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CN-121971149-A - Self-lubricating three-layer nested medicine-carrying hollow cervical ring binding belt and preparation method thereof

CN121971149ACN 121971149 ACN121971149 ACN 121971149ACN-121971149-A

Abstract

The invention discloses a high-strength self-lubricating three-layer nested medicine-carrying hollow cervical ring binding belt with an auxiliary tyre protection function and a preparation method thereof, and belongs to the technical field of medical appliances. The invention relates to a method for preparing a three-dimensional scaffold by weaving degradable polyester monofilaments into hollow round ropes and integrating the hollow round ropes with medical curved needles, carrying out double-layer modification on a copper-based metal organic framework (Cu-MOF) by polydopamine-polyethylene glycol and loading active molecules, mixing the drug-loaded Cu-MOF with collagen natural polymer sol, carrying out synchronous drawing type micro-infusion and photo-enzyme synergistic crosslinking to uniformly fill the inner cavities of the round ropes with the gel to form the three-dimensional scaffold, constructing a transient hydration lubrication layer on the surface, and finally carrying out terminal sterilization on ethylene oxide to obtain the finished product. The cervical ring binding belt device provided by the invention simultaneously provides degradable mechanical support, collagen support induction and long-acting slow-release regulation and control, has low friction implantation characteristics, and can be well used for preventing or treating middle and late abortion and premature delivery caused by cervical insufficiency.

Inventors

  • YU XIAOHUA
  • ZHOU YANGUANG
  • FANG QIAOLI
  • MA JINXIA
  • JIANG ZHUXIN

Assignees

  • 杭州贤石生物科技有限公司

Dates

Publication Date
20260505
Application Date
20260209

Claims (10)

  1. 1. The utility model provides a self-lubricating three-layer nested formula medicine-carrying cavity cervical ring ribbon which characterized in that includes following structure: (1) The circular ribbon matrix is a hollow circular rope formed by knitting poly (L-lactide-co-epsilon-caprolactone), the outer diameter of the circular rope is 2.0-3.0 mm, the inner diameter of the circular rope is 1.7-2.5 mm, and one end of the circular rope is cold-riveted with a 9-12 mm and 1 ⁄ round medical suture needle to form a needle-thread integrated structure; (2) The composite gel filled in the hollow cavity of the round rope consists of a bioabsorbable natural polymer-based biological scaffold material and copper-based metal organic frameworks dispersed in the bioabsorbable natural polymer-based biological scaffold material, wherein the mass fraction of the copper-based metal organic frameworks in the composite gel is 3-8%, and the copper-based metal organic frameworks are loaded with at least one bioactive molecule; The composite gel is filled in the hollow cavity channel of the round rope by adopting a synchronous drawing type hollow cavity micro-filling technology, and specifically comprises the steps of sleeving a hollow injection head with the outer diameter slightly smaller than the inner diameter of the cavity at the cavity opening of a ring binding belt, continuously injecting a composite gel solution at the speed of 0.10-0.25 mL min < -1 >, simultaneously withdrawing the injection head at the constant speed of 0.5-2.0 mm < -1 >, irradiating 30-60 s in real time by means of a coaxial 405 nm cylinder light source to perform primary photo-crosslinking to complete uniform bubble-free filling, and then incubating 30min at the temperature of 37 ℃ to enable microbial transglutaminase to catalyze epsilon- (gamma-Glu) -Lys to perform secondary covalent crosslinking; (3) The transient hydration lubricating layer is coated on the outer surface of the annular binding belt, is a water-soluble system of a hydrophilic polymer P capable of being water-soluble to form a film and a medical grade plasticizing and humectant H, the content of P is 0.2-3.0 wt%, the content of H is 5-20% wt%, and the balance is sterile pure water, wherein the P is one or more selected from hyaluronic acid, sodium carboxymethyl cellulose, polyvinyl alcohol, pullulan, dextran, hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the H is one or more selected from glycerol, sorbitol, mannitol, xylitol and polyethylene glycol 300-600; The transient hydration lubrication layer is obtained by dip-coating the annular ribbon in the water-soluble system at 5-15 s, vacuum-drying at 20-30 ℃ under absolute pressure of less than or equal to 20 kPa for 15-60 min, and obtaining a dry film with thickness of 1-5 μm, namely the transient hydration lubrication layer, wherein the dry film is completely hydrated in normal saline of less than or equal to 10 s at 37 ℃ and forms a viscoelastic lubrication layer, so that the dynamic friction coefficient in the implantation process is reduced by at least 60% compared with that in an uncoated state, and the viscoelastic lubrication layer is completely dissolved in 30 min in a body fluid environment without affecting subsequent cell adhesion and material degradation.
  2. 2. The self-lubricating three-layer nested drug-loaded hollow cervical ring binder of claim 1, wherein the copper-based metal organic framework is selected from one or more of PCN-224 (Cu), USTC-6, H3[ (Cu 4 Cl) 3- (BTTri) 8], cu-UiO-66-NH2, or USTC-6@go/chitosan.
  3. 3. The self-lubricating three-layer nested drug-loaded hollow cervical ring binder according to claim 1 or 2, wherein the copper-based metal organic framework surface is further coated with a polydopamine-polyethylene glycol double-layer coating, and the polydopamine-polyethylene glycol double-layer coating is formed by the following steps: a) Dispersing Cu-MOF particles in Tris-HCl buffer solution with pH=8.5, adding dopamine hydrochloride with mass concentration of 1-5 mg cm & lt-1 & gt, and magnetically stirring for 1-3 h at 20-30 ℃ to enable the Cu-MOF particles to be self-polymerized and deposited on the surface of the Cu-MOF to form a polydopamine layer with thickness of 5-20 nm; b) Washing the polydopamine coated Cu-MOF with deionized water or ethanol-water until the eluent is colorless and transparent; c) Resuspending the product obtained in the step b) in PBS with pH=7.2-7.4, adding polyethylene glycol containing active ester end groups to enable PEG to react with the surface of polydopamine, wherein the feeding amount of the PEG is 0.5-3.0 mu mol of sigma-2, and reacting at 20-30 ℃ for 0.5-2 h; d) Washing again and drying in vacuum at 4 ℃ to obtain PDA-PEG double-layer modified Cu-MOF particles with the surface coverage density of 0.5-3.0 mu mol seed m-2.
  4. 4. The self-lubricating three-layer nested drug-loaded hollow cervical ring binder of claim 1 or 2, wherein the hollow round rope is selected from any one or a combination of the following braiding modes, and the porosity of the whole cavity wall is 15-25%: a) 2/2 twill hollow circular knitting, namely 8-12 carrier yarns, 40-55 degrees of knitting angle and 34-42 picks cm < -1 > of knitting density; b) The 3/3 satin hollow circular knitting comprises 12-16 carrier yarns, a knitting angle of 45-58 degrees, a knitting density of 38-46 picks cm < -1 >, and an equivalent aperture of not more than 60 mu m under the condition that the viscosity of a gel precursor is 0.2-0.35 Pa s; c) Double-layer coaxial composite weaving, namely, inner layer high-density plain weave and outer layer 2/2 twill weave, wherein the two hole sites are mismatched to form a composite cavity wall, the comprehensive weaving density is equivalent to 34-42 picks cm < -1 >, and the equivalent aperture is not more than 60 mu m; d) Triaxial braiding, wherein +/-theta slant yarns are matched with 2-4 axial straight yarns, the braiding angle is 35-50 degrees, and the braiding density is 34-42 picks cm < -1 >; e) Interlocking hollow knitting, namely setting locking yarns or binding yarns on the staggered paths to limit Kong Chuangce to slide and expand, wherein the knitting density is 36-46 picks cm < -1 >, and the wall permeability is not higher than 1% (volume fraction) under the condition that the viscosity of a gel precursor is 0.3-0.6 Pa s; f) The programmed gradient knitting, in which knitting density is graded in a partition way at 34-46 picks cm < -1 > and/or knitting angle at 35-58 degrees along the length direction, and needle end area density is higher than that of middle section 2-8 picks cm < -1 >, so that the whole porosity is maintained and the anti-permeability and anti-wear performance are improved.
  5. 5. The self-lubricating three-layer nested medicine-carrying hollow cervical ring binder according to claim 4, wherein the equivalent aperture of the hollow circular rope knitting is controlled to be 35-60 μm and is matched with the synchronous drawing type hollow cavity micro-perfusion process so as to realize that the intra-cavity gel filling rate is more than or equal to 95% and no visible bubbles and leakage exist.
  6. 6. The self-lubricating three-layer nested drug-loaded hollow cervical ring binder of claim 1 or 2, wherein the molar ratio of lactide to caprolactone in the poly (L-lactide-co-epsilon-caprolactone) is 50:50-90:10.
  7. 7. The self-lubricating three-layer nested drug-loaded hollow cervical ring binder of claim 1 or 2, wherein the ring binder matrix has a breaking strength of not less than 150 n, a 180 ° bend radius of not more than 5mm, and retains a tensile strength of not less than 130N after soaking in PBS at 37 ℃ for 14 weeks.
  8. 8. The self-lubricating three-layer nested drug-loaded hollow cervical ring binder of claim 1 or 2, wherein the bioabsorbable natural polymer-based bioscaffold is selected from one or more of type I collagen, type III collagen, gelatin, chitosan, hyaluronic acid, and physical or chemical crosslinks thereof.
  9. 9. The self-lubricating three-layer nested drug-carrying hollow cervical ring binder according to claim 1 or 2, wherein the bioactive molecule is selected from one or more of IMP family peptides, retinoic acid, epigallocatechin gallate, procyanidins, progesterone and resveratrol, the total drug-carrying amount of the bioactive molecule is 0.1-10 wt%, the release curve of the bioactive molecule is in a double-stage form of 24 h, the release amount is 10-20%, and the accumulated release amount is not higher than 80% in 6 weeks.
  10. 10. A method of preparing a self-lubricating three-layer nested drug-loaded hollow cervical ring binder as claimed in any one of claims 1 to 9, comprising the steps of: s1, preparing P (LA-CL) monofilaments with the molar ratio of lactide to caprolactone of 50:50-90:10 by adopting a melt spinning-hot stretching process; S2, braiding the monofilaments into hollow round ropes on an 8-yarn 48-needle circular braiding machine according to a corresponding braiding mode, and performing 25 kGy gamma-ray sterilization after heat setting for 10 min under the tension of 75+/-5 ℃ and 2N x D-1; s3, adopting CYQY-2000 pneumatic needle pressing machines to fix the cold riveting of the round rope end part on 9-12 mm and 1 ⁄ 2 round medical suture needles under the conditions of 0.5-1.5 MPa and 1-5S, wherein the pulling-out force of the needle-thread joint part is more than or equal to 100N; S4, forming a polydopamine layer from polydopamine 2-4 h in Tris-HCl buffer solution with pH=8.5, then reacting with NHS-PEG for 0.5-2 h, constructing a polydopamine-polyethylene glycol double-layer coating on the surface of Cu-MOF, and adsorbing and loading the polydopamine-polyethylene glycol double-layer coating in buffer solution containing active molecules to obtain drug-loaded PDA-PEG-Cu-MOF; s5, mixing the drug-loaded PDA-PEG-Cu-MOF with a natural polymer-based biological scaffold precursor sol to form an injectable composite gel pre-solution; S6, sleeving a hollow injection head with the outer diameter slightly smaller than the inner diameter of the cavity at the cavity opening of the annular binding belt by adopting a synchronous drawing type hollow cavity micro-perfusion technology, continuously injecting the composite gel pre-solution in the step e) at the speed of 0.10-0.25 mL mu m/min-1, simultaneously retracting the injection head at the constant speed of 0.5-2.0 mu m/mm mu m/S-1, irradiating 30-60S in real time by virtue of a coaxial 405 nm cylinder light source to perform primary photo-crosslinking, completing uniform bubble-free filling, and then incubating 30min at 37 ℃ to enable microorganism transglutaminase to catalyze epsilon- (gamma-Glu) -Lys to perform secondary covalent crosslinking; S7, dip-coating the filled ring binder with 0.5-2.0 wt% of hyaluronic acid 5-15 wt% of glycerin solution 5-15S, and vacuum-drying at-80 kPa and 25 ℃ to form a transient hydration lubrication layer with the thickness of 1-5 mu m at 15-60 min; And S8, adopting ethylene oxide terminal sterilization under the packaging state, wherein the conditions are that the mass concentration of the ethylene oxide is 450-600 mg ℃ and L-1, the temperature is 45-50 ℃, the relative humidity is 50-70%, the action time is 3-4 h, then carrying out residue removal treatment at the forced ventilation temperature of 40-50 ℃ and the forced ventilation time of 8-24 h, so that the content of the residual ethylene oxide is lower than 25 ppm, and the instantaneous hydration and friction coefficient reduction function of the transient hydration lubricating layer is maintained.

Description

Self-lubricating three-layer nested medicine-carrying hollow cervical ring binding belt and preparation method thereof Technical Field The invention belongs to the technical field of medical instruments, relates to a cervical ring binding belt, and particularly relates to a three-layer nested degradable medicine-carrying hollow cervical ring binding belt which has the functions of mechanically supporting, inhibiting MMP from degrading collagen, promoting LOX enzyme family to crosslink collagen, reducing surface friction of the ring binding belt and reducing damage in operation and a preparation method thereof. Background The main physiological task of the gestational cervix is to maintain a closed state within 20-34 weeks of the rapid increase in fetal life and to withstand the increasing uterine pressure day by day. 54% -77% of the dry weight of the cervical matrix is collagen fibers, 80% of which are type I collagen and 15% of which are type III collagen, and the layered arrangement and Lysyl Oxidase (LOX) -mediated covalent cross-linking together determine the elastic modulus and ultimate tensile strength of the cervix. However, in cervical dysplasia (Cervical insufficiency, CI) patients, abnormal remodeling of cervical ECM occurs, ① fibroblast collagen synthesis rate decreases, ② matrix metalloproteinase (MMP-2, MMP-9) activity increases and tissue inhibitor (TIMP-1/2) expression is insufficient, resulting in increased collagen degradation rate, ③ I/III collagen ratio decreases from normal approximately 5:1 to less than or equal to 2:1, ④ collagen fiber orientation is disordered and bundle diameter becomes thin, ⑤ LOX dependent crosslinking density is significantly reduced due to copper ion supply insufficiency and inflammation microenvironment inhibition. Clinical and in vitro studies have shown that increased collagen degradation and decreased cross-linking are direct driving factors that lead to rapid decay in cervical elasticity and strength, and that ultimate tensile strength can be reduced by >40% in a short period of time, thereby failing to resist fetal and sheep water pressure, and inducing mid-late abortion or premature labor. Traditional cervical cerclage is mostly made of terylene (Mersilene Tape), nylon wire or polypropylene wire. Such non-degradable solid materials only provide passive tethered mechanical support, with the following drawbacks: (1) The surgical operation is taken out for the second time, and the infection and stripping risks are increased; (2) The weaving pore diameter is small and no cavity exists, and bioactive substances cannot be loaded, so that ECM abnormal remodeling cannot be reversed; (3) The interface hardness difference between the wire body and cervical tissue is large, and the shearing stress concentration and chronic inflammation are easy to form; (4) Repeated operation is needed for multiple gestation, and patient compliance is poor. Degradable sutures (such as polyglycolic acid) avoid secondary removal, but the mechanical decay during degradation is rapid and there is still a lack of molecular therapeutic function. Recent studies have attempted to coat the suture surface with a drug or polypeptide coating, but the effective drug loading is limited and the sustained release time is less than 1 week, which makes it difficult to cover the therapeutic window in the middle and late stages of pregnancy. On the other hand, copper is an essential cofactor of LOX, which can promote the crosslinking of collagen and elastin, while copper-based metal organic frameworks (Cu-MOFs) have large specific surface area and more coordination sites, can slowly release Cu 2+ in a slightly acidic/ROS environment, and have antibacterial and drug-carrying functions. The prior literature reports that Cu-MOFs such as PCN-224 (Cu), USTC-6 and the like can exist stably and degrade controllably under the condition of pH value of 6.5-7.4, but are not combined with degradable cerclage materials, and are not used for targeted repair of cervical ECM. In summary, four pain points generally exist in the conventional cerclage scheme (1) only rely on inert terylene or nylon to provide passive mechanical constraint, lack of controllable degradation and still need to be taken out for a second time after delivery, (2) the cerclage itself does not contain a three-dimensional support structure and cannot provide attachment support for cervical fibroblasts, so that regeneration and reconstruction of ECM are not facilitated, (3) local administration is usually one-time injection, so that effective concentration of collagen-promoting crosslinking molecules (Cu 2+, IMP peptide, retinoic acid and the like) is difficult to maintain for a long time, MMP-mediated collagen degradation cannot be synchronously inhibited, and (4) the surface friction coefficient of a braided rope is high, and micro-tearing and inflammatory exudation are easily caused when the cerclage passes through the essence of uterus. Therefor