An endovascular blood flow diverting device having a pro-endothelialization functional coating
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANGHAI SIXTH PEOPLES HOSPITAL
- Filing Date
- 2026-05-13
- Publication Date
- 2026-07-10
Smart Images
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of cerebral aneurysm treatment technology, and specifically relates to an intravascular blood flow guiding device with an endothelialization-promoting coating. Background Technology
[0002] Cerebral aneurysms (CA) are a common cerebrovascular disease. Rupture can cause subarachnoid hemorrhage, leading to high rates of disability and death. Minimally invasive interventional remodeling of the carrier artery is of paramount importance in clinical treatment. Currently, stent-assisted coil embolization can physically seal aneurysms, but its high operative complexity, high complication and recurrence rates, and difficulty in treating complex aneurysms limit its clinical application. Flow diverters (FDs) are considered a better approach, designed to regulate the local hemodynamic environment through their dense network structure, reducing blood flow shear stress within the aneurysm cavity while promoting carrier artery reconstruction. They have already shown good clinical efficacy. However, the relatively high blood flow velocity and low metal coverage at the aneurysm neck pose a significant challenge to endothelialization in this area. Continuous blood flow and the lack of cell-extracellular matrix connections make it difficult for endothelial cells to attach, leading to delayed endothelialization or even non-healing. Summary of the Invention
[0003] The technical problem to be solved by the present invention is to provide an intravascular blood flow guiding device with an endothelialization-promoting coating. After the coating is applied to the surface of the blood flow guiding device, it can regulate the key components of the extracellular matrix on the surface of the blood flow guiding device and the biological functions of circulating endothelial progenitor cells within the blood vessel.
[0004] This invention provides an intravascular blood flow guiding device with an endothelialization-promoting functional coating. The coating method is as follows: the intravascular blood flow guiding device is cleaned sequentially with water and ethanol; then it is immersed in a dopamine solution, cleaned, and then immersed in an OEG8 solution at room temperature in the dark, cleaned and dried; finally, the intravascular blood flow guiding device is immersed in an amphiphilic β-peptide polymer solution overnight, cleaned, and then reacted with mercaptoglycerol to cap unreacted groups.
[0005] Preferably, the intravascular blood flow guiding device is made of nickel-titanium alloy braiding.
[0006] Preferably, the preparation method of the amphiphilic β-peptide polymer includes: weighing β-lactam monomers with different positive charges and hydrophobicities in a positive charge to hydrophobicity ratio of 4:6, dissolving them in an organic solvent, adding an initiator, and then polymerizing them.
[0007] Preferably, the β-lactam monomers with different positive charges and hydrophobicities include and .
[0008] Preferably, the organic solvent is dimethylacetamide, until the solute is completely dissolved.
[0009] Preferably, the initiator is The amount of the initiator added is 1 / 40 of the total molar amount of the two monomers.
[0010] Preferably, the polymerization reaction is carried out under a nitrogen atmosphere.
[0011] Beneficial effects (1) The coating of the present invention can achieve selective adhesion to endothelial cells in in vitro experiments, while inhibiting non-specific adhesion of smooth muscle cells and platelets. While exerting the effect of promoting endothelialization, it ensures the biocompatibility of the coating and reduces the probability of in-stent restenosis.
[0012] (2) After the coating of the present invention is applied to the surface of the blood flow guiding device, it can regulate the biological function of circulating endothelial progenitor cells in blood vessels, including promoting the formation of oriented extracellular matrix, promoting cell-extracellular matrix adhesion and endothelial cell proliferation and maturation; thereby achieving: enhancing the adhesion, proliferation and migration ability of endothelial progenitor cells; significantly improving the acceleration of endothelialization process; excellent antiplatelet and anti-SMC adhesion properties; combined with the hemodynamic optimization effect of the blood flow guiding device, it achieves the result of accelerating the functional remodeling of tumor-bearing arteries. Attached Figure Description
[0013] Figure 1 a~e are schematic diagrams of the fabrication of the intravascular blood flow guiding device of the present invention and the material characterization results of the coating.
[0014] Figure 2 a~c represent the imaging evaluation results of the blood flow diversion device of the present invention.
[0015] Figure 3 a~c represent the histological evaluation results of the blood flow diversion device of the present invention. Detailed Implementation
[0016] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.
[0017] Example 1 I. Preparation of amphiphilic β-peptide polymers.
[0018] The synthesis of the amphiphilic β-peptide polymer was carried out entirely in a nitrogen-filled glove box. Positively charged monomer NM (0.24 mmol) and hydrophobic monomer CH (0.36 mmol) were weighed at a positive charge to hydrophobicity ratio of 4:6, dissolved in DMAC, and an initiator (0.015 mmol) was added. Subsequently, bis-(trimethylsilyl)aminolithium (0.045 mmol) was added, and polymerization was carried out at room temperature. After the monomer reaction was confirmed to be complete by TLC, the reaction solution was centrifuged three times using THF / PE. After deprotection with TFA and triethylsilane, the solution was centrifuged three times using methanol and MTBE. The final precipitate was lyophilized to obtain the amphiphilic β-peptide polymer, and its structure and composition were characterized using AFM and XPS.
[0019] II. Application method of endothelialization-promoting functional coating.
[0020] The blood flow diverting device was sequentially cleaned with water and ethanol. Hexamethylenediamine (HD, 2.44 mg / mL) and dopamine hydrochloride (DA, 1 mg / mL) were dissolved in Tris-HCl (pH=8.5) buffer, mixed thoroughly, and then immersed and shaken for 24 h. The device was then rinsed alternately with deionized water and ethanol, and dried with N2 to obtain an amination-treated device. The device was then immersed in OEG8 solution at room temperature in the dark, cleaned, and dried. Finally, the device was immersed overnight in an amphiphilic β-peptide polymer solution, cleaned, and then reacted with mercaptoglycerol to cap unreacted groups, yielding an intravascular blood flow diverting device with an endothelialization-promoting coating.
[0021] III. Material Characterization of Coatings.
[0022] The surface morphology was characterized using atomic force microscopy (AFM), the surface elements were analyzed using X-ray photoelectron spectroscopy (XPS), and the contact angle was measured using a contact angle meter.
[0023] Depend on Figure 1 As shown in b, the contact angle of the modified intravascular blood flow guiding device was not statistically different from that of the unmodified device, indicating that the coating had no significant effect on the mechanical properties of the stent.
[0024] Depend on Figure 1 As can be seen from c, the thickness of the modified coating is approximately 35 nm.
[0025] Depend on Figure 1 As can be seen from d, the surface of the modified intravascular blood flow guiding device shows uneven protrusions, indicating that the amphiphilic β-peptide polymer was successfully modified on the surface.
[0026] Depend on Figure 1 As can be seen from e, the modified coating contains C, O, and N elements, and the corresponding chemical bonds were detected, indicating that the effective components of the coating did not change during the modification process.
[0027] IV. Construction of the aneurysm model.
[0028] The right common carotid artery of the New Zealand rabbit was exposed through a small surgical incision, and the brachiocephalic trunk was dissected. The brachiocephalic trunk and subclavian artery were clamped. Under direct vision, the common carotid artery was punctured and elastase was injected. The range of elastase incubation at the origin of the carotid artery was controlled using aneurysm clips to adjust the width of the aneurysm neck. After digestion, the carotid artery was ligated, and the aneurysm model was established by suturing layer by layer.
[0029] V. Implantation and imaging evaluation of flow diversion devices.
[0030] Two weeks after modeling, the success was confirmed by postoperative digital subtraction angiography (DSA). Rabbits were randomly divided into 6 groups (n=5 per group), and intravascular flow diverters with endothelialization-promoting coatings and ordinary flow diverters were implanted, respectively. Angiographic follow-up was performed at 30, 90 and 180 days postoperatively.
[0031] DSA follow-up images were acquired, and the degree of aneurysm occlusion was assessed using the O'Kelly-Marotta (OKM) grading system, which classifies occlusion into four grades: Grade 1 = complete filling, Grade 2 = subtotal filling, Grade 3 = residual neck, and Grade 4 = no filling. Blood flow velocity in the rabbit common carotid artery was measured by ultrasound. The average flow velocity was calculated based on the average flow rate and the corresponding inlet cross-sectional area as the inlet boundary condition, while the outlet boundary condition was set according to Murray's law. Further computational fluid dynamics (CFD) data were obtained using the finite element method.
[0032] The results are as follows Figure 2 As shown in a and 2b, during the 1, 3, and 6-month follow-up, the intravascular flow diverter group with the endothelialization-promoting coating exhibited a lower OKM grade, which was reflected in smaller residual aneurysm volume and less intra-aneurysm blood flow, indicating better flow diversion performance.
[0033] Depend on Figure 2 As can be seen from c, intravascular flow diverting devices with endothelialization-promoting coatings can provide a hemodynamic environment with lower blood flow shear stress and blood flow velocity, significantly reducing the risk of delayed aneurysm rupture.
[0034] VI. Histological evaluation of the tumor-bearing artery.
[0035] Neck specimens of aneurysms were sequentially dehydrated with graded ethanol, cleared with xylene, and then soaked in resin impregnation solutions I, II, and III for one day each. Sections of 20-30 μm thickness were prepared using a hard tissue microtome. After treatment with a hematoxylin-eosin (H&E) staining kit, the specimens were observed using an automated microscope. Scanning electron microscopy (SEM) samples were washed with PBS, fixed with 2.5% glutaraldehyde for 24 hours, dehydrated with graded ethanol, and critically dried with carbon dioxide. After gold sputtering, images were acquired using an SEM (accelerating voltage 10 kV), with three fields of view per sample. Whole-Mount en Face immunofluorescence staining was performed according to the method described in the literature (Radiology vol. 270,2 (2014): 394-9. doi:10.1148 / radiol.1313079).
[0036] The results are as follows Figure 3 As shown in a and 3b, in the control group, only a layer of uneven ECM was observed on the surface of the ordinary flow diverter one month after surgery, and no obvious cell adhesion was observed on SEM. Complete endothelialization was not achieved until six months after surgery. In contrast, in the group with the intravascular flow diverter with an endothelialization-promoting coating, endothelial cells could complete adhesion within one month. More than 90% endothelial cell coverage was observed on SEM, and uniform and continuous neointimal formation was observed at the aneurysm neck, demonstrating the early completion of endothelialization.
[0037] Depend on Figure 3 c indicates that the ECM coverage of the intravascular blood flow diversion device group with the endothelialization-promoting coating is uniform and complete, with a coverage rate of over 95%, and uniform cell-extracellular matrix adhesion is visible on the surface. In contrast, the control group has reduced cell adhesion ability, manifested as uneven ECM thickness, with multiple areas of missing ECM coverage, resulting in uneven cell distribution.
Claims
1. An intravascular blood flow guiding device with an endothelialization-promoting coating, characterized in that: The coating method for the endothelialization-promoting functional coating is as follows: the intravascular blood flow guiding device is cleaned sequentially with water and ethanol; then it is immersed in a dopamine solution, cleaned, and then immersed in an OEG8 solution at room temperature in the dark, cleaned and dried; finally, the intravascular blood flow guiding device is immersed in an amphiphilic β-peptide polymer solution overnight, cleaned, and then reacted with mercaptoglycerol to cap unreacted groups.
2. The intravascular blood flow guiding device with an endothelialization-promoting coating according to claim 1, characterized in that: The intravascular blood flow guiding device is made of nickel-titanium alloy braiding.
3. The intravascular blood flow guiding device with an endothelialization-promoting coating according to claim 1, characterized in that: The preparation method of the amphiphilic β-peptide polymer includes: weighing β-lactam monomers with different positive charges and hydrophobicities in a positive charge to hydrophobicity ratio of 4:6, dissolving them in an organic solvent, adding an initiator, and then polymerizing them.
4. The intravascular blood flow guiding device with an endothelialization-promoting coating according to claim 3, characterized in that: The β-lactam monomers with different positive charges and hydrophobicities include and .
5. The intravascular blood flow guiding device with an endothelialization-promoting coating according to claim 3, characterized in that: The organic solvent is dimethylacetamide, until the solute is completely dissolved.
6. The intravascular blood flow guiding device with an endothelialization-promoting coating according to claim 3, characterized in that: The initiator is The amount of the initiator added is 1 / 40 of the total molar amount of the two monomers.
7. The intravascular blood flow guiding device with an endothelialization-promoting coating according to claim 3, characterized in that: The polymerization reaction was carried out under nitrogen atmosphere.