CN110527075A - A kind of preparation method for remembering biological support for the biodegradable body temperature inductive material of 4D printing and the induction of degradable body temperature - Google Patents

Abstract

The invention discloses a method for preparing a biodegradable body temperature sensing material for 4D printing and a biodegradable body temperature sensing memory biological scaffold. A multi-component biodegradable polymer that is a mercapto group or a norbornene group; the preparation method of the bioscaffold includes the steps of: a multifunctional mercapto group small molecule or a norbornene small molecule and a biodegradable body temperature sensing material generate norbornene by 4D printing ‑Mercapto group photopolymerization reaction to obtain bioscaffolds; the bioscaffolds are heated above the melting point or glass transition temperature and compressed along the diameter direction to reduce the size, and then the temporary shape is fixed near zero to obtain biodegradable body temperature sensing memory bioscaffolds. The invention has the characteristics of fast printing speed, no oxygen inhibition and no shrinkage, and has the advantages of narrow thermal transition peak width, fast recovery speed, accurate recovery temperature, and controllable degradation rate.

Description

A biodegradable body temperature sensing material and degradable body temperature sensor for 4D printing Method for preparing bioscaffolds should be memorized

technical field

The invention belongs to the technical field of 4D printing materials, and in particular relates to a preparation method of a biodegradable body temperature sensing material for 4D printing and a degradable body temperature sensing memory bio-stent.

Background technique

Cardiovascular disease has become the number one health killer worldwide. At present, the most effective treatment for this disease is balloon transluminal coronary angioplasty (PTCA), which uses stent materials to provide radial support for blood vessels to prevent restenosis, thereby achieving the purpose of treatment. The implantation of the most commonly used balloon-expandable stent is to press the stent on the guide wire with a balloon at the end, send the stent to the coronary lesion through the balloon catheter, and then use the pressure of the balloon to expand and release the stent. stand. According to statistics, in 2006, there were about 2.4 million cases of cardiovascular interventional operations in the world each year, and the annual growth rate was 40%. Therefore, the exploration of new scaffold materials and technologies has high scientific value and social significance.

At present, vascular stents have undergone three revolutionary developments, namely, the first-generation bare metal stents, the second-generation drug-eluting stents, and the third-generation biodegradable polymer stents. In recent years, it has been found that the most reliable method is to use a fully degradable stent, which does not leave any metal or polymer in the human body after playing a supporting role in a short period of time, and the drug is released at the same time. Therefore, the concept of fully degradable stent is proposed, which is considered to be the third revolution in the interventional treatment of cardiovascular diseases.

The current implantation of degradable stents can only be implanted into the human body under the condition of assisted surgery by using auxiliary materials such as balloons. The operation is extremely inconvenient, the operation process is cumbersome, and the excision wound that needs to place devices during treatment is relatively large. In terms of degradable stent manufacturing, vascular stents usually use traditional injection molding, weaving, laser processing, etc., which are difficult to achieve personalized customization due to problems such as complex equipment, complicated process, waste of materials, need to remove burrs after molding, and difficulty in forming microvascular stents. design. 3D printing molding technology is a new digital molding technology for rapidly manufacturing objects with arbitrary complex three-dimensional geometric shapes. It has the characteristics of high precision, fast speed and flexible design. At present, degradable thermoplastic biomedical materials such as polylactic acid and polycaprolactone have been 3D printed by fused deposition modeling to prepare various biomedical materials.

In 2013, at the TED (Technology, Entertainment, Design) conference held in California, USA, Skylar Tibbits from the Massachusetts Institute of Technology publicly demonstrated 4D printing technology for the first time. The main principle of 4D printing technology is based on 3D printing technology, using intelligent deformable materials (shape memory materials are the most widely used) as the drive execution unit, using the deformable characteristics of materials, the design parameters, molding process, deformation Information such as behavior and final structural goals are designed into the initial configuration. After forming, use external field excitation medium to stimulate, and obtain preset three-dimensional space configuration through self-deformation such as bending, twisting, and expansion. It is an innovative technology that integrates product design, manufacturing, and assembly, that is, 4D printing method.

Aiming at the current technical bottleneck of degradable polymer stents, the latest 4D printing technology can prepare intelligent fully absorbable polymer vascular stents with shape memory function. The vascular stent processed and formed by 4D printing technology can undergo self-deformation such as expansion under the excitation of body temperature, and finally achieve a preset three-dimensional space configuration, so that it can be realized through self-deformation without balloon expansion when implanted in the human body. The tight and stable fit between the stent and the inner wall of the blood vessel, this adaptability can reduce the strong impact on the blood vessel wall during the balloon expansion process, reduce the risk of tearing the blood vessel wall, greatly reduce the size of the excision wound, and relieve the pain of the patient. At the same time, the molding process is not limited by the complexity of the structure, and it is easier to meet the requirements of mechanical properties and medical properties compared with traditional manufacturing methods.

Using 4D printing technology to print shape memory vascular stent materials has related literature reports and patented technologies. Patent 201410344228.2 (a method for forming artificial vascular stents by 4D printing) uses 3D printing to prepare shape memory polymer vascular stents. Fused deposition 3D printing is used, and vascular stents have no degradable properties. Patent 201410832997.7 (a fully absorbable polymer vascular stent and its preparation method) uses melt extrusion 3D to prepare a degradable shape memory stent. The stent material does not have the function of body temperature induction shape memory. Patent 201610232704.0 (a method for preparing a biodegradable polymer self-expanding vascular stent based on 3D printing technology) uses melt extrusion 3D printing to prepare polylactic acid/iron oxide nanocomposites, and the shape memory response temperature is close to human body temperature. Patent 201710064389.X (degradable self-expanding 4D vascular stent based on shape memory polyurethane and its preparation method) uses melt extrusion 3D printing to prepare degradable shape memory polyurethane with a sensing temperature close to human body temperature. Patent 201710215735.X (a method for preparing a visualized shape memory polymer vascular stent) prepared a vascular stent by using a six-arm degradable polymer modified by photocuring 3D printing at the end of a double bond. Since the end of the macromolecule is an acrylate double bond Photocatalytic self-polymerization reaction, slow photopolymerization speed, oxygen inhibition and shrinkage. The literature (ACS Appl. Mater. Interfaces, 2017, 9, 876-883) reported that a polylactic acid/iron oxide vascular stent was prepared by extruding and photocuring. Since the preparation process is first extruded and cross-linked by light, the preparation process Slow, complex process steps, and shape memory response temperature is much higher than human body temperature.

At present, most of the degradable shape memory vascular stents that can realize 4D printing are prepared by melt extrusion 3D printing technology. The stents are printed by stacking layers, and there is no cross-linking with each other, and the mechanical properties are relatively weak. For the current direct photocuring 4D printed vascular stents, the macromolecules functionalized by acrylate end are prepared by photocrosslinking. Due to the photopolymerization of acrylate bonds, there is oxygen inhibition, photocuring is not complete, and the curing is prolonged. time. In addition, the acrylate bond is a self-polymerizing system, prone to premature gelation, resulting in stress concentrations that can cause wrinkling and warping of the sample. The step-growth thiol-ene photoreaction not only has the advantages of synergistic photopolymerization and step-growth free radical polymerization, but also has the characteristics of no oxygen inhibition, no stress concentration, less amount of initiator and fast polymerization rate.

The photochemical reaction system of photoinitiated thiol and homopolymerizable double bond monomer is a photopolymerization reaction in which the chain growth mechanism and stepwise growth mechanism compete with each other, while the photochemical reaction system of thiol and non-homopolymerizable double bond monomer is Simple stepwise polymerization mechanism. According to the order of reactivity of double-bond monomers in the click reaction (J.Am.Chem.Soc.2012,134,13804-13817), as shown in Figure 11, currently only norbornene (Norbornene), vinyl ether (Vinyl ether ) and propenyl ether (Propenyl ether) and a small number of monomers adopt a simple step-by-step polymerization mechanism, and the reaction speed of the mercaptoene photopolymer of the norbornene group is the fastest.

In view of this, there is still a lack of a 4D printing degradable body temperature sensing material with fast forming speed, no oxygen inhibition and no shrinkage, and a shape memory vascular stent made of this material.

Contents of the invention

In order to solve the above-mentioned problems existing in the prior art, the object of the present invention is to provide a biodegradable body temperature sensing material for 4D printing and a method for preparing a biodegradable body temperature sensing memory biological scaffold.

The technical scheme adopted in the present invention is:

A method for preparing a biodegradable body temperature sensing material for 4D printing, comprising the steps of: using a biodegradable polymer whose terminal is a hydroxyl group at a physiological temperature as the main body, and preparing a biodegradable polymer with a physiological temperature by capping the end of the main body. A multi-component biodegradable polymer that is degradable at temperature and terminated with mercapto or norbornene groups is used as a biodegradable body temperature sensing material for 4D printing.

Further, the glass transition temperature or melting point of the main body is 20°C-40°C.

Further, the preparation method of the main body includes: using D,L-lactide or caprolactone as the main monomer; L-lactide, caprolactone, glycolide, cyclic anhydride, cyclic carbonate, cyclic One or more of phospholipids or p-dioxanone is used as a comonomer; after being acted on by a catalyst and an initiator, a multi-component copolymer is obtained by copolymerization.

Further, the initiator is a dihydric hydroxy compound, a polyhydric hydroxy compound or an oligomer.

Further, the initiator is ethylene glycol, pentaerythritol, small molecule polyhydric alcohol, oligomeric two-arm polyethylene glycol, multi-arm polyethylene glycol, oligomeric two-arm polycaprolactone polyol, multi-arm poly Caprolactone polyol, oligomeric two-arm polyether polyol, three-arm polyether polyol, cyclodextrin or sugar alcohol.

Further, the catalyst is stannous octoate.

Further, when preparing a body with a glass transition temperature of 20°C-40°C, the mass fractions of the main monomer and comonomer used are determined according to the formula (1):

T _g is the glass transition temperature of the main body; T _g1 , T _g2 ... T _gn are the segment glass transition temperatures of each monomer participating in the reaction; n is a positive integer greater than or equal to 2; W ₁ , W ₂ ... W _n is the mass fraction of each monomer participating in the reaction in all monomers.

Further, when preparing a body with a glass transition temperature of 20° C.-40° C., the molar amount of the initiator accounts for 0.02 mol% of the total molar weight of all monomers.

Further, the molecular weight of the host whose glass transition temperature is 20°C-40°C is 400-2000.

Further, when preparing a host with a melting point of 20°C-40°C, the molar ratio of the initiator to each monomer is determined according to the molecular weight of the host with a melting point of 20°C-40°C.

Further, when preparing the main body with a melting point of 30°C-40°C, the amount of the initiator is 0.1 wt% of the total weight of all monomers; the molecular weight of the main body is 1000-4000.

Further, the end-capping treatment of the main body is a norbornene-based end-capping treatment, and the norbornene-based end-capping treatment includes the steps of: mixing and reacting the main body, norbornene acyl chloride and triethylamine with a solvent to obtain A multi-component biodegradable polymer terminated by a norbornene group.

Further, the solvent is dichloromethane; the molar ratio of norbornene acid chloride, triethylamine and main hydroxyl group is 1.2:1.2:1; the reaction time is 48h; the reaction temperature is room temperature.

Further, the end-capping treatment of the main body is a mercapto-capping treatment, and the mercapto-capping treatment includes the steps of: reflux reaction of the main body, thioglycolic acid, catalyst and solvent under a nitrogen atmosphere to obtain a multi-component biological compound with a mercapto group at the end. Degradable polymers.

Further, in the end-capping treatment of the main body, the molar ratio of the hydroxyl group of the main body to thioglycolic acid is 1:10.

Further, the catalyst in the end-capping treatment of the main body is p-toluenesulfonic acid monohydrate; the mass fraction of p-toluenesulfonic acid monohydrate to the monomer mass is 1 wt%; the reaction temperature is 120°C-126°C, The reaction time is 24h.

A method for preparing a biodegradable body temperature sensing material 4D printing degradable body temperature sensing memory biological scaffold, comprising the steps of: combining the biodegradable body temperature sensing material, a solvent, a photoinitiator with a multifunctional mercapto small molecule or a norbornene small molecule After the molecular mixing is adjusted to a suitable printing viscosity, the bioscaffold is obtained after the multifunctional mercapto small molecule or norbornene small molecule and the biodegradable body temperature sensing material undergo a norbornene-mercapto photopolymerization reaction through 4D printing; the bioscaffold Heating above the melting point or glass transition temperature and compressing along the diameter direction reduces the size, and then fixes the temporary shape near zero degrees to obtain a degradable bioscaffold with body temperature sensing memory.

Further, the biological stent is a vascular stent, and the printing conditions of the 4D printing are ultraviolet light intensity 30mW/cm ^-2 ; printing speed: 50mm/h, printed stent size: length 40mm, outer diameter 4mm, inner diameter 2mm.

Further, the biodegradable body temperature sensing material is a multi-component biodegradable polymer with a norbornene group at the end; the preparation of the bioscaffold includes the following steps: mixing the biodegradable body temperature sensing material, solvent, After the photoinitiator is mixed with the multifunctional mercapto small molecule to adjust the viscosity suitable for printing, the bioscaffold is obtained by 4D printing; the multifunctional mercapto small molecule is pentaerythritol tetrakis(3-mercaptopropionate).

Further, the biodegradable body temperature sensing material is a multi-component biodegradable polymer whose terminal is a sulfhydryl group; the preparation of the bioscaffold includes the following steps: mixing the biodegradable body temperature sensing material, a solvent, a photoinitiator After mixing with the norbornene small molecule to adjust the viscosity suitable for printing, the bioscaffold is obtained by 4D printing; the norbornene small molecule is 5-norbornene-2-carboxylic acid trimethylolpropane triester.

Further, the photoinitiator is 2,4,6 (trimethylbenzoyl) diphenylphosphine oxide; the solvent is chloroform; the mass fraction of the photoinitiator accounting for the total weight of each substance is 0.5wt %.

The beneficial effects of the present invention are: a preparation method of a biodegradable body temperature sensing material for 4D printing and a biodegradable body temperature sensing memory bioscaffold of the present invention, the main body is a biodegradable polymer with a hydroxyl group at the end, and the The end-capping treatment of the main body prepares multi-component biodegradable polymers with mercapto or norbornene groups at the end for 4D printing, which overcomes the disadvantage of shrinkage when acrylate monomers are photopolymerized in traditional 4D printing ; The bioscaffold of the present invention prepares a biodegradable body temperature-sensing memory bioscaffold through photocuring and printing of a multi-component biodegradable polymer with a thiol or norbornene group at the end and a thiol or norbornene small molecule; This norbornene-mercapto photocurable printing has the advantages of fast molding speed, no oxygen inhibition and no shrinkage. At the same time, compared with acrylate-based radical polymerization, the polymer network formed by norbornene-mercapto step-growth polymerization has regularity, narrow thermal transition peak width, faster shape recovery, and more accurate recovery temperature. In addition, its It can also take into account the controllable degradation rate; the biological scaffold of the present invention can undergo self-deformation such as expansion under the excitation of body temperature, and finally achieve a preset three-dimensional space configuration, so that it can be implanted into the human body without balloon expansion. The tight and stable fit between the stent and the inner wall of the blood vessel is realized through self-deformation. Because the biostent is biodegradable, it does not need to be taken out by secondary surgery, which can greatly reduce the suffering of patients.

Description of drawings

Figure 1 The printing principle diagram based on norbornene-mercapto photopolymerization 4D printing technology.

Figure 2 The H NMR spectrum of norbornene-terminated four-arm poly D,L-lactide.

Fig. 3 H NMR spectrum of mercapto-terminated four-arm poly D, L-lactide.

Fig. 4 Schematic diagram of gel formation of norbornene-terminated four-arm poly D, L-lactide and tetrakis(3-mercaptopropionate) pentaerythritol ester under 10mW/m2 ultraviolet light for 1-2s.

Fig. 5 Glass transition region diagram (narrow half-peak width) of norbornene-terminated four-arm poly D, L-lactide and tetrakis(3-mercaptopropionate) pentaerythritol ester cross-linked shape memory polymer.

Fig. 6 The shape memory properties of norbornene-terminated four-arm poly D, L-lactide and tetrakis (3-mercaptopropionate) pentaerythritol ester cross-linked shape memory polymer under different strains.

Fig. 7 The shape memory cycle performance diagram of norbornene-terminated four-arm poly D, L-lactide and tetrakis (3-mercaptopropionate) pentaerythritol ester cross-linked shape memory polymer.

Figure 8 The shape memory recovery of norbornene-terminated four-arm poly D, L-lactide and tetrakis (3-mercaptopropionate) pentaerythritol ester cross-linked shape memory recovery diagram (in hot water at glass transition temperature for 1 s to reply).

Fig. 9 Tanδ–temperature curve of hydroxyl-terminated four-arm poly D,L-lactide-co-trimethylene carbonate copolymer.

Figure 10 Melting point curve of hydroxyl terminated poly(caprolactone-co-trimethylene carbonate).

Figure 11 is a diagram of the reactivity sequence of double-bond monomers in the mercaptoene reaction.

Detailed ways

The present invention will be further explained below in conjunction with the accompanying drawings and specific embodiments.

A preparation method of a biodegradable body temperature sensing material and a biodegradable body temperature sensing memory bio-stent for 4D printing according to the present invention, including a preparation method of a biodegradable body temperature sensing material and a preparation method of a biodegradable body temperature sensing memory bio-stent a large technical solution. The specific descriptions are as follows:

A method for preparing a biodegradable body temperature sensing material, by using a biodegradable polymer terminal with a hydroxyl group (ie, a hydroxyl-terminated biodegradable polymer) as the basic main raw material to prepare a material that can be degraded at a physiological temperature and has a sulfhydryl group terminal. or norbornene-based multicomponent biodegradable polymers, that is, multicomponent biodegradable polymers terminated by mercapto or norbornene groups. The material is applied to the field of 4D printing. It is a multi-component biodegradable polymer terminated by a mercapto or norbornene group and a corresponding two-arm or multi-arm norbornene or mercapto-terminated degradable macromolecule. Next, photocatalytic norbornene-sulfhydryl click chemistry reaction occurred. The biostents prepared by this reaction, such as vascular stents, have the advantages of fast recovery of shape and structure, more accurate recovery temperature and controllable degradation rate.

In order to make the biodegradable body temperature sensing material of the present invention degrade at physiological temperature (that is, the temperature for maintaining physiological activities in the living body), the present invention first degrades the biodegradable polymer whose terminal is a hydroxyl group as the main material. Degradation improvements.

Specifically, it is guaranteed in the following two ways. One is by controlling the glass transition temperature of the main material at 20°C-40°C; the other is by controlling the melting point of the main material at 20°C-40°C.

The glass transition temperature of the present invention is mainly based on D, L-lactide or caprolactone at 20°C-40°C; L-lactide, caprolactone, glycolide, cyclic anhydride, cyclic One or more of carbonate, cyclophospholipid or p-dioxanone are used as comonomers; multi-component copolymers are obtained by copolymerization after the action of catalyst and initiator, and the composition of the product is controlled by formula (1) and Molecular weight is obtained. Specifically, examples are as follows:

Use stannous octoate as catalyst, binary or polyhydric hydroxyl compound or oligomer as initiator, D, L-lactide as the main monomer, L-lactide, caprolactone, glycolide, cyclic anhydride , cyclocarbonate, cyclophospholipid, p-dioxanone, etc., one, two, or more than three are comonomers. Add the above-mentioned required reactants, initiators and catalysts into an anhydrous and oxygen-free reaction flask, vacuumize, and pass nitrogen, and repeat three times. After the reaction system was sealed, it was reacted in an oil bath at 130°C for 24 hours. After the reaction was completed, the reaction system was cooled to room temperature, and an appropriate amount of chloroform was added to dissolve the product. The reaction mixture is slowly dropped into cold methanol for precipitation, wherein the volume of methanol is 5-10 times the volume of the chloroform solution of the reactant. After filtering, it dissolves and precipitates again, and precipitates continuously for three times to obtain the final product. Wherein, the molar dosage of the initiator accounts for 0.02mol% of the total molar weight of all monomers; the molar ratio of the initiator and the monomer is calculated according to the required molecular weight, and the molecular weight of the final synthesized macromolecule is about 400 to 2000; the main monomer The ratio of monomers and comonomers is calculated according to the FOX equation so that the glass transition temperature is around 20-40°C. For example, the calculation of the copolymerization of three monomers is as follows:

In the formula: T _g = 34-37°C, making the shape memory transition temperature close to the body temperature; T _g1 , T _g2 , and T _g3 are D, L-lactide (55-60°C), L-lactide The glass transition temperature of three segments of ester (60-65°C) and trimethylene cyclocarbonate (-15°C); W ₁ , W ₂ and W ₃ are D, L-lactide, L-lactide and the mass fractions of the three segments of trimethylene cyclocarbonate.

The main body of the present invention whose melting point is between 20°C and 40°C is D, L-lactide or caprolactone as the main monomer; L-lactide, caprolactone, glycolide, cyclic anhydride, and cyclic carbonate One or more of cyclophospholipids or p-dioxanone are used as comonomers; multi-component copolymers are obtained by copolymerization after the action of catalysts and initiators, and the molecular weight of the final synthesized body is restricted to 1000-4000 About, and control the amount of initiator to be 0.1wt% of the total weight of all monomers to realize. Specific examples are as follows:

Use stannous octoate as catalyst, binary or polyhydric hydroxyl compound or oligomer as initiator, caprolactone as main monomer, D, L-lactide, L-lactide, caprolactone, glycolide One, two or more of esters, cyclic anhydrides, cyclocarbonates, cyclophospholipids, p-dioxanone, etc. are comonomers. Add the above-mentioned required reactants, initiators and catalysts into an anhydrous and oxygen-free reaction flask, vacuumize, and pass nitrogen, and repeat three times. After the reaction system was sealed, it was reacted in an oil bath at 130°C for 24 hours. After the reaction was completed, the reaction system was cooled to room temperature, and an appropriate amount of chloroform was added to dissolve the product. The reaction mixture is slowly dropped into cold methanol for precipitation, wherein the volume of methanol is 5-10 times the volume of the chloroform solution of the reactant. After filtering, it dissolves and precipitates again, and precipitates continuously for three times to obtain the final product. Wherein, the amount of the initiator is 0.1wt% of (all) monomers; the molar ratio of the initiator and the monomer is calculated according to the required molecular weight, and the molecular weight of the final synthesized macromolecule is about 1000-4000, and the melting point is 30-40°C.

In the present invention, on the basis of the degradable improvement of the biodegradable polymer with a hydroxyl terminal, further norbornene group capping treatment and mercapto group capping treatment are carried out, so as to obtain a degradable 4D printing material. Specific examples are as follows:

Synthesis of norbornene-terminated biodegradable macromolecules Add hydroxyl-terminated biodegradable macromolecules, norbornene acyl chloride and triethylamine into a reaction flask. Wherein, the molar ratio of norbornene acid chloride, triethylamine and hydroxyl is 1.2:1.2:1, the solvent is dry dichloromethane, react at room temperature for 48h, filter after the reaction is completed, and the filtrate is precipitated three times in cold methanol, and vacuum Store at low temperature after drying.

Synthesis of mercapto-terminated biodegradable macromolecules: Take the hydroxyl-terminated degradable macromolecule and place it in a two-necked flask connected to the water separator, add thioglycolic acid with 10 times the molar amount of hydroxyl group and 1 wt% p-toluenesulfonate monohydrate Acid catalyst, then add solvent, pass nitrogen. The reactants were refluxed for 24 hours at 120-126°C. After the reaction was finished, it was cooled, and the solution was precipitated three times in methanol, dried in vacuum at room temperature, and stored in cold storage.

After the degradable 4D printing material is completed, the bioscaffold is prepared by 4D printing. The basic method of printing is to mix the biodegradable body temperature sensing material, solvent, photoinitiator and multifunctional mercapto small molecules or norbornene small molecules to adjust to a suitable printing viscosity, and then the multifunctional mercapto small molecules or Norbornene small molecules and biodegradable body temperature sensing materials are 4D printed, and under the catalysis of ultraviolet light, a norbornene-mercapto photopolymerization reaction occurs; the bioscaffold is heated above the melting point temperature or glass transition temperature and compressed along the diameter direction The size is reduced, and then the temporary shape is fixed near zero to obtain a degradable bioscaffold with body temperature sensing memory.

After the biostent is implanted into the human body, it can undergo self-deformation such as expansion under the excitation of body temperature, and finally achieve a preset three-dimensional space configuration, so that it can realize the stent through self-deformation without balloon expansion when implanted in the human body. Tight and stable fit with the inner wall of the blood vessel.

The polymer network of the bioscaffold is a cross-linked three-dimensional network, which has excellent shape memory fixation rate, recovery rate, shape memory cycle performance, high recoverable strain and degradable performance.

The printing principle of the 4D printing degradable body temperature-sensitive shape memory vascular stent of the present invention is based on the photocatalytic norbornene-mercapto click chemical reaction, which has the advantages of fast printing speed, no oxygen inhibition and no shrinkage. The shape-memory vascular stent material prepared based on this method has a fast shape recovery speed, a more accurate recovery temperature and a controllable degradation rate.

The optimized printing conditions are as follows: the printing conditions of the 4D printing are ultraviolet light intensity 30mW/cm ^-2 ; printing speed: 50mm/h, printing support size: length 40mm, outer diameter 4mm, inner diameter 2mm.

For the different biodegradable body temperature sensing materials synthesized above, the following methods can be used to perform 4D printing to make biological scaffolds.

When the biodegradable body temperature sensing material is a multi-component biodegradable polymer with a norbornene group at the end, the preparation of the bioscaffold includes the following steps: combining the biodegradable body temperature sensing material, a solvent, a photoinitiator and After the multifunctional mercapto small molecule is mixed and adjusted to a suitable printing viscosity (for example, the solid content of the solution during printing is kept at about 40%), the bioscaffold is obtained by 4D printing; the multifunctional mercapto small molecule is tetrakis(3-mercaptopropane acid) pentaerythritol ester. Preferably, the photoinitiator is 2,4,6(trimethylbenzoyl)diphenylphosphine oxide; the solvent is chloroform; and the mass fraction of the photoinitiator in the total weight of each substance is 0.5wt%.

When the biodegradable body temperature sensing material is a multi-component biodegradable polymer with a mercapto group at the end, the preparation of the bioscaffold includes the following steps: combining the biodegradable body temperature sensing material, a solvent, a photoinitiator and a norbornene small molecule After mixing and adjusting to a suitable printing viscosity, a bioscaffold is obtained by 4D printing; the norbornene small molecule is 5-norbornene-2-carboxylic acid trimethylolpropane triester. Preferably, the photoinitiator is 2,4,6(trimethylbenzoyl)diphenylphosphine oxide; the solvent is chloroform; and the mass fraction of the photoinitiator in the total weight of each substance is 0.5wt%.

Example 1

Add 0.076mmol of stannous octoate, 69.6mmol of trimethylene carbonate, 309.6mmol of D, L-lactide and 50mmol of pentaerythritol into an anhydrous and oxygen-free reaction flask, vacuumize and blow nitrogen, repeat three times. After the reaction system was sealed, it was reacted in an oil bath at 130°C for 24 hours. After the reaction was completed, the reaction system was cooled to room temperature, and an appropriate amount of chloroform was added to dissolve the product. Slowly add the reaction mixture dropwise into cold methanol for precipitation, where the volume of methanol is 5-10 times the volume of the chloroform solution of the reactant, and then dissolve and precipitate again after filtration to obtain the hydroxyl-terminated four-arm poly D,L-lactate Ester-co-trimethylene carbonate copolymer ( _Mn = 1568; _Mw = 1770; _Tg = 34 ~ 36 ° C), hydroxyl-terminated four-arm poly D, L-lactide as shown in Figure 9 Tan δ–temperature curves of -co-trimethylene carbonate copolymers.

Put hydroxyl-terminated four-arm poly D,L-lactide-co-trimethylene carbonate copolymer, norbornene acid chloride and triethylamine into a three-necked flask. Wherein, the molar ratio of norbornene acid chloride, triethylamine and hydroxyl is 1.2:1.2:1, the solvent is dry dichloromethane, react at room temperature for 48h, filter after the reaction is completed, and the filtrate is precipitated three times in cold methanol, and vacuum After drying, a norbornene-terminated four-arm poly D, L-lactide-co-trimethylene carbonate copolymer was obtained.

With chloroform as solvent, norbornene-terminated four-arm poly D,L-lactide-co-trimethylene carbonate copolymer, tetrakis(3-mercaptopropionic acid)pentaerythritol ester, 2,4,6( Trimethylbenzoyl)diphenylphosphine oxide is mixed evenly, the molar ratio of norbornene group and mercapto group is 1:1, and the mass fraction of photoinitiator is 0.5wt%. The solid content of the solution is adjusted to 40%, and the scaffold material is printed by norbornene-mercapto photocuring printing technology, and the ultraviolet light intensity is 20mW/cm ^-2 ; the size of the printed scaffold: length 40mm, outer diameter 4mm, inner diameter 2mm; printing speed : 80mm/h. The glass transition temperature of the material increased by 3°C after photocrosslinking. The printed stent is heated to 40°C, compressed in the diameter direction to reduce the size, and then the temporary shape is fixed near zero degrees to obtain a degradable body temperature-sensitive shape memory polymer vascular stent.

Example 2

Compared with Embodiment 1, this embodiment is the same except for the following differences. The only difference is that tetrakis(3-mercaptopropionate) pentaerythritol is replaced by trimethylolpropane tris(3-mercaptopropionate).

Example 3

Compared with Embodiment 1, this embodiment is the same except for the following differences. The only difference is that tetrakis(3-mercaptopropionate) pentaerythritol is replaced by tris[2-(3-mercaptopropionyloxy)ethyl isocyanurate].

Example 4

Compared with Embodiment 1, this embodiment is the same except for the following differences. The difference is: replace pentaerythritol with 1,4-butanediol to obtain linear poly-D,L-lactide-co-trimethylene carbonate copolymer. In addition, the selected polyfunctional mercapto compound has at least three mercapto groups.

Ethylene glycol, pentaerythritol, small molecule polyhydric alcohol, oligomeric two-arm polyethylene glycol, multi-arm polyethylene glycol, oligomeric two-arm polycaprolactone polyol, multi-arm polycaprolactone polyol, oligomeric Two-arm polyether polyol, three-arm polyether polyol, cyclodextrin or sugar alcohol

Example 5

Compared with Embodiment 1, this embodiment is the same except for the following differences. The difference is: 69.6mmol of trimethylene carbonate is replaced by: 90mmol of trimethylene carbonate and 10mmol of one or more of L-lactide or glycolide or cyclic anhydride or cyclophospholipid.

Example 6

Compared with Embodiment 1, this embodiment is the same except for the following differences. The difference is: replace pentaerythritol with oligomeric two-arm polyethylene glycol, oligomeric two-arm polycaprolactone polyol or oligomeric two-arm polyether polyol to obtain linear poly D,L-lactide-co- Trimethylene carbonate copolymer. In addition, the selected polyfunctional mercapto compound has at least three mercapto groups.

Example 7

Compared with Embodiment 1, this embodiment is the same except for the following differences. The difference is: replace pentaerythritol with multi-arm polyethylene glycol, multi-arm polycaprolactone polyol or three-arm polyether polyol oligomer to obtain linear poly-D,L-lactide-co-trimethylene carbonate copolymer. In addition, the selected polyfunctional mercapto compound has at least two mercapto groups.

Example 8

Compared with Embodiment 1, this embodiment is the same except for the following differences. The difference is: replace pentaerythritol with dipentaerythritol to obtain six-arm poly D, L-lactide-co-trimethylene carbonate copolymer. Small molecules with multifunctional mercapto groups can be: ethanedithiol, 1,4-butanedithiol, 1,6-hexanedithiol, tetrakis(3-mercaptopropionic acid) pentaerythritol ester, tri[2-isocyanurate (3-mercaptopropionyloxy)ethyl ester], trimethylolpropane tris(3-mercaptopropionate), etc.

Example 9

The synthesis of the hydroxyl-terminated four-arm poly D,L-lactide-co-trimethylene carbonate copolymer in this example is the same as that in Example 1.

Put the hydroxyl-terminated four-arm poly D, L-lactide-co-trimethylene carbonate copolymer in a two-necked flask connected to the water separator, add thioglycolic acid with 10 times the molar amount of hydroxyl groups and 1 wt% of the monomer mass One water p-toluenesulfonic acid catalyst, then add solvent, nitrogen. The reactants were refluxed for 24 hours at 120-126°C. After the reaction was finished, it was cooled, and the solution was precipitated three times in methanol, dried in vacuum at room temperature, and stored in cold storage.

With chloroform as solvent, mercapto-terminated four-arm poly D, L-lactide-co-trimethylene carbonate copolymer, 5-norbornene-2-carboxylic acid trimethylolpropane triester, 2 , 4,6 (trimethylbenzoyl) diphenylphosphine oxide) were mixed uniformly, the molar ratio of norbornene group and mercapto group was 1:1, and the mass fraction of photoinitiator was 0.5wt%. The solid content of the solution is adjusted to 40%, and the scaffold material is printed by norbornene-mercapto photocuring printing technology, and the ultraviolet light intensity is 30mW/cm ^-2 ; the size of the printed scaffold: length 40mm, outer diameter 4mm, inner diameter 2mm; printing speed : 50mm/h. The glass transition temperature of the material increased by 3°C after photocrosslinking. The printed stent is heated to 40°C, compressed in the diameter direction to reduce the size, and then the temporary shape is fixed near zero degrees to obtain a degradable body temperature-sensitive shape memory polymer vascular stent.

Example 10

Compared with Embodiment 9, this embodiment is the same except for the following differences. The only difference is that trimethylolpropane 5-norbornene-2-carboxylate triester is replaced by tetramethylolpropane 5-norbornene-2-carboxylate tetraester.

Example 11

Compared with Embodiment 9, this embodiment is the same except for the following differences. The only difference is: Trimethylolpropane 5-norbornene-2-carboxylate triester is replaced by 1,6-hexanediol 5-norbornene-2-carboxylate.

Example 12

Add ε-caprolactone, trimethylene carbonate, 1,6-butanediol and stannous octoate as catalysts in an anhydrous and oxygen-free reaction flask, depressurize and evacuate three times, and seal the reaction system in an oil bath at 130°C Under reaction 24h. After the reaction was completed, the reaction system was cooled to room temperature, and an appropriate amount of chloroform was added to dissolve the product. The reaction mixture is slowly dropped into cold methanol for precipitation, wherein the volume of methanol is 5-10 times the volume of the chloroform solution of the reactant. After filtration, it dissolves and precipitates again, and precipitates continuously for three times. The final product obtained is linear hydroxyl-terminated Poly(caprolactone-co-trimethylene carbonate). Wherein, the amount of the initiator is 0.1wt% of the monomer; the molar ratio of ε-caprolactone and trimethylene carbonate is 80:20; the molar ratio of the initiator and the monomer is 1:25, and the final synthesized hydroxyl-terminated Poly(caprolactone-co-trimethylene carbonate) has a melting point of 34-38°C, as shown in Figure 10.

The linear hydroxyl-terminated poly(caprolactone-co-trimethylene carbonate) copolymer of hydroxy-termination is placed in the two-necked flask connected to the water separator, and thioglycolic acid and monomer mass 1wt% of hydroxyl molar weight 10 times are added A water-based p-toluenesulfonic acid catalyst, and then add solvent, nitrogen. The reactants were refluxed for 24 hours at 120-126°C. After the reaction was finished, it was cooled, and the solution was precipitated three times in methanol, dried in vacuum at room temperature, and stored in cold storage.

In chloroform as solvent, linear thiol-terminated poly(caprolactone-co-trimethylene carbonate), 5-norbornene-2-carboxylic acid trimethylolpropane triester, 2,4,6 (Trimethylbenzoyl)diphenylphosphine oxide is mixed evenly, the molar ratio of norbornene group and mercapto group is 1:1, and the mass fraction of photoinitiator is 0.5wt%. The solid content of the solution is adjusted to 40%, and the scaffold material is printed by norbornene-mercapto photocuring printing technology, and the ultraviolet light intensity is 30mW/cm ^-2 ; the size of the printed scaffold: length 40mm, outer diameter 4mm, inner diameter 2mm; printing speed : 50mm/h. The glass transition temperature of the material increases by 3°C after photocrosslinking. The printed stent is heated to 40°C, compressed in the diameter direction to reduce the size, and then the temporary shape is fixed near zero degrees to obtain a degradable body temperature-sensitive shape memory polymer vascular stent.

Example 13

Compared with Embodiment 12, this embodiment is the same except for the following differences. The only difference is that trimethylolpropane 5-norbornene-2-carboxylate triester is replaced by tetramethylolpropane 5-norbornene-2-carboxylate tetraester.

Example 14

Compared with Embodiment 12, this embodiment is the same except for the following differences. The only difference is that trimethylolpropane 5-norbornene-2-carboxylate triester is replaced by a norbornene-terminated hyperbranched polymer.

Example 15

Compared with Embodiment 12, this embodiment is the same except for the following differences. The only difference is: Trimethylolpropane 5-norbornene-2-carboxylate triester is replaced by 1,6-hexanediol 5-norbornene-2-carboxylate.

Example 16

Compared with Embodiment 12, this embodiment is the same except for the following differences. The difference is: 1,6-hexanediol is replaced by polyethylene glycol, with a molecular weight of 500-1000; the trimethylene carbonate monomer is removed; the linear polycaprolactone that is polymerized by polyethylene glycol is prepared, and the melting point is also obtained Degradable polymer at 38-40°C.

Example 17

Compared with Embodiment 12, this embodiment is the same except for the following differences. The difference is: 1,6-hexanediol is replaced by pentaerythritol or cyclodextrin or sugar alcohol.

Example 18

Compared with Embodiment 12, this embodiment is the same except for the following differences. The difference is: 1,6-hexanediol is replaced by a hydroxyl-terminated hyperbranched polymer.

Example 19

Compared with Embodiment 12, this embodiment is the same except for the following differences. The difference is: the trimethylene carbonate is replaced by: one or more of trimethylene carbonate and L-lactide or glycolide or cyclic anhydride or cyclophospholipid.

Example 20

Compared with Embodiment 12, this embodiment is the same except for the following differences. The difference is: the trimethylene carbonate is replaced by: one or more of D, L-lactide and L-lactide or glycolide or cyclic anhydride or cyclophospholipid.

Example 21

The synthesis of linear hydroxyl-terminated poly(caprolactone-co-trimethylene carbonate) copolymer was the same as in Example 9.

Put hydroxyl-terminated linear hydroxyl-terminated poly(caprolactone-co-trimethylene carbonate) copolymer, norbornene acid chloride and triethylamine into a three-neck flask. Wherein, the molar ratio of norbornene acid chloride, triethylamine and hydroxyl is 1.2:1.2:1, the solvent is dry dichloromethane, react at room temperature for 48h, filter after the reaction is completed, and the filtrate is precipitated three times in cold methanol, and vacuum A norbornene-terminated linear poly(caprolactone-co-trimethylene carbonate) copolymer was obtained after drying.

The printing process of the copolymer is basically the same as in Example 12. The difference is that the linear thiol-terminated poly(caprolactone-co-trimethylene carbonate) and 5-norbornene-2-carboxylic acid trimethylolpropane triester were replaced by norbornene-terminated linear Poly(caprolactone-co-trimethylene carbonate) copolymer and pentaerythritol tetrakis(3-mercaptopropionate).

Example 22

Compared with Embodiment 21, this embodiment is the same except for the following differences. The only difference is that pentaerythritol tetrakis(3-mercaptopropionate) is replaced by a mercapto-terminated hyperbranched polymer.

Example 23

Compared with Embodiment 21, this embodiment is the same except for the following differences. The difference is: 1,6-hexanediol is replaced by one or more of oligomeric two-arm polyethylene glycol, multi-arm polyethylene glycol, oligomeric two-arm polyether polyol or three-arm polyether polyol species, the molecular weight is 500-1000; the trimethylene carbonate monomer is removed; the linear polycaprolactone that is polymerized by polyethylene glycol is prepared, and a degradable polymer with a melting point of 38-40 DEG C is also obtained.

Example 24

Compared with Embodiment 21, this embodiment is the same except for the following differences. The difference is: 1,6-hexanediol is replaced by pentaerythritol.

Example 25

Compared with Embodiment 21, this embodiment is the same except for the following differences. The difference is: 1,6-hexanediol is replaced by a hydroxyl-terminated hyperbranched polymer.

The present invention is not limited to the above optional embodiments, and anyone can obtain other various forms of products under the enlightenment of the present invention. The above specific implementation manners should not be understood as limiting the protection scope of the present invention, and the above descriptions are only preferred examples of the present invention, and are not intended to limit the present invention. Without violating the principle of the present invention, the present invention can carry out various changes and changes, and any modification, equivalent replacement, modification, etc. made to the present invention should be included in the protection scope of the present invention.

Claims (21)

1. a kind of preparation method of the biodegradable body temperature inductive material for 4D printing, it is characterised in that: comprising steps of with Based on the Biodegradable high-molecular that physiological temp lower end is hydroxyl, by the processing of body ends sealing endization, preparation The multicomponent biodegradable macromolecule that the degradable, end under physiological temp is sulfydryl or norbornene is obtained, is made Biodegradable body temperature inductive material for 4D printing uses.

2. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 1, Be characterized in that: the glass transition temperature or melting temperature of the main body are 20 DEG C -40 DEG C.

3. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 2, Be characterized in that: the preparation method of the main body includes: with D, and L- lactide or caprolactone are main monomer；L- lactide, caprolactone, One of glycolide, cyclic acid anhydride, cyclic carbonate ester, cyclic phosphorus or Lanthanum Isopropoxide are a variety of as comonomer；Through being catalyzed Copolymerization obtains multicomponent copolymer after agent, initiator effect.

4. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 3, Be characterized in that: the initiator is dihydroxylic compound, multi-hydroxy compound or oligomer.

5. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 3, Be characterized in that: the initiator is ethylene glycol, pentaerythrite, small molecule polyhydroxy-alcohol, oligomeric two arms polyethylene glycol, the poly- second of multi-arm Glycol, oligomeric two arms polycaprolactone polyol, multi-arm polycaprolactone polyol, oligomeric two arms polyether polyol, three arm polyethers are more First alcohol, cyclodextrin or sugar alcohol.

6. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 3, Be characterized in that: the catalyst is stannous octoate.

7. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 6, Be characterized in that: when the main body that preparation glass transition temperature is 20 DEG C -40 DEG C, the main monomer of use and the mass fraction of comonomer are pressed It is determined according to formula (1):

T_gBased on glass transition temperature；T_g1、T_g2…T_gnThe segment glass transition temperature of respectively each monomer for participating in reaction；n For the positive integer more than or equal to 2；W₁、W₂…W_nRespectively each monomer for participating in reaction accounts for the mass fraction of all monomers.

8. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 7, Be characterized in that: when the main body that preparation glass transition temperature is 20 DEG C -40 DEG C, the mole of initiator accounts for all monomer integral molar quantities 0.02mol%.

9. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 8, Be characterized in that: the molecular weight for the main body that the glass transition temperature is 20 DEG C -40 DEG C is 400-2000.

10. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 6, Be characterized in that: when preparing the main body that fusing point is 20 DEG C -40 DEG C, the molar ratio of initiator and each monomer is 20 according to the fusing point The molecular weight of DEG C -40 DEG C of main body determines.

11. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 10, It is characterized by: initiator amount is the 0.1wt% of the gross weight of all monomers when preparing the main body that fusing point is 30 DEG C -40 DEG C；It is main The molecular weight of body is 1000-4000.

12. a kind of biodegradable body temperature inductive material for 4D printing described in -11 any one according to claim 1 Preparation method, which is characterized in that the body ends sealing endization processing is norbornene termination process, the norbornene Termination process is comprising steps of it is drop ice that main body, norbornene acyl chlorides and triethylamine solvent, which are mixed reaction end is prepared, The multicomponent biodegradable macromolecule of piece alkenyl.

13. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 12, It is characterized in that, the solvent is methylene chloride；The molar ratio of the norbornene acyl chlorides, triethylamine and main body hydroxyl is 1.2: 1.2:1；Reaction time is 48h；Reaction temperature is room temperature.

14. a kind of biodegradable body temperature inductive material for 4D printing described in -11 any one according to claim 1 Preparation method, which is characterized in that the body ends sealing endization processing is sulfydryl termination process, and the sulfydryl termination process includes Step: by main body, thioacetic acid, catalysts and solvents, back flow reaction obtains the multicomponent biological that end is sulfydryl under nitrogen atmosphere Degradable macromolecule.

15. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 14, It is characterized in that, the hydroxyl of the main body and the molar ratio of thioacetic acid are 1:10 in the body ends sealing endization processing.

16. a kind of preparation method of biodegradable body temperature inductive material for 4D printing according to claim 15, It is characterized in that, catalyst is a water p-methyl benzenesulfonic acid in the body ends sealing endization processing；One water p-methyl benzenesulfonic acid accounts for list The mass fraction of weight is 1wt%；The temperature of the reaction is 120 DEG C -126 DEG C, and the reaction time is for 24 hours.

17. a kind of print degradable body using biodegradable body temperature inductive material 4D described in claim 1-16 any one Warming should remember the preparation method of biological support, which is characterized in that comprising steps of the biodegradable body temperature is incuded material After material, solvent, photoinitiator and polyfunctional group sulfydryl small molecule or the mixing of norbornene small molecule are adjusted to suitable printing viscosity, The polyfunctional group sulfydryl small molecule or norbornene small molecule and biodegradable body temperature inductive material are printed by 4D to be occurred Biological support is obtained after norbornene-sulfydryl photopolymerization reaction；By biological support be heated to melting temperature or glass transition temperature with Compressing above and diametrically reduces size, then fixes temporary shapes near zero to get the induction of degradable body temperature is arrived Remember biological support.

18. biodegradable body temperature inductive material 4D according to claim 17 prints degradable body temperature induction memory biology The preparation method of bracket, which is characterized in that the biological support is intravascular stent, and the print conditions of the 4D printing are ultraviolet light Intensity 30mW/cm^-2；Print speed: 50mm/h, print carriage size: length 40mm, outer diameter 4mm, internal diameter 2mm.

19. biodegradable body temperature inductive material 4D according to claim 17 prints degradable body temperature induction memory biology The preparation method of bracket, which is characterized in that the biodegradable body temperature inductive material is the multiple groups that end is norbornene Decomposing biological degradable macromolecule；The preparation of the biological support includes the following steps: the biodegradable body temperature incuding material After material, solvent, photoinitiator and the mixing of polyfunctional group sulfydryl small molecule are adjusted to suitable printing viscosity, are printed and given birth to by 4D Object bracket；The polyfunctional group sulfydryl small molecule is four (3- mercaptopropionic acid) pentaerythritol esters.

20. biodegradable body temperature inductive material 4D according to claim 17 prints degradable body temperature induction memory biology The preparation method of bracket, which is characterized in that the biodegradable body temperature inductive material is the multicomponent biological that end is sulfydryl Degradable macromolecule；The preparation of the biological support includes the following steps: the biodegradable body temperature inductive material, molten After agent, photoinitiator and the mixing of norbornene small molecule are adjusted to suitable printing viscosity, print to obtain biological support by 4D；Institute Stating norbornene small molecule is 5- norbornene -2- carboxylic acid trimethylolpropane triester.

21. biodegradable body temperature inductive material 4D described in 7-20 any one prints degradable body temperature according to claim 1 The preparation method of induction memory biological support, which is characterized in that the photoinitiator is 2,4,6 (trimethylbenzoyl) hexichol Base phosphine oxide；The solvent is chloroform；The mass fraction that photoinitiator accounts for each substance gross weight is 0.5wt%.