Electrospun cardiovascular implant

Abstract

The present disclosure relates to electrospun cardiovascular implants. A biodegradable cardiovascular implant is provided for growing cardiovascular tissue in a patient. The implant is distinguished from electrospun meshes of supramolecular compounds having hard segments covalently bonded to soft segments, thereby greatly improving durability and resistance to fatigue while maintaining the effectiveness of the cardiovascular implant.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880084445.9. Invention Field

[0002] This invention relates to electrospun cardiovascular implants. Background Technology

[0003] Current cardiovascular alternatives and implants face risks due to coagulation, infection, degeneration, and the potential for non-growth. Tissue engineering, a relatively new approach, uses the patient's own cells and biodegradable polymer scaffolds to create autologous tissue capable of growth, adaptation, and repair. Polymer scaffolds can be made from biocompatible, non-toxic polymers. The choice of polymer and the technology used to manufacture the scaffold influence the mechanical properties exhibited by the scaffold.

[0004] For cardiac tissue engineering, the most commonly used biodegradable synthetic scaffold materials are polyglycolic acid (PGA), polylactic acid (PLA), polyhydroxybutyrate (PHB), ε-polycaprolactone (PCL), or copolymers thereof. US20150173921 teaches the use of supramolecular compounds as the basis for biodegradable synthetic scaffolds in cardiovascular implants.

[0005] Despite recent progress, unmet medical needs remain, particularly because cardiovascular replacements and implants (such as heart valves, especially aortic or pulmonary valves) must meet the high standards set by the FDA and relevant regulations such as ISO 5840-1:2015, ISO 5840-2:2015, and ISO 5840-3:2015. Therefore, the focus of these high standards is on hydrodynamics, durability, and especially fatigue testing to ensure reasonable assurance of FDA approval, effectiveness, and safety.

[0006] This invention addresses this unmet need by providing enhanced durability and fatigue resistance to tissue-engineered cardiovascular implants while maintaining their effectiveness as cardiovascular implants. Summary of the Invention

[0007] A biodegradable cardiovascular implant for growing cardiovascular tissue in a patient is provided, comprising an electrospun web having a supramolecular compound {described in alternative embodiments as “consistent with” or “composed of”} having a hard segment covalently bonded to a soft segment, wherein the soft segment is a polycarbonate soft segment with a molecular weight ranging from 500 to 2000, and wherein the hard segment comprises a 2-ureido-4[1H]-pyrimidinone (UPy) compound and a chain extender having a chain extender ratio of 1.5 to 3 for the UPy compound.

[0008] The embodiments of the present invention exhibit greatly enhanced durability and fatigue resistance while maintaining effectiveness as a cardiovascular implant. Attached Figure Description

[0009] Figure 1 Multiple accelerated wear cycles (according to ISO 5840, aortic condition) relative to the R ratio are shown according to embodiments of the invention. Clearly, polycarbonate with 1000 g / mol and polymers with an R ratio of 1.5 or higher exhibit enhanced durability. Furthermore, the same polymers used in other valve designs with ratios of 1.5, 1.9, and 2 achieved AWT counts as high as 65 million, 123 million, and 78 million cycles, respectively.

[0010] Figure 2 Multiple accelerated wear cycles (according to ISO 5840, aortic condition) relative to fiber orientation are shown according to an embodiment of the invention. It was observed that aligned fibers achieved a higher cycle count compared to random fibers.

[0011] Figure 3A -C shows an image of the valve test results after 20 hours at 90 / 35 mmHg, according to an embodiment of the invention and relative to Table 2. It is clear that XP3 remains intact, while XP1 and XP2 show tears. Detailed Implementation

[0012] This invention provides enhanced durability and fatigue resistance for tissue-engineered cardiovascular implants while maintaining their effectiveness as cardiovascular implants.

[0013] A supramolecular compound is defined as a hard-block covalently bonded to a soft-block. The hard-block is based on the UPy moiety. The soft-block is the backbone of the supramolecular compound. Polycarbonate (PC) is used because it shows surprising benefits for the purposes and objectives of this invention, particularly compared to polycaprolactone.

[0014] The ratio between soft and hard segments affects material properties. Here, we describe the significant impact of component ratios within the hard segment on properties such as durability. We disclose specific combinations of ratios within the hard segment and the length of the polymer used to form the soft segment, resulting in enhanced mechanical properties (durability). Specifically, polycarbonates in the molecular weight range of 500-2000 provide enhanced durability and reduced fatigue compared to, for example, polycaprolactone. The hard segment comprises an Upy component, a diisocyanate, and a chain extender. For the ratio (R) of the 2-ureido-4[1H]-pyrimidinone (UPy) compound and the chain extender in the hard segment, the chain extender to UPy compound ranges from 1.5 to 3.

[0015] Example 1: Synthesis of supramolecular polymers

[0016] PCL polymers - XP1, XP2

[0017] To synthesize XP1, 30.0 g (37.5 mmol, vacuum dried) of telechelic hydroxyl-terminated polycaprolactone (800 g / mol), 4.4 g (37 mmol) of 1,6-hexanediol, and 6.3 g (37 mmol) of UPy monomer were dissolved in anhydrous DMSO (105 mL) at 80 °C. Hexamethylene diisocyanate (18.8 g, 111.5 mmol) was added to the reaction mixture with stirring, followed by one drop of tin dioctanoate. The reaction mixture was stirred overnight at 80 °C. The next day, the reaction mixture was cooled to 25 °C, and its viscosity was reduced by adding additional DMSO to precipitate the mixture in water. The polymer, collected as a white elastic solid, was redissolved in chloroform / methanol (7 / 3 v / v) and reprecipitated in excess methanol. After vacuum drying at 50 °C, a clear elastic solid was obtained. SEC (THF, PS-standard): Mn = 13 kg / mol, D = 1.6. See also WO2014185779A1. XP2 was synthesized in a similar manner, except that the amount of 1,6-hexanediol was increased to 74 mmol. Table 1 summarizes the composition of the XP1 and XP2 polymers.

[0018] PC Polymer-XP3

[0019] Polymers made of polycarbonate with molecular weights ranging from 500 to 3000 g / mol were synthesized in a manner similar to that of XP1. The ratios were varied according to the length of the polycarbonate and the desired proportions between the components. The molar ratios can be expressed as follows: A (polycarbonate) is fixed at 1; B (chain extender) varies between 0 and 3; D (upy) varies between 0.3 and 2; and C is always equal to 0.8 to 1.2 times the total molar amount of A, B, and D. The molar ratio B / D is denoted as R. For the purposes of this invention, XP3 was synthesized using a polycarbonate molecular weight of 2000 g / mol and selecting a molar ratio R of 2. The composition of XP3 is summarized in Table 1.

[0020] Unless otherwise specified, the thickness in the examples is 500 μm for all polymers.

[0021] Example 2: Fatigue Testing - Comparison of Heart Valves Based on PC and PCL

[0022] Test Description

[0023] Accelerated wear testing is a test designed to evaluate the durability of a device. The device is subjected to stress conditions simulating in vivo conditions, and the number of cycles before failure is recorded. Detailed information on durability assessment is described in ISO 5840-3:2013.

[0024] First, PV was tested for 20 minutes at 30 / 10 mmHg (20 mmHg) to examine lobular opening: maximum / mean systolic pressure gradient, effective orifice area, and reflux. This pressure condition was classified as a normal-blood pressure lung condition (ISO 5840-3:2013). Data and high-speed images were acquired at the start and after 20 minutes. The maximum systolic pressure gradient should be less than 25 mmHg (Drossner et al., Pediatr Cardiol. 2008 May; 29(3):649-52 doi:10.1007 / s00246-007-9191-y.), and the effective orifice area should be greater than 30% of the geometric orifice area.

[0025] Subsequently, the valves were tested at 90 / 35 mmHg for 20 hours, which was classified as a very severe hypertensive pulmonary condition (ISO 5840-3:2013). Data and high-speed images were acquired at the start, 20 minutes later, and 20 hours later (or after failure).

[0026] Table 1 summarizes the tested materials, and Table 2 shows the results. We observed that PC-based polymers provided better results after 20 hours compared to PCL-based polymers. XP3 showed the best fatigue resistance in the test series, with no tearing observed.

[0027] Table 1: List of Materials

[0028] Table 2: Valve test results after 20 hours at 90 / 35 mmHg

[0029] Pulmonary valves using PCL polyol (described in PCL / Synthesis) as leaflet material via electrospinning were tested in a valve testing instrument. Pulmonary valve catheters were evaluated at 90 / 35 mmHg after 20 hours (very severe hypertensive pulmonary condition according to ISO 5840-3:2013). Leaflets made with PCL polyol showed tearing and failure. Conversely, leaflets made with PC polyol showed good results (Table 2).

[0030] The enhanced fatigue resistance of the PC-based polymer was further tested under aortic conditions (120 / 80 mmHg). The polymer was dissolved and further electrospun and assembled onto a stent to form an aortic valve. The valve was further tested at 10 Hz under aortic conditions. This allows for the differentiation of which polymer in the PC-based polymer family provides the best results. Figure 1 The effect of the ratio R on fatigue resistance is shown. The ratio varies between 0 and 3. The length of the soft segment varies between 500 and 3000 g / mol. It was observed that polymers with an R value of 1.5 or higher provided the best fatigue resistance. In addition, there were unexpectedly optimal results in terms of fatigue resistance when the soft segment length was 1000 g / mol.

[0031] Another feature that can affect durability is the arrangement of the fibers within the stent. A preferred fiber arrangement is circumferentially arranged around an imaginary axis of the implant, where, in the case of a tubular implant, this axis points in the direction of blood flow. Figure 2 We can clearly see that the arrangement can increase fatigue resistance. The arrangement is limited to a maximum linear elastic stiffness ratio of 8:1 between the preferred fiber direction and the direction perpendicular to the preferred fiber direction.

[0032] Additional Information

[0033] 1. Scope (Durability Focus)

[0034] ● The ratio R varies between 0 and 3. Enhanced / optimal fatigue resistance is achieved when the ratio is 1.5 or higher.

[0035] ● The PC length varies between 500 and 3000 g / mol. Enhanced / optimal fatigue resistance is achieved when the PC length is 1000.

[0036] ● The mass ratio of chain extenders varies between 0 and 15. Higher HD ratios (9 w% and higher) yield enhanced / optimal fatigue resistance.

[0037] 2. Support structure

[0038] ● The thickness can vary from a few micrometers to a few millimeters, but the preferred thickness is between 200 and 800 micrometers, or even more preferably between 250 and 550 (average thicknesses of 300 and 500 provide good results).

[0039] ● Fiber diameters can be obtained in a wide range from 1 µm to 20 µm. Preferably, we operate in the range of 3-15 μm, and even more preferably in the range of 4-10 μm.

[0040] ● Fiber arrangement is another parameter for improving durability, especially when electrospinning results in a random 1:2 (circumferential:axial) distribution (meaning the axial stiffness is twice the circumferential stiffness). Fibers can be arranged in ratios from infinity:1 to 1:2. Ratios from 2:1 to 8:1 are preferred as they provide a good improvement in durability.

[0041] ● Pore size: The matrix material contains pores with a diameter of 1-300 micrometers, preferably 5-100 micrometers.

[0042] ●Porosity: The matrix material comprises a fiber web with a porosity of at least 60%, preferably between 70% and 85%.

Claims

1. A biodegradable cardiovascular implant for growing cardiovascular tissue in a patient, comprising an electrospun web having a supramolecular compound having a hard segment covalently bonded to a soft segment, wherein the soft segment is a polycarbonate soft segment with a molecular weight range of about 2000, and wherein the hard segment comprises a 2-ureido-4[1H]-pyrimidinone (UPy) compound and a chain extender having a chain extender ratio of 1.5 to 3 for the UPy compound, wherein the hard segment is synthesized from hexamethylene diisocyanate, the chain extender and the Upy compound.

2. The biodegradable cardiovascular implant of claim 1, wherein the electrospun web has electrospun fibers with a diameter of 4-10 μm.

3. The biodegradable cardiovascular implant of claim 1, wherein the electrospun mesh has a pore size of 5-100 micrometers.

4. The biodegradable cardiovascular implant of claim 1, wherein the electrospun mesh has electrospun fibers with a diameter of 4-10 μm, and wherein the electrospun mesh has a pore size of 5-100 micrometers.

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