. The manufacturing process of the pellets, wherein the buffer solution may be a phosphate buffer solution. 5. If so, please request the bioremediation of absorbable calcium phosphate as described in item 1 of the patent scope. " The process of making materials and granules, in which the mixed solution is dripped in-the oil phase is made by dripping in a container with a needle. Process 6. The preparation of the absorbing calcium phosphate biomedical particles as described in item 5 of the scope of the patent application, in which the mixed solution is dropped into an oil phase through Page 13 420 6 6. Scope of patent application Contains a process of squeezing the mixed liquid into ball drops by a syringe pump. 7. The manufacturing process of the absorbable calcium phosphate biomedical composite particle according to item 5 of the scope of the patent application, wherein the container may be a syringe. 8. According to the manufacturing process of the absorbable calcium phosphate biomedical composite granules described in item 1 of the scope of the patent application, the calcium phosphate-based ceramic powder in the mixed solution is an argon-based limestone. ~ 9 · According to the process of the absorbable calcium phosphate biomedical composite particles described in item 1 of the patent application scope, the mixing temperature is 4 ° C. 10. The process for producing absorbable calcium phosphate biomedical composite particles as described in item 1 of the scope of patent application, wherein the calcium phosphate-based ceramic powder is tricalcium phosphate. 0. 11. As described in item 1 of the scope of patent application Process for manufacturing absorbable calcium phosphate biomedical composite particles, wherein the oil phase may be olive oil or other non-biotoxic oils. 12 According to the manufacturing process of the absorbable calcium phosphate biomedical composite particle described in item 1 of the scope of the patent application, the cross-linking agent may be glutaraldehyde, peony extract or amine. 1 3 _ The manufacturing process of the absorbable calcium phosphate biomedical composite particles as described in item} of the kiss kiss patent scope, wherein the calcium phosphate-based ceramic powder has a particle size ^. • As described in item 1 of the patent scope of Ming, the process of the absorbable calcium phosphate biomedical composite particles' 纟, the size range of the particles is between 50 and 5 mm. The process for preparing the granules, wherein the weight ratio of the Taoman absorbable calcium phosphate biomedical composite powder to collagen is Page 14 42〇e 04 The scope of six 'patent applications ranges from 90:10 to 1:99. 1 6, An absorbable calcium phosphate biomedical composite particle, at least including-yaogen protein with a network fiber structure; a calcium phosphate-based ceramic powder with an average particle size of ^ is distributed in the collagen network fiber structure. It is evenly distributed. 1 · As in the patent application scope] 6 composite material particles, soy bean phosphate absorbable calcium phosphate biomedical compound stone. / 、 T The & calcium acid-based ceramic powder is hydroxyl-apatite 18. The absorbable gallic acid is about biomedical compound granules obtained as described in item 申请 β of the patent application scope, wherein the calcium phosphate-based ceramic powder is The bundle system is tricalcium phosphate.