WO2020062976A1 - 一种具有生物活性的可降解手术缝线及其制备方法 - Google Patents

一种具有生物活性的可降解手术缝线及其制备方法 Download PDF

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WO2020062976A1
WO2020062976A1 PCT/CN2019/093160 CN2019093160W WO2020062976A1 WO 2020062976 A1 WO2020062976 A1 WO 2020062976A1 CN 2019093160 W CN2019093160 W CN 2019093160W WO 2020062976 A1 WO2020062976 A1 WO 2020062976A1
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surgical suture
collagen
growth factor
solution
receiver
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PCT/CN2019/093160
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English (en)
French (fr)
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李校堃
吴疆
肖健
张宏宇
何华成
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温州医科大学
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Priority to AU2019210543A priority Critical patent/AU2019210543B1/en
Publication of WO2020062976A1 publication Critical patent/WO2020062976A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A61L17/12—Homopolymers or copolymers of glycolic acid or lactic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/005—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters containing a biologically active substance, e.g. a medicament or a biocide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A61L17/105—Polyesters not covered by A61L17/12
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors

Definitions

  • the invention belongs to the field of biomedical materials, and particularly relates to a biodegradable surgical suture and a preparation method thereof.
  • Non-degradable sutures include silk, polypropylene, polyethylene, etc. Although their mechanical properties are strong, their non-degradability often leads to disassembly after surgery. The pain of the thread even needs surgical removal; the degradable thread mainly includes sheep gut thread, chemical synthetic thread and pure natural collagen, which can be degraded and metabolized in the body, non-toxic and harmless, reducing unnecessary trouble and pain.
  • the sheep gut line in the degradable thread (specifically as described in Chinese invention patent CN1363397A) has different degrees of rejection to the human body, which easily causes postoperative rejection reactions in patients, and the suture tensile strength is low, which is Various postoperative adverse reactions have appeared; and fibers for surgical sutures, hernias, and body wall repair meshes and anti-adhesive membranes, as described in Chinese invention patent CN201543004U, which include a polypropylene core layer, a polyimide
  • the fluoroethylene cortex, the core layer and the cortex have concentric structures, and composite fibers are formed by composite spinning.
  • This chemical synthetic suture still has different levels of chemical residues after implantation, which easily causes subcutaneous induration of the body, and some patients have subcutaneous after surgery. Itching and other problems. At present, the more perfect is a pure natural collagen suture, which takes the tendon of the animal.
  • the above-mentioned degradable thread only serves to suture wounds after surgery. Sutured wounds heal slowly and are easily contaminated by bacteria in the surrounding environment. They are manifested as purulent secretions at the incision or exudation. Treatment with injection or oral antibiotics has a greater adverse effect on the human body.
  • the present inventors conducted intensive research, and found that: a biocompatible, degradable material was used as a matrix, and then collagen containing a bioactive substance was added, and electrospinning technology was used to set specific The parameters can be used to prepare a degradable surgical suture that can be absorbed and degraded, and has high biocompatibility and safety, thereby completing the present invention.
  • the present invention aims to provide the following aspects:
  • the present invention provides a bioactive degradable surgical suture, wherein the surgical suture is made of raw materials including the following weight ratios:
  • the load is 220 to 240 parts by weight.
  • the present invention provides a method for preparing a bioactive degradable surgical suture, wherein the method includes the following steps:
  • Step 1 preparing a solution of the load
  • Step 2 Add the matrix to the load solution and stir well to obtain a polymer solution
  • step 3 a polymer solution is prepared to obtain a surgical suture.
  • the biodegradable surgical suture provided by the present invention has strong mechanical properties, high biocompatibility, and high safety;
  • the surgical suture provided by the present invention can release growth factors at the suture site, can reduce wound infection, promote granulation tissue proliferation and collagen production, and effectively shorten the recovery time;
  • the surgical suture provided by the present invention has a small diameter and good uniformity
  • the method for preparing a surgical suture provided by the present invention has simple steps, easy-to-control conditions, strong versatility, and is suitable for large-scale production.
  • FIG. 1 is a schematic diagram of collagen and growth factors in a surgical suture according to the present invention
  • Fig. 2 shows the effect after suture using the surgical suture prepared in Example 1; 2a shows the effect on day 0 after suture; 2b shows the effect on day 13 after suture; Fig. 3 shows the use of comparative examples 7
  • the invention provides a biodegradable surgical suture, which is made of raw materials including the following weight ratios:
  • the load is 220 to 240 parts by weight.
  • the surgical suture is made of raw materials including the following weight ratios:
  • the load is 220 to 230 parts by weight.
  • the surgical suture is made of raw materials including the following weight ratios:
  • the load is 220 to 225 parts by weight.
  • the matrix is a degradable polymer material, preferably polylactic acid, polyvinyl alcohol, polycaprolactone, polyglycolide, polyparadioxane or polyethylene.
  • a degradable polymer material preferably polylactic acid, polyvinyl alcohol, polycaprolactone, polyglycolide, polyparadioxane or polyethylene.
  • lactide One or more of lactide.
  • the matrix is one or more of polylactic acid, polycaprolactone, polyglycolide, or polyparadioxohexanone.
  • the matrix is polycaprolactone.
  • polycaprolactone has good mechanical properties and good biocompatibility, is suitable for suture of internal organs, and can be completely degraded into CO 2 and H 2 O within 6-12 months
  • the degradation products can be excreted with the normal metabolism of the matrix, and will not accumulate in the body.
  • the accumulation of degradation products easily causes organ clogging and endangers the health of the body.
  • the use of the polycaprolactone in the present invention as a suture matrix material can effectively avoid such hazards.
  • the load includes collagen and a bioactive substance.
  • collagen is a class of macromolecular proteins commonly found in animals. Its content in mammals accounts for 25% of the total organism's total protein content. It is an extracellular matrix with good cell adhesion. Has a greater affinity for protein molecules on the skin surface, which is beneficial to tissue growth and repair. Adding collagen to surgical sutures can further increase the cell compatibility of sutures, promote tissue proliferation and repair, and biodegradation safety High sex.
  • the biologically active substance is a peptide, preferably a growth factor.
  • Growth factors are a class of polypeptides that regulate multiple effects such as cell growth and other cell functions by binding to specific, high-affinity cell membrane receptors. Growth factor, as an important extracellular signal, can help wound healing, and at the same time promote the growth of granulation tissue and collagen production, reducing the risk of late infection in patients.
  • the growth factor is a basic fibroblast growth factor or an epidermal growth factor.
  • fibroblast growth factor is an important mitogenic factor and an inducer of morphogenesis and differentiation. Its main biological functions are: promoting the formation of granulation tissue and wound healing; promoting microvascular formation and Improve microcirculation and participate in the whole process of neovascularization; promote the proliferation of osteoblasts, inhibit the formation of osteoclasts, and promote bone formation.
  • Epidermal growth factor is a heat-resistant single peptide chain and a strong mitogen. It can stimulate the proliferation and differentiation of cultured cells and cells in living animals, and can promote wound healing.
  • collagen and bioactive substances growth factors such as basic fibroblast growth factor
  • adding collagen and bioactive substances to the matrix to prepare a surgical suture will not change the mechanical properties of the matrix, and the matrix and collagen will not affect the growth.
  • Factor protein structure has an impact.
  • an outer diameter of the degradable surgical suture is 0.6 to 1.2 mm, preferably 0.7 to 1.1 mm, and more preferably 0.8 to 1.0 mm.
  • the present invention also provides a method for preparing a biodegradable degradable surgical suture.
  • the method includes the following steps:
  • Step 1 preparing a load solution
  • Step 2 adding the matrix to the support solution to obtain a polymer solution
  • step 3 a polymer solution is prepared to obtain a surgical suture.
  • Step 1 Prepare a solution of the load.
  • the load includes collagen and growth factors
  • the preparation of the load solution includes the following steps:
  • step a a certain amount of collagen is weighed and dissolved in a certain volume of solvent to prepare a collagen solution.
  • the solvent is one or more of acetic acid, phosphoric acid, hydrochloric acid, a phosphate buffer solution, hexafluoroisopropanol, or water.
  • the solvent is one or more of acetic acid, a phosphate buffer solution, hexafluoroisopropanol, or water.
  • the solvent is hexafluoroisopropanol and / or water.
  • hexafluoroisopropanol is very polar, easily mixed with a variety of organic solvents, can dissolve many high-molecular polymers, and is highly volatile.
  • the solution has few residues and is easy to remove; and water, as a green and environmentally friendly solvent, can effectively dissolve collagen and basic fibroblast growth factors, which is helpful to promote collagen to more effectively encapsulate growth factors.
  • the volume ratio of the two is (8 to 40): 1, preferably (10 to 30): 1, and more preferably (12 to 27): 1.
  • the collagen is mixed with a solvent in an ice bath condition, and stirred until completely dissolved.
  • mixing in an ice bath can simultaneously maintain collagen and growth factor activities.
  • the stirring time is 0.5 to 2 h, preferably 0.75 to 1.5 h, and more preferably 1 h.
  • the concentration of the collagen is 20 to 45 mg / mL, preferably 25 to 40 mg / mL, and more preferably 27 to 35 mg / mL.
  • step b the growth factor is added to the collagen solution, and after mixing for a certain period of time, a load solution is prepared.
  • the present invention preferably encapsulates them in a collagen solution so that the collagen and growth factors pass a covalent bond. It is connected with hydrogen bonds to form nanoparticles (as shown in Figure 1), thereby improving the stability of growth factors and enabling them to be effectively released at the suture site.
  • the growth factor is preferably a basic fibroblast growth factor or an epidermal growth factor, and more preferably a basic fibroblast growth factor.
  • the mixing is performed in an ice bath, and the mixing time is 18-30 hours, preferably 20-26 hours, and more preferably 24 hours.
  • the encapsulation of the growth factor under the ice bath can effectively reduce the degradation of the growth factor, and the encapsulation time is 18-30 hours, which can make the collagen fully and uniformly envelop the growth factor.
  • the loading time is less than 18h, the loading will be incomplete and the load will be less effective; when the loading time is more than 30h, the loading will be saturated with the extension of time, and the loading effect will no longer be Raising, extending time will reduce efficiency.
  • the volume ratio of the collagen solution to the growth factor is (4000-9000): 115, preferably (5000-8500): 115, and more preferably (5500-8200): 115.
  • the inventors have found through research that when the volume ratio of the collagen solution to the growth factor is greater than 9000: 115, the collagen solution has completely contained the growth factor, and excessive addition of the collagen solution will cause waste of resources and cause the system Uneven mixing will affect the later spinning and affect the effect of growth factors.
  • the volume ratio of the collagen solution to the growth factors is less than 4000: 115, some growth factors cannot be encapsulated, and then degraded, unable to Play a role of encapsulation.
  • step 2 the matrix is added to the support solution, and the mixture is stirred to obtain a polymer solution.
  • the stirring is performed under an ice bath condition, and the stirring time is 2 to 4 hours, preferably 2.5 to 3.5 hours, and more preferably 3 hours.
  • the weight ratio of matrix to collagen in the polymer solution is (200-1200): 225, preferably (250-1100): 225, and more preferably (350-1050) ): 225.
  • step 3 a polymer solution is prepared to obtain a surgical suture.
  • the electrospinning method is preferably used to prepare the polymer solution into a surgical suture.
  • the electrostatic spinning technology uses a static electric field of tens of thousands of volts to overcome the surface tension at the tip of the capillary to form a jet. As the solvent evaporates, the jet solidifies to form submicron to nanometer ultrafine. The fiber filament is received by the receiving device.
  • an electrospinning device is used to prepare a polymer to obtain a surgical suture, which includes the following steps:
  • step I the device is charged with a polymer solution.
  • the polymer solution prepared above is filled into a syringe of an electrostatic spinning device, the volume of the syringe is 10 mL, and then a fine needle is selected for spinning.
  • Step II adjusting various parameters of the device.
  • the parameters of the electrostatic spinning device include the output voltage, the distance between the spinning needle and the receiver, the pushing speed of the injection pump, the receiver speed and the receiving time.
  • the output voltage is 4 to 22 kV, preferably 4 to 20 kV, and more preferably 5 to 17 kV.
  • the inventor has found through research that when the output voltage of the electrostatic spinning device is 4 to 22 kV, preferably 4 to 20 kV, and more preferably 5 to 17 kV, the diameter of the prepared surgical suture is the smallest.
  • the output voltage is less than 4kV, due to insufficient power, the spinning solution will be ejected outward in the form of droplets; when the output voltage is higher than 22kV, as the voltage increases, the reduction rate of the fiber diameter becomes Extremely slow, and will cause the spinning solution to fly away from the needle in the form of electrospray, which can not perform electrostatic spinning normally.
  • the distance between the spinning needle and the receiver is 8-20 cm, preferably 9-18 cm, and more preferably 11-15 cm.
  • the pushing speed of the syringe pump is 0.5 to 3.8 mm / h, preferably 0.8 to 3.6 mm / h, and more preferably 1.0 to 3.4 mm / h.
  • the syringe pump is used to push the syringe to advance the spinning solution.
  • the inventors have found through research that when the pushing speed of the injection pump is less than 0.5 mm / h, during the spinning process, the electrolysis speed is faster than the liquid discharge speed, which will cause discontinuous spinning and the liquid discharge is not timely, resulting in silk formation. Breakage occurs during the process, and the ordering of the fibers will be reduced.
  • the pushing speed of the injection pump is greater than 3.8mm / h, the electrolysis speed is slower than the liquid discharge speed during the filament forming process, resulting in some solutions being too late for electrolysis and remaining in Needles, clogging the needles, or spattering on the receiver in the form of droplets, leading to the collection of misty droplets or fibers that stick together, will affect the performance of the fibers.
  • the speed of the receiver is 200 to 400 r / min, preferably 240 to 370 r / min, more preferably 280 to 320 r / min, and the receiving time is 4 to 12 min. It is preferably 5 to 10 minutes.
  • the receiver is a turntable receiver.
  • the inventors have found through research that during the collection of the electrospun fiber, the convection of air and the winding of the receiver will further stretch the fiber, so that the average diameter of the fiber is reduced.
  • the convection of the air around the turntable is not enough to change the trajectory of the fiber, so that it cannot form well on the receiver; when the speed of the receiver is greater than 400r / min, the surrounding of the turntable The strong air convection causes the movement trajectory of the fiber to change when it approaches the receiver, causing breakage, and reducing the order of the fiber arrangement.
  • Step III Turn on the device to prepare a bioactive degradable surgical suture.
  • the power is connected and prepared by an electrostatic spinning device. After the spinning is completed, the spinning formed on the turntable receiver is collected to obtain a biodegradable surgical suture.
  • collagen was extracted from rat rat tail collagen; basic fibroblast growth factor was prepared and purified by the research group; polycaprolactone was purchased from Sigma-Aldrich in the United States; hexafluoroisopropanol was purchased from Shanghai A Latin Biochemical Technology Co., Ltd.
  • An electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10ml syringe.
  • the output voltage was controlled at 5kv when the fine needle was selected for spinning.
  • the distance to the receiver is 11cm, the pushing speed of the injection pump is controlled to 1.0mm / h, the receiver speed is maintained at 280r / min, and the receiving time is controlled to within 5min.
  • Spinning formed on the turntable receiver, to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10mL syringe.
  • the output voltage was controlled at 7kv when the fine needle was selected for spinning.
  • the distance from the receiver is 15cm, the pushing speed of the injection pump is controlled at 1.2mm / h, the receiver speed is maintained at 320r / min, and the receiving time is controlled within 6min.
  • Spinning formed on the turntable receiver to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10mL syringe.
  • the fine needle was used to control the output voltage of 10kv.
  • the spinning needle was used.
  • the distance from the receiver is 15cm, the pushing speed of the injection pump is controlled at 1.2mm / h, the receiver speed is maintained at 300r / min, and the receiving time is controlled within 7min.
  • Spinning formed on the turntable receiver, to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10 mL syringe.
  • the output voltage was controlled at 15 kv when the fine needle was selected.
  • the spinning needle The distance from the receiver is 14cm, the pushing speed of the injection pump is controlled at 2.1mm / h, the receiver speed is maintained at 300r / min, and the receiving time is controlled within 7min.
  • Spinning formed on the turntable receiver to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10mL syringe.
  • the output voltage was controlled to 17kv when the fine needle was selected for spinning.
  • the distance from the receiver is 13cm, the pushing speed of the injection pump is controlled at 2.1mm / h, the receiver speed is maintained at 300r / min, and the receiving time is controlled within 7min.
  • Spinning formed on the turntable receiver to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10mL syringe.
  • the output voltage was controlled to 5kv when the fine needle was selected.
  • the distance from the receiver is 13cm
  • the pushing speed of the injection pump is controlled at 3.2mm / h
  • the receiver speed is kept at 300r / min
  • the receiving time is controlled within 7min.
  • Spinning formed on the turntable receiver gives polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10mL syringe.
  • the output voltage was controlled to 12kv when the fine needle was selected.
  • the distance from the receiver is 13cm
  • the pushing speed of the injection pump is controlled at 3.4mm / h
  • the receiver speed is maintained at 300r / min
  • the receiving time is controlled within 7min.
  • Spinning formed on the turntable receiver, to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10ml syringe.
  • the fine needle was used to control the output voltage of 12kv when spinning, and the spinning needle was used.
  • the distance to the receiver is 13cm, the pushing speed of the injection pump is controlled to 3.3mm / h, the receiver speed is kept at 300r / min, and the receiving time is controlled to be within 7min.
  • Spinning formed on the turntable receiver to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10ml syringe.
  • the fine needle was used to control the output voltage of 11kv.
  • the distance to the receiver is 13cm
  • the pushing speed of the injection pump is controlled to 3.3mm / h
  • the receiver speed is kept at 300r / min
  • the receiving time is controlled to be within 7min.
  • Spinning formed on the turntable receiver to obtain polycaprolactone Collagen complex encapsulates growth factor ultrafine fiber threads.
  • Electrostatic spinning device (model: Tianjin Yunfan Technology YFSP-GIII) was used to prepare the surgical suture.
  • the prepared polymer solution was placed in a 10ml syringe.
  • the fine needle was used to control the output voltage of 12kv when spinning.
  • the distance from the receiver is 13cm
  • the pushing speed of the injection pump is controlled at 1.2mm / h
  • the receiver speed is maintained at 300r / min
  • the receiving time is controlled within 7min.
  • Spinning formed on the turntable receiver to obtain polycaprolactone- Collagen complex encapsulates growth factor ultrafine fiber threads.
  • the method used in this embodiment is similar to that in Embodiment 1, except that the output voltage is 4kv.
  • the method used in this embodiment is similar to that in Embodiment 1, except that the output voltage is 22 kv.
  • the method used in this embodiment is similar to that in Embodiment 6, except that the pushing speed of the syringe pump is 0.5 mm / h.
  • the method used in this embodiment is similar to that in Embodiment 6, except that the pushing speed of the syringe pump is 3.8 mm / h.
  • the method used in this embodiment is similar to that in Example 5, except that 115 ⁇ L of epidermal growth factor is measured and contained in collagen.
  • the method used in this example is similar to that in Example 5, except that 0.45 g of polyglycolide is added to the system.
  • the method used in this comparative example is similar to that in Example 5, except that the solvent of the collagen is a phosphate buffer solution.
  • the method used in this comparative example is similar to that in Example 5, except that the output voltage is 3 kv.
  • the method used in this comparative example is similar to that in Example 5, except that the output voltage is 25 kv.
  • the method used in this comparative example is similar to Example 5, except that the advance speed of the syringe pump is 0.3 mm / h.
  • the method used in this comparative example is similar to that in Example 5, except that the advance speed of the syringe pump is 4.0 mm / h.
  • the method used in this comparative example is similar to that in Example 5, except that 225 mg of collagen is weighed and dissolved in 3.5 mL of hexafluoroisopropanol and 0.25 mL of water.
  • the method used in this comparative example is similar to that in Example 5, except that the collagen solution does not contain basic fibroblast growth factor.
  • Example 10 3 3 3 + Example 11 3 3 3 + Example 12 4 3 3 + Example 13 3 3 3 + Example 14 3 3 3 + Example 15 5 5 + Example 16 5 4 + Comparative Example 1 / / / / Comparative Example 2 1 1 1 +++ Comparative Example 3 2 2 2 +++ Comparative Example 4 3 2 2 +++ Comparative Example 5 3 2 2 +++ Comparative Example 6 / / / /
  • the surgical sutures prepared in Examples 1 to 16 of the present invention have a smaller diameter than the comparative example, the tensile strength and modulus are better than those of the comparative example, and the degradation time is much shorter than that of the comparative example. Suture degradation time.
  • Example 1 and Comparative Example 7 of the present invention were applied to a mouse epidermal suture model, which can be knotted smoothly during suture, has certain toughness and tension, and no suture breakage occurs.

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Abstract

一种具有生物活性的可降解手术缝合线及其制备方法。制备方法包括在具有生物相容性的基体中加入包载生物活性物质的胶原蛋白，通过静电纺丝技术制备得到可降解手术缝合线。可降解手术缝合线均一性好，生物相容性和安全性高。

Description

一种具有生物活性的可降解手术缝线及其制备方法
本申请要求于2018年9月30日提交中国专利局、申请号为201811157726.0、发明名称为“一种具有生物活性的可降解手术缝线及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于生物医用材料领域，具体涉及一种具有生物活性的可降解手术缝线及其制备方法。
背景技术
目前临床常用的医用手术缝合线可分为可降解和不可降解缝合线，不可降解缝合线包括丝线、聚丙烯线、聚乙烯线等，其虽然机械性能强，但是不可降解性常常导致术后拆线的痛苦，甚至还需进行手术拆除；可降解线主要包括羊肠线、化学合成线及纯天然胶原蛋白，其能够在体内被降解代谢，无毒无害，减少术后不必要的麻烦和痛苦。
但是，可降解线中的羊肠线(具体如中国发明专利CN1363397A所述)因对人体存在不同程度的排异现象，易引起患者术后排异反应，且缝线抗张强度偏低，临床已显现各种术后不良反应；又如中国发明专利CN201543004U中所述的用于外科缝线、疝和体壁修复网片和防粘连膜片的纤维，其包括聚丙烯芯层、聚偏二氟乙烯皮层，芯层和皮层为同心结构，经复合纺丝形成同心结构复合纤维，此化学合成缝线植入后仍存在不同程度的化学残留，易造成机体皮下硬结， 部分患者术后存在皮下瘙痒等问题。目前较为完善的是纯天然胶原蛋白缝合线，取自动物肌腱部位。
然而，上述可降解线仅是起到手术后缝合伤口的作用，经缝合的伤口愈合慢，很容易受周围环境细菌的污染，表现为切口处出现或渗出脓性分泌物等现象，一般采用注射或口服抗生素类药物来治疗，对人体产生的副作用较大。
因此，提供一种加速伤口愈合、副作用小、抗感染及具有生物活性的可降解手术缝线及其制备方法，是目前亟需解决的问题。
发明内容
为了克服上述问题，本发明人进行了锐意研究，结果发现：选用生物相容性强、可降解的材料作为基体，然后加入包载生物活性物质的胶原蛋白，采用静电纺丝技术并设置特定的参数，能够制备得到可吸收降解、生物相容性和安全性高的可降解手术缝合线，从而完成了本发明。
具体来说，本发明的目的在于提供以下方面：
第一方面，本发明提供了一种具有生物活性的可降解手术缝线，其中，所述手术缝线由包括以下重量配比的原料制成：
基体200～1200重量份
负载物220～240重量份。
第二方面，本发明提供了一种具有生物活性的可降解手术缝线的制备方法，其中，所述方法包括以下步骤：
步骤1，制备负载物的溶液；
步骤2，将基体加入负载物溶液中，搅拌均匀，得到聚合物溶液；
步骤3，将聚合物溶液制备得到手术缝线。
本发明所具有的有益效果包括：
(1)本发明所提供的具有生物活性的可降解手术缝线，机械性能强，生物相容性高，安全性高；
(2)本发明所提供的手术缝线，能够在缝合部位释放生长因子，可以减少伤口感染，促进肉芽组织增生和胶原的生成，有效缩短康复时间；
(3)本发明所提供的手术缝线，直径小，均一性好；
(4)，本发明所提供的手术缝线的制备方法，步骤简单，条件易控，通用性强，适合大规模生产。
附图说明
图1为本发明所述手术缝线中胶原蛋白和生长因子的示意图；
图2表示了利用实施例1制备的手术缝线进行缝合后的效果；其中2a表示了缝合后第0天的效果；2b表示了缝合后愈合第13天的效果；图3表示了利用对比例7制备的手术缝线进行缝合后的效果；其中3a表示了缝合后第0天的效果；3b表示了缝合后愈合第13天的效果。
具体实施方式
下面通过优选实施方式和实施例对本发明进一步详细说明。
通过这些说明，本发明的特点和优点将变得更为清楚明确。
本发明提供了一种具有生物活性的可降解手术缝线，该手术缝线通过包括以下重量配比的原料制成：
基体200～1200重量份，
负载物220～240重量份。
优选地，所述手术缝线由包括以下重量配比的原料制成：
基体250～1100重量份
负载物220～230重量份。
更优选地，所述手术缝线由包括以下重量配比的原料制成：
基体350～1050重量份
负载物220～225重量份。
根据本发明一种优选的实施方式，所述基体为可降解的高分子材料，优选为聚乳酸、聚乙烯醇、聚己内酯、聚乙交酯、聚对二氧环己酮或聚乙丙交酯中的一种或多种。
在进一步优选的实施方式中，所述基体为聚乳酸、聚己内酯、聚乙交酯或聚对二氧环己酮中的一种或多种。
在更进一步优选的实施方式中，所述基体为聚己内酯。
本发明人经过研究发现，聚己内酯具有良好的机械性能和很好的生物相容性，适合内脏器官的缝合，且其可在6～12个月内完全降解成CO 2和H 2O，降解产物可随基体正常代谢排出体外，不会在体内堆积。尤其在膀胱和尿道类的手术缝合过程中，降解产物的堆积容易造成器官的堵塞，危害机体健康，采用本发明中的聚己内酯为缝合线基体材料，能够有效避免此类危害。
根据本发明一种优选的实施方式，所述负载物包括胶原蛋白和生物活性物质。
本发明人经过研究发现，胶原蛋白是动物体普遍存在的一类大分子蛋白，在哺乳动物体内的含量占整个生物体自身总蛋白含量的25％，是具有良好的细胞黏附力的细胞外基质，对皮肤表面的蛋白质分子具有较大的亲和力，有利于组织生长、修复，在手术缝线中添加胶原蛋白，可进一步增加缝线的细胞相容性，促进组织的增生和修复，生物降解安全性高。
在进一步优选的实施方式中，所述生物活性物质为肽，优选为生长因子。
生长因子是一类通过与特异的、高亲和的细胞膜受体结合，调节细胞生长与其他细胞功能等多效应的多肽类物质。生长因子作为重要的细胞外信号，能够帮助伤口愈合，同时促进肉芽组织增生和胶原的生成，减少病人后期感染风险。
在更进一步优选的实施方式中所述生长因子为碱性成纤维生长因子或者表皮生长因子。
本发明人经过研究发现，碱性成纤维生长因子是重要的促有丝分裂因子，也是形态发生和分化的诱导因子，其主要生物学作用有：促进肉芽组织的形成和创面的愈合；促进微血管形成和改善微循环，参与新生血管形成的全过程；促进成骨细胞的增殖、抑制破骨细胞的形成，能够促进骨形成。而表皮生长因子是耐热的单肽链，是强有丝分裂原，能刺激培养细胞及活体动物体内细胞的增殖、分化，可促进伤口愈合。
在本发明中，将胶原蛋白和生物活性物质(碱性成纤维生长因子 等生长因子)添加至基体中制备手术缝线，不会改变基体的机械性能，且基体和胶原蛋白也不会对生长因子蛋白质结构产生影响。
根据本发明一种优选的实施方式中，所述可降解手术缝线的外径为0.6～1.2mm，优选为0.7～1.1mm，更优选为0.8～1.0mm。
本发明还提供了一种具有生物活性的可降解手术缝线的制备方法，所述方法包括以下步骤：
步骤1，制备负载物溶液；
步骤2，将基体加入负载物溶液中，得到聚合物溶液；
步骤3，将聚合物溶液制备得到手术缝线。
以下具体地描述本发明所述的手术缝线的制备方法：
步骤1，制备负载物的溶液。
在本发明中，所述负载物包括胶原蛋白和生长因子，所述负载物溶液的制备包括以下步骤：
步骤a，称取一定量的胶原蛋白，溶于一定体积的溶剂中，制备得到胶原蛋白溶液。
根据本发明一种优选的实施方式，所述溶剂为醋酸、磷酸、盐酸、磷酸盐缓冲溶液、六氟异丙醇或水中的一种或多种。
在进一步优选的实施方式中，所述溶剂为醋酸、磷酸盐缓冲溶液、六氟异丙醇或水中的一种或多种。
在更进一步优选的实施方式中，所述溶剂为六氟异丙醇和/或水。
本发明人经过研究发现，六氟异丙醇的极性很强，易于与多种有机溶剂混合，可以溶解很多高分子聚合物，且挥发性强，在后续制 备手术缝线时，纺丝后的溶液残留少，易于除去；而水作为一种绿色环保的溶剂，可有效溶解胶原蛋白和碱性成纤维生长因子，有利于促使胶原蛋白更有效的包载生长因子。
优选地，所述溶剂为六氟异丙醇和水时，二者的体积比为(8～40)：1，优选为(10～30)：1，更优选为(12～27)：1。
根据本发明一种优选的实施方式，所述胶原蛋白与溶剂在冰浴条件下混合，搅拌至完全溶解。
其中，在冰浴下混合能够同时保持胶原蛋白和生长因子的活性。
在进一步优选的实施方式中，所述搅拌的时间为0.5～2h，优选为0.75～1.5h，更优选为1h。
其中，待溶液变得澄清，即胶原蛋白完全溶解后停止搅拌。
根据本发明一种优选的实施方式，所述胶原蛋白的浓度为20～45mg/mL，优选为25～40mg/mL，更优选为27～35mg/mL。
步骤b，将生长因子加入胶原蛋白溶液中，混合一定时间后，制备得到负载物溶液。
本发明人经过研究发现，生长因子极容易降解，且随着温度的提升降解速度加快，因此，本发明优选将其包载在胶原蛋白溶液中，使得胶原蛋白与生长因子之间通过共价键和氢键连接，形成纳米颗粒(具体如图1所示)，从而提高了生长因子的稳定性，使其能够在缝合部位得到有效释放。
在本发明中，所述生长因子优选为碱性成纤维生长因子或者表皮生长因子，更优选碱性成纤维生长因子。
根据本发明一种优选的实施方式，所述混合在冰浴下进行，所述混合时间为18～30h，优选为20～26h，更优选为24h。
其中，在冰浴的过程中需要不停搅拌，以使包载充分、均匀。
在本发明中，在冰浴下对生长因子进行包载，能够有效减弱生长因子的降解，且包载时间为18～30h，能够使胶原蛋白对生长因子充分且均匀的包载。当包载时间低于18h时，会导致包载不完全，得到的负载物有效性较低；当包载时间高于30h时，随着时间的延长，包载已经饱和，包载效果不再提升，延长时间会降低效率。
在进一步优选的实施方式中，所述胶原蛋白溶液与生长因子的体积比为(4000～9000)：115，优选为(5000～8500)：115，更优选为(5500～8200)：115。
本发明人经过研究发现，当胶原蛋白溶液与生长因子的体积比大于9000:115时，胶原蛋白溶液已对生长因子包载完全，过多的加入胶原蛋白溶液会造成资源浪费，同时会使体系混合不均匀，进而影响后期纺丝，且会影响生长因子的作用效果；当胶原蛋白溶液与生长因子的体积比小于4000:115时，会使部分生长因子不能被包载，进而发生降解，无法起到包载作用。
步骤2，将基体加入负载物溶液中，搅拌混匀，得到聚合物溶液。
根据本发明一种优选的实施方式，所述搅拌在冰浴条件下进行，所述搅拌时间为2～4h，优选为2.5～3.5h，更优选为3h。
在进一步优选的实施方式中，所述聚合物溶液中基体与负载物中胶原蛋白的重量比为(200～1200)：225，优选为(250～1100)：225， 更优选为(350～1050):225。
步骤3，将聚合物溶液制备得到手术缝线。
本发明人经过研究发现，由静电纺丝制得的纤维直径小、均一性好，能够从纳米尺度上模仿天然细胞外基质。因此，在本发明中，优选采用静电纺丝的方法将聚合物溶液制备成手术缝线。
其中，静电纺丝技术是在数十千伏的直流电场中，带电聚合物溶液的静电斥力在毛细管尖端克服表面张力形成射流，随着溶剂的挥发，射流固化形成亚微米至纳米级的超细纤维丝，并被接收装置接收。
在本发明中，采用静电纺丝装置将聚合物制备得到手术缝线，包括以下步骤：
步骤I，在装置内装入聚合物溶液。
其中，将上述制备得到的聚合物溶液装入静电纺丝装置的注射器中，所述注射器的容积为10mL，然后选取细针头纺丝。
步骤II，调节装置的各项参数。
其中，所述静电纺丝装置的参数包括输出电压、纺丝针头与接收器的距离、注射泵的推动速度、接收器速度和接收时间。
根据本发明一种优选的实施方式，所述输出电压为4～22kV，优选为4～20kV，更优选为5～17kV。
本发明人经过研究发现，所述静电纺丝装置的输出电压为4～22kV，优选为4～20kV，更优选为5～17kV时，制备的得到的手术缝线的直径最小。当输出电压小于4kV时，由于电力不足，纺丝液会以液滴的形式向外喷射；当输出电压高于22kV时，随着电压的 增大，制得的纤维直径的减小速度变得极为缓慢，而且会导致纺丝液以电喷雾形式飞离针头，不能正常进行静电纺丝。
根据本发明一种优选的实施方式，所述纺丝针头与接收器的距离为8～20cm，优选为9～18cm，更优选为11～15cm。
本发明人经过研究发现，当纺丝针头与接收器的距离小于8cm时，接收距离太短，纺丝液中的溶剂来不及挥发，易收集到雾状液滴或者是粘连到一起的纤维，会影响纤维的性能；当纺丝针头与接收器的距离大于20cm时，由于接收距离太大，电场力会大大减弱，纤维的均匀性会下降。
根据本发明一种优选的实施方式，所述注射泵的推动速度为0.5～3.8mm/h，优选为0.8～3.6mm/h，更优选为1.0～3.4mm/h。
其中，所述注射泵用于推动注射器推进纺丝液。
本发明人经过研究发现，当注射泵的推动速度小于0.5mm/h时，在成丝过程中，电解速度比出液速度快，会使纺丝不连续，出液不够及时，导致丝在形成过程中产生断裂，且会使纤维的排列有序度下降；当注射泵的推动速度大于3.8mm/h，在成丝过程中，电解速度比出液速度慢，导致部分溶液来不及电解，残留在针头，堵塞针头，或以液滴形式溅射在接收器上，导致收集到雾状液滴或者是粘连到一起的纤维，会影响纤维的性能。
根据本发明一种优选的实施方式，所述接收器的速度为200～400r/min，优选为240～370r/min，更优选为280～320r/min，同时所述接收时间为4～12min，优选为5～10min。
其中，所述接收器为转盘接收器。
本发明人经过研究发现，在静电纺丝纤维的收集过程中，空气的对流以及接收器的卷绕会对纤维产生进一步的拉伸，使得纤维的平均直径减小。
当接收器的速度小于200r/min时，由于转盘周围空气的对流不足以改变纤维的运动轨迹，使其不能很好地在接收器上形成；当接收器的速度大于400r/min时，转盘周围强烈的空气对流使得纤维靠近接收器时运动轨迹改变，产生断裂，且会使纤维的排列有序度下降。
步骤III，开启装置，制备得到具有生物活性的可降解手术缝线。
其中，连通电源，通过静电纺丝装置制备，完成后收集在转盘接收器上形成的纺丝，得到具有生物活性的可降解手术缝线。
实施例
以下通过具体实施例进一步描述本发明，不过这些实例仅仅是范例性的，并不对本发明的保护范围构成任何限制。
在以下实施例中：胶原蛋白由大鼠鼠尾胶原提取得到；碱性成纤维生长因子由课题组制备纯化得到；聚己内酯购自美国Sigma-Aldrich；六氟异丙醇购自上海阿拉丁生化科技股份有限公司。
实施例1
(一)称取225mg的胶原蛋白溶于6mL六氟异丙醇和0.5mL水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.45g聚己内酯，于冰水浴中搅拌3小时，直 至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10ml注射器中，选取细针头纺丝时控制输出电压5kv，纺丝针头与接收器距离为11cm，注射泵的推动速度控制1.0mm/h，接收器速度保持在280r/min，接收时间控制在5min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例2
(一)称取225mg的胶原蛋白溶于6.75mL六氟异丙醇和0.25mL水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.45g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10mL注射器中，选取细针头纺丝时控制输出电压7kv，纺丝针头与接收器距离为15cm，注射泵的推动速度控制1.2mm/h，接收器速度保持在320r/min，接收时间控制在6min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例3
(一)称取225mg的胶原蛋白溶于6.5mL六氟异丙醇和0.5mL水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.7g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10mL注射器中，选取细针头纺丝时控制输出电压10kv，纺丝针头与接收器距离为15cm，注射泵的推动速度控制1.2mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例4
(一)称取225mg的胶原蛋白溶于6.75mL六氟异丙醇和0.25mL水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.7g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10mL注射器中，选取细针头纺丝时控制输出电压15kv，纺丝针头与接收器距离为14cm，注 射泵的推动速度控制2.1mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例5
(一)称取225mg的胶原蛋白溶于6.75mL六氟异丙醇和0.25mL水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.7g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10mL注射器中，选取细针头纺丝时控制输出电压17kv，纺丝针头与接收器距离为13cm，注射泵的推动速度控制2.1mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例6
(一)称取225mg的胶原蛋白溶于7mL六氟异丙醇，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.45g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10mL注射器中，选取细针头纺丝时控制输出电压5kv，纺丝针头与接收器距离为13cm，注射泵的推动速度控制3.2mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例7
(一)称取225mg的胶原蛋白溶于7mL六氟异丙醇，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.7g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10mL注射器中，选取细针头纺丝时控制输出电压12kv，纺丝针头与接收器距离为13cm，注射泵的推动速度控制3.4mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例8
(一)称取225mg的胶原蛋白溶于6.75mL六氟异丙醇和0.25ml水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰 浴条件下搅拌，24h后，向体系中加0.95g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10ml注射器中，选取细针头纺丝时控制输出电压12kv，纺丝针头与接收器距离为13cm，注射泵的推动速度控制3.3mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例9
(一)称取225mg的胶原蛋白溶于7mL六氟异丙醇和0.25ml水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.45g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10ml注射器中，选取细针头纺丝时控制输出电压11kv，纺丝针头与接收器距离为13cm，注射泵的推动速度控制3.3mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例10
(一)称取225mg的胶原蛋白溶于7mL六氟异丙醇和0.25mL水，在冰浴下搅拌1小时，待溶液变得澄清，胶原蛋白完全溶解之后，量取115μL碱性成纤维生长因子包载在胶原中，并置于冰浴条件下搅拌，24h后，向体系中加0.7g聚己内酯，于冰水浴中搅拌3小时，直至整个体系混合均匀，最终得到聚己内酯-胶原复合包载生长因子聚合物。
(二)采用静电纺丝装置(型号：天津云帆科技YFSP-GⅢ)制备手术缝线，将制备的聚合物溶液放置于10ml注射器中，选取细针头纺丝时控制输出电压12kv，纺丝针头与接收器距离为13cm，注射泵的推动速度控制1.2mm/h，接收器速度保持在300r/min，接收时间控制在7min内，在转盘接收器上形成的纺丝，得到聚己内酯-胶原复合包载生长因子超细纤维线。
实施例11
本实施例所用方法与实施例1相似，区别仅在于，所述输出电压为4kv。
实施例12
本实施例所用方法与实施例1相似，区别仅在于，所述输出电压为22kv。
实施例13
本实施例所用方法与实施例6相似，区别仅在于，所述注射泵的推动速度为0.5mm/h。
实施例14
本实施例所用方法与实施例6相似，区别仅在于，所述注射泵的推动速度为3.8mm/h。
实施例15
本实施例所用方法与实施例5相似，区别在于，量取115μL表皮生长因子包载在胶原中。
实施例16
本实施例所用方法与实施例5相似，区别在于，向体系中加0.45g聚乙交酯。
对比例
对比例1
本对比例所用方法与实施例5相似，区别在于，所述胶原蛋白的溶剂为磷酸缓冲溶液。
对比例2
本对比例所用方法与实施例5相似，区别在于，所述输出电压为3kv。
对比例3
本对比例所用方法与实施例5相似，区别在于，所述输出电压为25kv。
对比例4
本对比例所用方法与实施例5相似，区别在于，所述注射泵的推进速度为0.3mm/h。
对比例5
本对比例所用方法与实施例5相似，区别在于，所述注射泵的推进速度为4.0mm/h。
对比例6
本对比例所用方法与实施例5相似，区别在于，称取225mg的胶原蛋白溶于3.5mL六氟异丙醇和0.25mL水。
对比例7
本对比例所用方法与实施例5相似，区别在于，胶原蛋白溶液中不包载碱性成纤维生长因子。
对上述实施例1～14和对比例1～5中制备得到的手术缝线的性能参数进行检测，结果如表1所示。
表1实施例1～16和对比例1～6中制备得到的手术缝线的性能比较
  直径 抗张强度 模量 降解时间
实施例1 4 3 3 +
实施例2 4 3 3 +
实施例3 3 3 3 +
实施例4 4 4 4 +
实施例5 5 5 5 +
实施例6 3 3 3 +
实施例7 3 3 3 +
实施例8 3 4 4 +
实施例9 4 3 2 +
实施例10 3 3 3 +
实施例11 3 3 3 +
实施例12 4 3 3 +
实施例13 3 3 3 +
实施例14 3 3 3 +
实施例15 5 5 5 +
实施例16 5 4 4 +
对比例1 / / / /
对比例2 1 1 1 +++
对比例3 2 2 2 +++
对比例4 3 2 2 +++
对比例5 3 2 2 +++
对比例6 / / / /
由表1可知，本发明实施例1～16中制备得到的手术缝线，其直径较对比例小，抗张强度和模量均优于对比例中的缝线，降解时间远少于对比例中的缝线降解时间。
实验例
将本发明实施例1和对比例7中制备的手术缝合线应用于小鼠表皮缝合模型，在缝合过程中能够顺利打结，具有一定的韧性和张力，没有出现缝合线断裂的现象。
在愈合后第13天，所述小鼠表皮的愈合情况如图2和图3所示。
由图2中的2b可知，本发明实施例1所制备的手术缝合线在愈合的过程中已经完全降解，且皮肤没有任何红肿现象，也没有崩线，伤口愈合较为完成；而对比例7中的手术缝合线缝合的伤口愈合情况 如图3中的3b所示，伤口具有明显的未愈合面，且能够看到无法降解的手术缝线。
由此可知，本发明实施例1中制备的手术缝合线由于包含生物活性因子，其对伤口组织的修复速度明显快于对比例7中未加入生长因子的手术缝合线。
以上结合具体实施方式和范例性实例对本发明进行了详细说明，不过这些说明并不能理解为对本发明的限制。本领域技术人员理解，在不偏离本发明精神和范围的情况下，可以对本发明技术方案及其实施方式进行多种等价替换、修饰或改进，这些均落入本发明的范围内。

Claims (32)

  1. 一种具有生物活性的可降解手术缝线，其特征在于：所述的手术缝线通过包括以下原料制成：基体200～1200重量份，负载物220～240重量份；优选的，基体250～1100重量份，负载物220～230重量份；更优选的，基体350～1050重量份，负载物220～225重量份。
  2. 如权利要求1所述的手术缝线，其特征在于：所述基体为可降解的高分子材料，优选聚乳酸、聚乙烯醇、聚己内酯、聚乙交酯、聚对二氧环己酮或聚乙丙交酯中的一种或多种，进一步优选聚乳酸、聚己内酯、聚乙交酯或聚对二氧环己酮中的一种或多种，更优选聚己内酯。
  3. 如权利要求1-2之一所述的手术缝线，其特征在于，所述负载物包括胶原蛋白和生物活性物质。
  4. 如权利要求3所述的手术缝线，其特征在于，所述生物活性物质为肽，优选生长因子，进一步优选碱性成纤维生长因子或者表皮生长因子，更优选碱性成纤维生长因子。
  5. 如权利要求3-4之一所述的手术缝线，其特征在于，负载物还包括溶剂，胶原蛋白溶于溶剂形成胶原蛋白溶液，所述溶剂为醋酸、磷酸、盐酸、六氟异丙醇或水中的一种或多种，优选六氟异丙醇和水；当溶剂是六氟异丙醇和水时，二者的体积比为(8～40)：1，优选为(10～30)：1，更优选为(12～27)：1；当生物活性物质为生长因子时，所述胶原蛋白溶液与生长因子的体积比为(4000～9000)：115，优选为(5000～8500)：115，更优选为(5500～8200)：115。
  6. 如权利要求1-5之一所述的手术缝线，其特征在于，所述手术 缝线的外径为0.6～1.2mm，优选0.7～1.1mm，更优选0.8～1.0mm。
  7. 一种具有生物活性的可降解手术缝线，其特征在于，通过如下制备方法制得，所述方法包括以下步骤：
    步骤1，制备负载物溶液；
    步骤2，将基体加入负载物溶液中，得到聚合物溶液；
    步骤3，将聚合物溶液制备得到手术缝线。
  8. 如权利要求7所述的手术缝线，其特征在于，所述基体为可降解的高分子材料，所述负载物包括胶原蛋白和生物活性物质。
  9. 如权利要求8所述的手术缝线，其特征在于，基体优选聚乳酸、聚乙烯醇、聚己内酯、聚乙交酯、聚对二氧环己酮或聚乙丙交酯中的一种或多种，进一步优选聚乳酸、聚己内酯、聚乙交酯或聚对二氧环己酮中的一种或多种，更优选聚己内酯。
  10. 如权利要求8-9之一所述的手术缝线，其特征在于，所述生物活性物质为肽，优选生长因子，进一步优选碱性成纤维生长因子或者表皮生长因子，更优选碱性成纤维生长因子。
  11. 如权利要求8-10之一所述的手术缝线，其特征在于，所述基体与所述负载物中胶原蛋白的重量比为(200～1200)：225，优选为(250～1100)：225，更优选为(350～1050):225。
  12. 如权利要求7-11之一所述的手术缝线，其特征在于，所述制备负载物溶液包括如下步骤：
    步骤a，称取一定量的胶原蛋白，溶于一定体积的溶剂中，制备得到胶原蛋白溶液；
    步骤b，将生长因子加入胶原蛋白溶液中，混合一定时间后，制备得到负载物溶液。
  13. 如权利要求12所述的手术缝线，其特征在于，胶原蛋白溶于溶剂形成胶原蛋白溶液，所述溶剂为醋酸、磷酸、盐酸、六氟异丙醇或水中的一种或多种，优选六氟异丙醇和水；当溶剂是六氟异丙醇和水时，二者的体积比为(8～40)：1，优选为(10～30)：1，更优选为(12～27)：1；当生物活性物质为生长因子时，所述胶原蛋白溶液与生长因子的体积比为(4000～9000)：115，优选为(5000～8500)：115，更优选为(5500～8200)：115。
  14. 如权利要求12所述的手术缝线，其特征在于，所述胶原蛋白与溶剂在冰浴条件下混合，搅拌至完全溶解；所述搅拌的时间为0.5～2h，优选为0.75～1.5h，更优选为1h。
  15. 如权利要求12所述的手术缝线，其特征在于，所述步骤b中，混合在冰浴下进行，所述混合时间为18～30h，优选为20～26h，更优选为24h。
  16. 如权利要求7-15之一所述的手术缝线，其特征在于，所述步骤3中，采用静电纺丝装置将聚合物制备得到手术缝线，包括以下步骤：
    步骤I，在静电纺丝装置内装入聚合物溶液；
    步骤II，调节静电纺丝装置的各项参数；所述参数包括输出电压、纺丝针头与接收器的距离、注射泵的推动速度、接收器速度和接收时间；
    步骤III，开启装置，制备得到具有生物活性的可降解手术缝线。
  17. 如权利要求16所述的手术缝线，其特征在于，所述步骤I具体为：将上述制备得到的聚合物溶液装入静电纺丝装置的注射器中，所述注射器的容积为10mL，然后选取细针头纺丝。
  18. 如权利要求16-17之一所述的手术缝线，其特征在于，所述输出电压为4～22kV，优选为4～20kV，更优选为5～17kV；所述纺丝针头与接收器的距离为8～20cm，优选为9～18cm，更优选为11～15cm；所述注射泵的推动速度为0.5～3.8mm/h，优选为0.8～3.6mm/h，更优选为1.0～3.4mm/h；所述接收器为转盘接收器，所述接收器的速度为200～400r/min，优选为240～370r/min，更优选为280～320r/min；所述接收时间为4～12min，优选为5～10min。
  19. 如权利要求7-18之一所述的手术缝线，其特征在于，制得的手术缝线的外径为0.6～1.2mm，优选0.7～1.1mm，更优选0.8～1.0mm。
  20. 一种具有生物活性的可降解手术缝线的制备方法，其特征在于，包括以下步骤：
    步骤1，制备负载物溶液；
    步骤2，将基体加入负载物溶液中，得到聚合物溶液；
    步骤3，将聚合物溶液制备得到手术缝线。
  21. 如权利要求20所述的制备方法，其特征在于，所述基体为可降解的高分子材料，所述负载物包括胶原蛋白和生物活性物质。
  22. 如权利要求21所述的制备方法，其特征在于，基体优选聚乳酸、聚乙烯醇、聚己内酯、聚乙交酯、聚对二氧环己酮或聚乙丙交酯 中的一种或多种，进一步优选聚乳酸、聚己内酯、聚乙交酯或聚对二氧环己酮中的一种或多种，更优选聚己内酯。
  23. 如权利要求21-22之一所述的制备方法，其特征在于，所述生物活性物质为肽，优选生长因子，进一步优选碱性成纤维生长因子或者表皮生长因子，更优选碱性成纤维生长因子。
  24. 如权利要求21-23之一所述的制备方法，其特征在于，所述基体与所述负载物中胶原蛋白的重量比为(200～1200)：225，优选为(250～1100)：225，更优选为(350～1050):225。
  25. 如权利要求20-24之一所述的制备方法，其特征在于，所述制备负载物溶液包括如下步骤：
    步骤a，称取一定量的胶原蛋白，溶于一定体积的溶剂中，制备得到胶原蛋白溶液；
    步骤b，将生长因子加入胶原蛋白溶液中，混合一定时间后，制备得到负载物溶液。
  26. 如权利要求25所述的制备方法，其特征在于，胶原蛋白溶于溶剂形成胶原蛋白溶液，所述溶剂为醋酸、磷酸、盐酸、六氟异丙醇或水中的一种或多种，优选六氟异丙醇和水；当溶剂是六氟异丙醇和水时，二者的体积比为(8～40)：1，优选为(10～30)：1，更优选为(12～27)：1；当生物活性物质为生长因子时，所述胶原蛋白溶液与生长因子的体积比为(4000～9000)：115，优选为(5000～8500)：115，更优选为(5500～8200)：115。
  27. 如权利要求25所述的制备方法，其特征在于，所述胶原蛋 白与溶剂在冰浴条件下混合，搅拌至完全溶解；所述搅拌的时间为0.5～2h，优选为0.75～1.5h，更优选为1h。
  28. 如权利要求25所述的制备方法，其特征在于，所述步骤b中，混合在冰浴下进行，所述混合时间为18～30h，优选为20～26h，更优选为24h。
  29. 如权利要求20-28之一所述的制备方法，其特征在于，所述步骤3中，采用静电纺丝装置将聚合物制备得到手术缝线，包括以下步骤：
    步骤I，在静电纺丝装置内装入聚合物溶液；
    步骤II，调节静电纺丝装置的各项参数；所述参数包括输出电压、纺丝针头与接收器的距离、注射泵的推动速度、接收器速度和接收时间；
    步骤III，开启装置，制备得到具有生物活性的可降解手术缝线。
  30. 如权利要求29所述的制备方法，其特征在于，所述步骤I具体为：将上述制备得到的聚合物溶液装入静电纺丝装置的注射器中，所述注射器的容积为10mL，然后选取细针头纺丝。
  31. 如权利要求29-30之一所述的制备方法，其特征在于，所述输出电压为4～22kV，优选为4～20kV，更优选为5～17kV；所述纺丝针头与接收器的距离为8～20cm，优选为9～18cm，更优选为11～15cm；所述注射泵的推动速度为0.5～3.8mm/h，优选为0.8～3.6mm/h，更优选为1.0～3.4mm/h；所述接收器为转盘接收器，所述接收器的速度为200～400r/min，优选为240～370r/min，更优选为280～320r/min；所述 接收时间为4～12min，优选为5～10min。
  32. 如权利要求20-31之一所述的制备方法，其特征在于，所述制备方法所制得的手术缝线的外径为0.6～1.2mm，优选0.7～1.1mm，更优选0.8～1.0mm。
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CN112516372A (zh) * 2020-11-12 2021-03-19 盐城工学院 一种用于可吸收手术缝合线的复合载药纤维
CN113509588A (zh) * 2021-05-24 2021-10-19 温州医科大学 中药黄精多糖手术缝线及其制备方法
CN115245588A (zh) * 2021-07-28 2022-10-28 温州医科大学 一种具有抗血栓活性的可降解手术缝线及其制备方法

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