STENT APPARATUS AND TREATMENT METHODS

Abstract

There is disclosed a method of treating hypoxia in tissue of a blood vessel, the method comprising placing a stent in the vessel, the stent having a centre line which curves in three dimensions to promote the supply of oxygen from the blood flowing in the lumen of the stented vessel to the vessel wall. There is disclosed a method of treating a subject with diabetic atherosclerosis, the method comprising placing a stent in a blood vessel of the subject, the stent having a centre line which curves in three dimensions to promote the supply of oxygen from the blood flowing in the lumen of the stented vessel to the vessel wall.

Claims

1. Apparatus comprising a plurality of stents each having a centre line curving in three dimensions, the plurality of stents including at least one stent with a centre line having right-handed curvature and at least one stent with a centre line having left-handed curvature.

2. Apparatus as claimed in claim 1, comprising a plurality of right-handed curved stents and a plurality of left-handed curved stents.

3. A method of treating hypoxia in tissue of a blood vessel, the method comprising placing a stent in the vessel, the stent having a centre line which curves in three dimensions to promote the supply of oxygen from the blood flowing in the lumen of the stented vessel to the vessel wall.

4. A method of treating a subject with diabetic atherosclerosis, the method comprising placing a stent in a blood vessel of the subject, the stent having a centre line which curves in three dimensions to promote the supply of oxygen from the blood flowing in the lumen of the stented vessel to the vessel wall.

5. A method as claimed in claim 3 or 4, wherein the stent when expanded ex vivo has a helical centre line.

6. A method as claimed in claim 3, 4 or 5, wherein the stent comprises a shape memory material.

7. A method as claimed in claim 3, 4 or 5, wherein the stent comprises a plastically deformable material.

8. A method as claimed in any of claims 3 to 7, wherein the stent is expanded with the aid of a balloon.

9. A method of treating hypoxia in tissue of a blood vessel in which a stent is already disposed, the method comprising placing an expandable member in a collapsed condition thereof radially inwardly of the stent in the vessel, and expanding the expandable member from the collapsed condition to an expanded condition in which the expandable member has a centre line which curves in three dimensions, so as to cause the stent to adopt a shape in which it also has a centre line which curves in three dimensions.

10. A method as claimed in claim 9, wherein the expandable member is a balloon.

11. A method as claimed in claim 9 or 10, wherein the centre line of the expandable member when expanded ex vivo to the expanded condition is a helical centre line.

12. A method as claimed in claim 9, 10 or 11, wherein the stent comprises a plastically deformable material.

13. A method of treating a subject for whom blood vessel stenting is indicated, the method comprising placing a drug eluting stent in the vessel, the stent having a centre line which curves in three dimensions.

14. A method as claimed in claim 13, wherein the vessel is a main vessel and a branch vessel extends from the main vessel, and wherein the stent is placed in the main vessel so that at least a portion of the stent extends in the main vessel upstream of the branch vessel.

15. A method as claimed in claim 14, comprising stenting the branch vessel.

16. A method of treating a subject for whom blood vessel stenting is indicated, wherein the vessel is a main vessel and a branch vessel extends from the main vessel, the method comprising placing the stent in the main vessel so that at least a portion of the stent extends in the main vessel upstream of the branch vessel, and the stent having a centre line which curves in three dimensions.

17. A method of treating a blood vessel branching from another vessel having a stent therein with at least a portion of the stent being upstream of the branch vessel, the method comprising placing an expandable member in a collapsed condition thereof radially inwardly of the stent in the vessel, and expanding the expandable member from the collapsed condition to an expanded condition in which the expandable member has a centre line which curves in three dimensions, so as to cause the stent to adopt a shape in which it also has a centre line which curves in three dimensions.

18. A method as claimed in claim 17, wherein the stent comprises a plastically deformable material.

19. A drug eluting stent having a centre line which curves in three dimensions.

20. A method of treating a subject for whom blood vessel stenting is indicated, comprising identifying a treatment site, determining whether natural vessel geometry at that treatment site will impart right-handed swirl flow or left-handed swirl flow to the blood flow along the vessel, and selecting for placement at the treatment site a stent having a centre line with three-dimensional curvature, the selected stent having right-handed curvature if the vessel has been determined to naturally impart right handed swirl flow and the selected stent having left-handed curvature if the vessel has been determined to naturally impart left-handed swirl flow.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Certain preferred embodiments of the invention will now be described by way of example and with reference to the accompanying drawings, in which:

[0054] FIG. 1 is a perspective view of an embodiment of a helical stent in accordance with the invention;

[0055] FIG. 2 is a perspective view illustrating flow in a straight stent;

[0056] FIG. 3 is a perspective view illustrating flow in a helical stent;

[0057] FIG. 4 shows a pair of porcine carotid arteries implanted with straight and helical stents;

[0058] FIG. 5 shows a computational fluid dynamics (CFD) simulation of flows in porcine carotid arteries stented with straight and helical stents;

[0059] FIGS. 6a and 6b show transverse histology sections of proximal, middle and distal segments of carotid arteries one month after stent deployment; FIGS. 7a and 7b show graphs of intima/media thickness ratios for helical stented and straight stented carotid arteries, respectively;

[0060] FIGS. 8a to 8d show graphs of adventitial micro vessel counts at distal, middle and proximal locations, and the average of the distal, middle and proximal counts, respectively, for helical stented and straight stented carotid arteries;

[0061] FIG. 9 is a perspective view of a helical stent with right-handed curvature;

[0062] FIG. 10 is a perspective view of a helical stent with left-handed curvature;

[0063] FIG. 11 shows perspective views of a drug eluting helical stent at a vessel branch, with a straight stent in a collateral vessel;

[0064] FIG. 12 shows perspective views of a drug eluting helical stent at a vessel branch, without there being any stent in a collateral vessel; and

[0065] FIG. 13 shows a perspective view of a bare metal helical stent at a vessel branch, without there being any stent in a collateral vessel.

DETAILED DESCRIPTION

[0066] FIG. 1 shows a self-expanding stent 1 made from a shape memory alloy, in this case nitinol. The stent 1 has a helical centre line 2. The stent 1 comprises struts 22.

[0067] FIGS. 2 and 3 show the flow in straight and helical stented arteries respectively. The flow lines 3 in the straight stented artery shown in FIG. 2 are generally straight, whereas the flow lines 3 in the helical stented artery show a swirling pattern illustrating how fluid at the vessel wall is transported towards the centre of the flow and vice versa.

[0068] FIG. 4 shows an angiogram image of a pair of porcine carotid arteries 20 which have been stented. The straight stented artery 4 is shown on the right hand side, having downstream and upstream ends 6. The helical stented artery 5 is shown on the left hand side, having downstream and upstream ends 7. It can be seen that the straight stented artery is substantially straight and that the helical stented artery exhibits three dimensional curvature.

[0069] FIG. 5 shows vector diagrams produced by a computational fluid dynamic simulation of flow in stented arteries. At the upper left of the drawing the porcine carotid arteries are shown, and portions thereof are shown to an enlarged scale on the right of the drawing. The straight stented artery is indicated at reference 4 and the helical stented artery is indicated at reference 5. The vectors themselves are shown as brush like images, with each bristle of the brush being a flow vector. Each image represents the flow across the transverse section of the respective artery at the region shown. Each vector shows the so-called secondary component of the flow field, i.e. the component of flow at the relevant point on the transverse section which is perpendicular to the longitudinal axis of the artery, along which there is the primary flow. It will be seen that the helical stented artery 5 exhibits a distinctive swirling pattern and that this swirl flow involves relatively high secondary flow velocities, indicated by the relatively large length of the vectors, near the inside (medial) wall of the artery. On the other hand, the near wall vector length for the straight stented artery 4 is relatively small, indicating slower secondary near wall flow velocities.

[0070] Transverse sections of segments of the carotid arteries one month after implantation are shown in FIG. 6. FIG. 6a shows a proximal section 8, a middle section 9 and a distal section 10 for the straight stented artery 4, FIG. 6b shows a proximal section 11, a middle section 12 and a distal section 13 for the helical stented artery 5.

[0071] FIG. 9 shows a stent 1 with right-handed curvature, for use in a vessel which has been determined to naturally impart right handed swirl flow, and FIG. 10 shows a stent 1 with left-handed curvature for use in a vessel which has been determined to naturally impart left-handed swirl flow. In FIG. 9 an arrow indicates the clockwise, right-handed curvature and in FIG. 10 an arrow indicates the counter clockwise, left-handed curvature. The pair of stents form a kit, or apparatus, from which an appropriate stent may be selected. In such a kit, additional right- and left-handed curvature stents may be provided. When a clinician wishes to stent a vessel, the kit provides a choice of using a right-hand curved stent or a left-hand curved stent. A stent may be selected as appropriate to complement the natural direction of swirl and not to tend to cancel it.

[0072] FIG. 11 shows a drug eluting stent 1 having a centre line which curves in three dimensions. The stent has struts 22 and is placed in a main vessel 20. The direction of flow of blood in the main vessel 20 is indicated by the arrows, i.e. the blood inflow is at the lower end of the vessel as seen in the Figure, and the blood outflow is at the upper end of the vessel. Because the stent has a centre line which curves in three dimensions, it imposes a corresponding curved centre line on the main vessel 20. The effect is to promote swirling flow as indicated by the flow lines 3.

[0073] A branch vessel 21 branches from the main vessel 22. This is shown stented with a conventional stent 15 having a straight centre line. The secondary flow over the struts 22 which are coated with a drug causes the drug to be moved from the immediate vicinity of each strut to the areas between the struts. This may inhibit intimal growth in those areas, and therefore intimal growth overall. In addition, the drug may be carried by the secondary flow into the branch vessel 21. The stent 15 in the branch vessel is a non-drug eluting stent. However, the drug carried from the main vessel 20 can provide a therapeutic benefit in the branch vessel 21 where it is stented by the stent 15. Finally, the secondary flow in the main vessel may increase the flow into the branch vessel 21 (compared to a situation where the main vessel was stented with a straight stent), promoting secondary flow in the branch vessel and hence providing a therapeutic benefit.

[0074] FIG. 12 shows a similar arrangement to FIG. 11, with the difference being that there is no stent in the branch vessel 21. In this case the swirl flow again allows the drug on the struts 22 of the stent 1 in the main vessel 20 to be conveyed to the areas between the struts. The secondary flow in the main vessel assists conveyance of the drug into the secondary vessel, where it may inhibit the development of a stenosis at the proximal end of the branch vessel. The secondary flow in the main vessel may increase the flow generally (irrespective of the presence of the drug) to the branch vessel 20 and thereby also aid perfusion and inhibit stenosis development.

[0075] FIG. 13 shows a stent 1 having struts 22 in a main vessel 20. The stent 1 is a bare metal stent (i.e. it is not a drug eluting stent) having a centre line which curves in three dimensions. This increases secondary flow in the main vessel compared to a situation where the main vessel is provided with a straight stent. The secondary flow may act to increase the flow into the branch vessel 21, which may aid perfusion and inhibit stenosis development in the branch vessel 21.

[0076] The stent shown in FIG. 13 may be constructed to have a helical geometry when in an expanded condition from the outset. Therefore, it may be a balloon expandable stent or a self-expanding stent comprising a shape memory material, in each case being designed to adopt a helical shape when expanded. Alternatively, the stent shown in FIG. 13 may have been already installed in the vessel, and it has then been post dilated using a helical expandable member, such as a balloon, so as to adopt the helical shape shown in FIG. 3. This may provide a way of treating a stenosis which has developed in the branch vessel 21 following the initial straight stent placement in the main vessel 20. The shape of the stent in the main vessel is modified to have a centre line which curves in three dimensions, thereby providing this treatment.

Example

[0077] A study was undertaken using ten pigs. In each animal a straight stent was placed in one of the carotid arteries and a helical stent was placed in the contralateral carotid artery. Ultrasound was used to measure the arteries for stent diameter selection and the stents were oversized with respect to the internal artery diameter. Five of the straight stents were deployed in a right artery and five in the left, and five of the helical centre line stents were deployed in the left carotid artery and five in the right carotid artery. Digital subtraction angiography, using a contrast agent, was performed immediately after stent deployment to assess vessel geometry. An example is shown in FIG. 4. In addition, a small bolus of contrast agent was injected intraluminally to assess whether there was swirling. Doppler ultrasound was used to detect swirling flow in the helically stented artery. In the contralateral straight stented vessel, axial passage of the contrast agent was observed.

[0078] Implantation of both the straight stent and the helical stent caused immediate deformation of the vessels, but the latter stent caused additional helical deformation of vessels and swirling of intraluminal flow. The changes persisted to the end of the study at 30 days. In fact, the maximum stent amplitude increased from the time of implantation to the time of termination at 30 days.

[0079] The amplitude ratio is the helical amplitude divided by the internal diameter of the stent. The average maximum amplitude ratio for the ten helically stented arteries was 0.18 with a standard deviation of 0.11 at implantation and 0.31 with a standard deviation of 0.14 at day 30.

[0080] After termination at 30 days transverse sections of proximal (downstream), middle and distal (upstream) segments of the carotid arteries were studied. An example of a straight stented artery, showing these three segments, is shown in FIG. 6a, and an example of a helically stented artery, having these three segments, is shown in FIG. 6b.

[0081] Histological study showed the neointima to consist of smooth muscle cells in an organised extra-cellular matrix, with uniform endothelial cell coverage and no difference between the straight centre line stented and helical centre line stented groups, with respect to inflammation, mural thrombosis, or re-endothelialization scorings. Transverse sections from the proximal, middle and distal segments of the stented carotid arteries showed intimal thickness to be significantly less in the helical centre line stented than straight centre line stented vessels, as seen in FIG. 6. Averaged over the three segments, intimal thickness was 45% lower in the helical centre line stented artery than in the straight centre line stented artery.

[0082] In a healthy artery or vein the intima forms the innermost layer. It is made up of one layer of endothelial cells which are in direct contact with the blood flow and internal elastic membrane. Radially outwardly of the intima is a middle layer known as the media. In this example the intima/media thickness ratio was investigated.

[0083] The results are shown in FIG. 7. FIG. 7a shows a graph of intima/media thickness ratios for the helical stented artery and FIG. 7b shows a graph of intima/media thickness ratios for the straight stented artery. Comparing FIG. 7a showing the helically stented artery with FIG. 7b showing the straight stented artery, it will be seen that the intima/media thickness ratio was significantly higher overall in the straight centre line stented than the helical centre line stented vessels. In addition, the ratio was significantly lower in the distal than proximal or middle segments in the helical centre line stented vessels. Thus, the histology revealed the intima/media thickness ratio and intimal hyperplasia to be significantly lower in helical centre line stented arteries than in straight centre line stented arteries.

[0084] The number of adventitial micro vessels was determined for each sample, for both the helical centre line stented and straight stented arteries. Adventitial micro vessel number was not correlated with section thickness. The results shown in FIG. 8 therefore are presented as adventitial micro vessel density (number of micro vessels per unit adventitial area). FIG. 8a shows a graph of adventitial micro vessel counts at the distal location for the helical (3D) stented and straight stented carotid arteries, FIG. 8b shows a graph of adventitial micro vessel counts at the middle location for the helical (3D) stented and straight stented carotid arteries, FIG. 8c shows a graph of adventitial micro vessel counts at the proximal location for the helical (3D) stented and straight stented carotid arteries, and FIG. 8d shows a graph of the average of the distal, middle and proximal adventitial micro vessel counts, for helical (3D) stented and straight stented carotid arteries. Considering the averaged results for the proximal, middle and distal segments shown in FIG. 8b, adventitial micro vessel density was significantly lower in the helical centre line stented than straight centre line stented arteries, the values being: helical centre line stented 130.87.2; straight centre line stented 216.319.1. The difference between helical centre line stented and straight centre line stented vessels was pronounced in the proximal and middle segments, but not significant in the distal segments.

[0085] It was found that adventitial micro vessel density was significantly lower in the helical centre line stented vessels than in the straight centre line stented arteries. This supports the proposal that adventitial micro vessel density is representative of wall hypoxia. The lesser occurrence of intimal hyperplasia in the helical centre line stented arteries than in the straight centre line stent arteries resulted from improved intraluminal mixing and hence enhanced blood-wall mass transport, thereby reducing the effect of stent-induced wall hypoxia.

[0086] We also consider changes in the different (proximal, middle and distal) segments of the straight- and helical centre line stented arteries. The proximal segment is at the upstream end of the artery and the distal segment is at the downstream end. The flow can be expected to develop with distance along both types of stented artery. In the straight centre line case, presuming the vessel to be straight, circular, uniform in cross-section and unbranched, wall shear stress will fall with distance along it, due to the cylindrical shape imposed by the stent and hence the development of a thicker boundary layer where blood flow speeds are slow or even stagnant. In the helical centre line case, the flow will additionally depend on the curvature of the helical vessel and, assuming the diameter and other geometric parameters to remain constant along the vessel, wall shear stress will, in contrast with the straight case, rise with distance as swirl flow develops, with the consequent reduction in the thickness of the boundary layer. Assuming that increase of wall shear stress lessens intimal hyperplasia, the lower intima/media thickness ratio in the distal than proximal and middle segments of the helical centre line stented vessels, as shown in FIGS. 7a and 7b, could, therefore, relate to a rise of wall shear stress associated with development of the flow.

[0087] Measurements from angiograms show, however, that both the helical- and straight-stented carotid arteries taper in the downstream direction (the proximal to distal direction), their cross-sectional areas decreasing on average from 24 mm.sup.2 to 20 mm.sup.2 between the proximal and distal segments. Provided the mass flux remained essentially constant along the vessels, such tapering would increase wall shear stress proceeding downstream and could therefore contribute to explaining the lower intima/media thickness ratio seen in the distal than proximal and middle segments of helical centre line stented carotid arteries. Moreover, it could help explain the tendency for the intima/media thickness ratio to be lowerrather than predicted higherproceeding from the proximal to distal segments of straight centre line stented vessels, as seen in FIG. 7.

[0088] There is, however, evidence supportive of the hypothesis that helical centre line stented carotid arteries were less hypoxic than straight centre line stented vessels, namely that supplementary oxygen reduced the severity of intimal hyperplasia after arterial stenting in animals. It is clear that, whether the section considered is proximal, middle or distal, the density of adventitial micro vessels, which is representative of hypoxia, is greater for straight stented vessels than for helically stented vessels. The average adventitial micro vessel counts shown in FIG. 8d show a higher average adventitial micro vessel density in the straight stented arteries compared to the helically stented arteries.