Multi-layer electrospun heart valve leaflet

Abstract

The heart valve leaflets are provided with a multi-layered engineered design. The multi-layered design significantly improved the mobility of the valve leaflets without compromising durability compared to conventional single-layer designs. Furthermore, the folded, two-layered design significantly reduced the risk of fraying.

Description

Technical Field

[0001] The present invention relates to tissue engineering of heart valve leaflets.

Background Art

[0002] Heart valves are subject to large stresses with each heartbeat while blood is being pumped through the cardiovascular system. In addition to these stresses with each heartbeat, heart valves also require a high durability that lasts as long as possible.

[0003] Prosthetic or engineered heart valves replace natural heart valves when the natural heart valves are impaired or damaged. These prosthetic / engineered heart valves are single-layer heart valves and are usually made from chemically stabilized biological tissue (e.g., pericardium), but tend to calcify severely over time. As a result, there are limitations in terms of the mobility and durability of the valve leaflets, so there are limitations.

[0004] Some prosthetic / engineered heart valves use materials to enable endogenous tissue repair (ETR). Since this heart valve material has porosity and bioabsorbability, cells and nutrients can ingrow into the pores, allowing the heart valve to be absorbed by natural tissue and replaced. On the other hand, since such ETR-type heart valves are not long-term, there is a risk of further limitations in the durability of the heart valve.

[0005] The present invention addresses the problems caused by the durability and mobility of single-layer prosthetic / engineered heart valves and / or fraying of the valve leaflets, as well as the problems caused by heart valves that also desire ETR.

Summary of the Invention

Means for Solving the Problems

[0006] In one embodiment, the present invention provides a medical implant fabricated as one or more leaflets of a heart valve. The leaflet has two electrospun layers, and since only the edges of the two electrospun layers ( Electrospun fibers produced by electrospinning layers) are joined to each other, the unjoined portions in one layer of the leaflet are configured to be movable with respect to the other layer. Since the leaflet is porous and bioabsorbable, the leaflet can be absorbed by and replaced with natural tissue by the ingrowth of cells and nutrients into the pores (ETR).

[0007] In another embodiment, the present invention provides a medical implant fabricated as a leaflet of a heart valve. Here, the heart valve defines a base and a free edge. The leaflet has a two-layer design such that by folding a single electrospun layer ( Electrospun fibers produced by electrospinning layer), the free edge of the heart valve becomes the folded edge of the leaflet. Only the unfolded edge of the electrospun layer is joined to and incorporated into the base of the heart valve, and is configured such that one layer of the leaflet can move maximally independently of the other layer. As in the first embodiment, the leaflet may be porous and bioabsorbable, and by the ingrowth of cells and nutrients into the pores (ETR), the leaflet can be absorbed by and replaced with natural tissue.

[0008] The two-layer design significantly improves the mobility of the leaflet, but does not reduce the durability compared to conventional single-layer designs. Furthermore, in the folded two-layer design, the risk of abrasion is also significantly reduced.

[0009] In yet another embodiment, the present invention provides a medical implant fabricated as a leaflet of a heart valve. Here, an intermediate layer is provided between the two electrospun layers. In one example, the intermediate layer may be in a state that allows it to move independently of the two electrospun layers, and in another example, the intermediate layer may be adhered to the two electrospun layers.

[0010] In yet other embodiments, the present invention provides a medical implant fabricated as a leaflet of a heart valve. Here, the intermediate layer is provided between the layers of a two-layer design. In one example, the intermediate layer may be capable of moving independently from the layers of the two-layer design, and in other examples, the intermediate layer may be adhered to the layers of the two-layer design.

[0011] The intermediate layer may be various as follows. (i) Having porosity and bioabsorbability, cells and nutrients can ingrow into the pores, enabling the intermediate layer to be absorbed by and replaced with natural tissue. (ii) The intermediate layer of an electrospun layer ( Electrospun fibers produced by electrospinning layer) having porosity and bioabsorbability allows cells and nutrients to ingrow into the pores, enabling the intermediate layer to be absorbed by and replaced with natural tissue. Or, (iii) not having bioabsorbability but being able to penetrate natural tissue for cells and nutrients to ingrow into the pores.

[0012] The intermediate layer and the two electrospun layers are electrospun with the same material or different materials. In other embodiments, the two electrospun layers are electrospun with the same material or different materials respectively. Similarly, the intermediate layer and the two-layer design are electrospun with the same material or different materials.

[0013] Also, in the three-layer design, compared with the conventional single-layer design, the mobility of the leaflet is significantly improved without reducing durability. Further, the folded two-layer design used in this three-layer design also significantly reduces the risk of wear.

[0014] In yet other embodiments, the present invention provides a medical implant fabricated as a leaflet of a heart valve. Here, the leaflet has two electrospun outer layers and an intermediate layer, whereby the intermediate layer is laminated between the two outer layers and is not capable of moving independently from the two electrospun outer layers. The intermediate layer may be various as follows. (i) Having porosity and bioabsorbability, cells and nutrients grow into the pores, whereby the intermediate layer can be absorbed by the natural tissue and replaced. (ii) An electrospun layer having porosity and bioabsorbability, cells and nutrients grow into the pores, whereby the intermediate layer can be absorbed by the natural tissue and replaced. Or, (iii) not having bioabsorbability, but cells and nutrients grow into the pores, whereby it can penetrate into the natural tissue. The intermediate layer and the two electrospun layers are electrospun from the same material or different materials. Also, each of the two electrospun layers is electrospun from the same material or different materials.

Brief Description of the Drawings

[0015]

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MODE FOR CARRYING OUT THE INVENTION

[0016] Embodiments of the present invention advance the art by introducing a multi-layer structure to the leaflets of a heart valve, enabling the overcoming of problems such as durability, mobility, tearing, and / or abrasion. The first design of the dual-layer has a folded structure that forms a bi-layer structure, and the second design of the dual-layer forms a bi-layer structure by adhering the free edges of two independent electrospun layers to each other. The third design places one layer between the two layers of the dual-layer design.

[0017] In each design, the bi-layer leaflets of the heart valve are preferably defined by two electrospun layers that allow for maximum movement between the layers in order to improve and ensure flexibility and mobility. In one embodiment, each layer of the bi-layer leaflet design may be manufactured from the same material, such as the materials described hereinafter. In other embodiments, each layer of the bi-layer leaflet design may be manufactured from different materials. The latter is mainly suitable for two independent electrospun layers whose free edges are adhered to each other.

[0018] Behind the bi-layer leaflet design is the idea that two individual layers that move independently within the design structure are more flexible than a single-layer leaflet when the overall thickness is the same. The total thickness of the two layers combined in the bi-layer leaflet design is configured to be 200 - 500 μm, preferably 300 - 400 μm.

[0019] In the second design, it is preferable that the entire surfaces are not adhered to each other so that the two layers can move independently of each other to the maximum extent. To achieve this effect, the two layers are adhered or connected to each other at the edges corresponding to about 10 - 15% of the overall height of the heart valve leaflet. This may be achieved by adhesion, heat welding, or edge stitching (or equivalent methods). As described above, in the first design, the concept is achieved by folding the sheet and adhering only the edge without a fold, so it is not necessary to adhere the entire surface. By allowing the two layers to move to the maximum extent, the flexibility during bending is improved. This flexibility improves mobility and reduces the pressure gradient.

[0020] Turning to the first design, the fiber is electrospun in a cylindrical metal mandrel 110 to produce an electrospun fiber 120 (FIG. 1). A list of useful fibers is provided at the end of this specification. Next, when the electrospun fiber 120 is disposed on the cylindrical metal mandrel 110, it is laser cut according to a laser cut pattern 300 (FIGS. 2-3). The curved edge 210 refers to the heart valve base (see also FIG. 6), and the rhomboid shape 220 indicates the shape of the commissures of the heart valve (see also FIG. 6). Once laser cut, the electrospun heart valve shape 400 is removed from the cylindrical metal mandrel. Next, the shape 400 is folded along a line 510 across the rhomboid shape 220 (FIG. 5). In one example, it is cut into approximately three waveforms and approximately three rhomboids.

[0021] Figure 5 shows the fold line 510 along which the shape 400 of FIG. 4 is folded in accordance with an exemplary embodiment of the present invention (note that this is a 2D representation of a 3D shape). When folded, the fold line becomes the free edge 610 in the shape of a heart valve (FIG. 6). When folded, the curved edge 210 becomes the heart valve base 620 (see also FIG. 2), and the rhombus shape 220 becomes the V-shaped commissure 630 of the heart valve (see also FIG. 2). FIG. 7 shows a cross-sectional view of the folded heart valve shape 600 with the folded free edge 610 and heart valve base 620. Note that this is two layers of electrospun fiber that are folded along the fold line 510 (FIGS. 5-6) and the fold becomes the free edge 610. As described above, in other designs and the second design, the valve leaflets of the heart valve may then be processed using two independent electrospun layers in which only the edges (similar to those referring to the free edge) are joined / adhered to each other, and the electrospun layers allow one layer of the valve leaflet to move maximally independently of the other layer. FIG. 8 shows the folded heart valve 800 after electrospinning, obtained before suturing, adhering, stitching, or generally attaching the heart valve to the heart valve frame. FIG. 9 shows an image of an assembly 900 in which a folded heart valve, similar to reference numeral 800, after electrospinning, is assembled to the heart valve base 910.

[0022] Each layer of the two-layer valve leaflet (first and second) design may be characterized as follows. · A layer having micropores that enable endogenous tissue regeneration (ETR). The pore size is configured to be about 1-100 μm. · An electrospun layer configured such that the fiber diameter is about 4-10 μm in one example and 1-20 μm in other examples. · A (bio)absorbable layer is not essential but may be required depending on the application. · Made from the polymers described later. · In one example, the layer thickness is configured to be typically 80-200 μm and in other examples 50-300 μm. · In the design of the two-layer valve tip, the total combined thickness of the two layers is configured to be 200 - 500 μm, preferably 300 - 400 μm.

[0023] In the third design, an intermediate layer is disposed between the two layers of the two-layer design. This means adding an intermediate layer to the first design as described above, and adding an intermediate layer to the second design. Thereby, the first design becomes a two-layer structure due to the folded structure, and the second design forms a two-layer structure by adhering the free edges of the two independent electrospan layers to each other. In one option, the intermediate layer is incorporated in between such that the non-folded edges of the electrospan layer and the intermediate layer are joined to each other, enabling each layer to move as independently as possible relative to each other. In another option, the intermediate layer allows for maintaining maximum independent mobility without using any attachments.

[0024] In one embodiment, the three-layer valve tip design may be manufactured from the same material, for example, the materials described later. In other embodiments, the three-layer valve tip design may be manufactured from different materials. The important point of the intermediate layer with respect to the outer layer is that while the intermediate layer has material properties that enhance the durability of the heart valve, it maintains the mobility of the entire valve tip and thus the associated heart valve. Generally, the intermediate layer preferably has greater durability in order to further improve the overall durability of the device. This can be achieved by selecting different materials and different textures (such as a solid / woven fabric / electrospan sheet etc. that is the same as or has a lower porosity than the outer layer, for example, as shown in FIG. 14).

[0025] Generally, the intermediate layer may be manufactured from biodegradable or non - biodegradable materials. Preferably, the intermediate layer is manufactured in a way that its degradation time is shortened compared to the outer layer. The intermediate layer may have ETR compatibility or not (the one to be incorporated into the fabricated tissue later). When a biodegradable setup is selected, those with ETR compatibility are preferred. If possible (ideally), the intermediate layer has micropores for enabling ETR through its pores and / or for enabling the outer layers to be bonded to each other through electrospinning (the latter requires macropores and a relatively thin intermediate layer).

[0026] In other embodiments, the intermediate layer may be manufactured by electrospinning. It is necessary to adapt the electrospinning parameters to create higher strength (due to variations such as fiber arrangement, pore size, material, fiber thickness, etc.). In particular, the fibers preferably have an orientation along the circumference of the valve tip, similar to the orientation of the original valve tip. Alternatively, the intermediate layer may be a film or a 3D printed structure.

[0027] In one embodiment, the material of the intermediate layer needs to be biocompatible, durable, and either degrade over a long time or remain in the body. In one example, a thin fabric made of PET may be used. This layer has a different texture from the electrospun outer layer that always weaves in bundles of filaments to increase strength. The permeability of the intermediate layer may be introduced by creating patterned perforations in the support structure. The PET fabric structure is preferably highly durable against dynamic shear stress compared to the outer layer, and its thickness is configured to be 60 - 100 μm (micrometers). The configuration of the fabric structure (e.g., number of filaments per bundle, thread angle, permeability, patterned perforations, holding force of the suture, etc.) may be adjusted and adapted to fit a specific valve tip design (i.e., conform to a specific valve frame) (for example, see Figure 14).

[0028] In a second example, a thin film (not electrospun) cast from a polymer solution to a thickness of 60 to 100 μm (micrometers) may be used for an intermediate layer that potentially has high durability and a slow pace of degradation. This intermediate layer stabilizes the valve leaflet, after which the ETR process occurs throughout the entire lifespan of the artificial valve within the body. According to experiments, this three-layer design exhibits higher durability compared to a simple two-layer or single-layer design. Thereby, the intermediate layer absorbs stress. The permeability of the intermediate layer may be introduced by creating patterned perforations in the support structure.

[0029] In other examples, the PET structure includes macro and / or micro pores that enable bonding between outer layers by ETR and / or electrospinning.

[0030] There are several methods for manufacturing such multilayer films or valve leaflets. According to one embodiment, the outer layers are manufactured (e.g., by electrospinning). These layers are then bonded around the intermediate layer by heat welding, adhesion, or other methods. The intermediate layer can also be described as a heart valve leaflet support structure embedded between electrospun layers. The heart valve leaflet support structure may be, but is not limited to, the following. · Configured to have sufficient porosity to enable ETR. · Have sufficient "openness" such that the inner and outer electrospun layers can be laminated to each other. · May or may not be a non-degradable layer. · Configured to be a woven (PET) mesh, suture wire, (metal, e.g., nitinol) braided / knitted mesh. · There may be post-treatment to create a local porous / open cell structure.

[0031] Furthermore, the intermediate layer can also be said to be a heart valve leaflet support structure embedded between electrospun layers. The heart valve leaflet support structure may be, but is not limited to, the following. ·It is configured to have sufficient porosity to enable ETR. ·It is configured to be made of a film (of the same material or material classification as the electrospun outer layer). ·It is laminated to the electrospun layer, but it does not necessarily have to have sufficient openness so that the electrospun layers can be laminated to each other (i.e., in this case, it is already attached to the film).

[0032] When the free edge of the layer is adhered, the adhesive portion is assumed to correspond to about 10 - 15% of the height of the valve tip (about 1 mm). The reason is to prevent the free edge from delaminating and is considered based on about 10 - 15% of the height at which it is (completely) laminated. The intermediate layer above the adhesive portion does not reach the free edge but reaches about 1 mm below it. In yet other embodiments, in a two - layer design or a three - layer design with an intermediate (heart valve tip support structure), lamination may be required, in which case the layers should be able to move freely relative to each other.

[0033] Testing

[0034] To evaluate and quantify the in - vitro mobility of the valves tested, a classical commercially available pulse duplicator (the "Hydrodynamic Tester" from BDC Labs in the United States) was used. In this classical test apparatus, the valve is placed in a flow chamber that controls flow rate and pressure. Compressed air combined with a test fluid is used to mimic physiological conditions and vascular compliance. The hydrodynamic test apparatus interface analyzes the life performance of the valve and measures and quantifies the essential parameters in the open state of the valve (i.e., effective orifice area (EOA) [cm 2 , maximum and mean pressure - pressure difference (PPD) [mmHg], etc.) and in the closed state of the valve (i.e., closure volume (CV) [%], regurgitation fraction (RF) [%]).

[0035] The test apparatus can reproduce the range of physiological conditions of the cardiovascular system and can correspond to various heart rates and cardiac outputs at any pressure.

[0036] To evaluate and quantify the improved durability of the multilayer valve, a classical commercially available valve durability tester (the "Accelerated Wear Tester" of BDC Labs in the United States) was used. In such a test device, the valve is placed in a pressure-controlled sealed chamber, and the test is conducted by exposing the valve tip to the flowing fluid pushed out using a linear motor and a piston. The position of the piston controls the opening and closing of the valve tip, and the frequency of the motor indicates the speed (Hz) of the valve cycle. The dynamic pressure gradient of the closed valve is configured to simulate the physiological state. The valves tested usually operate at a frequency of 5 - 25 Hz, but in this application, considering the polymer and its viscoelastic properties, a frequency of 10 Hz was selected. Only when the valve withstood more than 5% of the cycle duration while the valve was closed under a specific pressure gradient (i.e., the target pressure), it was counted as one cycle. In this application, the target pressure was set at 100 mmHg.

[0037] Additional parameters were measured to evaluate the mobility of the valve from various perspectives using a high-speed camera. These parameters are not necessarily (in accordance with ISO-5840) standardized, but for example, they may be useful for evaluating the characteristics of the dynamic performance of the valve, such as the synchronization and overall balance between the valve tips in the open and closed states, the deflection of the closed valve tip, and the deviation of the commissure. Some of these parameters are mainly used in product design and development.

[0038] Figures 10 and Table 1 show the results of in vitro tests on the mobility of two-layer and single-layer valves with valve tips of various thicknesses as shown in Figure 11. Figure 10 shows the fully closed and open states of the prototype of the heart valve assembly, which was captured using a high-speed camera during the hydrodynamic test. The experiment showed that the two-layer design significantly improved the mobility of the valve tip without reducing the durability compared to the normal single-layer design. Furthermore, the folded two-layer design also significantly reduced the risk of abrasion.

[0039] Table 1 shows a comparison between a single-layer valve tip and a double-layer valve tip in a hydrodynamic tester. In the first comparison, the mode of the double-layer valve tip with a thickness of 400 μm (n = 2) had mobility equivalent to that of the single-layer valve tip while the valve was in the open state (the effective orifice area and pressure gradient were relatively equivalent), and was inferior while in the closed state (the higher the closing volume, the higher the backflow rate). In the second comparison, the mode of the double-layer valve tip with a thickness of 300 μm (n = 1) had higher mobility than the single-layer valve tip in the open state (higher effective orifice area, lower pressure gradient) and showed the same mobility as the single-layer valve tip in the closed state (equivalent closing volume).

[0040]

Table 1

[0041] Table 2 shows the results of a durability comparison between a three-layer prototype and three single-layer prototypes, indicating that the number of cycles until the valve tip breaks, which could not reach the required pressure gradient, improved by at least one level. As a result, the three-layer prototype reached and passed the ISO standard for the durability of a heart valve at 400 M cycles. This shows the possibility of pursuing ETR using a heart valve with equivalent durability compared to the state-of-the-art technology (biological tissue valve tip).

[0042]

Table 2

[0043] Material

[0044] The electrospun materials referred to in this specification may include ureido-pyrimidinone (UPy) quadruple hydrogen bonding motifs (developed by Sijbesma (1997), Science 278, 1601-1604) and a polymer backbone, such as polyurethanes, polycarbonates, poly(orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinyl alcohol, polypropylene fumarate, selected from the group of biodegradable polyesters. Examples of polyesters include polycaprolactone, poly(L-lactide), poly(DL-lactide), poly(valerolactone), polyglycolide, polydioxanone, and their copolyesters. Examples of polycarbonates include poly(trimethylene carbonate), poly(dimethyltrimethylene carbonate), poly(hexamethylene carbonate).

[0045] Similar results may be obtained with other non-supramolecular polymers by carefully selecting properties and treating the materials to ensure the required surface properties. These polymers may include biodegradable or non-biodegradable polyesters, polyurethanes, polycarbonates, poly(orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinyl alcohol, polypropylene fumarate. Examples of polyesters include polycaprolactone, poly(L-lactide), poly(DL-lactide), poly(valerolactone), polyglycolide, polydioxanone, and their copolyesters. Examples of polycarbonates include poly(trimethylene carbonate), poly(dimethyltrimethylene carbonate), poly(hexamethylene carbonate).

Claims

1. A medical implant comprising a cusp of a processed heart valve, wherein the cusp is formed by bonding two layers of electrospun nanofibers produced by electrospinning, with the unbonded portions in one layer being movable with respect to the other layer, and the two layers being bonded only at their edges so as to allow such movement; and further comprising an intermediate layer held between the two layers of electrospun nanofibers and configured to be at least partially movable with respect to the two layers of electrospun nanofibers.

2. The medical implant according to claim 1, wherein the cusp is porous and bioabsorbable, and cells and nutrients can grow into the pores, enabling the cusp to be absorbed and replaced by natural tissue.

3. The medical implant according to claim 1, wherein the intermediate layer (i) is porous and bioabsorbable, and cells and nutrients can grow into the pores, enabling the intermediate layer to be absorbed and replaced by natural tissue; (ii) is a layer of electrospun nanofibers produced by electrospinning and having porosity and bioabsorbability, and cells and nutrients can grow into the pores, enabling the intermediate layer to be absorbed and replaced by natural tissue; or (iii) is non-bioabsorbable, and cells and nutrients can grow into the pores, enabling it to penetrate into natural tissue.

4. The medical implant according to claim 1, wherein the intermediate layer and the two layers of electrospun nanofibers are produced by electrospinning the same or different materials.

5. The medical implant according to claim 1, wherein the two layers of electrospun nanofibers are produced by electrospinning the same or different materials respectively.

6. A medical implant comprising a cusp of a heart valve, wherein the heart valve has a free edge, and the cusp comprises a single layer of electrospun nanofibers produced by electrospinning, and the layer of electrospun nanofibers is folded such that the free edge of the heart valve becomes the folded edge of the cusp, resulting in a two-layer design of the cusp. A medical implant further comprising an intermediate layer held between the two-layer design and configured to be at least partially movable relative to the two-layer design. **Claim 7** The non-folded edges of the layer of electrospun fibers are joined and incorporated into the base of the heart valve, At the valve tip, the portion excluding the edge of the valve tip in one layer and the portion joined to the other layer is configured to be movable relative to the other layer. The medical implant according to claim 6. **Claim 8** The valve tip is porous and bioabsorbable, and cells and nutrients can grow into the pores, enabling the valve tip to be absorbed and replaced by natural tissue. The medical implant according to claim 6. **Claim 9** The intermediate layer has (i) porosity and bioabsorbability, and cells and nutrients can grow into the pores, enabling the intermediate layer to be absorbed and replaced by natural tissue; (ii) is composed of a layer of electrospun fibers produced by electrospinning with porosity and bioabsorbability, and cells and nutrients can grow into the pores, enabling the intermediate layer to be absorbed and replaced by natural tissue; or (iii) has no bioabsorbability, and cells and nutrients can grow into the pores, enabling it to penetrate into natural tissue. The medical implant according to claim 6. **Claim 10** The intermediate layer and the two-layer design are manufactured by electrospinning the same material or different materials. The medical implant according to claim 6.

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