WO2016206180A1

WO2016206180A1 - Bioresorbable bone repair material and application and manufacturing method thereof

Info

Publication number: WO2016206180A1
Application number: PCT/CN2015/087598
Authority: WO
Inventors: 吴天根
Original assignee: 东莞天天向上医疗科技有限公司
Priority date: 2015-06-24
Filing date: 2015-08-20
Publication date: 2016-12-29
Also published as: CN105013006A

Abstract

A bioresorbable bone repair material and an application and manufacturing method thereof. The bioresorbable bone repair material comprises a bioresorbable polyester polymer and calcium phosphate. The material is prepared by extrusion or a chemical method, and can be further manufactured as a bone prosthesis via injection molding or an additive manufacturing (3D printing) method according to requirements. The bone prosthesis can have a surface coated with an osteoinductivity improving substance and is used to repair bone damages due to a variety of causes.

Description

Bioresorbable bone repairing material and application and manufacturing method thereof

Technical field

The invention belongs to the technical field of artificial prosthesis, and particularly relates to a bioresorbable bone repairing material and a method and a manufacturing method thereof for bone repair.

Background technique

Bone defects caused by various reasons on the bed are very common. It is estimated that in China, traumatic fractures, spinal degenerative diseases, bone tumors, bone tuberculosis and other orthopedic diseases are caused by traffic accidents and production safety accidents each year, causing more than 3 million patients with bone defects or dysfunction. The clinical repair of bone defects has become the consensus of bone surgeons.

Clinical requirements for ideal bone repair materials include: (1) Good biocompatibility: in addition to meeting the general requirements of medical materials (such as non-toxic, non-teratogenic, etc.), it is also conducive to seed cell adhesion, proliferation, degradation The product has no toxic and side effects on cells, does not cause inflammatory reaction, and even facilitates cell growth and differentiation; (2) Good biodegradability: the matrix material should be degraded after completion of the scaffold, and the degradation rate should be compatible with the growth rate of the tissue cells. The degradation time should be artificially regulated according to the growth characteristics of the tissue; (3) It has a three-dimensional porous structure: the matrix material can be processed into a three-dimensional structure, which is beneficial to cell adhesion and extracellular matrix deposition, nutrition and oxygen into the human body, and metabolites are discharged. Conducive to vascular and nerve ingrowth; (4) Plasticity and certain mechanical strength: The matrix material has good plasticity and can be pre-made into a certain shape. It has a certain mechanical strength, provides support for new tissue, and maintains a certain time until the new tissue has its own biomechanical properties: (5) Bone guiding activity: bone tissue engineering materials first consider its osteoinductive and osteoconductivity; 6) Easy to disinfect.

The traditional bone repair materials mainly include plexiglass, methyl methacrylate bone cement, titanium plate, silicone rubber plate, polymer fiber reinforced material and diacetal acrylate microporous plastic artificial bone. Most of these materials have shortcomings such as poor tissue compatibility, no pressure resistance, no temperature/cold protection, difficulty in shaping, and processing.

Up to now, the most used artificial materials are mainly titanium alloys. Because titanium alloy materials are non-toxic, have low inflammation and sensitization, have good biocompatibility, low biodegradability and high corrosion resistance. The wider the clinical application. Because the titanium mesh has strong compressive performance and good tissue compatibility, after being implanted into the human body, the fibroblasts can grow into the micropores of the titanium mesh, so that the titanium mesh and the tissue are integrated, and there is a tendency of calcification and ossification. It is an ideal artificial repair material. Although the titanium alloy mesh is better in appearance, it is expensive, difficult to process and non-degradable, and the patient needs to carry it for life. As of now, no material can fully meet the requirements. In contrast, some scholars believe that the autologous skull is the most ideal material for repairing skull defects. The earliest applied autologous skull still occupies an important position in clinical applications. The autologous skull conforms to its own physiology, there is no immune rejection, and there are few common complications of artificial materials such as infection, effusion, and loosening. Ordinary cryopreservation of the autologous skull can survive after implantation, especially for children, and artificial materials cannot increase with the increase of the skull. The autologous skull has the advantages of economy and no need to shape, but its tissue compatibility, whether the bone flap has normal physiological characteristics after ex vivo, and whether the periosteal osteoblasts still survive is not clear. In addition, there is bone flap transplantation. Post-absorption and hyperplasia issues deserve further study.

Polylactide (PLA) has good thermoformability, and its degradation rate can be adjusted by adjusting molecular weight and structure to meet different clinical requirements. Therefore, it can basically satisfy the cell growth carrier in the field of bone tissue engineering. The requirements of the material, but the polylactic acid material has poor mechanical strength, and the degradation product is slightly acidic. There are two major disadvantages in the preparation of the implanted/repaired material: First, the polylactic acid material will be acidic when degraded in the body. Products that cause non-infectious inflammation (poor biocompatibility) in implanted peripheral tissues; second, existing polylactic acid materials lack sufficient mechanical strength to meet the normal needs of human organs, especially bone organs. Calcium phosphate is the main inorganic component of natural bone. It accounts for about 60% by weight in bone. Its basic unit is acicular apatite crystal. It can be tightly combined with the soft and hard tissues of human body in a short time after being implanted into human body. It is a very good bone repair material. However, the apatite single crystal is fragile, poor strength, poor toughness and difficult to process, which restricts its clinical application.

Summary of the invention

In order to solve the above problems, an object of the present invention is to provide a bioabsorbable bone repairing material which can satisfy the conditions for a bone repairing material, has good biocompatibility, sufficient mechanical strength and osteoinductive function. .

The second object of the present invention provides the use of the bioabsorbable bone repair material and a method of making the same.

The third object of the present invention provides a prosthetic bone.

The present invention is achieved by the following technical solutions:

A bioabsorbable bone restorative material comprising a bioabsorbable polyester polymer and calcium phosphate calculated by mass ratio, the mass ratio of the bioabsorbable polymer to calcium phosphate being from 1 to 99:99 to 1.

Preferably, the bioabsorbable polyester polymer is a high molecular polylactic acid material.

Preferably, the high molecular polylactic acid material is polyglycolide (PLGA), polylactic acid (PLA), poly L lactic acid (PLLA), poly D, L-lactic acid (PDLA), polyglycolide (PGA). One or several compositions of poly D, L-glycolide.

Preferably, the calcium phosphate is nano-sized amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), hydroxyapatite pentacalcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) One or several of the compositions.

The preparation method of the bioabsorbable bone repair material, the amount of the bioabsorbable polyester polymer and the calcium phosphate are passed through a high speed (greater than 1000 rpm) mixer, a twin screw extruder at 100 to 400 ° C Prepared by extrusion; or by chemically adding the amount of bioabsorbable polyester polymer and calcium phosphate (for example, changing the positive and negative charges on the surface of the calcium phosphate, or adding a binder to the composite to increase its aggregation The degree of bonding in the lactic acid polymer, etc., but not limited to these methods) is obtained by suspending the nanoparticles in a polymer material.

A method for preparing an artificial prosthetic bone obtained by injection molding or additive manufacturing.

Wherein, the injection molding method is specifically:

When the injection molding method is used, the CT/MRI scan image of the patient's damaged bone is first digitized and converted into a note. The CAD file recognizable by the press is then injection molded into a model of damaged bone at 100-400 ° C on an injection molding machine; the artificial prosthesis is obtained and finally implanted into the injured bone by a bone surgeon.

The additive material manufacturing method is specifically:

A. Convert the CT/MRI image data of the damaged bone into an STL file using open source software, or a file identifiable by other 3D printers, and establish a model of the damaged bone;

B. processing the bioabsorbable bone repair material into a wire that can be used in a 3D printer;

C. The wire processed in B is melted and sintered according to the model established in A, and the artificial prosthesis bone is obtained by layer-by-layer sintering through a 3D printer.

In 3D printing, the polymer polylactic acid-calcium phosphate composite material wire is melted and layer by layer according to the established bone model through a printer, and finally the prosthesis of the original damaged bone is formed. Printers used in additive manufacturing can be, but are not limited to, fused deposition 3D printers. A variety of 3D printers already on the market can meet the needs of this printing.

In the application of the artificial prosthesis bone, the outer surface of the artificial prosthesis is coated with a bone growth inducing substance and implanted into the damaged bone. The invention is applicable to any bone damage, especially the skull.

In the application of the artificial prosthesis bone, the bone growth inducing substance is one or several compositions of the injured patient's own bone marrow stem cells, artificially cultured osteogenic stem cells, osteogenic factors and drugs.

In the invention, the nano calcium phosphate particles are added to the polylactic acid polymer material through a special process to form a polymer polylactic acid-nano calcium phosphate composite material. Calcium phosphate is one of the main components of human bones, also known as bioceramics, with many different combinations, including but not limited to hydroxyapatite (Ca.sub.10(PO.sub.4).sub.6( OH).sub.2), fluoroapatite (Ca.sub.10(PO.sub.4).sub.6F.sub.2), carbonized apatite (Ca.sub.10 (PO.sub. 4).sub.6CO.sub.3), tricalcium phosphate (Ca.sub.3 (PO.sub.4).sub.2), octacalcium phosphate (Ca.sub.8H.sub.2 (PO. Sub.4)6-5H.sub.2O), calcium pyrophosphate (Ca.sub.2P.sub.2O.sub.7-2H.sub.2O), tetracalcium phosphate (Ca.sub.4P.sub. 2O.sub.9) with calcium hydrogen phosphate dihydrate (CaHPO.sub.4-2H.sub.2O). Calcium phosphate is weakly alkaline, and when combined with high molecular polylactic acid, it can neutralize the acidic degradation products of polylactic acid materials and improve its biocompatibility. Phosphate Calcium can adjust the spatial structure of polylactic acid polymer material, and increase the mechanical strength of the composite; the composite material of polylactic acid/calcium phosphate blend has nano-microporous structure, and the microporous structure can also induce rapid bone growth. Thus, the polylactic acid/calcium phosphate composite material of the present invention is an ideal material for degradable human bone skull.

among them:

Skull repair method: The repair of skull defect caused by trauma and surgery, etc., unless it is an autologous bone flap, it is very difficult to completely conform to the original defect. The location, size and shape of the skull defect are different, and the traditional mold and hand-made and the defect area are difficult to match before and during the operation. In particular, the shaped titanium plate restoration does not conform to the physiological curvature of the original defect area. After the left and right symmetry is not good, the cosmetic effect is poor. In the past, most clinicians used simple tools to perform on-site processing of titanium mesh. Doctors repeatedly designed, cut, and shaped before and during surgery. Due to the experience of the surgeon and the influence of the manufacturing tools, the surgical results were uneven and delayed. The operation time often fails to achieve a symmetrical cosmetic effect. Moreover, more than 70% of patients with defect areas in the forehead, eyebrow arch contour and its adjacent frontal dome area, the cosmetic effect directly affects the patient's psychological and physical health.

With the application of computer and 3D image reconstruction technology and the use of automatic mold to make titanium plates, the shape is more perfect and more accurate. The digital design and manufacturing technology of titanium alloy skull restorations that have been used clinically. The advantage of this technology is that digital technology combined with CT scanning three-dimensional imaging can make the restoration made before surgery more accurate. The symmetry of the repaired titanium mesh prosthesis and the healthy side of the skull determines the cosmetic effect of the operation. However, the computer-aided design of the cranioplasty is based on the skull information of the patient's skull CT during the surgical design, and the soft tissue information is discarded. If the implanted material is placed between the scalp and the diaphragm, the implant material designed according to the skull information cannot be matched.

3D printing technology and skull repair: 3D printing is the technology of additive manufacturing, relying on 3D CAD design data, the technology of manufacturing solid parts by discrete materials (liquid, powder, silk, etc.). Compared to traditional material removal processing techniques, additive manufacturing is a bottom-up material additive manufacturing process. “Additive manufacturing” eliminates the need for original embryos and molds, and can directly generate objects of any shape by adding materials according to computer graphics data, simplifying the manufacturing process of products, shortening the development cycle of products, improving efficiency and reducing costs. The technical characteristics of 3D determine its outstanding advantages in the field of small-volume customization and complex product manufacturing, such as artificial skull printing.

In summary, the materials of the present invention have enhanced mechanical strength, good biocompatibility, osteoinductive function, and biodegradability when used for bone repair. The implant implanted in the bone is automatically absorbed by the body after the injury has healed, thereby avoiding the side effects of conventional metal or other non-degradable prosthesis. The manufacturing method of the invention has the advantages of quickness, simplicity and precision, and can rapidly and individually produce an absorbable bone repair prosthesis, thereby benefiting patients with bone injury.

DRAWINGS

1 is a flow chart of a 3D printed bioabsorbable skull prosthesis of the present invention;

2 is a diagram showing the nanopore structure of the bioresorbable bone repair material of the present invention. As shown in the figure, the cross-sections (F and H) of the prosthesis made of the material are microporous structures of nanometers to micrometers, and the micropores are enlarged as the polylactic acid is degraded in the body, which is itself during the bone repair process. The space for bone cell growth.

Figure 3 is an implantable device (vascular stent) made of bioresorbable bone repair material (C) and non-degradable PEVA/PBMA (A) and degradable polylactic acid material (B) in the blood vessel of an animal. Comparison of biocompatibility after the month. As shown in the figure, the vascular stent made of the bioabsorbable composite material of the present invention is covered with a thin layer of endothelial cells after being implanted into the blood vessel for one month, and is a manifestation of vascular repair (C, arrow) ), while the rods of PEVA/PBMA and polylactic acid stents are full of proliferating inflammatory tissues (A and B, black lines). In the figure, A: non-absorbable material PEVA/PBMA composite material; B: high molecular polylactic acid material; C: polylactic acid/calcium phosphate composite material. Top: low power microscope (4X); bottom: high power microscope (20X).

Figure 4 is a comparison of the enhanced mechanical strength of the bioabsorbable bone repair material of the present invention. As shown, the bioabsorbable bone repair material (green) of the present invention has significantly enhanced mechanical strength compared to the individual polylactic acid material (blue).

FIG. 5 is a schematic diagram showing the process of converting a human body bone tissue series CT tomogram (1 mm/frame) into a 3D printed STL file or an injection moldable CAD file according to the present invention.

Figure 6 is a schematic illustration of an artificial skull printed with a bioabsorbable bone restorative material using the additive manufacturing method of the present invention. As shown, the bioabsorbable wire of the present invention is printed on the bioabsorbable skull by a 3D printing device, according to the STL file converted in Figure 5.

Figure 7 is a clinical repair process for an artificial skull of the present invention. As shown in the figure, a series of CT scans of the injured skull were performed, and the scanned image was converted into an STL file as shown in Fig. 5, and printed into a complete bioabsorbable skull (as shown in Fig. 6), and finally the lesion was taken out in the printed skull. The artificial bone piece of the site is implanted into the injured part of the patient.

Specific embodiment

The present invention can be applied to any bone injury. The present invention will be further described in detail below with reference to specific embodiments to help those skilled in the art understand the present invention, but is not intended to limit the present invention to other bone injuries. application.

Example 1

A bioresorbable skull repairing material, the composition of the skull repair prosthesis is a composite of 10 kg of bioabsorbable polyester polymer (polyethylene lactide) and calcium phosphate (amorphous calcium phosphate (ACP)) 90 kg .

The composite material constituting the absorbable skull prosthesis can be obtained by a polymer and nano processing technology, such as a high-speed mixer, a twin-screw extruder, or the like, or can be obtained by suspending the nanoparticles in a polymer material by a chemical method.

The preparation method of the prosthesis bone is an injection molding method:

A. Digitize the CT/MRI image of the injured skull and convert it into a CAD file;

B. On the injection molding machine, the bioresorbable bone repair material is injection molded into a model of the damaged skull according to the CAD file converted above;

The prepared absorbable skull is coated with a bone growth inducing substance (injured patient's own bone marrow stem cells) into the skull of the patient's injury.

Example 2

A bioabsorbable bone repairing material comprising a composition of 20 kg of a bioabsorbable polyester polymer (polylactic acid (PLA)) and 80 kg of calcium phosphate (dicalcium phosphate (DCP)).

The composite material constituting the absorbable skull prosthesis can be obtained by a polymer and nano processing technology, such as a high-speed mixer, a twin-screw extruder extrusion method, or a chemical method for suspending the nano particles in a polymer material.

The preparation method of the prosthesis bone:

A. Convert the CT/MRI image data of the damaged skull into an STL file using open source software, or a file recognizable by other 3D printers, and establish a model of the damaged skull;

B. Processing the bioabsorbable bone repair material into a wire that can be used in a 3D printer.

C. The wire processed in B is melted and sintered according to the model established in A, and laminated by the 3D printer to form the absorbable artificial skull prosthesis.

The prepared absorbable skull is coated with a bone growth inducing substance (osteogenic stem cells cultured in vitro) into the injured skull of the patient.

Example 3

A bioabsorbable bone repairing material, the composition of the skull repair prosthesis is a composite of 30 kg of bioabsorbable polyester polymer (poly L lactic acid (PLLA)) and calcium phosphate (tricalcium phosphate (TCP)) 70 kg .

The preparation method is the same as in the first embodiment, and the prepared absorbable skull bone piece is implanted into the injured skull of the patient.

Example 4

A bioabsorbable bone repairing material, the composition of the skull repair prosthesis is bioabsorbable polyester polymer (poly D, L-lactic acid (PDLA)) 40 kg and calcium phosphate (hydroxyapatite pentacalcium (HAP) )) 60 kg of composite, the surface of the prosthesis is also coated with a bone growth inducing substance (drug).

The preparation method was the same as in Example 2. The prepared absorbable skull was coated with a bone growth inducing substance (osteogenic factor) into the injured skull of the patient.

Example 5

A bioabsorbable bone repairing material, the component of the skull repair prosthesis being bioabsorbable 50 kg of a polyester polymer (poly D, L-glycolide) complex with calcium phosphate (tetracalcium phosphate monocarbonate (TTCP)) 50 kg.

The preparation method was the same as in Example 2. The prepared absorbable skull was coated with a bone growth inducing substance (injured patient's own bone marrow stem cells) into the skull of the patient's injury.

Example 6

A bioabsorbable bone repairing material, the composition of the skull repair prosthesis is bioabsorbable polyester polymer (polyethylene glycol (PLGA) 20kg, polylactic acid (PLA) 20kg, poly L lactic acid (PLLA) 20kg) 60kg complex with calcium phosphate (amorphous calcium phosphate (ACP) 20kg, hydroxyapatite pentacalcium (HAP) 20kg) 40kg

The preparation method was the same as in Example 2. The prepared absorbable skull was coated with a bone growth inducing substance (osteogenic factor + drug) into the injured skull of the patient.

Example 7

A bioresorbable bone repairing material, the composition of the skull repair prosthesis is bioabsorbable polyester polymer (poly L-lactic acid (PLLA) 10kg, poly D, L-lactic acid (PDLA) 20kg, polyglycolide (PGA) 20kg, poly D, L-glycolide 20kg) 70kg and calcium phosphate (hydroxyapatite pentacalcium (HAP)) 30kg complex.

The preparation method is the same as in the first embodiment, and the prepared absorbable skull is coated with a bone growth inducing substance (damaged patient's own bone marrow stem cells) into the skull of the patient's injury.

Example 8

A bioresorbable bone repairing material, the composition of the skull repair prosthesis is a bioabsorbable polyester polymer (polyglycolide (PGA)) 80 kg and calcium phosphate (amorphous calcium phosphate (ACP) 5 kg, phosphoric acid Dicalcium (DCP) 15kg) 20kg complex.

The preparation method was the same as in Example 2. The prepared absorbable skull was coated with a bone growth inducing substance (osteogenic stem cells cultured in vitro) into the injured skull of the patient.

Example 9

A bioresorbable bone repairing material, the composition of the skull repair prosthesis is a bioabsorbable polyester polymer (polylactic acid (PLA) 10kg, polyglycolide (PGA) 80kg) 90kg and calcium phosphate (hydroxyl Apatite Pentacalcium (HAP) 10kg complex.

The preparation method is the same as in the second embodiment, and the prepared absorbable skull is coated with a bone growth inducing substance (damaged patient's own bone marrow stem cells) into the skull of the patient's injury.

The above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and equivalent changes or modifications made by the features and principles of the present invention should be included in the present invention. Within the scope of the claims.

Claims

A bioabsorbable bone restorative material comprising a bioabsorbable polyester polymer and calcium phosphate calculated by mass ratio, wherein the mass ratio of the bioabsorbable polymer to calcium phosphate is from 1 to 99:99 1.
The bioabsorbable bone repair material according to claim 1, wherein said bioabsorbable polyester polymer is a high molecular polylactic acid material.
The bioabsorbable bone repairing material according to claim 2, wherein the high molecular polylactic acid material is polylactide, polylactic acid, polylactic acid, poly D, L-lactic acid, polyglycolide, One or several compositions of poly D, L-glycolide.
The bioabsorbable bone repairing material according to claim 1, wherein the calcium phosphate is nanometer-sized amorphous calcium phosphate, dicalcium phosphate, tricalcium phosphate, hydroxyapatite pentacalcium, and tetracalcium phosphate carbon monoxide. One or several compositions.
An artificial prosthetic bone, characterized in that the bioabsorbable bone repair material according to any one of claims 1 to 4, further comprising a bone growth inducing substance; the bone growth inducing substance Coating on the surface of the bioabsorbable bone restorative material.
The artificial prosthesis bone according to claim 5, wherein the bone growth inducing substance is one or more of a bone marrow stem cell damaged by the patient, an osteogenic stem cell cultured in vitro, an osteogenic factor, and a drug.
A method for preparing a bioabsorbable bone repairing material, characterized in that the amount of the bioabsorbable polyester polymer and calcium phosphate are extruded through a high speed mixer or a twin screw extruder; or The bio-absorbable polyester polymer and calcium phosphate are prepared by chemical methods in which the nanoparticles are suspended in a polymer material.
The method of producing a bone restorative material according to claim 7, wherein the stirring speed in the high speed mixer is 1000 rpm or more.
The method of producing a bone restorative material according to claim 7, wherein the twin-screw extruder has an extrusion temperature of from 100 to 400 °C.
The method of preparing a bone restorative material according to claim 7, wherein the chemical method is to change the positive and negative charges on the surface of the calcium phosphate.
The method of preparing a bone restorative material according to claim 7, wherein the chemical method adds a binder to the composite material.
A method for preparing artificial prosthesis bone, characterized in that the bone repairing material obtained by the method for preparing the bioabsorbable bone repairing material according to any one of claims 7-11 is further processed by injection molding or additive manufacturing. Prepared.
The method for preparing an artificial prosthesis bone according to claim 12, wherein the injection molding method comprises: digitizing a CT/MRI image of the damaged bone into a CAD file, and then converting the same on the injection molding machine. The CAD file is obtained by injection molding the above bioabsorbable bone repair material into a model of damaged bone to obtain the artificial prosthetic bone.
The method of producing artificial prosthesis bone according to claim 13, wherein the injection temperature is 100 to 400 °C.
The method for preparing an artificial prosthesis bone according to claim 12, wherein the method of manufacturing the additive material is specifically:

A. Convert the CT/MRI image data of the damaged bone into an STL file using open source software, or a file identifiable by other 3D printers, and establish a model of the damaged bone;

B. processing the bioabsorbable bone repair material into a wire that can be used in a 3D printer;

C. Using the melt-sintering method, the wire processed in B is superposed by layer-by-layer sintering according to the model established in A to obtain the artificial prosthetic bone.