TEMPERATURE-DEPENDENT SHAPE MEMORY POLYMER

Abstract

The present invention relates to a shape memory polymer that can be restored to an original shape from a deformed shape by means of body temperature in the body. When using the shape memory polymer of the present invention and a device for wrapping the outer wall of blood vessels prepared thereby, it is possible to effectively prevent abnormal blood vessel dilatation, and prevent stenosis by effectively inhibiting neointimal formation.

Claims

1. A shape memory polymer comprising a compound represented by Chemical Formula 1 below: ##STR00002## wherein, x is an integer of 1 to 20; m and n represent the mole % of repeating units, respectively; and m+n is 100 and m is 80 to 96.

2. The memory shape polymer according to claim 1, wherein x is an integer of 2 to 10.

3. The memory shape polymer according to claim 1, wherein m is 92 to 96.

4. A device for wrapping an outer vascular wall, the device comprising the shape memory polymer of any one according to claim 1.

5. The device according to claim 4, wherein the outer vascular wall is an outer vascular wall at a blood vessel anastomosis site.

6. The device according to claim 5, wherein the blood vessel anastomosis site is an anastomosis site between two different blood vessels selected from a vein, an artery, and an artificial blood vessel.

7. The device according to claim 6, wherein the blood vessel anastomosis site is a vein-artery anastomosis site.

8. The device according to claim 6, wherein the blood vessel anastomosis site is a vein-artificial blood vessel anastomosis site or an artificial blood vessel-artery anastomosis.

9. The device according to claim 4, which has an original shape or a temporary shape, wherein the original shape is in a hollow cylindrical tube shape or a hollow Y-tube shape, one side of which is cut in a lengthwise direction to enable a blood vessel to be inserted into a hollow space, wherein the temporary shape is maintainable at room temperature and is in a curved surface shape or a planar surface shape with both ends formed by the cutting being separated from each other, and wherein when applied to an outer vascular wall, the temporary shape is bent in a direction of increasing the curvature to wrap the outer vascular wall, thereby recovering to the original shape.

10. A method for manufacturing a device for wrapping an outer vascular wall, the method comprising: (a) photo-crosslinking a mixture of the shape memory polymer according to claim 1 and a photo-initiator to a hollow cylindrical tube shape or a hollow Y-tube shape to prepare a tube-type device; (b) cutting one side of the tube-type device in a length direction parallel to the central axis of a hollow space formed in the cylindrical tube or Y-tube; and (c) inducing the tube-type device with one side cut, into a temporary shape allowing the insertion of a blood vessel under a temperature condition exceeding the body temperature and then fixing the tube-type device by cooling at a temperature lower than room temperature.

11. The method according to claim 10, wherein the mixture of the shape memory polymer and the photo-initiator in step (a) further contains a porogen.

12. The method according to 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.

13. The method according to claim 10, wherein the photo-crosslinking in step (a) is performed by a 3D printer such that pores are formed.

14. The method according to claim 13, wherein the 3D printer is driven in any one manner selected from stereo lithography apparatus (SLA), digital light processing (DLP), and photopolymer jetting technology (PolyJet).

15. The method according to claim 10, wherein the temperature condition exceeding the body temperature is 42° C. to 65° C.

16. The method according to claim 10, further comprising an additional porosity providing step after any one of steps (a) to (c).

Description

BRIEF DESCRIPTION OF DRAWINGS

[0058] FIG. 1 illustrates a schematic diagram of an example of synthesis of a 4-arm structured copolymer. The monomers CL and GMA were added together with pentaerythritol as an initiator and reacted at 110° C. for 6 hours, thereby synthesizing 4-arm PCL-PGMA.

[0059] FIG. 2 illustrates NMR data for identifying a 4-arm PCL-PGMA copolymer as an example of a 4-arm structured copolymer. PCL peaks were confirmed at δ=4.10 [m, —OCH.sub.2, (E)], 2.41 [m, —CH.sub.2, (A)], 1.74 [m, —CH.sub.2, (B and D)], and 1.45 [m, —CH.sub.2, (C)], and PGMA peaks were confirmed at δ=6.13 [s, ═CH.sub.2, (G2)], 5.58 [s, ═CH2, (G1)], 1.97 [s, —CH.sub.3, (F)], indicating that 4-arm PCL-PGMA was synthesized.

[0060] FIG. 3 illustrates a GPC measurement graph to determine the molecular weight of the synthesized polymer. The 4-arm polymer had a peak at a longer retention time than the linear polymer, and thus had a larger molecule weight.

[0061] FIG. 4 illustrates a DSC measurement graph before crosslinking of the synthesized polymer. The reason that two peaks are shown in the linear PCL-PGMA (comparative example) and the 4-arm PCL-PGMA (example) compared with PCL is that the random binding of PGMA to PCL lowers the crystallinity of PCL to result in a difference in crystallinity. In addition, the peaks of the 4-arm PCL-PGMA are lower than those of the linear PCL-PGMA due to structural differences.

[0062] FIG. 5 illustrates a DSC graph before and after crosslinking of the example (4-arm PCL-PGMA). The random binding of PGMA to the comparative example (PCL) to lower crystallinity and thus lower the melting temperature of PCL, and the lowering of the crystallinity of PCL by PGMA makes a difference in crystallinity, thereby forming two peaks. After crosslinking, a network structure is formed by reaction of methacrylate, and thus one peak is shown and the melting temperature is lowered.

[0063] FIG. 6 illustrates a DSC graph after crosslinking of the linear PCL-PGMA (comparative example) and the 4-arm PCL-PGMA (example). As a result of comparing thermal characteristics of the two polymers, the melting temperature of the 4-arm polymer was lower. Therefore, the shape recovery was attained at a low temperature and the recovery rate to the original shape at the body temperature could be increased.

[0064] FIG. 7 illustrates tensile strength measurement graphs after polymer crosslinking. FIG. 7A shows strain-stress curves of the comparative example (linear PCL-PGMA) and the example (4-arm PCL-PGMA) measured at the body temperature, 37° C.; and FIG. 7B illustrates a graph comparing Young's modulus between the comparative example and the example at room temperature (25° C.) and the body temperature (37° C.). In the tensile strength measurement at 37° C., the example showed a higher elongation than the comparative example due to its rubbery properties (FIG. 7A). The example showed a lower Young's modulus at 25° C. and 37° C. than the comparative example and thus had an advantage of being rubbery, resulting in easier deformation at 25° C. and 37° C., so that when inserted into a curved part in the body, the example was less bent to reduce a foreign-object sensation (FIG. 7B).

[0065] FIG. 8 illustrates images confirming the shape recovery ability of the 4-arm polymer of the present invention. The sample with an original shape was deformed by pulling or folding at 55° C. or higher. The deformed sample was fixed with liquid nitrogen to be converted to a temporary shape, which was then subjected to heating at Tm value or higher to investigate the shape memory ability. The 4-arm PCL-PGMA was well recovered from the temporary shape to the original shape.

[0066] FIG. 9 illustrates schematic diagrams of cylinder shape and Y-shape devices for wrapping an outer vascular wall and schematic diagrams of the arrangement of an artery, a vein, and an artificial blood vessel (graft) at regions at which the respective types of devices were applied. The respective diagrams show: a cylinder shape device for wrapping an outer vascular wall, the device being applied to a side to side model for connecting a side of the artery and a side of the vein (top left); a Y-shape device for wrapping a outer vascular wall, the device being applied to a side to end model for connecting a side of the artery and an end of the vein (top right); when a side of the vein and a side of the artery are separately connected to ends of the artificial blood vessel, a Y-shape device for wrapping an outer vascular wall, the device being applied to an end to side model for connecting the side of the vein and the end of the artificial blood vessel (bottom left); and a Y-shape device for wrapping an outer vascular wall, the device being applied to an end to side model for connecting the side of the artery and the end of the artificial blood vessel (bottom right).

[0067] FIG. 10 illustrates manufacturing schematic diagrams through the control of the mesh type or size of a device for wrapping an outer vascular wall by using a 3D printer. The drawings show a large circular mesh structure (A), a small circular mesh structure (B), a large square mesh structure (C), and a small square mesh structure (D).

[0068] FIG. 11 illustrates designs for manufacturing devices for wrapping an outer vascular wall by using a 3D printer. The diagrams show a Y-shape and small circular mesh design (A, top), a cylinder shape and small circular mesh design (A, bottom), a Y shape and small square mesh design (B, top), and a cylinder shape small square mesh design (B, bottom).

[0069] FIG. 12 illustrates schematic diagrams showing an arteriovenous fistula model (side-to-side) prepared using the femoral vein and the femoral artery of a beagle dog and a state in which a device for wrapping an outer vascular wall was placed on the arteriovenous fistula model.

[0070] FIG. 13 illustrates histological analysis (H&E staining) results of a blood vessel anastomosis site on which a device for wrapping an outer vascular wall was placed or not placed.

[0071] FIG. 14 illustrates confocal laser scanning microscopy results through immunostaining of Flk-1 and α-SMA and its quantitative graph in order to investigate the migration pattern of smooth muscle cells and neo-blood vessel formation according to whether or not a device for wrapping an outer vascular wall was placed.

MODE FOR CARRYING OUT THE INVENTION

[0072] Hereinafter, the present invention will be described in more detail with reference to exemplary embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present invention in more detail, and therefore, according to the present invention, it would be apparent to a person skilled in the art that these examples are not construed to limit the scope of the present disclosure.

EXAMPLES

Example 1

Compound Synthesis

[0073] In a 3-neck round bottom flask, a magnetic bar was placed, and pentaerythritol (initiator, 0.5 mmol, Sigma Aldrich) and hydroquinone (inhibitor, HQ, 2.5 mmol, Sigma Aldrich) were added. The flask was capped, vacuumed for 10 minutes, and then purged with nitrogen gas at a rate of 50 cc/min. Purified c-caprolactone (monomer, CL, 225 mmol, Sigma Aldrich) was injected into the flask by a 20 G syringe needle. The stirring was conducted at 180 rpm for 10 minutes at 110° C. Glycidyl methacrylate (monomer, GMA, 25 mmol, Sigma Aldrich) was injected by a 20 G syringe needle. Ten minutes after the injection of glycidyl methacrylate, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, catalyst, 2.5 mmol, Sigma Aldrich) dissolved in 1 mL of acetonitrile (ACN, Sigma Aldrich) was injected by a 20 G syringe needle (2.5 mmol TBD/1 mL ACN). Thereafter, the mixture in the flask was reacted at 110° C. for 6 hours. The final reaction product was dissolved in 15 mL of chloroform (Daejung chemicals & metals CO., LTD., Korea) and then precipitated in 400 mL of cold ethyl ether (Daejung chemicals & metals CO., LTD., Korea) at 4° C. The precipitate thus obtained was filtered and then dried under vacuum.

Comparative Example 1

Control Compound Synthesis

[0074] In a 3-neck round bottom flask, a magnetic bar was placed, and 1,6-hexanediol (initiator, 0.5 mmol, Sigma Aldrich) and hydroquinone (inhibitor, HQ, 1 mmol, Sigma Aldrich) were added. The flask was capped, vacuumed for 10 minutes, and then purged with nitrogen gas at a rate of 50 cc/min. Purified c-caprolactone (monomer, CL, 90 mmol, Sigma Aldrich) was injected into the flask by a 20 G syringe needle. The stirring was conducted at 180 rpm for 10 minutes at 110° C. Glycidyl methacrylate (monomer, GMA, 10 mmol, Sigma Aldrich) was injected by a 20 G syringe needle. Ten minutes after the injection of glycidyl methacrylate, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, catalyst, 2.5 mmol, Sigma Aldrich) dissolved in 1 mL of acetonitrile (ACN, Sigma Aldrich) was injected by a 20 G syringe needle (1 mmol TBD/1 mL ACN). Thereafter, the mixture in the flask was reacted at 110° C. for 6 hours. The final reaction product was dissolved in 15 mL of chloroform (Daejung chemicals & metals CO., LTD., Korea) and then precipitated in 400 mL of cold ethyl ether (Daejung chemicals & metals CO., LTD., Korea) at 4° C. The precipitate thus obtained was filtered and then dried under vacuum.

[0075] The raw material mixing for copolymer synthesis is shown in Table 1 below.

TABLE-US-00001 TABLE 1 Penta- eryth- HD ritol TBD HQ CL GMA (mmol) (mmol) (mmol) (mmol) (mmol) (mmol) Linear PCL- 0.5 — 1 1 90 10 PGMA 4-arm PCL- — 0.5 2.5 2.5 225 25 PGMA

[0076] 1,6-Hexanediol (HD) and pentaerythritol were used as an initiator; 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was used as a catalyst; hydroquinone (HQ) was used as an inhibitor; and ϵ-caprolactone (CL) and glycidyl methacrylate (GMA) were used as monomers.

Example 2

Compound Crosslinking

[0077] Each polymer was dissolved in N-methyl-2-pyrrolidone (NMP, Sigma Aldrich) at a ratio of 100 w/v %. Irgacure 2959 (photo-initiator, Sigma Aldrich) was added to the solution at a ratio of 0.1 w/v %. Thereafter, the solution was crosslinked (265 mW/cm.sup.2, 200 s) in the form of a film by using a UV lamp (Omnicure S2000, Lumen Dynamics Group Inc., Canada).

Example 3

Structure Analysis (NMR Measurement)

[0078] Structure analysis was conducted using H.sup.1-NMR (AVANCE III HD 400, Bruker Biospin, USA) along with each polymer and Chloroform-D (Sigma Aldrich) at a concentration of 10 mg/Ml. The NMR measurement results are shown in FIG. 2.

[0079] PCL peaks were confirmed at δ=4.10[m, —OCH.sub.2, (E)], 2.41[m, —CH, (A)], 1.74[m, —CH.sub.2, (B and D)], and 1.45 [m, —CH.sub.2, (C)], and PGMA peaks were confirmed at δ=6.13[s, ═CH.sub.2, (G2)], 5.58[s, ═CH.sub.2, (G1)], and 1.97[s, —CH.sub.3, (F)], indicating that linear PCL-PGMA(A) and 4-arm PCL-PGMA(B) were synthesized.

Example 4

Molecular Weight Analysis (GPC)

[0080] Example 1-1 of PCL-co-PGMA in Korean Patent Registration No. 10-1906472 was used as a comparative example.

[0081] Molecular weight analysis was conducted using the PLgel 5 μm MIXED-D column (Agilent Technologies Inc., USA) of gel permeation chromatography (GPC) along with each polymer and tetrahydrofuran (THF, J. T. Baker) at a concentration of 5 mg/mL. THF was used as an eluent, and the flow rate and the column temperature were 1 mL/min and 40° C., respectively. The standard curve was obtained using polystyrene (PS).

[0082] The molecular weight analysis results are shown in FIG. 3 and Table 2.

TABLE-US-00002 TABLE 2 Mn Mw Polymer (Da) (Da) PDI Comparative example 8,976 13,418 1.49 (Linear PCL-PGMA) Example (4-arm PCL-PGMA) 11,381 15,708 1.38

[0083] As shown in FIG. 3, the peak of the example was observed at a longer retention time than the peak of the comparative example, indicating a larger molecular weight. The GPC data measured to identify the molecular weight of the synthesized polymers are shown in Table 2. Compared with the comparative example, the example showed a higher molecular weight by about 2,300 Da and a smaller PDI value. Compared with the comparative example, the example showed a PDI value closer to 1, indicating a more uniform polymer chain size.

Example 5

Differential Scanning Calorimetry (DSC)

[0084] Thermal characteristics were measured using a differential scanning calorimeter (DSC, Discovery DSC25, TA instrument Inc., USA). The sample was subjected to measurement at a rate of 10° C./min from −80° C. to 150° C.

[0085] The DSC measurement Data before the crosslinking of the synthesized polymers are shown in Table 3.

TABLE-US-00003 TABLE 3 Tm, 1 Tm, 2 Hm Tc Hc Polymer (° C.) (° C.) (J/g) (° C.) (J/g) Comparative Example 1 53.04 — 79.41 28.49 80.42 (PCL) Comparative Example 2 46.08 51.18 72.61 21.3 70.93 (Linear PCL-PGMA) Example 43.60 48.98 63.07 18.15 64.43 (4-arm PCL-PGMA)

[0086] The reduction in crystallinity of a crystalline polymer results in reductions in the melting point (Tm), melting enthalpy (Hm), crystallization temperature (Tc), and crystallization enthalpy (Hc). When PGMA randomly bound to the crystalline polymer PCL, PGMA interfered with the formation of PCL crystals to reduce crystallinity thereof, so that compared with comparative example 1, comparative example 2 and the example showed reductions in the melting point (Tm), melting enthalpy (Hm), crystallization temperature (Tc), and crystallization enthalpy (Hc). In addition, in the comparison between comparative example 2 and the example, the example having a 4-arm structure was less crystallized than comparative example 2 having a linear structure, and such a structural difference resulted in lower melting and crystallization temperature. The example showed lower melting and crystallization temperatures and thus could be recovered to its shape at a lower temperature after crosslinking.

[0087] The DSC measurement results before and after the crosslinking of the synthesized polymer are shown in Table 4.

TABLE-US-00004 TABLE 4 Tm Hm Tc Hc Polymer Crosslinking (° C.) (J/g) (° C.) (J/g) Comparative Example — 53.04 79.41 28.49 80.42 (PCL) Example Before 43.60/ 63.07 18.15 64.43 (4-arm PCL-PGMA) crosslinking 48.98 After 32.81 33.22 −14.40 30.99 crosslinking

[0088] The DSC measurement results after the crosslinking of the synthesized linear PCL-PGMA and 4-arm PCL-PGMA are shown in Table 5 and FIG. 6.

TABLE-US-00005 TABLE 5 XTm XHm XTc XHc Polymer (° C.) (J/g) (° C.) (J/g) Comparative Example 39.40 44.39 1.20 43.84 (Linear PCL-PGMA) Example 32.81 33.22 −14.40 30.99 (4-arm PCL-PGMA)

[0089] As for the crosslinking of a polymer, the acryloyl group of PGMA acts as a crosslinking point to allow the polymer to have a network structure, and the branches linking chains in the network structure interfere with crystallizing, thereby reducing crystallinity and further reducing the Tm value after crosslinking. The example had a 4-arm structure and thus had a reduced crystallinity as shown in Table 3, resulting in reductions in the melting point (Tm), melting enthalpy (Hm), crystallization temperature (Tc), and crystallization enthalpy (Hc), which were further reduced after crosslinking. The polymer compound of the present invention had reduced crystallinity and thus had a lower Tm value by about 6° C. compared with the linear polymer, thereby recovering to its shape at a lower temperature and increasing the recovery rate to its original shape at the body temperature. Since the body temperature is higher than the Tm value of the polymer compound of the present invention, the polymer compound was almost a rubbery state in the body, and therefore, the insertion of the polymer compound into the body can reduce a foreign-object sensation.

Example 6

Dynamic Mechanical Analysis (DMA)

[0090] Each sample crosslinked in a film form (W: 5 mm×L: 45 mm×T: 0.45 mm) was measured for mechanical properties by using dynamic mechanical analysis (DMA, Discovery DMA850, TA instruments Inc., USA). The sample was subjected to a tensile test at the body temperature 37° C. at a rate of 10%/min to 190% strain. To measure the Young's modulus over temperature over time, the tensile test was conducted at 25° C. (room temperature) and 37° C. (body temperature) up to 190% strain at a rate of 10%/min, respectively.

[0091] The test results for tensile stress are shown in Table 6 and FIG. 7.

TABLE-US-00006 TABLE 6 Young's modulus Stress Max. strain Polymer (MPa) (MPa) (%) Comparative Example 22.06 ± 1.12 2.03 ± 0.04 121.31 ± 10.31 (Linear PCL-PGMA) Example 10.00 ± 1.79 1.67 ± 0.04 More than 190% (4-arm PCL-PGMA)

[0092] Since the difference in Young's modulus value at 37° C. between the comparative example and the example was 12 MPa or more, the example can more easily deform the shape than the comparative example. When tensioned with strain 190%, the comparative example was fractured at an average of 121.31%, but the example was not fractured even at 190%. Therefore, from the tensile test results at 37° C., the example has greater rubbery properties and showed a higher elongation than the comparative example.

Example 7

Shape Recovery Ability

[0093] Each crosslinked film was placed in water at 55° C., deformed, and then fixed with liquid nitrogen (temporary shape), and thereafter, water having a temperature of a Tm value or higher was added to investigate its shape recovery. As a result of investigating the shape recovery ability, the 4-arm shape memory polymer had a shape recovery ability (see FIG. 8).

Example 8

Prevention of Stenosis of Arteriovenous Fistula Model (Side-to-Side) Using Mammal

8-1. Preparation of Arteriovenous Fistula Model

[0094] An incision of approximately 0.5 cm was made on the side of the femoral vein and the side of the femoral artery of a beagle dog weighing 8-10 kg, and the incised portions were allowed to face each other and subjected to side-to-side anastomosis using a suture, thereby constructing a vein to artery graft model. A temporary shape device for wrapping a outer vascular wall was placed at the blood vessel including the anastomosis site and treated with saline at 40° C. to recover to its existing tube shape, thereby wrapping the blood vessels at the anastomosis site (see FIG. 12).

8-2. Blood Vessel Stenosis Level and Organ Patency Rate

[0095] The condition and size of blood vessels were investigated through histological analysis (H&E staining) of the vein graft according to whether or not a device for wrapping an outer vascular wall was placed.

[0096] As a result, the group without the placement of a device for wrapping an outer vascular wall showed that the vein was blocked or the neointima formation progressed significantly, resulting in poor patency, but the group with the placement of a device for wrapping an outer vascular wall showed that the neointima formation hardly progressed, indicating good patency (see FIG. 13).

[0097] These results established that the device for wrapping an outer vascular wall of the present invention suppressed the vortex formation caused by a difference in blood flow between the artery and the vein, thereby preventing blood vessel stenosis and improving organ potency rates.

8-3. Smooth Muscle Cell Migration Pattern

[0098] The smooth muscle cell migration pattern was investigated by immunostaining of an endothelial cell marker (Flk-1) and smooth muscle cell marker (alpha smooth muscle actin, α-SMA).

[0099] As a result, the group without the placement of a device for wrapping an outer vascular wall showed that the migration of smooth muscle cells to the intima was promoted to lead to neointima formation, but the group with the placement of a device for wrapping an outer vascular wall showed that smooth muscle cells migrate in a direction of the adventitia to inhibit neointima formation, leading to the formation of neo-adventitia (see FIG. 14).

[0100] These results established that the device for wrapping an outer vascular wall of the present invention induced smooth muscle cells of the media of a blood vessel in a direction of the adventitia, thereby preventing stenosis inside the blood vessel and reinforcing the vein with relatively weaker properties than the artery.

8-4. Induction of Neo-Vasa Vasorum Formation Outside Vein Graft

[0101] The neo-blood vessel formation was investigated by immunostaining of an endothelial cell marker (Flk-1) and smooth muscle cell marker (alpha smooth muscle actin, α-SMA).

[0102] As a result, a comparatively large amount of neo-blood vessels was formed in the adventitia in the group with the placement of a device for wrapping an outer vascular wall (see FIG. 14). During the construction of a vein-to-artery graft model, the stripping of the vein causes adventitia damage and vasa vasorum loss, thereby inducing a hypoxic state in the blood vessel wall, and this state causes an imbalance in the supply of nutrients and oxygen in the blood vessel to promote the mitigation of smooth muscle cells (SMCs) to the intima, causing neointimal hyperplasia and increasing the likelihood of blood vessel stenosis. Therefore, it is necessary to induce the formation of neo-vasa vasorum on the blood vessel wall for the smooth supply of nutrients and oxygen. It was established that the use of the device for wrapping an outer vascular wall of the present invention induced a light inflammatory response around the blood vessel, thereby inducing the formation of neo-blood vessels, and the formed neo-blood vessels act as a vasa vasorum to supply nutrients and oxygen and thus can prevent the development of neointimal hyperplasia and the occurrence of blood vessel stenosis.

INDUSTRIAL APPLICABILITY

[0103] The present invention relates to a shape memory polymer capable of recovering to its original shape from its deformed shape by the body temperature in the body.