CN1433818A - Polyhydroxyalkanoates (PHA) blood vessel support and making method thereof - Google Patents

Abstract

A polyhydroxyalkanoate vascular stent and a preparation method thereof belong to the field of biomedical engineering. The vascular stent provided by the present invention is composed of a porous inner membrane, a solid adventitia and a reinforcing rib, and the reinforcing rib is wound on the surface of the solid adventitia in a band shape; the porous inner membrane, the solid adventitia and the reinforcing rib are made of polyhydroxybutyric acid One of esters, polyhydroxybutyrate-valerate or polyhydroxybutyrate-caproate or their blends and polyethylene glycol/polybutylene terephthalate copolymer blends Prepared. In addition to good biocompatibility, anticoagulant property, cell adhesion and proper degradation speed, the vascular stent greatly improves the mechanical strength and suturing strength of the vascular stent.

Description

A kind of polyhydroxyalkanoate vascular stent and preparation method thereof

technical field

The invention relates to a blood vessel stent made by blending polyhydroxyalkanoate and polyethylene glycol/polybutylene terephthalate copolymer and a preparation method thereof, belonging to the technical field of biomedical engineering.

Background technique:

At present, the main medical method for diseased blood vessels with a diameter of no more than 6mm is to use autologous blood vessels as a detour bypass to replace diseased blood vessels, but because many patients do not have appropriate and sufficient blood vessels for detour bypasses, synthetic materials are used to prepare blood vessels. Bracket ideas. The basic idea of using a blood vessel made of synthetic material as a detour is to adsorb tissue cells on a scaffold material with good biocompatibility that can be gradually degraded and absorbed in the human body, and provide nutrients to the cells to expand them. While the scaffold material is gradually degraded and absorbed by the human body, the cells continue to proliferate and secrete the matrix, and finally form new blood vessels with corresponding original functions and shapes to achieve the purpose of repairing and reconstructing functions. At present, the vascular stent materials used are mainly polymer materials, which are divided into bionon-degradable polymer materials and biodegradable polymer materials. The materials used to make blood vessels in the early days usually use non-degradable polymer materials, such as polytetrafluoroethylene (PTFE), polyvinylchliride (PVC), polyethylene (polyethylene, PE), polyester fiber (Dacron), etc. After the artificial blood vessels made of materials are directly implanted in the body, a series of adverse reactions will occur, such as the formation of thrombus and blockage of blood vessels. Biodegradable polymeric materials are gradually developed with the development of the new field of tissue engineering. Biodegradable polymer materials usually include polyglycolic acid (polyglycolic acid, PGA), polyhydroxyoctanoate (polyhydroxyoctanoate, PHO), polylactic acid (polylactic acid, PLA), or a copolymer of PLA and PGA (polylactic-glycolic acid, PLGA) . The blood vessels constructed by such materials have poor affinity with cells, and the degradation rate cannot match the tissue regeneration rate. Although the biocompatibility, cell adhesion and degradation speed of blood vessels prepared by the new biodegradable material polyhydroxyalkanoate (PHA) have been significantly improved compared with traditional materials, the mechanical properties and suture Performance still needs to be improved.

For the non-degradable polymeric materials mentioned above, the traditional method is to weave the material into a sheet, then cut it into a suitable size as needed, and sew the sheet into a tube with sutures. How to prepare degradable polymer materials into vascular stents with good mechanical properties and suturing properties remains to be further studied.

Contents of the invention

The object of the present invention is to provide a kind of vascular stent prepared by the blend of polyhydroxyalkanoate and polyethylene glycol/polybutylene terephthalate copolymer and preparation method thereof, to further improve polyhydroxyalkanoate Mechanical strength and suturing performance of vascular stents prepared from acid esters.

The purpose of the present invention is achieved through the following technical solutions:

A polyhydroxyalkanoate vascular stent is characterized in that: the vascular stent is composed of a porous intima, a solid adventitia and a reinforcing rib, and the reinforcing rib is wound on the surface of the solid adventitia in a band shape; the porous intima, solid The outer membrane and reinforcing ribs are prepared from a blend of polyhydroxyalkanoate and polyethylene glycol/polybutylene terephthalate copolymer.

The polyhydroxyalkanoate is one of polyhydroxybutyrate (PHB), polyhydroxybutyrate-valerate (PHB-HV), polyhydroxybutyrate-hexanoate (PHB-HH) or their blends.

A method for preparing a polyhydroxyalkanoate stent, characterized in that the method comprises the steps:

(1) Preparation of blend solid film:

①Mix 30-80% of polyhydroxyalkanoate and 20-70% of polyethylene glycol/polybutylene terephthalate copolymer, use chloroform as solvent, heat in water bath, and prepare a concentration of 0.03g /ml～0.1g/ml homogeneous solution;

②Adopt the method of cast film formation, cool the solution in step ① and pour it into a pair of petri dishes, fasten the upper and lower petri dishes, let the chloroform volatilize naturally, dry in vacuum, and make a solid film;

(2) Preparation of blend porous membrane

① Pass the salt through a standard sieve to select NaCl particles with a diameter within the range of 50-300 μm;

②Mix 30-80% of polyhydroxyalkanoate and 20-70% of polyethylene glycol/polybutylene terephthalate copolymer, use chloroform as solvent, heat in water bath, and prepare a concentration of 0.03g /ml～0.1g/ml homogeneous solution;

③ Add NaCl particles to the solution in ②, where NaCl is 10 to 20 times the total mass of polyhydroxyalkanoate and polyethylene glycol/polybutylene terephthalate copolymer, then heat and stir to make a suspension liquid;

④Using the method of tape casting to form a film, cool the suspension prepared in ③ and pour it into a pair of petri dishes, and fasten the upper and lower petri dishes to make the chloroform volatilize naturally;

⑤ Take out the sample in ④, immerse it in deionized water, change the water regularly, take out the porous membrane after a period of time, first dry it in the room, then vacuum dry it, and set it aside;

(3) Preparation of blend reinforcement

① Cut the solid film prepared in (1) into strips with a width ranging from 1 to 3 mm;

②Heat the strip-shaped solid film evenly at a temperature lower than the melting point, stack 2 to 3 layers and glue them together with chloroform to make a reinforcing rib;

(4) Preparation of stent

① Cut the solid film, porous film and reinforcing ribs prepared in (1), (2) and (3) into appropriate sizes according to actual needs; then lay the solid film and porous film flat, heat evenly, and press lightly Bonding to make a double-layer composite film;

② Roll up the obtained composite membrane, and use chloroform as an adhesive to thermally bond the seams to obtain a tubular object with a composite inner and outer membrane; then wind the reinforcing ribs on the tubular object to obtain a complete vascular stent.

The vascular stent provided by the present invention has the following advantages: the present invention adopts polyhydroxyalkanoate and polyethylene glycol/butylene terephthalate with good biocompatibility, good biodegradability and good mechanical properties The blood vessels constructed by blending glycol ester copolymers not only have obvious improvements in biocompatibility, cell adhesion and degradation speed compared with traditional materials, but also solve the problems of similar materials in terms of mechanical properties. Insufficient, its elongation at break and tensile strength have been greatly improved.

Description of drawings

Fig. 1 is a schematic structural diagram of a vascular stent provided by the present invention.

In the figure: the outer gray is the outer solid membrane 1; the inner black is the inner porous membrane 2; the dark gray is the rib 3.

Detailed ways

Fig. 1 is a schematic structural diagram of a vascular stent provided by the present invention. The vascular stent is composed of a solid adventitia 1, a porous inner membrane 2 and a reinforcing rib 3, and the reinforcing rib 3 is wound on the surface of the solid adventitia 1 in a band shape; the porous inner membrane 2, the solid adventitia 1 and the reinforcing rib 3 It is prepared from a blend of polyhydroxyalkanoate and polyethylene glycol/polybutylene terephthalate copolymer.

The polyhydroxyalkanoate described in the present invention comprises polyhydroxybutyrate (PHB), polyhydroxybutyrate-valerate (PHB-HV), polyhydroxybutyrate-hexanoate (PHB-HH) and its blends.

The mass ratio of PEG to PBT in polyethylene glycol/polybutylene terephthalate copolymer (PEG-CO-PBT) is 7:3.

The molecular weight of polyhydroxyalkanoate is between 300,000 and 800,000.

The following examples further illustrate the preparation method of the present invention.

Example 1:

80% polyhydroxybutyrate-valerate (PHB-HV) and 20% polyethylene glycol/polybutylene terephthalate (PEG-CO-PBT) copolymer blended to prepare a diameter of 8mm, a length of 50mm vascular stent.

(1) Preparation of blend solid film

① Mix 80% polyhydroxybutyrate-valerate (PHB-HV) with 20% polyethylene glycol/polybutylene terephthalate (PEG-CO-PBT) and chloroform, heat in a water bath and fully Stir to prepare a solution with a uniform concentration of 0.05g/ml;

②Using the method of cast film formation, cool the solution prepared in ① and pour it into a pair of petri dishes with a diameter of 10cm (the diameter is adjustable, the same below), and fasten the upper and lower evaporating dishes to let the chloroform volatilize naturally. Prepare a solid film, and control the amount of raw materials so that the film thickness is 1 to 2 mm;

(2) Preparation of blend porous membrane

① Pass the salt through a standard sieve, select NaCl particles with a diameter of 50-300 μm,

② Mix 80% polyhydroxybutyrate-valerate (PHB-HV) with 20% polyethylene glycol/polybutylene terephthalate (PEG-CO-PBT) and chloroform, heat in a water bath and fully Stir to prepare a solution with a uniform concentration of 0.05g/ml;

③ Add NaCl particles 10 times the total mass of the blend to the above solution, then heat and stir to make a suspension;

④Using the method of cast film formation, cool the solution prepared in ③ and pour it into a pair of petri dishes (10cm in diameter), fasten the upper and lower petri dishes together, let the chloroform volatilize naturally, control the amount of raw materials so that the film thickness is 1 to 2 mm;

⑤ Take out the sample in ④, immerse it in deionized water, change the water every 8 hours, take out the porous sheet after soaking for 3 days, and dry it indoors first to make a porous membrane;

(3) Preparation of blend reinforcement

① Cut the solid film prepared in (1) into strips with a width ranging from 3 to 5 mm;

②Heat the strip-shaped solid film evenly at a temperature lower than the melting point, stack 2 to 3 layers and glue them together with chloroform to make a reinforcing rib;

(4) Preparation of stent

① Cut the spare solid membrane and porous membrane in (1) and (2) into a size with a width of 25mm and a length of 50mm;

② Lay the solid membrane obtained in ① flat, heat it evenly, spread the porous membrane on it, use a small amount of chloroform as an adhesive, and press it into a composite membrane;

③Roll up the composite film with a circular paper tube with a diameter of 8mm, and thermally bond the joints with chloroform as an adhesive to obtain a tubular material;

④Wrap the reinforcing rib in (3) on the tubular material obtained in ③, thus obtaining a complete vascular stent.

Example 2:

A vascular stent with a diameter of 3 mm and a length of 10 mm was prepared using 70% polyhydroxybutyrate (PHB) and 30% polyethylene glycol/polybutylene terephthalate (PEG-CO-PBT).

(1) Preparation of blend solid film

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT solid film in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PEG-CO-PBT, wherein PHB accounts for 70%, PEG-CO-PBT accounts for 30%, the solution concentration is 0.03g/ml, and the diameter of the petri dish is adjusted to 6cm;

(2) Preparation of blend porous membrane

The preparation method is the same as the method for preparing the PHB-HV/PE-CO-PBT porous membrane in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PEG-CO-PBT, wherein PHB accounts for 70%, PEG-CO-PBT accounted for 30%, the added NaCl was 15 times the total mass of the blend, and the particle size of NaCl was adjusted to 200-300 μm; the diameter of the petri dish was adjusted to 6cm,

(3) Preparation of ribs

The preparation method is the same as the method for preparing PHB-HV/PEG-CO-PBT reinforcing ribs in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PEG-CO-PBT;

(4) Vascular stent

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT vascular stent in Example 1, except that the PHB-HV/PEG-CO-PBT is replaced by PHB/PEG-CO-PBT, and the film is cut to a width of 10mm , 10mm in length, roll up the double-layer film with a round paper tube with a diameter of 3mm.

Example 3:

Using 60% polyhydroxybutyrate-hexanoate (PHB-HH) and 40% polyethylene glycol/polybutylene terephthalate (PEG-CO-PBT) blend to prepare 100mm vascular stent.

(1) Blend solid film preparation

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT solid film in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB-HH/PEG-CO-PBT, wherein PEG-CO -PBT accounts for 40% of the total mass, the solution concentration is 0.06g/ml, and the diameter of the petri dish is changed to 19cm;

(2) Preparation of blend porous membrane

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT porous membrane in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB-HH/PEG-CO-PBT, wherein PEG-CO - PBT accounts for 40% of the total mass, the added NaCl is 20 times the total mass of the blend, and the particle size of NaCl is changed to 200-300 μm;

(3) Preparation of blend reinforcement

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT reinforcing rib in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB-HH/PEG-CO-PBT;

(4) Preparation of blend vascular stent

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT vascular stent in Example 1, except that the PHB-HV/PEG-CO-PBT is replaced by PHB-HH/PEG-CO-PBT, and the film is cut into For a size of 38 mm in width and 100 mm in length, the double-layer film is rolled up with a circular paper tube with a diameter of 12 mm.

Example 4:

A blend of 50% polyhydroxybutyrate (PHB)/polyhydroxybutyrate-valerate (PHB-HV) and 50% polyethylene glycol/polybutylene terephthalate (PEG- CO-PBT) copolymer to prepare a vascular stent with a diameter of 3 mm and a length of 10 mm.

(1) Preparation of blend solid film:

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT solid film in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PEG-CO-PBT, wherein PEG - CO-PBT accounts for 50% of the total mass, the solution concentration is 0.05g/ml, and the diameter of the evaporating dish is adjusted to 6cm;

(2) Preparation of blend porous membrane

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT porous membrane in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PEG-CO-PBT, wherein PEG -CO-PBT accounts for 50% of the total mass, adding NaCl is 15 times the total mass of the blend, and adjusting the diameter of the evaporating dish to 6cm;

(3) Preparation of blend reinforcement

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT reinforcing rib in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PEG-CO-PBT;

(4) Preparation of stent

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT vascular stent in Example 1, except that the PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PEG-CO-PBT, and the membrane Cut into strips with a width of 10mm and a length of 10mm, and roll up the double-layer film with a circular paper tube with a diameter of 3mm.

Example 5:

Using 40% polyhydroxybutyrate (PHB)/polyhydroxybutyrate-hexanoate (PHB-HH) blend with 60% polyethylene glycol/polybutylene terephthalate (PEG-CO-PBT) ) copolymer (PEG-CO-PBT) to prepare a vascular stent with a diameter of 8mm and a length of 50mm

(1) Blend solid film preparation

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT solid film in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HH/PEG-CO-PBT, wherein PEG - 60% of the total mass of CO-PBT, the solution concentration is 0.1g/ml, and the diameter of the evaporating dish is adjusted to 10cm;

(2) Preparation of blend porous membrane

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT porous membrane in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HH/PEG-CO-PBT, wherein PEG -CO-PBT accounts for 60% of the total mass, adding NaCl is 18 times the total mass of the blend, and adjusting the diameter of the evaporating dish to 10cm;

(3) Preparation of blend reinforcement

The preparation method is the same as the method for preparing PHB-HV/PEG-CO-PBT reinforcing ribs in the examples, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HH/PEG-CO-PBT;

(4) Preparation of blend stent

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT vascular stent in Example 1, except that the PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HH/PEG-CO-PBT, and the membrane Cut into strips with a width of 25mm and a length of 50mm, and roll up the double-layer film with a circular paper tube with a diameter of 8mm.

Embodiment 6:

Using 30% polyhydroxybutyrate-valerate (PHB-HV)/polyhydroxybutyrate-hexanoate (PHB-HH) blend with 70% polyethylene glycol/polybutylene terephthalate ( PEG-CO-PBT) copolymer preparation diameter is 10mm, the vascular stent that length is 50mm

(1) Blend solid film preparation

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT solid film in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB-HV/PHB-HH/PEG-CO-PBT, Among them, PEG-CO-PBT accounts for 70% of the total mass, the solution concentration is 0.08g/ml, and the diameter of the evaporating dish is adjusted to 12cm;

(2) Preparation of blend porous membrane

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT porous membrane in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB-HV/PHB-HH/PEG-CO-PBT, Wherein PEG-CO-PBT accounts for 70% of the total mass, adding NaCl is 10 times of the total mass of the blend, and the diameter of the evaporating dish is adjusted to 12cm;

(3) Preparation of blend reinforcement

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT reinforcing rib in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB-HV/PHB-HH/PEG-CO-PBT;

(4) Vascular stent

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT vascular stent in Example 1, except that the PHB-HV/PEG-CO-PBT is replaced by PHB-HV/PHB-HH/PEG-CO-PBT, Cut the film into strips with a width of 32 mm and a length of 50 mm, and roll up the double-layer film with a circular paper tube with a diameter of 10 mm.

Example 7

Using 70% polyhydroxybutyrate (PHB)/polyhydroxybutyrate-valerate (PHB-HV)/polyhydroxybutyrate-hexanoate (PHB-HH) blend with 30% polyethylene glycol/ Polybutylene terephthalate (PEG-CO-PBT) copolymer was used to prepare vascular stents with a diameter of 10 mm and a length of 80 mm.

(1) Blend solid film preparation

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT solid film in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PHB-HH/PEG-CO- PBT, wherein PEG-CO-PBT accounts for 30% of the total weight, the solution concentration is 0.03g/ml, and the diameter of the evaporating dish is adjusted to 12cm;

(2) Preparation of blend porous membrane

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT porous membrane in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PHB-HH/PEG-CO- PBT, wherein PEG-CO-PBT accounts for 30% of the total weight, adding NaCl is 15 times of the total mass of the blend, and the diameter of the evaporating dish is adjusted to 12cm;

(3) Preparation of blend reinforcement

The preparation method is the same as the method for preparing PHB-HV/PEG-CO-PBT reinforcing ribs in Example 1, except that PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PHB-HH/PEG-CO- PBT;

(4) Preparation of stent

The preparation method is the same as the method for preparing the PHB-HV/PEG-CO-PBT vascular stent in Example 1, except that the PHB-HV/PEG-CO-PBT is replaced by PHB/PHB-HV/PHB-HH/PEG-CO- For PBT, cut the film into strips with a width of 32 mm and a length of 80 mm, and roll up the double-layer film with a circular paper tube with a diameter of 10 mm.

Claims (4)

1. polyhydroxyalkanoate intravascular stent, it is characterized in that: this intravascular stent is made of porous inner membrance, solid adventitia and reinforcement, and reinforcement is wrapped in solid adventitia top layer with band shape; Described porous inner membrance, solid adventitia and reinforcement are that the blend by polyhydroxyalkanoate and Polyethylene Glycol/polybutylene terephthalate (PBT) copolymer is prepared from.

2. according to the described intravascular stent of claim 1, it is characterized in that: described polyhydroxyalkanoate is a kind of in poly butyric ester, poly butyric-valerate, the poly butyric-alkyl caproate or their blend.

3. according to the described intravascular stent of claim 1, it is characterized in that: 1～2 millimeter of the thickness of described porous inner membrance and solid adventitia; The thickness of described reinforcement is 2～4 millimeters, and its width is 3～5 millimeters.

4. one kind prepares the method for intravascular stent as claimed in claim 1 or 2, it is characterized in that this method comprises the steps:

(1) preparation of blend solid membrane:

1. 30～80% polyhydroxyalkanoate, Polyethylene Glycol/polybutylene terephthalate (PBT) of 20～70% is copolymer blended, be solvent with the chloroform, heating in water bath is mixed with the uniform solution that concentration is 0.03g/ml～0.1g/ml;

2. adopt the method for casting film-forming, will pour in the secondary culture dish after the solution cooling of step in 1., culture dish fastening up and down, chloroform is volatilized naturally, vacuum drying makes solid membrane;

(2) preparation of blend perforated membrane

1. Sal is crossed standard screen, choose the NaCl particle of diameter in the 50-300 mu m range;

2. Polyethylene Glycol/the polybutylene terephthalate (PBT) of 30～80% polyhydroxyalkanoate and 20～70% is copolymer blended, be solvent with the chloroform, heating in water bath is mixed with the uniform solution that concentration is 0.03g/ml～0.1g/ml;

3. add the NaCl particle in 2. solution, wherein NaCl accounts for polyhydroxyalkanoate and Polyethylene Glycol/polybutylene terephthalate (PBT) gross mass 10～20 times, heats then, stirs, and makes suspension;

4. adopt the method for casting film-forming, pour in the secondary culture dish after the prepared suspension liquid cooling in will be 3.,, chloroform is volatilized naturally culture dish fastening up and down;

5. sample in taking out 4. immerses it in deionized water, regularly changes water, takes out perforated membrane after a period of time, and earlier in indoor seasoning, vacuum drying is stand-by then;

(3) preparation of blend reinforcement

1. the solid membrane that makes in (1) being cut into width range is 3～5mm strip;

2. the strip solid membrane is being lower than even heating under the temperature of fusing point, is stackedly putting and be bonded together 2～3, making reinforcement with chloroform;

(4) preparation of intravascular stent

1. according to actual needs the solid membrane, perforated membrane and the reinforcement that make in (1), (2), (3) are cut out and become suitable dimensions; Then solid membrane and perforated membrane are kept flat, behind the even heating, gently press the bonding double-layered compound film of making;

2. the composite membrane that obtains is rolled, seam crossing is done the binding agent heat bonding with chloroform, the compound tube of adventitia in obtaining; Again reinforcement is wrapped on the tube, can obtains complete intravascular stent.