CN115006609A

CN115006609A - Degradable material suitable for pre-operation preparation of fracture internal fixation and preparation method and application thereof

Info

Publication number: CN115006609A
Application number: CN202210568093.2A
Authority: CN
Inventors: 曹建中; 曹琼; 李涛; 余寒; 龚亮
Original assignee: Individual
Current assignee: Individual
Priority date: 2022-05-24
Filing date: 2022-05-24
Publication date: 2022-09-06

Abstract

The invention discloses a degradable material which is suitable for being manufactured before fracture internal fixation aiming at fracture with small shearing stress and a preparation method and application thereof, and the degradable material is prepared by proportioning raw materials of beta-tricalcium phosphate, polyglycolic acid, polylactic acid, polyhydroxybutyrate, ethyl acetate, polypropylene fumarate and N-vinyl pyrrolidone; the preparation method comprises the following steps: stirring beta-tricalcium phosphate to prepare superfine particle powder to obtain a material A, adding polyglycolic acid, polylactic acid and polyhydroxybutyrate into an ester organic solvent for crosslinking reaction to obtain a polymer material B and the like; the polymer material formed by the invention can enhance the rigidity (hardness) and flexibility of the material, improve the fracture strength of the internal fixation material, is suitable for treating fractures with small shearing stress and rebuilding fractures and bone defects, has wide application range, is suitable for manufacturing degradable internal fixation pieces with small shearing stress, has the functions of shortening the fracture healing time and enhancing the fracture strength, and can better promote fracture healing.

Description

Degradable material suitable for pre-operation preparation of fracture internal fixation and preparation method and application thereof

Technical Field

The invention relates to the field of biomedical materials, in particular to a degradable material suitable for being manufactured before fracture internal fixation, a preparation method and application thereof.

Background

When the fracture is serious and obvious displacement occurs, the fracture part needs to be cut and reset, and then is fixed through a steel plate, a screw and the like, which is called internal fixation. The fracture internal fixation can maintain the stability of the fracture end and better promote the fracture recovery. The methods for internal fixation of fracture are very many, and the fixation method is usually determined according to specific parts and specific anatomical structures of the fracture, for example, the clavicle fracture can be fixed by a clavicle S-shaped steel plate and a clavicle hook steel plate; the proximal humerus fracture mainly uses a proximal humerus condyle locking steel plate, a proximal humerus condyle locking steel plate and a proximal humerus condyle steel plate; other parts are also provided with special locking steel plates, or hollow compression screws and interlocking intramedullary nails; and also pedicle screws and the like. The fracture parts are different, the fixing method is very different, and the fixing method needs to be determined and selected according to the specific part and the operation experience of a doctor. The internal fixation material is generally removed after one to about one and a half years of operation under the condition that the fracture is completely recovered. However, the removal of the internal fixation after fracture recovery brings secondary operation pain to patients, causes side damage to the tissues which are just rebuilt and healed, causes difficult healing and slow healing, has the risk of secondary infection, and even needs secondary operation treatment.

In recent years, fracture internal fixation theory and technology have achieved unprecedented development, and play an important role in guiding clinical orthopedic diseases. Autograft and synthetic material implantation methods are mostly adopted for treating bone defects, but the number of autograft bones is limited by sources, accurate molding according to defect parts is difficult, and allograft can become a disease infection source; synthetic materials, although permanently implanted, may cause a number of side effects such as infection, bone erosion, and the like. For the artificial bone material implanted into human body, it is required to be able to withstand the corrosion and dissolution of body fluid, have good biocompatibility and bioactivity, and also have good chemical stability and mechanical properties.

The biomedical material has special performance and special function, is used in the medical and health care fields of surgical repair of human organs, physical therapy rehabilitation, diagnosis, examination, treatment of patients and the like, and does not have adverse effect on human tissues and blood. The "biomaterial" specifically defined by the international organization for standardization (ISO) french conference is a biomedical material, which refers to "non-living material for medical purposes, which is used to come into contact with tissues to form functions". Biomaterials are classified by the nature of the application, and are classified as: anticoagulant materials (cardiovascular materials), dental materials, orthopedic materials, ophthalmic materials, adsorption detoxification materials (for blood perfusion), prosthetic materials, sustained release materials, bioadhesive materials, membrane materials for dialysis and ultrafiltration, disposable medical materials, and the like. The medical material is classified according to the use requirements of the medical material and is divided into: non-implantable materials, blood-contacting materials, degradable and absorbable materials.

The biomedical polymer material is an important component of biomedical materials, is a material for diagnosis, treatment and organ repair and regeneration, has the effects of prolonging the life of a patient and improving the life quality of the patient, is a development field of material science and chemistry and student medicine crossing in the life department, and has important social requirements and important economic requirements for research and development. High-performance medical high polymer materials and apparatuses are the foundation on which various diagnostic and therapeutic technologies of modern medicine are based, and the emergence of innovative products is continuously promoted. The research on medical polymer materials has been carried out for over 70 years so far, 1949, and the united states first published a prospective paper on medical polymers. In the article, the use of polymethyl methacrylate as human and cranial bones and joints is described for the first time. The polyamide fiber is used as the clinical application condition of the operation suture. Molecular design of polymers is an important issue for biomacromolecule scientists at present, and the problems of inference, prediction, constituent atoms of macromolecular biomaterials, molecular species, binding and aggregation states and the like are analyzed, and the specific conformation of the structure, the organization and the form of the molecules is described. Molecular design of medical biopolymer polymers has been carried out with the goal of how to synthesize and manufacture a high molecular biomaterial with specified properties and structure. The further practical connection of molecular design is "material design", which belongs to the field of objective science and is the subject of engineering.

Tissue engineering (tissue engineering) is a new subject that is emerging in recent years and belongs to the field of biotechnology. The first term of tissue engineering was originally proposed by the society of bioengineering held in Washington in 1987, and the first term was formally defined in 1988 as an emerging discipline for the research and development of biological substitutes for repairing, maintaining and promoting the functions and morphology of various tissues or organs of the human body after injury, based on the correct understanding of the tissue structure and functional relationship of mammals in both normal and pathological states, by applying the principles and techniques of life sciences and engineering. The discussion of the high molecular material of the tissue engineering scaffold, theoretically on the replacement and repair of soft and hard tissues, relates to the research hotspot of tissue engineering, in particular bone tissue engineering. The tissue engineering scaffold material, a biological material for tissue engineering, is the basis of tissue engineering and an indispensable link in the field of tissue engineering, so that the tissue engineering scaffold naturally forms a branch of tissue engineering. In recent years, research in the field of scaffold materials for tissue engineering has been actively conducted, and not only research and development have been more perfected in the field of artificial skin, the earliest product of tissue engineering, but also a great deal of research and research has been conducted on various systems such as artificial bone, cartilage, nerve, and vascular materials. The tissue material is designed according to the functions of different human tissues and specific substitute tissues, and comprises the following components: bone, cartilage, blood vessels, nerves, skin and artificial organs such as liver, spleen, kidney, bladder, etc.

Repeated in vivo biological animal experiments show that when the polymer is implanted into a body, edema is easy to occur around the implantation, inflammatory cell infiltration and multinucleated giant cells occur, and fibroblasts proliferate to form fibers; meanwhile, the particles formed by degrading the polymer are swallowed by macrophages, and have delayed inflammatory reaction when being implanted into bones, and the incidence is still high.

The absorbable biodegradable material is an ideal bone tissue engineering material, a good substitute and repair material, is a superior substitute and repair material compared with the polymer biodegradability studied in the past for decades, and has creativity and novelty. The absorbable biodegradable material as an ideal bone tissue engineering material can meet the following 3 basic conditions: has good biocompatibility. The product or the degradation product has no toxicity to cells, tissues and organisms, and can not cause immunological rejection after being implanted. The material can be absorbed and biodegraded, and the degradation speed is matched with the tissue regeneration speed; and the material has certain rigidity (hardness), elasticity and flexibility so as to meet the requirement of conducting stress when bones and joints move. The biodegradable polymer has the advantages of excellent mechanical property, good biocompatibility and the like, and has more and more applications in the biomedical field such as bone transplantation, bone cement, drug controlled release, tissue engineering scaffolds and the like.

For decades, China adopts medical bone cement to fill and repair bones. The bone cement is a bone repair material which is convenient to operate in clinical surgery, can be freely plasticized and automatically solidified as cement according to requirements, and is widely applied to the fields of bone repair and the like. One material currently available as bone cement is Polymethylmethacrylate (PMMA), which has significant problems with biocompatibility due to its completely different organization from natural bone tissue. The traditional inorganic calcium phosphate cement has good compatibility and high bioactivity, but the strength is too low, the compressive strength is low, the tensile strength is low, the brittleness is high, and the elastic modulus is greatly higher than that of natural bone. In addition, there are rejection, chronic pain, macrophage reaction, etc., which cannot be treated according to the filling and repair of the defect site, and also problems in that body fluid and blood are hard to solidify and are not absorbable, rejection, etc. are encountered.

The biodegradable material for orthopedics is a new material developed internationally in the last 80 th century.Biodegradable internal fixation materials have been studied for decades, and recently developed materials are polyglycolic acid (Polyglycolide) and polylactic acid (polylactade) -based polymers, which are made into screws and internal fixation rods for internal fixation of clinical fractures. Can be degraded and absorbed in vivo after fracture healing, and is not taken out after operation. Has become a commercial market at present, and a plurality of countries are abroad used for internally fixing the fracture in and around the joint and the fracture of the hand. Of these, 2 million cases have been accumulated in the biodegradable absorbable screws of finland, which was also introduced since 1993 in china. However, the biodegradable absorbable screw is gradually discovered to have toxic and side effects in the application process, and has the problems of macrophage reaction, non-inflammatory reaction, delayed union or nonunion of fracture. This is because the internal fixation materials made of absorbable screws and absorbable rods, which have been studied in the past, are characterized in that there is no covalent bond between macromolecules of two components polymerized from polyglycolic acid and polylactic acid, but the structure thereof determines the properties and depends on the compatibility of the two components, and the internal fixation materials have large irritation to bone tissues and cause complications such as rejection, macrophage reaction and the like because there is no covalent bond and the molecular weight thereof is a macromolecular structure. Previous studies have shown that biodegradable materials eventually decompose to H in the human body ² And CO ₂ The toxicity is extremely low, but the irritation to tissues is large, so that effusion and swelling of the tissues can be caused; the particles degraded by the material can be considered as foreign body stimulation by human body to induce rejection reaction-macrophage reaction. Therefore, the tissue compatibility is still not as good as the internal fixation performance of the currently applied metal.

There are 206 bones in the human body, which are often fractured in four limbs, but fractures in four limbs, such as tibiofibular trunk double fracture and femoral shaft fracture, all perform fracture internal fixation on titanium alloy steel plates, screws and the like which are commonly used for fracture fixation in terms of biomechanics. For example, the femoral shaft is an important bone structure for supporting the human body, is the thickest tubular bone throughout the body, has the highest strength, and is usually fractured only by a high-energy direct impact (traffic accident, firearm injury, etc.). The titanium alloy material is used for internal fixation because it is hard, not easily deformed, not easily corroded, and lightweight. However, different bone tissue sites carry different forces and functions of the human body. For example, the fracture of the far radius is the fracture within 3 cm from the lower end joint surface of the radius. However, the wrist joint has a high frequency of movement and a high requirement for functional recovery. The improper treatment can easily cause chronic pain and stiffness of joints, seriously affect the functions of hands and cause no change to the life of patients. The more suitable bone repair material is reasonably selected according to the position and the function of the fracture, and different polymers have different biocompatibility and degradation speed and different mechanical strength and flexibility. Large-size fracture parts to be repaired and sheared need materials with high rigidity, but the flexibility is low; the fracture internal fixation with large shearing stress (such as tibiofibula fracture, femoral shaft fracture and the like) cannot be achieved through multiple biomechanics of materials with good flexibility, and the defect of low rigidity (hardness) exists.

However, the existing degradable materials for internal fixation of fracture on the market generally can be used for manufacturing a replacement part for internal fixation of fracture in a factory before operation, the manufactured part is not easy to store, volatilization and deterioration (the surface is gradually sticky and the hardness is reduced) can be caused after long-time storage, so that the standard of the materials is difficult to control, and the success rate of operation and the recovery of patients are directly influenced. If the product is deteriorated and volatilized due to long-term storage, the product cannot be used as an internal fixation degradable material to meet the biomechanical requirements of internal fixation of fracture.

beta-TCP (beta-tricalcium phosphate), a powder, has been used clinically since the 70 s as an artificial bone substitute material. The components of the beta-TCP are similar to the composition of bone minerals, the ratio of Ca ions to P ions in the beta-TCP is 1.5:1, the beta-TCP is degraded into the Ca ions and the P ions in vivo and then provided for new bone tissues to gradually replace the new bone tissues, and the beta-TCP has good biocompatibility. As an implant material, the beta-TCP has good biodegradability. In general, there are two pathways for biodegradation processes, i.e., humoral and cell-mediated processes. And the beta-TCP has a communicated macroporous structure which is beneficial to the immersion of body fluid and a microporous structure which is beneficial to the growth of tissue cells. After being implanted into a body for a period of time, the beta-TCP is subjected to ceramic biodegradation, no foreign matter is finally left, the material is completely absorbed to form new bone modeling, and the influence of the material is not absorbed any more, and the strength of the new bone is changed by different preparation processes due to the bonding strength of the new bone and the material, so that the pore mechanism and the physical and chemical properties (biological absorptivity, mechanical strength, pore structure and the like) of the material can meet different clinical application requirements. But the beta-TCP has low fatigue strength and large brittleness, and the fracture resistance and the impact resistance can not meet the requirements of high-load artificial bones.

The degradable biomaterials widely applied at present comprise polyglycolic acid (PGA) and polylactic acid (PLA), but the degradable biomaterials have the defects of lacking of reactive functional groups due to chemical structures, no hydrophilicity and the like, so that the application of the degradable biomaterials as bone repair materials is greatly limited. Therefore, the synthesis of a new biodegradable material is a subject of development in the medical field.

Polyglycolic acid (PGA) has good biocompatibility, so that the extracellular matrix used as chondrocytes can better induce and promote the adhesion, proliferation and differentiation of the chondrocytes to form cartilage tissues, lipid bonds in the polymer are easy to hydrolyze, and a product which belongs to the degradation of non-ester hydrolysis in vivo is glycolic acid which is easy to participate in vivo metabolism. However, PGA is degraded quickly and is easy to disintegrate, so that the whole stent collapses, and monomer glycolic acid formed by PGA degradation is locally accumulated to cause local P ^H Decline, leading to cell poisoning and death.

Polylactic acid (PLA) has good mechanical strength. But is liable to cause local non-specific aseptic inflammation, which is currently believed to be possibly associated with the frequent acidic degradation of PLA during degradation causing local P ^H The drop is relevant.

Polyhydroxybutyrate (PHB) is a thermoplastic polyester synthesized by prokaryotic microorganisms as a carbon source and energy storage in the presence of carbon and nitrogen nutrient imbalances. Compared with other natural polymers, PHB has good mechanical properties, better histocompatibility compared with synthetic degradable polyester, and is synthesized by biology without chemical raw materials, which may generate some byproducts harmful to human body. One disadvantage of PHB as a scaffold is its greater brittleness and poor mechanical strength.

Poly (hydroxypropyl) fumarate (PPF) is an unsaturated linear polyester, belongs to a water degradation substance, is an ideal biodegradable material, can be degraded in a living body to generate degradation products of fumaric acid and Propylene Glycol (PG), can be discharged out of the body through normal metabolism, and has no influence on in-vivo systems such as pH value and the like. PPF with proper polymerization degree can be solidified at body temperature, and a material with good mechanical property can be obtained by controlling the molecular weight of the PPF. And the fumaric acid unsaturated double bond of the PPF can react with other cross-linking agent molecules to generate a cross-linked reticular polymer material which is used as a scaffold material to induce the regeneration of bones. Degradable propylene glycol fumarate. The PPG is biodegradable and can be molded at any time at body temperature, and the PPF has good fluidity before solidification, so that the PPG can be used as an injectable filling material and can be well used for repairing and reconstructing bone defect parts with different sizes.

N-vinyl pyrrolidone, i.e., N-vinyl pyrrolidone. N-ethyl-2-pyridone, a Chinese synonym; 1-vinyl-2-pyrrolidone; 1-vinyl-2-pyridone; 1-vinyl-2-pyrrolidone; 99% STAB. WITH0.1% SODIUMHYDROXID; chemical book 1-vinyl-2-pyrrolidone (with stabilizer N, N' -di-sec-butyl p-phenylenediamine); 1-vinyl-2-pyrrolidone, 99% STAB. WITH0.1% SODIUMHYDROXIDE; vinyl-2-pyrrolidone. English name: N-Vinyl-2-pyrollidone. Chemical formula C6H9NO, molecular weight 111.142. The density is 20 ℃, and the concentration is 1.030-1.060 g/mL; 25 ℃ and 1.04 g/mL. Molar volume: 97.1 cm ³ And (c) the mole ratio is greater than the mole ratio. A colorless liquid. Easy to polymerize into polyvinylpyrrolidone. Can be mixed with water, ethanol, ether and other organic solvents, and can be easily copolymerized with other vinyl compounds. The ultraviolet curing coating is mainly used for polymers or copolymers, and can also be used for reactive diluents of polymer systems, and ultraviolet curing coatings for wall, floor and other decorations.

The ultrafine particles are fine powder materials having a diameter of 1 μm or less. Particles having a size of 0.5nm to 100nm and located in a region where an atomic cluster and a macroscopic object are connected are generally called ultrafine particles. The ultrafine particle material has the characteristics of electricity, heat, optics and the like, and has good application in the fields of electronics, chemical engineering, nuclear technology rights and the like.

Disclosure of Invention

The invention aims to provide a degradable material which is suitable for being manufactured before fracture internal fixation aiming at fractures with small shearing stress (such as clavicle fracture, rib fracture, distal radius fracture, finger fracture, double ankle fracture, talus fracture, metatarsal fracture, toe bone fracture and the like), and a preparation method and application thereof.

The invention adopts the following technical scheme to realize the purpose of the invention, and discloses a degradable material suitable for being manufactured before a fracture internal fixation operation, which is prepared from the following raw materials in parts by weight:

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =440mg to 880 mg: 230 mg-360 mg: 120 mg-340 mg: 160 mg-440 mg: 10 ml-20 ml: 15 ml-25 ml: 10ml to 25 ml.

Preferably, the β -tricalcium phosphate of the present invention: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =480mg to 880 mg: 260 mg-300 mg: 160 mg-260 mg: 220 mg-300 mg: 15 ml-20 ml: 15 ml-25 ml: 15ml to 20 ml.

The N-vinyl pyrrolidone is produced by Jiangsu Nantong Runfeng petrochemical company Limited.

The ethyl acetate of the present invention is commercially available as analytical grade.

Ethyl acetate is a five-color transparent liquid, has no toxicity, is used as an extract, is used for the production of medicines, organic acids and other products, has certain binding capacity, and is the most suitable dissolving agent for polyglycolic acid, polylactic acid and polyhydroxybutyrate.

A preparation method of a degradable material suitable for being manufactured before fracture internal fixation operation comprises the following steps:

taking beta-tricalcium phosphate according to a ratio, stirring to prepare ultrafine particle powder to obtain a material A for later use;

adding polyglycolic acid, polylactic acid and polyhydroxybutyrate into an ester organic solvent according to a ratio for crosslinking reaction to obtain a polymer material B for later use;

performing crosslinking reaction on the polypropylene fumarate and the N-vinyl pyrrolidone according to the proportion to obtain a polymer material C for later use;

fourthly, mixing the material A and the polymer material B at the temperature of 6-10 ℃, stirring for 10-15 minutes at the stirring speed of 1000 rpm, continuously stirring under the magnetic force condition until the ultrafine particles are solidified, and drying the obtained polymer material after the crosslinking reaction into powder to obtain mixed ultrafine particle powder for later use;

carrying out centrifugal separation on the polymer material C obtained in the step three at 1000 rpm to obtain a liquid polymer material standby liquid;

sixthly, separating and stirring the liquid polymer material standby liquid obtained in the step of the fifth and the mixed ultrafine particle powder obtained in the step of the fourth for 10-15 minutes at 1000 revolutions per minute to obtain mixed ultrafine particle wet powder, and then filling the mixed ultrafine particle wet powder with a penicillin bottle for standby.

The preparation method comprises the steps of preparing 440-880 mg of beta-tricalcium phosphate; the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ester organic solvent =230mg to 360 mg: 120 mg-340 mg: 160 mg-440 mg: 10ml to 20ml, wherein the ester organic solvent is ethyl acetate; the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone =15ml to 25 ml: 10ml to 25 ml.

Preferably, the proportion of the beta-tricalcium phosphate in the first step of the invention is 480mg to 880 mg; the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ethyl acetate =260mg to 300 mg: 160 mg-260 mg: 220 mg-300 mg: 15ml to 20 ml; the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone =15ml to 25 ml: 15ml to 20 ml.

The drying in the fourth step of the invention is drying for 1-2 hours at 60-120 ℃ or freeze drying, and then sterilizing by cobalt 60 radiation (168 hours).

The water content of the mixed ultrafine particle wet powder is 2% -3%.

The application of the degradable material suitable for the preparation before the internal fixation of the fracture, the preparation before the clinical application requirement of the internal fixation of the fracture is taken to mix the ultra-micro wet powder, the 3D printing is carried out by utilizing the existing 3D printing equipment to print the artificial bone, and the degradable internal fixing piece (a plastic steel plate, a screw, a fracture fixing rod and the like) is prepared.

Due to the adoption of the technical scheme, the invention better realizes the purpose of the invention, the prepared mixed ultrafine particle wet powder belongs to fracture internal fixation absorbable biodegradable materials, has wide application range of fracture cases, is suitable for various fracture internal fixation materials with small shearing stress to fix the fracture, and can be manufactured and printed into plastic steel plates, screws, fracture fixing rods and the like suitable for different parts and different fracture types by 3D before operation according to the classification of the fracture; in the formula, beta-tricalcium phosphate, polyglycolic acid, polylactic acid and polyhydroxybutyrate are compounded into a bone repair material with good toughness and strength; polyglycolic acid (PGA) has good biocompatibility, so that the extracellular matrix used as chondrocytes can better induce and promote the adhesion, proliferation and differentiation of the chondrocytes to form cartilage tissues, lipid bonds in the polymer are easy to hydrolyze, and a product which belongs to the degradation of non-ester hydrolysis in vivo is glycolic acid which is easy to participate in vivo metabolism; however, PGA is degraded quickly and is easy to disintegrate, so that the whole stent collapses, and monomer glycolic acid formed by PGA degradation is locally accumulated to cause local P ^H The reduction, leading to cell poisoning and death, the invention adopts the cross-linking with polylactic acid to solve the problem, the polylactic acid (PLA) has good mechanical strength; but is liable to cause local non-specific sterile inflammation, which is currently believed to be likely to cause local P together with acidic degradation products during PLA degradation ^H The present invention adopts a thermoplastic polyester synthesized by crosslinking polymerization of Polyhydroxybutyrate (PHB), which is a prokaryotic microbial element under the condition of carbon and nitrogen nutrient imbalance, and can be used as carbon source and energy storage. Compared with other natural polymers, PHB has good mechanical property, better histocompatibility compared with synthetic degradable polyester, and is biosynthesized without byproducts which are possibly generated by chemical raw material synthesis and harmful to human bodyThe product has the advantages of absorbability, biodegradability, controllability, no toxic or side effect, and avoidance of secondary operation; the material bone has good biomechanical property, has proper mechanical property when being implanted into a human body to fix fracture, has certain rigidity (hardness) and high fracture resistance and elasticity (flexibility) so as to meet the requirement of continuous application; the physical properties are stable, and the preoperative preparation can effectively avoid volatilization and deterioration.

The mixed ultrafine particle wet powder used for preoperative preparation of the degradable material for internal fixation of fracture is prepared preoperatively according to the fracture position, the fracture type and the fracture shape of a patient: firstly, internal fixing materials (steel plates and screws) suitable for different fracture shapes can be manufactured through 3D printing, and fracture can be firmly fixed; secondly, the problem that materials suitable for fracture bone fixation are lacked before the operation, so that pain and delay of the disease period are brought to patients is solved; the degradable material for internal fixation of fracture can not be used as the degradable material for internal fixation and can not meet the biomechanical requirement of internal fixation of fracture if the product is deteriorated and volatilized after long-term storage after being prepared before operation; solves the problems of the secondary operation caused by adopting the traditional peptide alloy steel plate and the screw, reduces the pain of the patient and reduces the medical expense.

The degradable material prepared before the fracture internal fixation of the invention has good biocompatibility and bone conduction performance, the polymer material formed by the correlation reaction of beta-TCP and polyglycolic acid, polylactic acid and polyhydroxybutyrate can enhance the rigidity (hardness) and flexibility of the material, greatly improve the breaking strength of the internal fixation material, the fracture setting tool can be suitable for fractures with small shearing stress, is applied to clavicle fractures, rib fractures, proximal humerus fractures, internal and external humerus fractures, small head fractures of radius, Kelei fractures, finger fractures, tibial plateau fractures, double ankle fractures, talus fractures, metatarsal fractures and toe fractures, and treatment of reconstruction fractures and bone defects, is suitable for manufacturing degradable internal fixing parts of small screws and small steel plates (with small shearing stress), has the effects of shortening fracture healing time and enhancing fracture strength, and can better promote fracture healing.

Detailed Description

The present invention will be further described with reference to the following examples.

Example 1:

a degradable material suitable for being made before fracture internal fixation is prepared from the following raw materials in parts by weight:

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =440mg to 880 mg: 230 mg-360 mg: 120 mg-340 mg: 160 mg-440 mg: 10 ml-20 ml: 15 ml-25 ml: 10ml to 25ml (the raw material ratio of the embodiment is beta-tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: N-vinylpyrrolidone =480 mg: 260 mg: 160 mg: 220 mg: 15 ml: 15 ml: 15 ml).

taking beta-tricalcium phosphate according to a proportion, stirring to prepare ultrafine particle powder to obtain a material A for later use;

thirdly, performing crosslinking reaction on the polypropylene fumarate and the N-vinylpyrrolidone according to the proportion to obtain a polymer material C for later use;

fourthly, mixing the material A and the polymer material B at the temperature of 6-10 ℃ (8 ℃ in the embodiment), stirring at the stirring speed of 1000 rpm for 10-15 minutes (12 minutes in the embodiment), continuously stirring under the magnetic force condition until the ultrafine particles are solidified, and drying the obtained polymer material after the crosslinking reaction into powder to obtain mixed ultrafine particle powder for standby;

The preparation method comprises the steps of firstly, preparing 440-880 mg of beta-tricalcium phosphate (480 mg of beta-tricalcium phosphate in the embodiment);

the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ester organic solvent =230mg to 360 mg: 120 mg-340 mg: 160 mg-440 mg: 10ml to 20ml, wherein the ester organic solvent is ethyl acetate (the mixture ratio of the embodiment is 260 mg: 160 mg: 220 mg: 15 ml);

the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone =15ml to 25 ml: 10ml to 25ml (the compounding ratio in this example is 15 ml: 15 ml).

The drying in the fourth step of the present invention is oven-drying at 60 to 120 ℃ for 1 to 2 hours or freeze-drying (in this embodiment, oven-drying at 60 ℃ for 2 hours), and then sterilizing by cobalt 60 radiation.

The water content of the mixed ultrafine particle wet powder obtained in the step sixteenth is 2% -3% (2% in this embodiment).

The application of the degradable material is suitable for being manufactured before fracture internal fixation, mixed ultramicron wet powder is manufactured before a fracture internal fixation clinical application requirement, 3D printing is carried out on artificial bones by utilizing the existing 3D printing equipment, and the degradable internal fixation piece is manufactured.

Example 2:

the degradable material suitable for being manufactured before the fracture internal fixation in the embodiment is prepared from the following raw materials in proportion:

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =880 mg: 360 mg: 340 mg: 300 mg: 15 ml: 25 ml: 25 ml.

In the preparation method of the degradable material suitable for being manufactured before the fracture internal fixation in the embodiment, the proportion of the beta-tricalcium phosphate in the steps is 880 mg;

the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ethyl acetate =360 mg: 340 mg: 300 mg: 15 ml;

the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone = 25 ml: 25 ml.

In the step of the present embodiment, the material a and the polymer material B are mixed at 6 to 10 ℃ (10 ℃ in the present embodiment) and stirred at a stirring speed of 1000 rpm for 10 to 15 minutes (15 minutes in the present embodiment); the drying is drying for 1-2 hours at 60-120 ℃ or freeze drying (in this embodiment, drying for 1 hour at 120 ℃), and then sterilizing by cobalt 60 radiation.

In this embodiment, the moisture content of the mixed ultrafine particle wet powder described in the sixteenth step is 2% to 3% (in this embodiment, 3%).

The same as in example 1.

Example 3:

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =880 mg: 360 mg: 340 mg: 300 mg: 10 ml: 25 ml: 25 ml.

the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ethyl acetate =360 mg: 340 mg: 300 mg: 10 ml.

In the step of this embodiment, the drying is performed by baking at 60 to 120 ℃ for 1 to 2 hours or freeze drying (baking at 110 ℃ for 1 hour in this embodiment), and then the obtained product is sterilized by cobalt 60 radiation.

In this embodiment, the moisture content of the mixed ultrafine particle wet powder described in the sixteenth step is 2% to 3% (2.7% in this embodiment).

The same as in example 2.

Example 4:

the degradable material suitable for being manufactured before fracture internal fixation in the embodiment is prepared from the following raw materials in parts by weight:

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =440 mg: 230 mg: 120 mg: 160 mg: 10 ml: 15 ml: 10 ml.

In the preparation method of the degradable material suitable for being manufactured before the fracture internal fixation in the embodiment, the proportion of the beta-tricalcium phosphate is 440 mg;

the preparation method comprises the following steps: polylactic acid: polyhydroxybutyrate: ethyl acetate =230 mg: 120 mg: 160 mg: 10 ml;

in the step three in the embodiment, the mixture ratio of the polypropylene fumarate is as follows: n-vinylpyrrolidone =15 ml: 10 ml;

in the step fourth, the material a and the polymer material B are mixed at 6 ℃ to 10 ℃ (6 ℃ in the present embodiment) and stirred at a stirring speed of 1000 rpm for 10 to 15 minutes (10 minutes in the present embodiment); the drying is drying for 1-2 hours at 60-120 ℃ or freeze drying (in this embodiment, drying for 1.5 hours at 70 ℃), and then sterilizing by cobalt 60 radiation.

In this embodiment, the moisture content of the mixed ultrafine particle wet powder described in the sixteenth step is 2% to 3% (2% in this embodiment).

The same as in example 1.

Example 5:

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =800 mg: 300 mg: 260 mg: 440 mg: 20 ml: 20 ml: 20 ml.

In the preparation method of the degradable material suitable for being manufactured before fracture internal fixation in the embodiment, the proportion of the beta-tricalcium phosphate in the steps is 800 mg;

the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ethyl acetate =300 mg: 260 mg: 440 mg: 20ml of the solution;

the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone = 20 ml: 20 ml.

In the step of the present embodiment, the material a and the polymer material B are mixed at 6 to 10 ℃ (10 ℃ in the present embodiment) and stirred at a stirring speed of 1000 rpm for 10 to 15 minutes (15 minutes in the present embodiment); the drying is drying for 1-2 hours at 60-120 ℃ or freeze drying (in this embodiment, drying for 1 hour at 110 ℃), and then sterilizing by cobalt 60 radiation.

In this embodiment, the moisture content of the mixed ultrafine particle wet powder described in the sixteenth step is 2% to 3% (2.5% in this embodiment).

The same as example 2.

Test examples

Test (1):

the novel bone fracture internal fixation absorbable material prepared before the operation has the advantages of strength, rigidity (hardness), stability of fixed fracture, understanding of external force influence on bones, stress of bones, biomechanical functions of bones and the like, and is very important for researching the internal fixation absorbable material and biomechanical research on the bone fracture internal fixation material.

Bones and joints are the frame or framework of a human body, are the main carriers of force, have biological characteristics and mechanical characteristics, the biological characteristics are the basis of existence of living bones and adaptation to mechanical environments thereof, and the mechanical characteristics are the mechanical conditions of bone stress molding, stress strain, bone structure reconstruction and the like (see table 1).

TABLE 1 biomechanical analysis of fracture internal fixation absorbable materials and bones

Name (R)	Biomechanical requirements of bone	Bone biomechanical analysis
			Strength of bone	Ability of bones to resist destruction by external forces	Under the action of external force, the continuity and the integrity of the self-body are kept, no mid-range capability occurs. If the external force exceeds the maximum load of the bone When in capacity, fractures can occur.
Rigidity of bone	Bone ability to resist external forces without deformation	The bone can maintain the inherent shape and size under the action of external force Ability not to change when external force is greater than its maximum stiffness In time, the fracture is deformed.
			Bone stabilization Property of (2)	Under the action of external force, the bones still keep the original relative positions Ability to produce changes	When the external force exceeds its stability, the relative position of the bones occurs And (4) shifting. The mechanical property is called displacement.
External force of bone	The force acting on the bone is collectively referred to as the external force of the bone	The method comprises the following steps: self-gravity, muscle group contraction, muscle tension, violence, etc.
			Stress of bone	Under the action of an external force, the bone tissue is displaced into the phase produced The interaction force is called stress.	Stress and bone healing, new bone formation, osteoporosis, of bone tissue The shape and structure, remodeling of bone, and plastic deformation are closely related.
Biological of bone Mechanical function	(1) Bearing external force, generating stress and conducting stress; (2) to gather for muscle group Contracting to provide an acting point; (3) protection of organs and vital tissues; (4) generating Bioelectricity; (5) a sound conductor; (6) a muscle joint; (7) stress of bone The change in shape and size of bone tissue caused by strain and stress is called And (4) stress strain.
			Elastic deformation	After the bone tissue is stressed, the change of shape and size occurs The shape is changed.	The deformation of bone tissue after the stress action disappears is recovered In this manner, such stress strain is called elastic deformation.
Fatigue deformation	Although the stress applied to the bone is not great, the period of application is short, and the frequency is high The rate is high, forming a cross stress effect.	If the transformation rate exceeds the rate of restoration of the deformation, the resulting bone set The tissue is in the stress environment of unrecoverable deformation, and the bone finally appears And (4) plastic deformation. Therefore, fatigue fracture is also called cumulative stress fracture.

Through animal test research, 10 rabbits are subjected to artificial fracture on the radius, a post-fracture test group is implanted into the degradable material (degradable internal fixing piece with the specification of 6.67 cm, the length of 100 mm, the width of 3.8 mm and the thickness of 4 mm, which is printed by 3D) prepared before the fracture internal fixation operation, so as to fix the fracture, a contrast group is used for fixing the fracture by Beijing Heshi bone cement, the fracture is manually treated after 12 weeks, the fracture parts of the test group and the contrast group are subjected to mechanical test on healing of the fracture parts through a hydraulic universal detector, the test requirements are tested on stretching, weight pressing, bending and the like, and the bending strength of the test group is obviously higher than that of the contrast group.

The research of orthopedics biomechanics also shows that the mechanical environment of sufficient blood supply and complete stress bone structure, which bears external force, stress generated and stress transmission continuously, must try to protect or recover the blood circulation of the bone and the integrity of the bone when a treatment plan and a treatment method are made. The invention can print out plastic material according with fracture biomechanics according to fracture position and type before operation and 3D to fix fracture, and can degrade surface and body of clinical healing material along with bone healing, thereby ensuring blood circulation of local fracture, and overcoming and applying the bone biomechanics change, stress shielding, even steel plate screw loosening and fracture, causing blood circulation disturbance and recrudescence complications brought by strong internal fixation of titanium alloy or metal internal fixation material.

Clinical application analysis: the internal fixation material of the invention is 3D printed and analyzed for clinical indications (see Table 2).

Table 2: the invention relates to a fracture internal fixation 3D printing clinical indication

Table 3: table made of absorbable steel plate for internal fixation of fracture

Specification (& lt & gtcm)	Body length L (mm)	Wide surface B (mm)	Body thickness (mm)
				6.67	100	3.8	4
8.34	125	4.8	6
				10	150	5.8	6
13.34	200	7.8	6
				16.67	250	8.8	8

The fracture internal fixation of the invention adopts the steel plate and the screw made of the biomaterial to treat the fracture with small shearing stress, thereby greatly reducing the treatment cost and the pain of the patient in the second operation. Reduce the original fracture and various side effects caused by stress shielding and fixation. The biomaterial steel plate and screw of the invention have no toxic and side effects to human body, can be biodegraded, have good compatibility with bone, can promote the advantage of union of fracture.

The material is used for 3D printing clinical indication analysis before fracture internal fixation, the product is suitable for fractures with small human fracture shear stress, and can effectively replace part of the previous bone cement and clinical application of various metal steel plates, screws and metal fixing rod materials. Reduce the treatment cost of patients, reduce the pain caused by the second operation, and reduce the occurrence of the internal fixation complications of the metal steel plate and the screw, the recrush and various complications.

Table 4: specification design table for degradable screw for internal fixation of fracture

Note: the degradable screw is manufactured according to the fracture position and the shape of the fracture and the thickness of the fracture of the implanted fracture position, and is generally clinically applied to internal and external humeral condyle fracture, finger bone fracture, radius capitulum fracture, tibial plateau fracture, double ankle fracture, talus fracture, metatarsal fracture and toe bone fracture.

The degradable material for internal fixation of fracture of the invention selects the steel plate and the screw made of biomaterial to treat the fracture with small shearing stress, thus greatly reducing the cost of treatment cost and relieving the pain of the patient in the second operation. Reduce the original fracture and various side effects caused by stress shielding and fixation. The biomaterial steel plate and screw of the invention have no toxic and side effects to human body, can be biodegraded, have good compatibility with bone, can promote the advantage of union of fracture.

The material is used for 3D printing clinical indication analysis before fracture internal fixation, the product is suitable for fractures with small human fracture shear stress, and can effectively replace part of the previous bone cement and clinical application of various metal steel plates, screws and metal fixing rod materials. Reduce the treatment cost of patients and reduce the occurrence of internal fixation complications and re-fracture and various complications caused by the strong strength of metal steel plates and screws.

The fracture internal fixation material 3D printing artificial bone provided by the invention has the advantages that the designed length, thickness and rigidity of the internal fixation material can be greater than the manufacturing requirements of stainless steel. The degradable internal fixation material has certain rigidity (hardness), and the material has certain elasticity and flexibility, so that complications such as steel plate fracture, bone healing delay, non-inflammatory reaction and the like caused by strong internal fixation and stress shielding of stainless steel can be overcome. The invention relates to a degradable material for internal fixation of fracture. Is suitable for the stress requirement of the biomechanics of the orthopedics department, does not need secondary operation, and can change the material into CO after the fracture reaches the clinical healing period (full of three months) ₂ And H ₂ O, excreted out of the body by human metabolism.

Claims

1. The degradable material is prepared from the following raw materials in parts by weight:

2. The degradable material of claim 1 for use in pre-operative fracture fixation

β -tricalcium phosphate: polyglycolic acid: polylactic acid: polyhydroxybutyrate: ethyl acetate: polypropylene fumarate: n-vinylpyrrolidone =480mg to 880 mg: 260 mg-300 mg: 160 mg-260 mg: 220 mg-300 mg: 15 ml-20 ml: 15 ml-25 ml: 15ml to 20 ml.

3. A preparation method of a degradable material suitable for being manufactured before fracture internal fixation is characterized by comprising the following steps:

fourthly, mixing the material A and the polymer material B at the temperature of 6-10 ℃, stirring for 10-15 minutes at the stirring speed of 1000 rpm, continuously stirring under the magnetic force condition until the ultrafine particles are solidified, and then drying into powder to obtain mixed ultrafine particle powder for later use;

carrying out centrifugal separation on the polymer material C obtained in the step fifthly at 1000 revolutions per minute to obtain liquid polymer material standby liquid;

4. The preparation method of the degradable material suitable for being manufactured before the internal fracture fixation according to claim 3, is characterized in that the mixing ratio of the beta-tricalcium phosphate in the step is 440-880 mg;

the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ester organic solvent =230mg to 360 mg: 120 mg-340 mg: 160 mg-440 mg: 10ml to 20ml, and the ester organic solvent is ethyl acetate;

the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone =15ml to 25 ml: 10ml to 25 ml.

5. The preparation method of the degradable material suitable for being manufactured before the internal fracture fixation surgery according to claim 4, is characterized in that the proportion of the beta-tricalcium phosphate in step I is 480-880 mg;

the preparation method comprises the following steps of: polylactic acid: polyhydroxybutyrate: ethyl acetate =260mg to 300 mg: 160 mg-260 mg: 220 mg-300 mg: 15ml to 20 ml;

the step three is that the mixture ratio of polypropylene fumarate: n-vinylpyrrolidone =15ml to 25 ml: 15ml to 20 ml.

6. The method for preparing a degradable material suitable for being prepared before fracture internal fixation according to claim 3, 4 or 5 is characterized in that the drying in the step four is oven drying at 60-120 ℃ for 1-2 hours or freeze drying and then cobalt 60 radiation sterilization.

7. The method for preparing a degradable material suitable for being manufactured before fracture internal fixation as recited in claim 3, 4 or 5, wherein the moisture content in the mixed ultrafine particle wet powder in step sixty percent is 2% to 3%.

8. The method for preparing the degradable material suitable for being manufactured before the internal fixation of fracture as claimed in claim 6, wherein the moisture content in the mixed ultrafine particle wet powder in the step sixteenth is 2% -3%.

9. The application of the degradable material suitable for being manufactured before fracture internal fixation is characterized in that mixed ultramicron wet powder is taken to perform 3D printing on an artificial bone to manufacture a degradable internal fixation piece.