DEVICE FOR WRAPPING OUTER WALL OF BLOOD VESSEL

Abstract

The present invention relates to a device capable of wrapping the outer wall of a blood vessel, and a method for manufacturing the device. If the device for wrapping the outer wall of a blood vessel of the present invention is used, the outer wall of a blood vessel is wrapped, and, thereby, vortex generation can be significantly decreased by controlling abnormal expansion of the blood vessel which can occur due to the difference in the characteristics of blood vessels in a vein-artery graft model. The present invention saves a blood vessel from a low-oxygen state by promoting generation of new blood vessels on the outer wall of the blood vessel via a regenerative inflammatory response caused by the material of the device, and provides synergy effects such as prevention of vascular stenosis and reinforcement of an outer muscular layer by guiding venous muscular cells to the outside.

Claims

1. A porous, outer vascular wall-wrapping device, comprising a biocompatible polymer material.

2. The outer vascular wall-wrapping device of claim 1, wherein the outer vascular wall is an outer vascular wall at an anastomosed site.

3. The outer vascular wall-wrapping device of claim 2, wherein the anastomosed site is a vein to artery graft site.

4. The outer vascular wall-wrapping device of claim 1, being in an original shape or a temporary shape, wherein the original shape is in a hollow cylindrical structure one side of which is cut in a lengthwise direction to allow a blood vessel to be inserted into the hollow space of the device, and the temporary shape is temporarily formed by application of an external stimulus, has a curved or planar surface with the opposite ends formed by the cutting being apart from each other, and is recovered to the original shape as the device is bent in the direction of increasing the curvature by controllably decreasing the external stimulus so as to wrap the outer vascular wall.

5. The outer vascular wall-wrapping device of claim 4, wherein the external stimulus is a change in temperature, physical power, pH, light, voltage, or osmotic pressure.

6. The outer vascular wall-wrapping device of claim 5, wherein the change in temperature condition is a change to a temperature higher than the body temperature.

7. The outer vascular wall-wrapping device of claim 4, wherein the outer vascular wall-wrapping device is recovered to the original shape and retain the original shape in an in-vivo environment.

8. The outer vascular wall-wrapping device of claim 1, wherein the polymer material is a biodegradable polymer material.

9. The outer vascular wall-wrapping device of claim 8, wherein the polymer material is a copolymer of an ?-caprolactone monomer and glycidyl methacrylate.

10. The outer vascular wall-wrapping device of claim 9, wherein the polymer material comprises x % PCL (poly-?-caprolactone)-co-y % PGMA (poly-glycidyl methacrylate), wherein x % and y % each represent mol % for corresponding units, with x+y=100 under the condition of x being 92 to 96.

11. A method for fabrication of an outer vascular wall-wrapping device, the method comprising the steps of: (a) photo crosslinking a mixture of a biocompatible polymer material, a photoinitiator, and a porogen into a tube shape to prepare a tube-type device; (b-1) removing the porogen from the prepared tube-type device; (b-2) cutting one side of the prepared tube-type device in a lengthwise direction parallel to the central axis of the tube-type device; and (c) inducing the one side-cut tube-type device in a temperature condition higher than the body temperature into a temporary shape allowing blood vessel to be inserted thereinto, and then fixing the one side-cut tube-type device in a temperature condition lower than room temperature.

12. The method of claim 11, wherein the polymer material is a copolymer of an ?-caprolactone monomer and glycidyl methacrylate.

13. The method of claim 12, wherein the polymer material comprises x % PCL (poly-?-caprolactone)-co-y % PGMA (poly-glycidyl methacrylate), wherein x % and y % each represent mol % for corresponding units, with x+y=100 under the condition of x being 92 to 96.

14. The method of claim 11, wherein the porogen is at least one selected from the group consisting of gelatin, sodium chloride, sodium bicarbonate, ammonium bicarbonate, polyethylene glycol, and hexane.

15. The method of claim 11, wherein the temperature condition higher than the body temperature ranges 42? C. to 65? C.

16. The method of claim 11, further comprising a step of additionally providing pores subsequently to any one of steps (a) to (c).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0058] FIG. 1 shows a structure of the porous, blood vessel-wrapping device.

[0059] FIG. 2 shows a mold structure in a tube shape.

[0060] FIG. 3 illustrates the working mechanism of the porous, blood vessel-wrapping device.

[0061] FIG. 4 shows observation results of cell adhesion and proliferation after hSMCs were incubated in the blood vessel-wrapping device.

[0062] FIG. 5 shows morphologies of human smooth muscle cells incubated in the blood vessel-wrapping device and quantitative results of their circularity.

[0063] FIG. 6 shows histological assay results. In the pentachrome staining, nuclei and elastic fibers are expressed in black, collagen in yellow, ground substance and mucin in blue, fibrinoids and fibrins in intense red, and muscles in red.

[0064] FIG. 7 shows immunofluorescent results, indicating that the mild inflammation induced resulted in neoadventitia and angiogenesis (neo-vasa vasorum).

[0065] FIGS. 8a, 8b, 8c, 8d, 8e and 8f illustrate the stenosis-preventing mechanism of the blood vessel wrapping.

DETAILED DESCRIPTION

[0066] A better understanding of the present disclosure may be obtained through the following examples, which are set forth to illustrate, but are not to be construed as limiting the present disclosure.

EXAMPLES

Example 1: Fabrication of Porous, Blood Vessel-Wrapping Device with ?-Caprolactone Monomer (CL) and Glycidyl Methacrylate (GMA) Copolymer

[0067] A solution of 94% PCL-co-6% PGMA in 0.1 w/v % photoinitiator (Irgacure)-containing dichloromethane was mixed at a ratio of 1:1 w/w % with a porogen (gelatin). A silicone tube was inserted into a Teflon tube having a blood vessel outer diameter to be installed (device outer/inner) and the polymeric mixture was sprayed into a space between the tubes to form a tube shape, followed by UV crosslinking for a specific time (600 s) in a UV curing lamp system (OmniCure S2000). The gelatin was dissolved out by leaving the cured structure in 40? C. distilled water for 24 hours. Following removal of the Teflon tube and the silicone tube, the tube structure thus obtained was washed in 25? C. distilled water for one week while shaking. The tube-type device was cut in a lengthwise direction (see FIG. 1) and induced to be transformed into a temporary shape in 55? C. which was fixed by freezing on dry ice (?80? C.). Subsequently, a porous structure having a predetermined number of pores (size: 300-500 ?m) per unit area of the device was made using a biopsy punch and then sterilized with EO gas.

Example 2: Effect of Porous, Blood Vessel-Wrapping Device

[0068] 2-1. Assay for Cellular Behaviors in Porous, Blood Vessel-Wrapping Device

[0069] Comparison cytotoxicity, adhesion, proliferation for human venous smooth muscle cells (hSMCs) was made between the porous, blood vessel-wrapping device or a tissue culture polystyrene (TCPS) after in vitro incubation. The device was evaluated for compatibility with cell by a live & dead assay and for cell adhesion and proliferation by CCK-8 (cell counting kit-8) assay. Also, cell circularity was assayed by F-actin staining (phalloidin staining).

[0070] On day 3 after cell plating, the porous, blood vessel-wrapping device was found to induce no death of hSMCs as measured by Live & Dead assay. On day 1 after cell plating, the relative cell adhesion was examined using CCK-8 assay. Also, the proliferation phenotype was determined by dividing the number of cells on day 1 by that on day 3. The cell adhesion and proliferation were decreased in the porous, blood vessel-wrapping device, compared to TCPS. In light of the fact that healthier smooth muscle cells are, the slower their proliferation rate is, the wrapping device was indirectly demonstrated to have no adverse influences on behaviors of the smooth muscle cells (see FIG. 4). On day 3 after hSMCs plating, F-actin staining (phalloidin staining) was performed. No significant differences in cell morphology were found between the wrapping device and TCPS. Normal smooth muscle cells have a long, elongated shape, so their circularity is low. Similar circularity was observed on TCPS and the shape memory polymer. As a result, it was confirmed that the shape memory polymer did not significantly affect the phenotypic change of smooth muscle cells compared to TCPS (see FIG. 5).

[0071] 2-2. Establishment of Vein to Artery Graft Rabbit Model and Introduction of Porous, Blood Vessel-Wrapping Device

[0072] The jugular vein in a rabbit was dissected at two sites and excised after blood flow was blocked therebetween. A segment of the carotid artery was removed by blocking the blood flow with clamps and dissecting. The excised jugular vein segment was anastomosed to the dissected carotid artery with 9-0 suture. Thereafter, blood flows at anastomosed sites were confirmed. The porous, blood vessel-wrapping device was applied to the anastomosed sites and recovered to the original shape by flowing 40? C. saline.

[0073] 2-3. Inhibitory Effect of Porous, Blood Vessel-Wrapping Device on Vein to Artery Graft Stenosis

[0074] For four weeks after blood vessel wrapping in the rabbit model, vascular stenosis was monitored by tissue analysis. Immediately after the vein to artery graft model was established, vascular wrapping using the porous, blood vessel-wrapping device was applied. Four weeks later, the vein region including the anastomosed sites was examined for stenosis. Examination was made of the vein shape and size by H&E staining and of the neointima and neo-adventitia formed in the vein by pentachrome staining.

[0075] Compared to normal vein, the group to which the wrapping had not been applied (w/o external wrapping) was observed to undergo excessive dilatation of the vein lumen and vascular wall. In this group, the mean vein size was measured to be 1,450 mm for the inner diameter of the media layer. Neointimal formation was also observed. In contrast, the vein was suppressed from undergoing excessive dilatation in the wrapping-applied group (w/ external wrapping) (mean media diameter=1270 mm) and neointimal formation was not observed, either. On the other hand, neo-adventitia was detected due to mild inflammation between existing blood vessels and the porous wrapping device (see FIG. 6).

[0076] The device was examined for effects on angiogenesis and neointimal formation by immunostaining to Flk1 and ?-SMA (alpha smooth muscle actin).

[0077] Vasa vasorum exist in the adventitial layer. During vein dissection, the adventitial layer and vasa vasorum are damaged to induce a hypoxic condition in the vascular wall. This hypoxic condition provokes unbalanced vascular nutrition and oxygen supply to promote the intimal influx of smooth muscle cells, leading to neointimal formation. Thus, it is necessary to induce angiogenesis in the outer vascular wall. Entry of a foreign matter into the body from the outside spontaneously induces a foreign body response leading to mild inflammation. That is, when the shape memory polymer is inserted into the body during the blood vessel wrapping procedure, mild inflammation occurs around vessels. This mild inflammation induces angiogenesis and the newly generated capillary vessels act as vasa vasorum. Immunostaining to capillary vessels (Flk1) and smooth muscle cells (?-SMA) revealed the existence of capillary vessels in normal vein and smooth muscle cells in the media layer and the adventitia. After establishment of the vein to artery model, capillary vessels were damaged and were not regenerated in the non-wrapping group (w/o external wrapping) so that the intimal influx of smooth muscle cells was accelerated, provoking vascular stenosis. In contrast, microvascular structures were found in the porous structure in the wrapping-applied group (w/ external wrapping), so that smooth muscle cells migrate toward adventitia to form neo-adventitia with the resultant inhibition of neointimal formation (see FIG. 7).

[0078] After establishment of the vein to artery graft model, the vein did not endure the relatively strong arterial pressure due to its poor physical properties compared to the artery, but underwent excessive dilatation. In the foregoing, the vascular wrapping was confirmed to have a suppressive effect on vascular dilatation. Such dilatation and suppression thereof may have influence on the pattern of blood flow from the artery to the dilated vein and then to the artery. If the blood flow is in turbulence, endothelial dysfunction occurs to inhibit anti-thrombotic and anti-inflammatory functions of vascular endothelial cells and induce the intimal influx of smooth muscle cells, resulting in stenosis. Shapes of the vein-to-artery graft inner wall immediately after the vein-to artery graft intervention and before and after the application of the wrapping device were depicted in a CAD file format. Using this CFD was performed to determine changes in blood flow pattern according to pulsatile flow. In this regard, it was assumed that there was no expansion/contraction movement of blood vessels according to the physical properties of blood vessels and polymers, and blood flow because simulations were performed using only the shape of the inner wall of blood vessels. As a result, the simulations indicated that the vein dilatation to up to 1270 mm after application of the wrapping device did not induce turbulence in the pulsatile flow whereas remarkable turbulence occurred in the vein dilated to about 1450 mm in the non-wrapping group. That is to say, it was indirectly confirmed that the vascular wrapping suppresses vascular dilatation and inhibits the formation of an eddy in blood flow, with the consequent prevention of stenosis.