CN108066815A - A kind of bone implant material and its preparation method and application - Google Patents
A kind of bone implant material and its preparation method and application Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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Abstract
The present invention provides a kind of bone implant material and its preparation method and application.The bone implant material preparation method is：By black phosphorus ultrasonic disperse in the first solvent, dispersion liquid A is obtained；High molecular material is dissolved in the second solvent, obtains solution B；Dispersion liquid A and solution B are mixed and then be ultrasonically treated, obtains the solution of finely dispersed BP@high molecular materials；It is then injected into die for molding or carries out 3D printing shaping, bone implant material is prepared in solvent flashing.There is the bone implant material photo-thermal to promote osteogenesis function, it can degrade under physiological environment, it is applied as the implant at bone defect filling position on clinical treatment bone defect, near-infrared can not only be improved and penetrate the efficiency that biological tissue facilitates bone with heat, it can also be combined with clinical physical therapy, reach more preferably promotion bone defect healing curative effect, while the bone implant material catabolite is human body necessary material, can participate in knitting and regenerative process.
Description
Technical field
The invention belongs to biomedical technical field of polymer materials, be related to a kind of bone implant material and preparation method thereof and
Using.
Background technology
With the arrival of Chinese society aging of population, the number that bone wound or bone tumour occurs is significantly increased.Clinically
For bone defect caused by bone wound and bone tumour etc., it is difficult to heal the fracture at position and the case of bone nonunion rises year by year,
And treatment acquires a certain degree of difficulty.
There are many factor for causing bone defect, common are fracture, extraneous wound (such as traffic accident, war, unexpected injury etc.)
It performs the operation with bone tumour.The bone defect wherein caused by fracture caused by the elderly's bone loss and extraneous wound, accounts for total factor
More than 75%.Aging of population is the common problem of developed country and developing country, China early in 1999 just in advance into
Aging society is entered, the elderly fractures caused by osteoporosis or bone defect increasingly increases severely.In addition, the incidence of bone tumour
Also rise year by year, particularly in younger population, this trend is more obvious.
Bone material implantation is to be clinically used for the common methods for the treatment of bone defect sufferer at present, and biggest advantage is to keep away
Viral infection risk caused by autologous bone transplanting secondary injury and allogenic bone transplantation to caused by patient and serious immune is exempted from
Rejection.The medicine direction new as one, although bone implant material with higher success rate of operation, in recent years also repeatly
Occurs the report of implant failure repeatly.Failure cause mainly includes：Histocompatbility is poor, infect, healing is impaired etc..Implantation material loses
Effect or partial loss of function are the two big key issues for being implanted into material application at this stage, improve the compatible of implantation material and surrounding tissue
Property, raising or enhancing damage location knitting ability, be the main path solved the problems, such as.
The use of bone implant material is the common method of current clinical treatment bone defect, therefore new bone renovating material is ground
Send out most important.Bone implant material can be divided into metal, ceramics and macromolecule three categories according to material.Wherein, degradable macromolecule
Bone implant material becomes grinding in recent years because of many advantages, such as its elasticity modulus is low, degradation is controllable, catabolite has no toxic side effect
Study carefully hot spot.Medical field and material educational circles attempt a variety of methods and improve the ability of knitting around implantation material to reduce implant mistake
Effect.Mainly include following two thinkings：
(1) by systemic or local administration, rejection of patient's body to implantation material is reduced, damage location is promoted to be cured
It closes；Or stimulate the knitting of damage location by external auxiliary means, such as the modes such as physical therapy.
Conventional therapy means are included using drugs such as injection growth factor, oral osteocalcin.Growth factor is in the blood of human body
Content is little in liquid and tissue, but main effector can be used as to promote the functions such as cell division, matrix synthesis and tissue differentiation.
Recent domestic scholar promotes bone defect healing to carry out numerous studies growth factor.At present frequently with growth factor master
There are bone morphogenetic protein (BMP) and insulin-like growth factor (IGF).Other growth factors for still locating under study for action further include
Fibroblast growth factor (FGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and turn
Change grouth factor beta (TGF-β) etc..
Physical therapy, such as：Electro photoluminescence, mechanical stimulation, ultrasound stimulation and laser stimulation etc. are normally used as promoting bone
The supplementary means of healing.Electro photoluminescence is mainly stimulated by micro-current promotes local blood circulation, induces a variety of bone growth factors
Generation, so as to accelerate the connection in bone defect area and the formation of new bone and reconstruction.Traction is most common mechanical stimulation means,
Apply the tractive force in given pace and direction in bone section by bone tractor, be drifted apart from bone section, in the gap of generation
New bone is generated, while extends and expands surrounding soft tissue, achievees the purpose that extension, broadening or reparation bony defect.With low intensive
Impulse ultrasound stimulates, and can not only increase the synthesis of angiogenesis relevant cell factor, promotes vascularization, can also cause cell
The change of membrane permeability promotes the expression of related gene, promotes the reconstruction of new bone formation and poroma.It is infrared or near infrared spectrum
Laser stimulation can promote vascularization, fibrosis hyperplasia and collagen deposition, can not only accelerate the process of knitting, also
The elasticity modulus of bone density and bone can be increased.In addition, it is reported that the photochemistry and photobiology performance of laser can slow down controls
The inflammation at position is treated, clinical signs are the symptoms such as the discomfort of reduction postoperative patient and oedema.
(2) implantation material is modified and is modified, to improve the compatibility of implantation material and tissue.
At present, the research for surface and body processing being carried out for implant mainly includes two aspects：Using machinery or object
Reason, chemical method make implant surface it is loose, roughening, so as to make it have better Bioadhesive force, surface tension and bone
Tissue affinity；Its biology energy is improved by changing material surface energy, surface charge, surface composition.Utilize biochemistry
Method introduces active group, loading bioactive molecule or drug on the surface of implant material or inside, and implantation material is made to exist
It is had both on the machinery mount exposure basis of itself and promotes ostosis and the local function of carrying medicine.
Clinical treatment or bone defect scheme just under study for action are many now, such as pharmaceutical intervention treatment, physical therapy, group
Weaver's engineering support etc..But each method has certain limitation.
Administered either systemically or locally mode, particularly growth factor class drug, are mostly protein or polypeptide, in vivo pole
Degradable, biological half-life is short, and the action time of action is shorter, and the diffusion and metabolism of drug occur on the whole body, really arrive
Up to target site and the effective dose of action is well below dosage.It, may be to liver, kidney if increasing dosage
Or other organs bring larger side effect.In addition, such drug cost is higher, heavy economy can be brought to patient by frequently using
Burden.
The period of traction of distraction osteogenesis is longer, it is possible that new bone formation is bad or the situation of delayed union；Tractor
Insert the risk for not only having rejection, infecting, loosening, the nerves and muscles function of distracted position will also be caused a degree of
Damage.Ultrasound stimulation is at present still in controversial state, although some researches show that ultrasound can accelerate the formation of new bone and change
Build it is moulding, but in middle and later periods effect unobvious.Photothermal laser stimulate skeletonization due to infrared/near-infrared laser penetration capacity compared with
It is weak, it usually needs to increase the exposure intensity of laser so as to obtain preferable therapeutic effect, and increase exposure intensity and often burn
The skin or musculature on surface layer.
Currently used degradable macromolecule bone implant material is mostly inert material, and it is to restrict it to answer to facilitate bone active deficiency
Key factor.Therefore, the promotion ostosis ability of degradable macromolecule bone implant material how is improved, is its research and hair
The most important thing of exhibition.
The content of the invention
In order to solve the above-mentioned technical problem, it is an object of the invention to provide a kind of bone implant material and preparation method thereof,
The ability of knitting around implantation material can be improved.
The present invention also aims to provide above-mentioned bone implant material as the implant at bone defect filling position in clinic
Treat the application on bone defect.
The purpose of the present invention is achieved by the following technical programs：
The present invention provides a kind of preparation method of bone implant material, comprises the following steps：
Step 1 by black phosphorus ultrasonic disperse in the first solvent, obtains dispersion liquid A；
High molecular material is dissolved in the second solvent, obtains solution B by step 2；
Dispersion liquid A and solution B are mixed, are then ultrasonically treated, obtain finely dispersed BP@high molecular materials by step 3
Solution；
The solution of the BP@high molecular materials obtained in step 3 is injected die for molding or carries out 3D printing by step 4
Bone implant material is prepared in shaping, solvent flashing；
Wherein, the mass ratio of the black phosphorus and the high molecular material is (0.1%-1.0%)：1.
In above-mentioned preparation method, it is preferable that it is sub- that first solvent can include absolute ethyl alcohol, deionized water, dimethyl
One or more combinations in sulfone, halogenated hydrocarbon solvent, dimethylformamide, tetrahydrofuran etc..
In above-mentioned preparation method, it is preferable that second solvent includes halogenated hydrocarbon solvent, dimethylformamide and tetrahydrochysene
One or more combinations in furans etc.；
It is further preferred that the halogenated hydrocarbon solvent can include dichloromethane and/or chloroform, but not limited to this.
In above-mentioned preparation method, the effect of the first solvent is that cleaning and auxiliary black phosphorus disperse, therefore the first amount of solvent
It can be carried out according to practical operation, ensure covering black phosphorus precipitation.
In above-mentioned preparation method, it is preferable that the high molecular material can include Poly(D,L-lactide-co-glycolide
(PLGA), polycaprolactone (PCL), polylactic acid (PLA), poly butylene succinate (PBS) and polytrimethylene carbonate
(PTMC) one or more combinations in such as.
In above-mentioned preparation method, it is preferable that in the Poly(D,L-lactide-co-glycolide, polylactic acid and hydroxyacetic acid
Mass ratio can be 75：25、85：15 or 90：10.Different mass ratioes can adjust final bone implant material film or stent
The parameters such as hardness, Young's modulus.
In above-mentioned preparation method, the additive amount of the second solvent is carried out according to practical operation, guarantees thoroughly to dissolve high score
The not high disease of sub and solution stickiness has water sample circulation, ensures that energy is more uniform during ultrasonic disperse black phosphorus, it is preferable that described
High molecular material and the second solvent dosage ratio can be (25mg-50mg)：1mL.
In above-mentioned preparation method, it is preferable that solvent flashing carries out under room temperature or low temperature；It is it is further preferred that described low
Temperature refers to be less than or equal to 4 DEG C.
In above-mentioned preparation method, it is preferable that the black phosphorus can include black phosphorus nanometer sheet and/or black phosphorus quantum dot；
It is further preferred that the black phosphorus nanometer sheet is less than the two-dimensional layer black phosphorus of 100nm for thickness；
It is further preferred that the black phosphorus quantum dot is less than the extra small black phosphorus nanometer sheet of 10nm for thickness.
In above-mentioned preparation method, it is preferable that the preparation method of the two-dimensional layer black phosphorus is：
Block black phosphorus is weighed, is gradually added N- N-methyl 2-pyrrolidone Ns, ice-water bath supersound process, Ran Houjin are carried out after grinding fully
Row centrifuges for the first time and takes supernatant, obtains the suspension of two-dimensional layer black phosphorus；The suspension of two-dimensional layer black phosphorus is carried out the
Secondary centrifuging simultaneously takes precipitation, obtains two-dimensional layer black phosphorus；
Wherein, the amount ratio of the block black phosphorus and the N- N-methyl 2-pyrrolidone Ns is less than 2mg：1mL；The time of supersound process
For 4-12h, first time centrifugal rotational speed is 4000-7000rpm, centrifugation time 10-20min；Second of centrifugal rotational speed be
12000-14000rpm, centrifugation time 10-20min；
It is further preferred that the amount ratio of the bulk black phosphorus and the N- N-methyl 2-pyrrolidone Ns is 1mg：1mL；It is ultrasonically treated
Time is 6h, and first time centrifugal rotational speed is 4000rpm, centrifugation time 15min；Second of centrifugal rotational speed is 12000rpm, from
The heart time is 15min.
In above-mentioned preparation method, it is preferable that the preparation method of the extra small black phosphorus nanometer sheet is：
Block black phosphorus is weighed, N- N-methyl 2-pyrrolidone Ns is gradually added, places it in after grinding fully and carried out on ice using probe
It is ultrasonically treated, then carries out first time centrifugation and takes supernatant, obtain the suspension of extra small black phosphorus nanometer sheet；Extra small black phosphorus is received
The suspension of rice piece is centrifuged and taken and precipitated to get to extra small black phosphorus nanometer sheet for the second time；
Wherein, the amount ratio of the block black phosphorus and the N- N-methyl 2-pyrrolidone Ns is less than 2mg：1mL；The time of supersound process
For 4-12h, first time centrifugal rotational speed is 7000-12000rpm, centrifugation time 10-20min；Second of centrifugal rotational speed be
12000-14000rpm, centrifugation time 10-20min；
It is further preferred that the amount ratio of the bulk black phosphorus and the N- N-methyl 2-pyrrolidone Ns is 1mg：1mL；It is ultrasonically treated
Time is 10h, and first time centrifugal rotational speed is 10000rpm, centrifugation time 15min；Second of centrifugal rotational speed is 12000rpm,
Centrifugation time is 15min.
In above-mentioned preparation method, two-dimensional layer black phosphorus is with extra small black phosphorus nanometer piece preparation method difference：Ultrasonic power
With the difference of centrifugal speed after ultrasound.Two-dimensional layer black phosphorus is substantially to apply external mechanical power, by black phosphorus layer from black phosphorus block
On strip down.From ultrasonic power, the power of water bath sonicator generally in 300W, Probe Ultrasonic Searching it is more powerful, can reach
700-900W.From centrifugal condition, the centrifugal speed of two-dimensional layer black phosphorus is mainly 4000-7000rpm, and extra small black phosphorus is received
The centrifugal speed of rice piece is mainly 7000-12000rpm.
In above-mentioned preparation method, since black phosphorus nature is more active, it is oxidized easily and drops when running into oxygen and moisture
Solution, loses the special property of black phosphorus in itself, so the two-dimensional layer black phosphorus being typically prepared and extra small black phosphorus nanometer sheet preserve
In NMP (N-Methyl pyrrolidone), play the role of stablizing and protect.
However, the black phosphorus dispersion liquid concentration prepared according to the method described above is relatively low, can by way of centrifugation into
Row concentration.NMP boiling points itself are higher, it is difficult to volatilize, if not removing the preparation for being unfavorable for next step film or stent；And
NMP has stronger cytotoxicity, it is therefore desirable to centrifugation removal NMP.BP after centrifugation disperses in organic solvent, on the one hand right
BP precipitations are cleaned, and thoroughly remove NMP, and BP on the other hand can be helped to be uniformly dispersed in Polymer Solution.
In above-mentioned preparation method, the additive amount of the second solvent is carried out according to practical operation, guarantees thoroughly to dissolve high score
The not high disease of sub and solution stickiness has water sample circulation, ensures that energy is more uniform during ultrasonic disperse black phosphorus, it is preferable that described
High molecular material and the second solvent dosage ratio can be (25mg-50mg)：1mL.
In above-mentioned preparation method, the shape of used mold can be that film shape, three-dimensional rack shape or cylinder are empty
Heart shape, but not limited to this.
In above-mentioned preparation method, the mass ratio of the black phosphorus and the high molecular material is (0.1%-1.0%)：1, it uses
This ratio can be warming up to required temperature (40.5 ± 0.5 DEG C) after can ensureing near-infrared laser irradiation first, secondly high
For molecular material with being in acidity after black phosphorus degradation, strong acidity environment has the osteogenic induction of stem cell certain negative effect, will
The mass ratio of black phosphorus and high molecular material is controlled at above-mentioned (0.1%-1.0%)：The negative effect can be overcome in the range of 1,
Obtain preferable actual effect.
In above-mentioned preparation method, the solution for obtaining BP@high molecular materials is poured into mold and treats that organic solvent volatilizees.It is organic molten
The evaporation rate of agent can be adjusted by controlling environment temperature, this can further influence the film of preparation or the surface of stent
Pattern.Using room temperature and/or cryogenic conditions, if organic solvent can be slowed down by being placed under lower temperature environments (such as in 4 DEG C of refrigerators)
Evaporation rate, place and solvent allowed slowly to volatilize in 3-10 days, obtained film or rack surface flat smooth；If environment temperature exists
20 DEG C or so, it is very fast that organic solvent is volatilizable, and the film of preparation or the surface of stent are more coarse, there is hundred nanometers of even microns
Grade pore structure generates.According to experiment before, the surface of relatively low environment temperature and flat smooth is more advantageous to existence conditions
Under osteogenic induction.To ensure the abundant volatilization of organic solvent, the issuable cytotoxicity of dissolvent residual is reduced, is waved in solvent
The final step of hair can will be positioned over already close to molding sample in vacuum drying chamber, and room temperature, which vacuumizes, to be dried overnight (about
When 10-12 is small).Sample after taking-up is last molding sample.
The present invention also provides the bone implant materials that above-mentioned preparation method is prepared, it is preferable that the knot of the bone implant material
Structure be membrane structure, three dimensional scaffold structure or column solid construction, but not limited to this.
The implant at position is filled in clinical treatment bone defect as bone defect the present invention also provides above-mentioned bone implant material
On application.
There is bone implant material provided by the invention photo-thermal to promote osteogenesis function, and black phosphorus can be as the built in light in implantation material
Thermoconverter is greatly improved the efficiency that near-infrared laser penetrates biological tissue, heightens the effect of a treatment；The degradation of high molecular material is received simultaneously
The regulation and control of black phosphorus ratio are mixed, as high molecular material is slowly gradually released, black phosphorus runs into the water in tissue, is aoxidized
Phosphate anion is produced, reaches bone defect position.Phosphate is essential substance, Ke Yican in knitting and regenerative process
With the knitting of defect, reach the therapeutic effect of " one two effect ".
Long-term existence is needed after implanting in view of implantation material as foreign matter, there are the risk of rejection, therefore degradable plant
Enter the research hotspot that material is current orthopedic implanting material.The degradable most fundamental starting point for being implanted into material is selected to be desirable to adjoint
The generation of new bone, implantation material gradually degrade and are finally metabolized or are absorbed completely by human body.Therefore preferably degradable implantation material exists
Necessary element while degradation for local osteanagenesis can also be gradually provided, promote osteanagenesis.
New Two Dimensional optothermal material black phosphorus innovatively applied in the preparation of bone implant material, is utilized black phosphorus by the present invention
In the photo-thermal effect for the stabilization that near infrared region generates, the stem cell of people is stimulated to regulate and control toward skeletonization direction, so as to reach bone implantation material
The effect of material facilitates bone.The two-dimensional material of photo-thermal effect can be generated with other, such as graphene, golden stick etc. are compared, black phosphorus is in itself
It is a kind of degradable two-dimensional material, and its catabolite is phosphate anion, has certain facilitation to the generation of bone.
Meanwhile P elements are also one of essential elements being widely present in human body.Using black phosphorus as heat generating medium, it is right that other will not be introduced
The substance that human body is harmful to enters vivo environment, effectively avoids the potential hazard that may be brought using other media.
There is bone implant material provided by the invention photo-thermal to promote osteogenesis function, can degrade under physiological environment, will
It is applied as the implant at bone defect filling position on clinical treatment bone defect, can not only be improved near-infrared and be penetrated
Biological tissue facilitates the efficiency of bone with heat, additionally it is possible to the bone implant material is combined with clinical physical therapy, reaches and more preferably promotees
Into bone defect healing curative effect, while the bone implant material catabolite is human body necessary material, can participate in knitting and regeneration
Process, and will not residual harmful substance in human body.
Description of the drawings
Fig. 1 is BP@PLGA films and PLGA degradation experiment weightless test comparison diagrams in the embodiment of the present invention 2；
Fig. 2 is " degradation time-quality retention rate " in BP@PLGA films and PLGA degradation experiments in the embodiment of the present invention 2
Contrast curve；
Fig. 3 is " degradation time-phosphorus acid ion concentration " curve of black phosphorus in BP@PLGA films in the embodiment of the present invention 2
Figure；
Fig. 4 is the osteocalcin table that BP@PLGA films promote skeletonization under near-infrared laser stimulation in the embodiment of the present invention 3
Up to schematic diagram；
Fig. 5 is the osteocalcin table that BP@PLGA films promote skeletonization under near-infrared laser stimulation in the embodiment of the present invention 3
Up to schematic diagram；
Fig. 6 is the musculature that BP@PLGA film near-infrared lasers penetrate pig in biological tissue's experiment in the embodiment of the present invention 4
Illustraton of model；
Fig. 7 is that BP@PLGA film near-infrared lasers penetrate biological tissue's effect curve figure in the embodiment of the present invention 4.
Specific embodiment
In order to which technical characteristic, purpose and the advantageous effect to the present invention are more clearly understood, now to the skill of the present invention
Art scheme carry out it is described further below, but it is not intended that the present invention can practical range restriction.
Block black phosphorus, PLGA, PCL, PLA, PBS, the PTMC provided in the present embodiment is commercially available.
Embodiment 1
The present embodiment provides a kind of preparation methods of bone implant material BP@PLGA films, comprise the following steps：
Step 1 prepares two-dimensional layer black phosphorus first：Block black phosphorus is weighed in mortar, is gradually added N- methylpyrroles
The amount ratio of ketone, block black phosphorus and N- N-methyl 2-pyrrolidone Ns is 1mg：1mL, row ice-water bath is ultrasonic after grinding fully, after ultrasonic 6h, in
The speed centrifugation 15min of 4000rpm, takes supernatant to get to the suspension of two-dimensional layer black phosphorus；By the outstanding of two-dimensional layer black phosphorus
Supernatant liquid centrifuges 15min in the speed of 12000rpm and takes precipitation to get to two-dimensional layer black phosphorus；
By two-dimensional layer black phosphorus ultrasonic disperse in a small amount of absolute ethyl alcohol, the addition of absolute ethyl alcohol can cover two-dimensional layer
Black phosphorus precipitates, and obtains dispersion liquid A.
Step 2, weighs Poly(D,L-lactide-co-glycolide (PLGA), polylactic acid and the quality of hydroxyacetic acid in the PLGA
Than for 75：25, PLGA is dissolved in dichloromethane, the amount ratio of PLGA and dichloromethane is 50mg：1mL obtains solution B.
Step 3 dissolves each other above-mentioned dispersion liquid A and solution B, carries out water bath sonicator processing after mixing, obtains scattered equal
Even BP@PLGA Polymer Solutions；Wherein, the mass ratio of two-dimensional layer black phosphorus and PLGA are 0.2%：1.
Step 4, by the BP@PLGA Polymer Solutions injection mold in step 3, which is the mould of film shape
Tool, is placed in 4 DEG C of low temperature environments, places 3-4 days, and after solvent slowly volatilization, it is thin that bone implant material BP@PLGA are prepared
Film.
Bone implant material BP@PLGA film degradations are tested in 2 embodiment 1 of embodiment
The bone implant material BP@PLGA films prepared using embodiment 1 carry out degradation experiment.The BP@PLGA films are made
For the research object of degradation, sampling weekly carries out weightless measurement, carries out a sample every two weeks and takes pictures observation, as a result such as Fig. 1, scheme
Shown in 2 and Fig. 3, Fig. 1 is the present embodiment BP@PLGA films and PLGA degradation experiment weightless test comparison diagrams；Fig. 2 is the present embodiment
" degradation time-quality retention rate " contrast curve in BP@PLGA films and PLGA degradation experiments；Fig. 3 is the present embodiment BP@
" degradation time-phosphorus acid ion concentration " graph of black phosphorus in PLGA films.
As shown in Figure 1, film can be observed from 4th week partial fracture and the situation of blistering, by the 6th week when is thin
Film is substantially chipping, until film has degraded major part at the 8th week.Specific reduced gravity situations are with " degradation time-quality
Retention rate " is mapped (as shown in Figure 2), it can be seen that and the common PLGA and BP@PLGA of preceding surrounding occur to degrade on a small quantity, but from the
The degradation rate for starting BP@PLGA is gradually accelerated (as shown in Figure 3) within five weeks.
The degradation of adjoint PLGA films, after moisture enters film inside so that the black phosphorus (BP) being wrapped in inside film
Also gradually degradation, and ultimately generate phosphate anion.As shown in following reaction equations：
" degradation time-phosphorus acid ion concentration " is carried out to the solution after immersion BP@PLGA films to measure (such as Fig. 3 institutes
Show), the results show phosphorus acid ion concentration will be gradually increased with the increase of degradation time, and show " slowly to degrade, slowly
The feature of release ".
The present embodiment the experimental results showed that：PLGA and BP in BP@PLGA films manufactured in the present embodiment can be in physiology
It degrades under environment, uses it for the implant at bone defect filling position, with the growth of new bone and the healing of defect,
Implant will be progressively metabolized.
BP@PLGA films promote New born formation experiment in 3 near-infrared laser additional embodiments 1 of embodiment
The bone implant material BP@PLGA films prepared using embodiment 1 are carried out near-infrared laser auxiliary and promote New born formation
Experiment.
The present embodiment most preferably facilitates the bone condition to be：The irradiation of 808nm near-infrared lasers is warming up to 40.5 ± 0.5 DEG C, and keeps
The temperature 1 minute, subsequent Temperature fall.Process cycle is 4 days/time, for 3 weeks.7 days, 14 days and 21 days dry is measured respectively
Cell skeletonization GAP-associated protein GAP, such as osteocalcin (osteocalcin, OCN) and the table of osteopontin (osteopontin, OPN)
It reaches, as a result as shown in Figure 4 and Figure 5.Fig. 4 is the osteocalcin table that BP@PLGA films promote skeletonization under near-infrared laser stimulation
Up to schematic diagram；Fig. 5 is that BP@PLGA films promote the osteocalcin of skeletonization to express schematic diagram under near-infrared laser stimulation；Fig. 4 again
With Fig. 5 as can be seen that being grown in people's stem cell on BP@PLGA films, the auxiliary near-infrared laser by above-mentioned condition
Treatment, the protein expression the 14th day and the 21st day significantly improve, this also means that the formation speed of new bone is more common
PLGA films are dramatically speeded up.
BP@PLGA film near-infrared lasers penetrate biological tissue's experiment in 4 embodiment 1 of embodiment
The bone implant material BP@PLGA films prepared using embodiment 1, using the musculature of pig as tissue model (such as
Shown in Fig. 6), block of the thickness from 1mm to 7mm is cut out respectively, is carried out external near-infrared and is penetrated compliance test result.Under normal circumstances,
The muscle layer of 2-3mm thickness can stop the laser that 808nm near infrared lasers are sent.And in the present invention, by 7mm muscle layers
The BP@PLGA films of stop still can be 5 DEG C by 808nm laser heat temperature raising.With 37 DEG C of calculating of normal human body temperature, heat up 3-4 DEG C
It can reach 40-41 DEG C (as shown in Figure 7) needed for optimal treatment.Therefore, the near-infrared laser mentioned using the present invention is aided in
Photo-thermal facilitates the therapy of bone material that can realize treatment in the relatively thin bone defect tissue of muscle layer.
Embodiment 5
The present embodiment provides a kind of preparation method of the solid implantation material of bone implant material BP@PCL columns, including following
Step：
Step 1 prepares two-dimensional layer black phosphorus first：Block black phosphorus is weighed in mortar, is gradually added N- methylpyrroles
The amount ratio of ketone, block black phosphorus and N- N-methyl 2-pyrrolidone Ns is 1.5mg：1mL, row ice-water bath is ultrasonic after grinding fully, after ultrasonic 5h,
10min is centrifuged in the speed of 5000rpm, takes supernatant to get to the suspension of two-dimensional layer black phosphorus；By two-dimensional layer black phosphorus
Suspension centrifuges 15min in the speed of 12000rpm and takes precipitation to get to two-dimensional layer black phosphorus；
By two-dimensional layer black phosphorus ultrasonic disperse in deionized water, the addition of deionized water can cover two-dimensional layer black phosphorus
Black phosphorus precipitates, and obtains dispersion liquid A.
Step 2 weighs polycaprolactone (PCL), PCL is dissolved in dimethylformamide, PCL and dimethylformamide
Amount ratio be 25mg：1mL obtains solution B.
Step 3 dissolves each other above-mentioned dispersion liquid A and solution B, carries out water bath sonicator processing after mixing, obtains scattered equal
Even BP@PCL Polymer Solutions；Wherein, the mass ratio of the quality of two-dimensional layer black phosphorus and PCL are 0.1%：1.
Step 4, by the BP@PCL Polymer Solutions injection mold in step 3, which is cylindric hollow mould,
It is placed in 4 DEG C of low temperature environments, places 3-4 days, after solvent slowly volatilization, it is solid that bone implant material BP@PCL columns are prepared
It is implanted into material.
Embodiment 6
The present embodiment provides a kind of preparation methods of bone implant material BP@PLA three-dimensional racks, comprise the following steps：
Step 1 prepares extra small black phosphorus nanometer sheet first：Block black phosphorus is weighed in mortar, is gradually added N- methylpyrroles
The amount ratio of ketone, block black phosphorus and N- N-methyl 2-pyrrolidone Ns is 1.5mg：1mL is placed it in super using probe on ice after grinding fully
Sound 5h centrifuges 15min in the speed of 10000rpm, takes supernatant, obtain the suspension of extra small black phosphorus nanometer sheet；By extra small black phosphorus
The suspension of nanometer sheet centrifuges 15min in the speed of 14000rpm and takes precipitation to get to extra small black phosphorus nanometer sheet；
By extra small black phosphorus nanometer sheet ultrasonic disperse in absolute ethyl alcohol, the addition of absolute ethyl alcohol can cover extra small black phosphorus and receive
The precipitation of rice piece, obtains dispersion liquid A.
Step 2 weighs polylactic acid (PLA), PLA is dissolved in dimethylformamide, PLA and dimethylformamide
Amount ratio is 50mg：1mL obtains solution B.
Step 3 dissolves each other above-mentioned dispersion liquid A and solution B, carries out water bath sonicator processing after mixing, obtains scattered equal
Even BP@PLA Polymer Solutions；Wherein, the quality of two-dimensional layer black phosphorus and PLA mass ratioes are 0.5%：1.
Step 4, by the BP@PLA Polymer Solutions injection mold in step 3, which is three-dimensional porous rack shape
The mold of shape is placed in 4 DEG C of low temperature environments, is placed 3-4 days, and after solvent slowly volatilization, bone implant material BP@are prepared
PLA three-dimensional racks.
Embodiment 7
The present embodiment provides a kind of preparation methods of bone implant material BP@PLGA three-dimensional racks, comprise the following steps：
Step 1 prepares extra small black phosphorus nanometer sheet first：Block black phosphorus is weighed in mortar, is gradually added N- methylpyrroles
The amount ratio of ketone, block black phosphorus and N- N-methyl 2-pyrrolidone Ns is 1.5mg：1mL is placed it in super using probe on ice after grinding fully
Sound 10h centrifuges 15min in the speed of 8000rpm, takes supernatant, obtain the suspension of extra small black phosphorus nanometer sheet；By extra small black phosphorus
The suspension of nanometer sheet centrifuges 15min in the speed of 12000rpm and takes precipitation to get to extra small black phosphorus nanometer sheet；
By extra small black phosphorus nanometer sheet ultrasonic disperse in absolute ethyl alcohol, the addition of absolute ethyl alcohol can cover extra small black phosphorus and receive
The precipitation of rice piece, obtains dispersion liquid A.
Step 2, weighs Poly(D,L-lactide-co-glycolide (PLGA), polylactic acid and the quality of hydroxyacetic acid in the PLGA
Than for 85：15, PLGA is dissolved in tetrahydrofuran, the amount ratio of PLGA and tetrahydrofuran is 40mg：1mL obtains solution B.
Step 3 dissolves each other above-mentioned dispersion liquid A and solution B, carries out water bath sonicator processing after mixing, obtains scattered equal
Even BP@PLGA Polymer Solutions；Wherein, the mass ratio of the quality of extra small black phosphorus nanometer sheet and PLGA are 0.3%：1.
Step 4, by the BP@PLGA Polymer Solutions injection mold in step 3, which is three-dimensional rack shape
Mold is placed in 4 DEG C of low temperature environments, is placed 3-4 days, and after solvent slowly volatilization, bone implant material BP@PLGA tri- are prepared
Dimensional scaffold.
Embodiment 8
The present embodiment provides a kind of preparation methods of bone implant material BP@PBS three-dimensional racks, comprise the following steps：
Step 1 prepares two-dimensional layer black phosphorus first：Block black phosphorus is weighed in mortar, is gradually added N- methylpyrroles
The amount ratio of ketone, block black phosphorus and N- N-methyl 2-pyrrolidone Ns is 1.0mg：1mL is placed it in ultrasonic in ice-water bath after grinding fully
6h centrifuges 20min in the speed of 6000rpm, takes supernatant, obtain the suspension of two-dimensional layer black phosphorus；By two-dimensional layer black phosphorus
Suspension centrifuge 15min in the speed of 12000rpm and take precipitation to get to two-dimensional layer black phosphorus；
By two-dimensional layer black phosphorus ultrasonic disperse in dimethyl sulfoxide (DMSO) (DMSO), the addition of DMSO can cover super two-dimensional layer
The precipitation of shape black phosphorus obtains dispersion liquid A.
Step 2 weighs poly butylene succinate (PBS), PBS is dissolved in tetrahydrofuran, PBS and tetrahydrofuran
Amount ratio be 40mg：1mL obtains solution B.
Step 3 dissolves each other above-mentioned dispersion liquid A and solution B, carries out water bath sonicator processing after mixing, obtains scattered equal
Even BP@PBS Polymer Solutions；Wherein, the mass ratio of the quality of two-dimensional layer black phosphorus and PBS are 0.4%：1.
Step 4, by the BP@PBS Polymer Solutions injection mold in step 3, which is three-dimensional porous rack shape
The mold of shape, is placed in room temperature environment, places 7-10 days, places into vacuum drying chamber and vacuumize, after solvent slowly volatilization,
Bone implant material BP@PBS three-dimensional racks are prepared.
Embodiment 9
The present embodiment provides a kind of preparation methods of bone implant material BP@PTMC three-dimensional racks, comprise the following steps：
Step 1 prepares two-dimensional layer black phosphorus first：Block black phosphorus is weighed in mortar, is gradually added N- methylpyrroles
The amount ratio of ketone, block black phosphorus and N- N-methyl 2-pyrrolidone Ns is 0.5mg：1mL is placed it in ultrasonic in ice-water bath after grinding fully
8h centrifuges 20min in the speed of 7000rpm, takes supernatant to get to the suspension of two-dimensional layer black phosphorus；Two-dimensional layer is black
The suspension of phosphorus centrifuges 15min in the speed of 12000rpm and takes precipitation to get to two-dimensional layer black phosphorus；
By two-dimensional layer black phosphorus ultrasonic disperse in absolute ethyl alcohol, it is black that the addition of absolute ethyl alcohol can cover super two-dimensional layer
The precipitation of phosphorus obtains dispersion liquid A.
Step 2 weighs polytrimethylene carbonate (PTMC), PTMC is dissolved in dichloromethane, PTMC and dichloromethane
The amount ratio of alkane is 30mg：1mL obtains solution B.
Step 3 dissolves each other above-mentioned dispersion liquid A and solution B, carries out water bath sonicator processing after mixing, obtains scattered equal
Even BP@PTMC Polymer Solutions；Wherein, the mass ratio of the quality of super two-dimensional layer black phosphorus and PTMC are 0.3%：1.
BP@PTMC Polymer Solutions in step 3 are carried out stent structure by step 4, and the present embodiment is built using stent
Method is 3D printing method.After macromolecule 3D printer design porous structure stent, print and complete under cryogenic conditions, be placed in 4 DEG C
It in low temperature environment, places 3-4 days, after solvent slowly volatilization, the porous branch of bone implant material BP@PTMC 3 D-printings is prepared
Frame.
In conclusion there is bone implant material provided by the invention photo-thermal to promote osteogenesis function, can be sent out under physiological environment
Raw degradation is applied on clinical treatment bone defect as the implant at bone defect filling position, can not only improved
Near-infrared penetrates the efficiency that biological tissue facilitates bone with heat, additionally it is possible to the bone implant material is combined with clinical physical therapy,
Reach more preferably promotion bone defect healing curative effect, while the bone implant material catabolite is human body necessary material, can participate in bone
Healing and regenerative process, and will not residual harmful substance in human body.
Claims (10)
1. a kind of preparation method of bone implant material, comprises the following steps：
Step 1 by black phosphorus ultrasonic disperse in the first solvent, obtains dispersion liquid A；
High molecular material is dissolved in the second solvent, obtains solution B by step 2；
Dispersion liquid A and solution B are mixed, are then ultrasonically treated, obtain the molten of finely dispersed BP@high molecular materials by step 3
Liquid；
The solution of the BP@high molecular materials obtained in step 3 is injected die for molding or carries out 3D printing shaping by step 4,
Bone implant material is prepared in solvent flashing；
Wherein, the mass ratio of the black phosphorus and the high molecular material is (0.1%-1.0%)：1.
2. preparation method according to claim 1, it is characterised in that：First solvent includes absolute ethyl alcohol, deionization
One or more combinations in water, dimethyl sulfoxide (DMSO), halogenated hydrocarbon solvent, dimethylformamide, tetrahydrofuran；
Second solvent includes one or more combinations in halogenated hydrocarbon solvent, dimethylformamide and tetrahydrofuran；
Preferably, the halogenated hydrocarbon solvent includes dichloromethane and/or chloroform.
3. preparation method according to claim 1, it is characterised in that：The high molecular material includes polylactic acid-glycolic base second
One or more groups in acid copolymer, polycaprolactone, polylactic acid, poly butylene succinate and polytrimethylene carbonate
It closes；
Preferably, in the Poly(D,L-lactide-co-glycolide, the mass ratio of polylactic acid and hydroxyacetic acid is 75：25、85：15
Or 90：10.
4. according to the preparation method described in claim 1-3 any one, it is characterised in that：The high molecular material and described the
The amount ratio of two solvents is (25mg-50mg)：1mL.
5. preparation method according to claim 1, it is characterised in that：Solvent flashing carries out under room temperature or low temperature, excellent
Selection of land, the low temperature refer to be less than or equal to 4 DEG C.
6. preparation method according to claim 1, it is characterised in that：The black phosphorus includes black phosphorus nanometer sheet and/or black phosphorus
Quantum dot；
Preferably, the black phosphorus nanometer sheet is less than the two-dimensional layer black phosphorus of 100nm for thickness；
Preferably, the black phosphorus quantum dot is less than the extra small black phosphorus nanometer sheet of 10nm for thickness.
7. preparation method according to claim 6, which is characterized in that the preparation method of the two-dimensional layer black phosphorus is：
Block black phosphorus is weighed, is gradually added N- N-methyl 2-pyrrolidone Ns, ice-water bath supersound process is carried out after grinding fully, then carries out the
It once centrifuges and takes supernatant, obtain the suspension of two-dimensional layer black phosphorus；The suspension of two-dimensional layer black phosphorus is carried out second
It centrifuges and takes precipitation, obtain two-dimensional layer black phosphorus；
Wherein, the amount ratio of the block black phosphorus and the N- N-methyl 2-pyrrolidone Ns is less than 2mg：1mL；The time of supersound process is 4-
12h, first time centrifugal rotational speed are 4000-7000rpm, centrifugation time 10-20min；Second of centrifugal rotational speed is 12000-
14000rpm, centrifugation time 10-20min；
Preferably, the amount ratio of the block black phosphorus and the N- N-methyl 2-pyrrolidone Ns is 1mg：1mL；The time of supersound process is
6h, first time centrifugal rotational speed are 4000rpm, centrifugation time 15min；Second centrifugal rotational speed is 12000rpm, centrifugation time
For 15min.
8. preparation method according to claim 6, which is characterized in that the preparation method of the extra small black phosphorus nanometer sheet is：
Block black phosphorus is weighed, N- N-methyl 2-pyrrolidone Ns is gradually added, is placed it in after grinding fully and carry out ultrasound using probe on ice
Then processing carries out first time centrifugation and takes supernatant, obtains the suspension of extra small black phosphorus nanometer sheet；By extra small black phosphorus nanometer sheet
Suspension centrifuged for the second time and take precipitation to get to extra small black phosphorus nanometer sheet；
Wherein, the amount ratio of the block black phosphorus and the N- N-methyl 2-pyrrolidone Ns is less than 2mg：1mL；The time of supersound process is 4-
12h, first time centrifugal rotational speed are 7000-12000rpm, centrifugation time 10-20min；Second of centrifugal rotational speed is 12000-
14000rpm, centrifugation time 10-20min；
Preferably, the amount ratio of the block black phosphorus and the N- N-methyl 2-pyrrolidone Ns is 1mg：1mL；The time of supersound process is
10h, first time centrifugal rotational speed are 10000rpm, centrifugation time 15min；Second centrifugal rotational speed is 12000rpm, during centrifugation
Between be 15min.
9. the bone implant material that the preparation method described in claim 1-8 any one is prepared, it is characterised in that：The bone is planted
The structure for entering material is membrane structure, three dimensional scaffold structure or column solid construction.
10. the bone implant material described in claim 9 fills the implant at position on clinical treatment bone defect as bone defect
Application.
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