Apparatus and method for preparing a leaflet for a bioprosthetic heart valve

Abstract

Apparatus (100) for preparing a leaflet (L) for a bioprosthetic heart valve (10), the apparatus (100) comprising a station (200) for digitizing a patch (P) of animal tissue, the station (200) comprising a 2D optical sensor (225, 235) for imaging the patch (P) with at least one of a brightfield epi-illumination device and a transillumination device (220, 230) for detecting at least one of defects in the patch (P) and assessing collagen density in the patch (P), a 3D optical sensor (240) for obtaining a thickness profile (250) of the patch (P), and a small angle light scattering (SALS) system (300) for obtaining a thickness-wise orientation and dispersion profile (255) of collagen fibers in the patch (P). The invention also provides a station (400) for automatically selecting regions in a patch (P) most suitable for forming a qualified leaflet (L) from a leaflet model (L'), a leaflet cutting station (500), a station (600) for final inspection, qualification and certification of cut leaflets (L), and a grouping station (700).

Description

[0001] This disclosure relates to bioartificial heart valves. More specifically, this disclosure relates to an apparatus for preparing leaflets for manufacturing bioartificial heart valves. This disclosure also relates to a method for preparing leaflets for bioartificial heart valves using said apparatus. Background Technology

[0002] Biological or bioprosthetic heart valves (BHVs) are currently widely used in mechanical heart valves. Mechanical heart valves are made of metal alloys or plastic materials. Due to thrombosis, mechanical heart valves require anticoagulation therapy, which involves the risk of bleeding.

[0003] Bioartificial heart valves (BHVs) can be divided into transcatheter aortic valves (TAVs) and surgical aortic valves (SAVs).

[0004] Over the past few decades, the surgical and transcatheter implantation of artificial heart valves in patients with valvular heart diseases (VHD) has increased significantly. An example of artificial heart valve implantation is aortic valve replacement (AVR). This is a common intervention in which a natural heart valve is replaced by an artificial one.

[0005] Although SAVs are commonly used to treat aortic valve disease, transcatheter aortic valve replacement (also known as percutaneous transcatheter aortic valve implantation (TAVI)) has become a treatment option for inoperable patients with severe aortic stenosis.

[0006] BHVs typically consist of valvular elements, called leaflets or apex, assembled into a flexible stent within the BHV. The flexible stent allows the leaflets to work together to replicate the natural valve.

[0007] The leaflets are typically made from animal tissue, such as bovine or porcine pericardium. Animal tissue includes collagen fibers that reinforce the leaflets, thus providing them with structural integrity. This makes them an optimal choice for manufacturing BHVs.

[0008] Although biomechanical heart valves (BHVs) are superior to mechanical heart valves, when BHVs are implanted, the leaflets are subjected to cyclic mechanical stress due to the periodic opening and closing of the valve. This stress leads to failure because the mechanical response of the leaflet tissue depends largely on the density, dispersion, and orientation of collagen fibers, as described by S. Hamed Alavi et al. Characterizing the collagen fiber orientation in pericardial leaflets under mechanical loading conditions As reported in Ann Biomed Eng. 2013 Mar; 41(3):547-61.

[0009] It has been found that selecting a given orientation of collagen fibers relative to flow during the manufacture of BHVs can yield a good tissue response to flow-related shear stresses. However, leaflet degeneration is inevitable, which can lead to valvular dysfunction. Therefore, the average lifespan of BHVs in elderly patients is estimated to be 15 years. This is why they are currently the most popular choice for patients over 65 years of age.

[0010] In this regard, existing bioartificial heart valves (BHVs) have focused on improving durability. Therefore, attempts have been made to develop durable BHVs, such as those in US6245105B1 and US6553681B2. Their approach involves selecting leaflets for the production of multileaflet bioartificial heart valves to ensure maximum functional compatibility. A method for evaluating and cutting bioartificial tissue is disclosed in WO 2013 / 003842 A1.

[0011] In known prior art apparatuses and methods for processing valve leaflets for BHVs, the thickness of pericardial tissue is measured, and a useful area is selected to become a valve leaflet. However, this is done in an inefficient manner, making the process insufficient for effectively manufacturing durable heart valves.

[0012] More efficient devices and methods are still needed to produce leaflets for manufacturing durable bioartificial heart valves (BHVs). Summary of the Invention

[0013] In view of the above needs, this disclosure aims to provide an apparatus for efficiently preparing leaflets for manufacturing bioartificial heart valves (BHVs). A method for preparing leaflets for bioartificial heart valves using said apparatus is also disclosed herein.

[0014] As described below, this device can effectively analyze animal pericardial tissue, automatically select the most suitable region in the patch of the analyzed tissue, automatically cut the selected region to be used as leaflets for manufacturing BHVs, and perform final quality control, certification, and grouping of the cut leaflets.

[0015] To clarify some terms used throughout this specification and claims, the following definitions are given below.

[0016] Throughout this specification, the term "leaflet" should be understood as each of the elements or portions that form the bioartificial heart valve and provide its primary opening and closing mechanism, also known as the valve tip. Aortic valves typically have three leaflets.

[0017] The term "patch" in this article refers to a piece of tissue, such as a pericardial patch, that has been cut to the size required to manufacture the leaflets of a heart valve.

[0018] In the context of this disclosure, “tissue” means any animal material comprising stacks of collagen fiber layers.

[0019] The term “automatically” in this disclosure should be interpreted as any action or step performed with little or no direct human control.

[0020] Also within the meaning of this disclosure, “preparation of leaflets” means arranging leaflets by means of the method steps described below, such that they are ready for use in the manufacture of a bioartificial heart valve.

[0021] As used in this article, "examination leaflets" refers to optical examination of leaflets.

[0022] Within the meaning of this disclosure, "through thickness dispersion and orientation" defines the architecture of collagen fibers in a patch or leaflet, namely the average dispersion and dominant orientation of collagen fibers through all layers of the patch or leaflet.

[0023] The term "dispersion" in this disclosure refers to the variation in the orientation of collagen fibers in different layers of the pericardial tissue.

[0024] The term “orientation” in this disclosure refers to the direction in which collagen fibers are arranged, and “dominant orientation” refers to the direction in which most collagen fibers are arranged in the total thickness of the tissue.

[0025] As used in this article, “fiber size” refers to the diameter of collagen fibers. Furthermore, “interfiber spacing” in this article refers to the space between collagen fibers that defines the intervals between them.

[0026] In the context of this disclosure, "sensor" or "optical sensor" is understood to include at least one sensor camera, corresponding sensor optics, and suitable illumination device.

[0027] In a first aspect, an apparatus is provided for preparing leaflets for use in bioartificial heart valves. This apparatus is designed to process patches derived from animal pericardial tissue, with a maximum size of 120 × 120 mm. However, other values ​​may be conceived as needed.

[0028] This device includes a digitization station for digitizing at least one patch of animal pericardial tissue.

[0029] The station for digitizing at least one patch of animal pericardial tissue includes at least one 2D optical sensor. The 2D optical sensor is adapted to image the patch using at least one of a bright-field incident illumination device and a transillumination device for detecting defects in the patch and assessing at least one of collagen density in the patch. To assess collagen density in the patch, the 2D optical sensor may include a polarized transillumination device.

[0030] The station for digitizing at least one patch of animal pericardial tissue also includes at least one 3D optical sensor. The 3D optical sensor is adapted to obtain a thickness distribution map of the patch. For this purpose, the 3D optical sensor can be one of dynamic fringe projection, confocal, interferometry, and focus variation. In another example, the 3D optical sensor may include a 5-megapixel camera with a lateral resolution better than 15 micrometers (μm) and a vertical resolution better than 1 μm.

[0031] In the context of this disclosure and as will be apparent to those skilled in the art, superior lateral resolution of an optical sensor means resolving smaller distances on the surface of the tissue. Therefore, in the example above, a resolution better than 15 μm means a resolution value less than 15 μm. In the context of this disclosure and as will be apparent to those skilled in the art, superior vertical resolution means resolving smaller distances in a direction perpendicular to the tissue surface. Therefore, in the example above, a vertical resolution better than 1 μm means a resolution value less than 1 μm.

[0032] The station used for digitizing at least one patch of animal pericardial tissue also includes a small-angle light scattering (SALS) sensor. This SALS sensor has been improved to obtain thickness-direction dispersion and orientation distribution maps of collagen fibers in the patch.

[0033] Specifically, this SALS sensor has been improved to allow for rapid tissue analysis of features at the micrometer scale, thereby allowing the fiber dispersion and orientation of collagen fibers to be rapidly characterized to provide an architectural mapping of collagen fibers, thus avoiding a large amount of manual intervention.

[0034] This SALS sensor provides a precise method for rapidly quantifying collagen fibers using lasers with wavelengths on the order of magnitude of fiber size and interfiber spacing (e.g., a He-Ne laser with a wavelength of 632.8 nm), as described by MSSacks et al., “ A small angle light scattering device for planar connective tissue microstructural analysis This is reported in Annals of Biomedical Engineering, vol. 25, pp. 678-589, 1997. Compared to standard known SALS sensors, this SALS sensor is also highly compact in terms of the short distance between the projection screen and the patch, while maintaining far-field diffraction conditions. This SALS sensor provides high-resolution information on local collagen fiber dispersion and orientation, thus avoiding the need for expensive equipment and time-consuming tissue preparation, while allowing for rapid analysis of large-area tissues.

[0035] When a laser beam passes through the thickness of the pericardial tissue, a characteristic image of a far-field diffraction pattern corresponding to an ellipse is obtained. More specifically, the improved SALS sensor allows for the acquisition of a far-field diffraction pattern in which diffraction patterns generated in each of the corresponding layers of collagen fibers in the pericardial tissue through which a focused laser beam of the aforementioned wavelength passes are superimposed. This far-field diffraction pattern obtained by the improved SALS sensor is an ellipse. The ellipse is characterized by its eccentricity value and the orientation of its major and minor axes. The thickness direction orientation of the collagen fibers coincides with the orientation of the minor axis of the ellipse, and the thickness direction dispersion of the collagen fibers is evaluated by the eccentricity value of the ellipse.

[0036] The results obtained using the improved SALS sensor regarding the eccentricity and orientation of the major axis of the ellipse are consistent with the fiber architecture observed by second harmonic generation (SHG) microscopy.

[0037] The eccentricity of the ellipse is related to the dispersion of collagen fibers in the patch. The more fibers arranged in the same orientation in different layers of the patch, the sharper the aggregated diffraction pattern and the higher the eccentricity of the ellipse. Another relevant parameter from the diffraction pattern is the angle of the ellipse's major axis, which corresponds to the direction perpendicular to the dominant orientation of the fibers in the total thickness of the patch tissue. These parameters, obtained from the improved SALS sensor, will allow for the optimal selection of the angular orientation of the leaflets in the patch.

[0038] This device also includes a selection station. The selection station is configured to automatically select the region in the patch deemed most suitable for forming a qualified leaflet based on the digital results obtained from the aforementioned digitization station and according to at least one leaflet model.

[0039] The device may also include a cutting station for cutting a selected, most suitable area of ​​the patch to form a leaflet. The cutting station may include a laser cutting device adapted to cut the selected, most suitable area of ​​the patch as described above. Preferably, the laser cutting device is a CO2 laser cutting device. However, other different configurations are not excluded, such as those in which the cutting station includes a die-cutting device. Other suitable cutting devices for cutting the selected, most suitable area of ​​the patch to form a leaflet are also not excluded.

[0040] If desired, the station described above for digitizing the patch can also be configured for examining the leaflets. However, it may be preferable to provide a separate leaflet examination station. Therefore, in the latter case, the device may include a station for examining the leaflets in addition to the station for digitizing the patch.

[0041] The inspection station is configured to perform dimensional verification in the leaflets, measure the thickness distribution of the leaflets, detect critical defects in the leaflets, assess the collagen density in the leaflets, and measure the thickness orientation dispersion and orientation of collagen fibers in the leaflets, and classify the leaflets as acceptable or unacceptable when compared with a leaflet model.

[0042] A grouping station may be included in this device. If provided, the grouping station allows eligible leaflets to be arranged into groups of at least two leaflets for integration into a BHV. For example, in the case of an aortic BHV, eligible leaflets would be grouped into groups of three leaflets.

[0043] In this equipment, the transport of patches or leaflets from one station to another can be performed automatically by a suitable conveying device. A suitable conveying device is used to automatically transport patches or leaflets through the stations. The conveying device may include a robot. Alternatively, the transport of patches or leaflets from one station to another can be performed manually by an operator. A combination of automated and operator-managed operation of this equipment is possible.

[0044] This device may also include a support device for pericardial tissue, i.e., a support device for supporting the patch or leaflet. The support device exhibits an optically diffuse surface in a dry state and an optically transparent surface in a wet state (i.e., when in contact with a hydrated patch or leaflet).

[0045] Preferably, the aforementioned support device for pericardial tissue comprises a planar parallel glass plate. This planar parallel glass plate has an upper textured side and a lower polished side. The upper side of the planar parallel glass plate is intended to receive hydrated pericardial tissue from a patch or leaflet.

[0046] In another aspect of this disclosure, a method for preparing leaflets for BHVs using the apparatus described above is also provided.

[0047] The method for preparing leaflets for BHVs includes loading a patch of animal pericardial tissue onto the aforementioned digitization station for digitizing at least one patch of animal pericardial tissue.

[0048] This method yields at least one of a 2D bright-field image and a 2D radiographic image of the patch. It also obtains a 3D thickness distribution map of the patch, as well as thickness orientation and dispersion maps of the collagen fibers within the patch.

[0049] Based on at least one leaflet model, regions within the patch considered most suitable for forming a qualified leaflet are selected. The selection of one or more most suitable regions within the patch is based on digital results obtained from the aforementioned digitization station, designed for digitizing at least one patch of animal pericardial tissue. The selection is performed by applying an optimization process based on mathematical optimization techniques. Preferably, the mathematical optimization technique is a metaheuristic simulated annealing probability technique.

[0050] The selection step described above (in which one or more regions of the patch considered most suitable for forming a qualified leaflet are selected according to the leaflet model) may involve at least one of two additional optimization variables, which are generated by the average tissue thickness at the commissure region being higher than the average tissue thickness of the leaflet, and the average collagen density at the commissure region being higher than the average collagen density of the leaflet.

[0051] In the cutting step according to this method, the area of ​​the cutting patch selected is considered most suitable for forming a qualified leaflet. The cutting step may also include forming holes in the leaflet for subsequent suturing of the leaflet to a scaffold in the BHV. Preferably, the scaffold of the BHV is constructed of metal.

[0052] The selection step may further include excluding regions in the patch that have critical defects or low-density collagen fibers. The selection step may also include determining the optimal location of the leaflets, which satisfies the thickness orientation and dispersion of collagen fibers, as well as thickness parameters, previously defined in the leaflet model. Critical defects in the regions to be excluded are detected from at least one of a 2D bright-field image and a 2D radiograph, obtained from a 2D optical sensor in the aforementioned digitizing station.

[0053] The method for preparing leaflets for BHVs may further include an inspection step in which the leaflets are inspected. This inspection step involves performing dimensional verification in the leaflets, measuring the thickness distribution map of the leaflets, detecting critical defects in the leaflets, assessing collagen density, and measuring the thickness orientation dispersion and orientation of collagen fibers in the leaflets. Finally, in the inspection step, the leaflets are deemed acceptable or unacceptable when compared to a leaflet model. Acceptable leaflets are arranged in groups of at least two leaflets for incorporation into the BHV. If desired, the method may also include rehydration of the already cut leaflets prior to the inspection step.

[0054] As described above, this device and method involve the digitization of patches, the automated selection and cutting of leaflets, and the inspection, verification, certification, and grouping of leaflets used in the manufacture of BHVs. This advantageously results in improved quality and productivity of the final product. Because this device automates the inspection and manufacturing of leaflets used in the manufacture of BHVs, it has been found to advantageously improve efficiency, durability, and quality while reducing costs. Improvements in traceability during the manufacturing process are also achieved. All of these represent significant benefits for patients requiring BHV implantation. Attached Figure Description

[0055] The exemplary detailed description given below is intended to provide a further explanation of this disclosure. Other advantages and features will become apparent from the following description and drawings.

[0056] In the attached diagram: Figure 1a The image shows a top view of the Sapien® bioartificial heart valve with the leaflets in the closed position (diastolic heart). Figure 1b It shows Figure 1a The image shown is a top view of the Sapien® bioartificial heart valve, with the leaflets in the open position (heart contraction). Figure 1c It shows Figure 1a and Figure 1b A stereoscopic view of the Sapien® bioartificial heart valve shown; Figure 2 This is a top view of the leaflets to be assembled into a bioartificial heart valve; Figure 3 This is a schematic block diagram of the station for fabricating leaflets for bioartificial heart valves; Figure 4 It is shown schematically. Figure 3 A block diagram of the station used by the device shown for digitizing patches of animal pericardial tissue; Figure 5 It is shown schematically. Figure 3 A block diagram of the station for automatically selecting the most suitable area for the patch in the device shown; Figure 6 It is shown schematically. Figure 3 The diagram shows a block diagram of the device used for leaflet inspection and a pass / fail determination station. Figure 7 This is a schematic diagram of an example of a 2D optical sensor used to image patches or leaflets using an incident illumination device; Figure 8 This is a schematic diagram of an example of a 2D optical sensor used for imaging patches or leaflets using a transillumination device; Figure 9 This is a schematic diagram of an example of a dynamic stripe projection 3D optical sensor used to obtain a thickness distribution map of a patch or leaflet. Figure 10 It is shown schematically. Figure 3 A block diagram of the small-angle light scattering (SALS) system of the device shown; and Figure 11 It shows the coordinates of the ellipse corresponding to the far-field diffraction pattern displayed on the screen when the laser beam of the improved SALS sensor passes through the thickness of the pericardial tissue of the patch or leaflet, and also shows the orientation of the major axis of the ellipse E relative to the horizontal reference axis X. Detailed Implementation

[0057] The attached diagram Figure 3-11 A non-limiting example of the device is shown. In the accompanying drawings, the device is generally indicated by reference numeral 100.

[0058] The apparatus 100, which will be described in detail below, is designed for the fabrication of leaflets L for a bioartificial heart valve 10. The bioartificial heart valve 10 is referred to hereinafter as BHVs10. As will be described in detail below, the apparatus 100 allows for the automated fabrication and certification of leaflets L for BHVs10, meeting the requirements of heart valve manufacturers. For this purpose, the apparatus 100 provides digitization, automated selection, leaflet cutting, and verification, certification, and grouping of leaflets L for the fabrication of BHVs10.

[0059] As shown in the attached diagram Figure 2 as well as Figure 1a , Figure 1b and Figure 1c As shown in detail, the leaflet L is the valve element of the BHV10. Each BHV10 includes a flexible metallic stent 15. Figure 1a , Figure 1b , Figure 1c The leaflets L in the BHVs10 are connected to a flexible metal stent 15, allowing them to work together to replicate the natural valve.

[0060] The leaflet L is made of animal tissue, such as bovine or porcine pericardium, which includes collagen fibers. The collagen fibers reinforce the leaflet L, thereby providing it with structural integrity.

[0061] like Figure 2 As shown, each leaflet L includes a side connector or merging portion 20, a mating edge 21, and an arcuate leaflet tip edge 22.

[0062] The device 100 for preparing the leaflets for BHVs10 is modular and flexible, and it is based on optical sensors 225, 235, 240 and 300, which will be described in further detail below.

[0063] Refer to the attached diagram. Figure 3 and Figure 4 The device 100 includes a digitization station 200 for digitizing at least one patch P.

[0064] As used in this article, patch P refers to a small portion of animal pericardial tissue with stacked layers of collagen fibers.

[0065] The digitization station 200 is configured to digitize at least one patch P. The patch P to be digitized is placed on the upper side 951 of a planar parallel glass plate 950, which is adapted to be driven by an XY motor (not shown). The glass plate 950 is part of a support device 900, which will be described further below.

[0066] More specifically, the analysis of patch P is performed in the digitization station 200. Based on the analysis, the most suitable area of ​​patch P is automatically selected, and the most suitable area of ​​patch P can be converted into the leaflet L for manufacturing BHVs10.

[0067] To perform the analysis described for patch P, digitization station 200 includes, as follows: Figure 4 , Figure 7 and Figure 8 The 2D optical sensors 225 and 235 are shown. The 2D optical sensors 225 and 235 include corresponding sensor cameras 221 and 231 and sensor optics 215, as shown in the attached figures. Figure 7 and Figure 8 As shown. The 2D optical sensor 225 also includes, as shown... Figure 7 The bright-field incident illumination device 220 shown, and the 2D optical sensor 235 also include a transmission device 230, such as... Figure 8The image shown is used to image patch P. A 2D optical sensor 225 is configured to acquire a 2D bright-field image 226 of patch P. A 2D optical sensor 235 is configured to acquire at least one 2D transilluminated image 236 of patch P for detecting defects and evaluating collagen density in patch P. To evaluate collagen density, the 2D optical sensor may include a polarized light transillumination device.

[0068] refer to Figure 9 Digital Station 200 also includes, for example, Figure 4 and Figure 9 The 3D optical sensor 240 shown is a sensor camera 241 and sensor optics 245, such as... Figure 9 As shown. The 3D optical sensor 240 also includes, for example... Figure 9 The 3D lighting device 246 is shown. In particular, the 3D lighting device 246 is a stripe projection lighting device 246, which is configured to illuminate the patch P placed on the upper side 951 of the aforementioned planar parallel glass plate 950 of the support device 900.

[0069] The 3D optical sensor 240 of the digitizing station 200 is configured to obtain a high-resolution thickness distribution map 250 of the patch P. For this purpose, the 3D optical sensor 240 can be as follows: Figure 9 The example shown is a dynamic fringe projection optical sensor, although the optical sensor 240 can be other types of optical sensors (such as confocal optical sensors, interferometric optical sensors, focus-change optical sensors, etc.). Figure 9 In the example shown, the sensor optics 245 of the 3D optical sensor 240 includes a telecentric optical system, a 5-megapixel camera 241, and the aforementioned fringe projection illumination device 246. As a result, a depth of focus greater than 1 mm, a lateral resolution better than 15 μm, and a vertical resolution better than 1 μm are advantageously achieved. Such a depth of focus allows for the measurement of thickness distribution maps of pericardial tissue with a thickness less than 1 mm.

[0070] The mean and standard deviation of the tissue thickness of patch P can be determined by the thickness distribution map 250 of patch P, which is obtained via the 3D optical sensor 240 of the digitizing station 200. Based on the thickness distribution map 250 of patch P, a selection algorithm can be fed to determine the optimal position of the leaflet L in patch P, which satisfies the parameters set from the leaflet model L'. The selection algorithm will be referred to below.

[0071] The digitization station 200 includes a compact and automated improved small-angle light scattering (SALS) system 300, as shown in the attached figure. Figure 4 and Figure 10As shown schematically, the improved SALS sensor 300 is an essential component for the automated manufacturing process of the leaflets L to be assembled into the BHV10.

[0072] exist Figure 10 In the example shown, the improved SALS sensor 300 includes a camera 301, an imaging optics 302, a projection screen 303, and a helium... The helium laser source 304, the beam shaping optics 306, and the curved reflector 307, The neon laser source 304 is adapted to emit a laser beam 305 with a power of at least 5 mW and a wavelength of 632.8 nm. This wavelength is within the order of magnitude of the fiber size and interfibrillary spacing of collagen fibers in pericardial tissue. The projected laser beam 305 is reflected by a curved mirror 307 after passing through the beam-shaping optics 306. After passing through the curved mirror 307, the laser beam 305 passes through a planar parallel glass plate 950 and through the patch P of the pericardial tissue, and is scattered by the fibrous structure of the patch P. Therefore, the resulting far-field diffraction pattern is projected onto the projection screen 303 and then imaged onto the camera 301 by the imaging optics 302.

[0073] As the laser beam 305 passes through patch P, the aforementioned far-field diffraction pattern is obtained using a modified SALS sensor 300. This far-field diffraction pattern is the result of superimposing the diffraction patterns generated in each layer of collagen fibers in the pericardial tissue through which the laser beam 305 passes, as shown by MS Sacks et al., “ A small angle light scattering device for planar connective tissue microstructural analysis The far-field diffraction pattern reported in Annals of Biomedical Engineering, Vol. 25, pp. 678-589, 1997, corresponds to an ellipse E, which is projected onto screen 303 and imaged onto camera 301 via imaging optics 302, as shown in the attached figure. Figure 11 As shown. Based on the ellipse E, the thickness orientation and dispersion of collagen fibers in patch P are determined, so that the thickness orientation and dispersion distribution of collagen fibers in patch P can be obtained quickly and reliably in diagram 255.

[0074] The ellipse E is characterized by the value of its eccentricity ε and the orientation of its major axis A and minor axis B. The value of the eccentricity ε of ellipse E refers to how round the ellipse E is. The larger the value of the eccentricity ε, the flatter the ellipse E; and the smaller the value of the eccentricity ε, or the closer it is to zero, the rounder the ellipse E is. The eccentricity ε ranges between 1 and 0 and can be calculated as follows:

[0075] Where a and b are as follows Figure 11The lengths of the major axis A and minor axis B of the ellipse E shown are given. The eccentricity ε is a dimensionless parameter. Therefore, the lengths a and b can be expressed in arbitrary units (AU).

[0076] exist Figure 11 In the example shown in the image, the length a of the major axis A of ellipse E is 371 AU, and the length b of the minor axis B of ellipse E is 268 AU. Therefore, in this case, the eccentricity ε is:

[0077] The thickness-direction dispersion of collagen fibers was evaluated by the eccentricity ε, which was obtained by the major axis A and minor axis B of the ellipse E as described above, and as per A. Whelan et al. Collagen fiber orientation and dispersion governs ultimate tensile strength, stiffness and fatigue performance of bovine pericardium The reported structures show that tissues with highly aligned fibers exhibit an eccentricity ε equal to or greater than 0.65, while tissues with highly dispersed fibers (i.e., fibers oriented in multiple directions) show an eccentricity ε less than 0.65. Generally, the more fibers in patch P are aligned in the same direction within its tissue layer, the flatter the aggregated diffraction pattern, and the higher the eccentricity ε of the ellipse E. In this case, as... Figure 11 In the example shown, the eccentricity value of ε=0.69 means that patch P can be considered as tissue with highly aligned fibers.

[0078] Another relevant parameter obtained from the diffraction pattern is the orientation angle α of the major axis A of the ellipse E. For example... Figure 11 As shown, the orientation angle α is defined by the major axis A of the ellipse E and the horizontal reference axis x. The orientation of the major axis A of the ellipse E corresponds to a direction perpendicular to the dominant orientation of collagen fibers in the total thickness of the tissue of patch P. Figure 11 In the non-limiting example shown, the orientation angle α of the major axis A of the ellipse E is α = 45°.

[0079] The optimal angular orientation of the leaflet L is determined using the two parameters: the eccentricity ε of the ellipse E and the orientation angle α of the major axis A, obtained from the SALS sensor 300. Furthermore, it has been found that the improved SALS sensor 300 in the digitizer 200 of this device 100 can rapidly and accurately measure fiber orientation in patches with a thickness range from 100 μm to 1000 μm with an angular resolution better than 1 degree and a lateral resolution better than 500 μm.

[0080] Utilizing the 2D sensors 225, 235 and 3D sensor 240, as well as the improved SALS sensor 300, included in the digitization station 200 of the device 100 as described above, the necessary parameters for the proper selection of leaflet L can be obtained quickly and reliably. Therefore, effective non-contact examination of pericardial tissue can be performed both for the manufacture of leaflet L and for final quality control and certification of leaflet L prior to suturing it to the metal stent 15 of the BHVs 10.

[0081] The device 100 also includes a selection station 400. The selection station 400 is configured to automatically select the region in the patch P that is considered most suitable for forming a qualified leaflet L. The automatic selection of the region in the patch P is based on the digital results obtained by the aforementioned digitization station 200 and according to at least one leaflet model L'.

[0082] The selection of patch P as the most suitable region for leaflet L (i.e., qualified leaflet L) is performed using a suitable algorithm in a sequential manner including the following steps. An initial step is performed to exclude regions in patch P affected by critical defects or low collagen density, which have been detected by 2D radiographic images of patch P.

[0083] Another step in selecting the optimal region for patch P involves determining the optimal positioning of leaflet L based on at least one leaflet model L' as described above, using a thickness distribution map obtained by 3D optical sensor 240 and the optimal leaflet orientation obtained by improved SALS sensor 300. This is performed using an optimization algorithm based on the tissue thickness distribution of the aforementioned 3D thickness distribution map 250 of patch P.

[0084] Selecting the region in patch P considered most suitable for forming a qualified leaflet L based on leaflet model L' involves at least two additional optimization variables. These additional optimization variables are derived from: the average tissue thickness at the commissure region being higher than the average tissue thickness of leaflet L, and the collagen density at the commissure region being higher than the average collagen density of leaflet L.

[0085] The device 100 also includes a cutting station 500 for cutting the patch P into a selected optimal region to form the leaflet L. In a non-limiting example shown in the figures, the cutting station 500 includes a laser cutting device 550. In this example, it is a CO2 laser cutting device 550. A low-power CO2 laser cutting device 550 capable of delivering no more than 10W of power is preferred, particularly a VLS2.30 type laser cutting device 550 available from Universal Laser Systems Inc., which includes a beam focusing head with aspherical optics. The cutting of the leaflet L is optimized while advantageously minimizing the heat-affected zone of the tissue. However, in other examples, the cutting station 500 may include other types of cutting devices, such as a die-cutting device. In any case, the leaflet L is cut in the cutting station 500 at the optimal location based on the information provided by the digitizing station 200 and the selection station 400 as described above. The leaflet L is cut in the cutting station 500 on the aforementioned planar parallel glass plate 950.

[0086] The outline of patch P defines the boundary for the selected leaflet L. The outline of patch P is converted into a drawing file or a vector file format, such as a portable file format (pdf) or a vector file format such as Corel Draw® (cdr). Once the drawing files have been created, they are transmitted to the laser cutting apparatus 550 to perform the corresponding cutting operations to form the leaflet L. Information included in the drawing files may also include the locations corresponding to small holes to be formed in the tissue of patch P for subsequently suturing the formed leaflet L to the metal support 15 of the BHV10.

[0087] Several operating parameters of the laser cutting device 550, such as power and pulse frequency, can be set. These can be appropriately adjusted to obtain the optimal quality-speed ratio during the cutting operation of the pericardial tissue of patch P. In particular, since the thickness of the leaflet L to be cut is known, the power and cutting speed of the laser cutting device 550 can be set for each leaflet L to be obtained.

[0088] As described above, a support device 900 is provided to support the pericardial tissue patch P or leaflet L, thereby ensuring its accurate positioning. By using the support device 900, there is no need to process the patch P, and the leaflet L is accurately obtained at the most suitable position.

[0089] Specifically, in Figures 7-10The support device 900 shown in the example includes the aforementioned planar parallel glass plate 950. The planar parallel glass plate 950 is 150 × 150 mm and includes an upper side 951 and a lower side 952. The upper side 951 of the planar parallel glass plate 950 is slightly textured and is used to receive the hydrated pericardial tissue of the patch P. The lower side 952 of the planar parallel glass plate 950 is polished.

[0090] As a result of the above construction, when the hydrated pericardial tissue of patch P contacts the textured upper side 951 of the planar parallel glass plate 950, the textured upper side 951 acts as an optically transparent surface for a 2D optical sensor 235 having a light transmission device 230.

[0091] One advantage of the planar parallel glass plate 950 with its textured upper side 951 is that it completely absorbs the laser beam from the CO2 laser cutting device. As a result, reflections of the remaining laser beam after tissue cutting are avoided, thus achieving good cutting quality in the cutting station 500.

[0092] refer to Figure 6 The device 100 also includes an inspection station 600 for inspecting the cut leaflet L. The leaflet inspection station 600 is configured to perform dimensional verification, detect critical defects in the leaflet L, assess collagen density, and dually inspect the 3D thickness distribution map of the leaflet L and the thickness orientation and dispersion of collagen fibers in the leaflet L by means of the aforementioned 2D optical sensors 225 and 235 with bright field illumination device 220 and transmissive device 230, the aforementioned 3D optical sensor 240 with 3D stripe projection illumination device 246, and the improved SALS sensor 300.

[0093] Since leaflet L is best positioned in selection station 400, the dominant orientation of collagen fibers in leaflet L is expected to be horizontal, i.e., parallel to... Figure 2 The junction edge 21 of the leaflet L shown.

[0094] The operation in leaflet inspection station 600 results in determining whether leaflet L is qualified or unqualified based on at least one leaflet model L', thereby minimizing risk and providing traceability. If leaflet L is qualified, it can be certified, a mark can be assigned to it, and a set of characteristic parameters can be provided to appropriately group leaflet L into groups of at least two units to be assembled into BHV10.

[0095] Before grouping the leaflets L, a final inspection, quality control, and certification of the leaflets L are performed at inspection station 600. Grouping of the leaflets L is performed at grouping station 700, which will be described below. Inspection station 600 may disregard this if the aforementioned digitization station 200 is also configured for inspecting the leaflets L.

[0096] The device 100 also includes a grouping station 700 as described above. The grouping station 700 is configured to arrange qualified leaflets L into groups of at least two leaflets L (typically three) for integration into the BHV 10. More specifically, qualified leaflets L are arranged in the grouping station 700 into multiple units (e.g., three units in a transcatheter aortic valve implantation (TAVI)) for assembly into the metallic stent 15 of the BHV 10 for optimal operation. Prior to grouping, the certified leaflets L are appropriately stored and managed using suitable software.

[0097] A conveying device 800 is also provided for conveying the patch P or leaflet L through the stations of the device 100. The conveying device 800 is configured to transfer the patch P or leaflet L on the planar parallel glass plate 950 from one station to another. The transfer operation can be performed as a manual transfer operation, an automatic transfer operation, or a combination of manual and automatic transfer operations.

[0098] Manual transfer operations may include, for example, manually loading the patch P or leaflet L onto the planar parallel glass plate 950 of the support device 900.

[0099] Preferably, the device 100 for preparing leaflet L has a U-shaped unit layout, which is used in the bioartificial heart valve 10. This is superior to a linear layout for the transfer of patch P and leaflet L. The U-shaped unit layout provides good scalability of the productivity of device 100 and proper integration of the cutting station 500. The U-shaped unit layout can be flexibly operated by an operator or robot as needed. This preferred unit layout of device 100 is advantageous in terms of access to the laser cutting device 550, since currently available laser cutting devices operate in a closed chamber with no other entrance except for a hinged top cover. With the currently preferred U-shaped unit layout, lateral access to the cutting platform is not required, eliminating the need to remove or modify the protective housing for access. The U-shaped unit layout facilitates the flow of patch P and leaflet L through the stations. Patch P enters at one end of device 100, and as they move around the “U” space, they are processed at different stations, i.e., digitized, cut, etc. At the other end, qualified and certified leaflet L exits device 100. As a result, the optimal lean manufacturing process was obtained.

[0100] This device 100 is suitably controlled by a computer program. The computer program includes instructions that, when executed by the computer, cause the computer to perform the steps of the methods already described above.

[0101] The computer program includes software modules, which include one or more of the following.

[0102] The computer program includes a digitization module for acquiring and analyzing pericardial tissue patch P and selecting the most suitable region to be converted into leaflet L. The digitization module is based on... Figure 4 , Figures 7-9 The 2D sensors 225, 235 and 3D sensor 240 shown operate based on information provided by the accompanying drawings, and also according to the information provided by the accompanying drawings. Figure 4 and Figure 10 The improved SALS sensor 300 shown in the diagram operates based on the information provided.

[0103] The computer program also includes a simple leaflet cutting module, which converts the lines defining the boundaries of the selected leaflet L into computer information delivered in the aforementioned format (i.e., PDF or CDR format). This information is sent via a suitable means to the laser cutting device 550 of the cutting station 500, which cuts the patch P into leaflets L.

[0104] This article refers to the attached figures. Figure 4 A method for preparing leaflets L for BHVs10 using the apparatus 100 described above is disclosed.

[0105] Now return to the attached diagram for reference. Figure 4 A patch P of animal pericardial tissue is mounted on the digitization station 200 of device 100. In step 1100, a 2D bright-field image 226 of patch P is obtained by 2D optical sensor 225. In step 1200, at least one 2D radiographic image 236 of patch P is obtained by 2D optical sensor 235. In step 1300, a 3D thickness distribution map 250 of patch P is obtained by 3D optical sensor 240. In step 1400, a thickness orientation and dispersion distribution map 255 of collagen fibers in patch P is obtained by modified SALS sensor 300.

[0106] In step 1500, patch P is selected as the region considered most suitable for forming a qualified leaflet L. Based on both at least one leaflet model L' and the digital results obtained from digitization station 200, the most suitable region for patch P is selected in selection station 400. Selection is performed by applying an optimization process based on mathematical optimization techniques. Figure 5 As shown, the optimal location of the potential qualified leaflet L was obtained as a result of the application of the optimal positioning process based on the above leaflet model L'.

[0107] Instead of algorithms such as gradient descent or branch and bound, the mathematical optimization technique used in this method is the metaheuristic simulated annealing (SA) probabilistic technique. SA is a probabilistic technique that uses an algorithm to approximate the global optimum of a given function, and it is useful when finding an approximate global optimum in a fixed amount of time is more important than finding an exact local optimum. Specifically, SA performs approximate global optimization over a large search space for the optimization problem.

[0108] Step 1500 also involves excluding areas of patch P that have been found to have critical defects or low collagen density. Critical defects and low collagen density areas are detected from at least one of the aforementioned 2D bright-field image 226 and 2D transillumination image 236, which are obtained by the aforementioned 2D optical sensor 225 and 2D optical sensor 235, respectively.

[0109] Step 1500 further includes determining the optimal location of the leaflet L, which satisfies the thickness orientation and dispersion of collagen fibers, as well as thickness parameters, previously defined in the leaflet model L'. This corresponds to the location of the leaflet L oriented according to the dominant direction of the collagen fibers, which has been identified from the thickness orientation and dispersion distribution map 255 obtained by the improved SALS sensor 300.

[0110] The SA probability technique according to this method involves at least one of two additional optimization variables, which are generated by the average tissue thickness at the side joint or commissure 20 of leaflet L being higher than the average tissue thickness of leaflet L, and the collagen density at the side joint or commissure 20 of leaflet L being higher than the average collagen density of leaflet L.

[0111] In step 1600, the most suitable area selected for patch P is cut using laser cutting device 550 in cutting station 500 to form leaflet L. Cutting step 1600 also involves forming holes in the qualified leaflet L for subsequent suturing to BHV stent 15. The cut leaflet is rehydrated before being transferred to final inspection in step 1700.

[0112] In step 1700, the leaflet L is inspected at inspection station 600. The inspection involves performing dimensional verification on the leaflet L, detecting critical defects in the leaflet L, assessing collagen fiber density, measuring the thickness distribution map 250 of the leaflet, and measuring the thickness orientation and dispersion of collagen fibers in the leaflet L. The inspection also involves classifying the leaflet L as acceptable or unacceptable when compared to the leaflet model L'. The inspected and acceptable leaflet L is then certified.

[0113] In step 1800, the certified leaflet L is arranged into a group of at least two leaflets L (e.g., three in a transcatheter aortic valve implantation (TAVI)) to be incorporated into the BHV10. This is performed in grouping station 700.

[0114] The performance of the aforementioned device 100 and method used to prepare leaflets L for BHVs10 was tested to evaluate its effectiveness.

[0115] The technique described above for measuring the thickness of the pericardial tissue patch P has been thoroughly validated. Tests were conducted to compare the results measured using the aforementioned 3D optical dynamic stripe projection sensor 240 with values ​​obtained from mechanical contact measurements. It was observed that the thickness measurement performed by the sensor 240 in this device 100 was consistent with the result involving a pressure (equal to 0.01 N / mm) applied by the contact sensor to the pericardial tissue surface of patch P. 2 The measurements were consistent. Testing was conducted using a Litematic 0.01N system from Mitutoyo, which is considered a reference for measuring the thickness of soft samples.

[0116] Furthermore, as mentioned above, such as Figure 11 The ellipse E shown corresponds to the far-field diffraction pattern obtained by the modified SALS sensor 300 of this device 100 when the laser beam 305 passes through the thickness of the pericardial tissue of patch P. The eccentricity ε of the ellipse E is correlated with the dispersion of collagen fibers in the pericardial tissue of patch P. In the performed tests, the results of the eccentricity ε of the ellipse E and the orientation of the major axis A and minor axis B were found to perfectly match the fiber architecture observed by nonlinear second harmonic generation (SHG) microscopy.

[0117] More specifically, an SHG microscope was used to verify the thickness orientation and dispersion distribution of collagen fibers obtained by the modified SALS sensor 300 of this device 100 (map 255). The SHG microscope used in the test allowed imaging of individual collagen fibers in the patch P or leaflet L down to a depth of approximately 100 μm. It was found that the results of the eccentricity ε of the ellipse E and the orientation of its major axis A obtained using the SALS sensor 300 perfectly matched the fiber architecture observed using the SHG microscope.

[0118] The accuracy of the gauges was also checked through gauge repeatability and reproducibility (GR&R) tests. Similarly, excellent results were obtained in the measurement of the thickness distribution maps of patch P and leaflet L.

[0119] The present device 100 and method for preparing leaflets L for BHVs10 have many advantages.

[0120] The most important advantage is that this device has been found to significantly improve the hemodynamic efficiency and durability of BHVs10, thus benefiting patients who require its implantation.

[0121] Furthermore, it has been found that non-contact optical examination is highly effective for both the leaflet manufacturing stage and the final quality control and certification of the leaflet L before it is sutured to the heart valve stent 15. Improved 2D optical sensors 225, 235 and 3D optical sensors 240 enable rapid and reliable acquisition of the required parameters to obtain a suitable selection of the optimal leaflet L for manufacturing BHVs 10. In particular, the acquisition and analysis speeds of the 2D optical sensors 225, 235, 3D optical sensors 240 and the improved SALS sensor 300 have been optimized. In this regard, it has been found that the digitization, analysis, and cutting of the patch P can be performed in less than 5 minutes, which is the time required without tissue rehydration. Rapid analysis of large tissue areas can be performed to avoid expensive equipment and time-consuming tissue pretreatment steps.

[0122] Furthermore, by developing new 2D optical sensors 225 and 235, a 3D optical sensor 240, and an improved SALS sensor 300, the expanded digitization capabilities of this device 100 allow for reliable acquisition of pericardial tissue thickness distribution maps 250, as well as detection of key defects, collagen density, and collagen fiber architecture in the pericardial tissue patch P. These are crucial factors for improving the quality of the leaflet L, and thus improving the efficiency and durability of BHVs 10 implanted in patients with aortic stenosis.

[0123] The aforementioned device 100 is intended, but not limited to, managing patch P with a maximum size of 120 × 120 mm. It has been found that this maximum size of the patch P to be processed allows for advantageous mitigation of the risk of dehydration of the pericardial tissue patch P.

[0124] This equipment 100 also offers improved productivity and performance, enabling partial or full automation of the manufacturing and inspection processes for BHVs 10. In this regard, the equipment 100 has been found to have a leaflet processing capacity on the order of 20 certified leaflets L per hour, equivalent to 30,000 leaflets L per year on a single shift. This means that, using a single equipment 100, a heart valve manufacturer can produce enough leaflets L to manufacture 10,000 aortic heart valves per year. Furthermore, due to the modular and scalable nature of the equipment 100, productivity can be easily increased. This is particularly advantageous for heart valve manufacturers. Moreover, assuming a two-year payback period for the capital investment, the projected cost of manufacturing each leaflet L is extremely low compared to current manual manufacturing costs.

[0125] In addition to the aforementioned competitive improvements in cost and inherent improvements in quality and reliability, it should be noted that traceability during the manufacturing process has also been improved to meet the requirements of the Medical Device Regulation (MDR).

[0126] Although examples of the device 100 and methods for preparing leaflets L for BHVs10 have been disclosed herein, other alternatives, modifications, and / or equivalents are possible. All possible combinations of the described examples are also covered. The scope of this disclosure should not be limited to the examples disclosed herein but should be determined solely by a fair reading of the appended claims.

[0127] Reference numerals placed in parentheses within the claims and relating to the drawings are used only to attempt to increase the comprehensibility of the claims and should not be construed as limiting the scope of the claims.

Claims

1. An apparatus (100) for preparing leaflets (L) for a bioartificial heart valve (10), said apparatus (100) comprising: - A digitization station (200) for digitizing at least one patch (P) of animal pericardial tissue comprising stacks of collagen fiber layers, the digitization station (200) comprising: - At least one 2D optical sensor (225) is used to image the patch (P) using at least one of a bright-field incident illumination device (220) and a transmissive device (230) for detecting defects in the patch (P) and evaluating at least one of the collagen density in the patch (P); - At least one 3D optical sensor (240) is used to obtain a thickness distribution map (250) of the patch (P); and - A small-angle light scattering (SALS) system (300) for obtaining a thickness orientation and dispersion distribution map (255) of collagen fibers in the patch (P), wherein the SALS sensor (300) is configured to obtain a far-field diffraction pattern in which diffraction patterns generated in each of the corresponding layers of collagen fibers in the pericardial tissue through which a focused laser beam (305) passes are superimposed, the focused laser beam (305) having a wavelength on the same order of magnitude as the diameter and interfiber spacing of the collagen fibers; and - Selection station (400), which is used to automatically select the region in the patch (P) that is considered most suitable for forming a qualified leaflet (L) based on the digital results obtained by the digitization station (200) and according to at least one leaflet model (L').

2. The device (100) according to claim 1, wherein, The device (100) further includes one or more of the following: - Cutting station (500), the cutting station (500) is used to cut the most suitable area selected by the patch (P) to form a leaflet (L); - Inspection station (600), the inspection station (600) is used to inspect leaflet (L), the inspection station (600) is configured to perform dimensional verification in the leaflet, measure the thickness distribution of the leaflet (L), detect critical defects in the leaflet (L), evaluate the collagen density in the leaflet (L), and measure the thickness orientation and dispersion of collagen fibers in the leaflet (L), and consider the leaflet (L) as qualified or unqualified when compared with the leaflet model (L'); as well as - Grouping station (700), the grouping station (700) is used to arrange qualified leaflets (L) into groups of at least two leaflets (L) for integration into a bioartificial heart valve (10).

3. The device (100) according to claim 2, wherein, The cutting station (500) for cutting the most suitable area selected for the patch (P) includes a laser cutting device (550).

4. The device (100) according to claim 3, wherein, The laser cutting device (550) is a CO2 laser cutting device.

5. The device (100) according to claim 2 or 3, wherein, The cutting station (500) for automatically cutting the patch (P) to the most suitable area includes a die-cutting device.

6. The device (100) according to any one of the preceding claims, wherein, The digitizing station (200) used for digitizing the patch (P) is also configured for examining the leaflet (L).

7. The device (100) according to any one of the preceding claims, wherein, The patch P (P) has a maximum size of 120×120mm.

8. The device (100) according to any one of the preceding claims, wherein, If the device (100) further includes a conveying device (800) for conveying patches (P) or leaflets (L) through the station.

9. The device (100) according to any one of the preceding claims, wherein, The 3D optical sensor (240) is one of dynamic fringe projection, confocal, interferometry, and focus change.

10. The device (100) according to any one of the preceding claims, wherein, The 3D optical sensor (240) has a 5-megapixel camera with a horizontal resolution better than 15 μm and a vertical resolution better than 1 μm.

11. The device (100) according to any one of the preceding claims, wherein, The SALS sensor (300) includes helium with a wavelength of 632.8 nm. Neon laser.

12. The device (100) according to any one of the preceding claims, wherein, The device (100) further includes a support device (900) for the pericardial tissue, the support device (900) performing the following when in contact with the hydrated pericardial tissue: - For the optical diffuser surface used in the 3D optical sensor (240) and the 2D optical sensor (225) with bright field illumination device (220); as well as - An optically transparent surface for the 2D optical sensor (225) having a light transmission device (230).

13. The device (100) according to claim 12, wherein, The support device (900) for the pericardial tissue includes a planar parallel glass plate (950) having a polished side and a textured side on which the hydrated pericardial tissue is to be placed.

14. A method for preparing leaflets (L) for a bioartificial heart valve (10) by means of an apparatus (100), said apparatus (100) being the apparatus (100) according to any one of claims 1-13, said method comprising: - Load animal pericardial tissue into the digitization station (200) for digitizing at least one patch (P) of the animal pericardial tissue; - Obtain at least one of a 2D bright-field image and a 2D radiograph of the patch (P); - Obtain a 3D thickness distribution map (250) of the patch (P); - Obtain the thickness orientation and dispersion distribution map (255) of the collagen fibers in the patch (P); and - Select the region in the patch (P) that is considered most suitable for forming a qualified leaflet (L) according to at least one leaflet model (L'), the selection step being carried out by applying an optimization process based on mathematical optimization techniques, based on digital results obtained from the digitization station used for digitization.

15. The method according to claim 14, wherein, The method further includes: - Cut the patch (P) to select the most suitable area to form a leaflet (L); - Inspect the leaflet (L), the inspection steps including performing dimensional verification in the leaflet, measuring the thickness distribution map (250) of the leaflet (L), detecting critical defects in the leaflet (L), measuring the thickness orientation and dispersion of collagen fibers in the leaflet, and classifying the leaflet (L) as acceptable or unacceptable when compared with the leaflet model (L'); and - Arrange qualified leaflets (L) into groups of at least two leaflets (L) to be incorporated into a bioartificial heart valve (10).

16. The method according to claim 14 or 15, wherein, Based on the leaflet model (L'), the regions in the patch considered most suitable for forming a qualified leaflet (L) include: - Exclude areas where the patch (P) has critical defects; and - Determine the optimal position of the leaflet (L) that satisfies the thickness orientation and dispersion of the collagen fibers and the thickness parameters previously defined in the leaflet model (L').

17. The method according to any one of claims 14-16, wherein, The far-field diffraction pattern obtained by the small-angle light scattering (SALS) system (300) is an ellipse (E), characterized by the value of the eccentricity (ε) of the ellipse (E) and the orientation of the major axis (A) and the minor axis (B).

18. The method according to claim 17, wherein, The thickness direction orientation of the collagen fibers is aligned with the orientation of the minor axis (B) of the ellipse (E), and the thickness direction dispersion of the collagen fibers is obtained from the eccentricity (ε) of the ellipse (E).

19. The method according to any one of claims 15-18, wherein, The method also includes rehydrating the cut leaflets (L).

20. The method according to any one of claims 15-19, wherein, The cutting step includes forming a hole in the qualified leaflet (L) for subsequently suturing the leaflet (L) to the stent (15) of the bioartificial heart valve (10).

21. The method according to any one of claims 14-20, wherein, The selection of the region in the patch (P) considered most suitable for forming a qualified leaflet (L) according to the leaflet model (L') involves at least one of two additional optimization variables, which are generated by the average tissue thickness at the commissure region being higher than the average tissue thickness of the leaflet, and the collagen density at the commissure region being higher than the average collagen density of the leaflet.

22. The method according to any one of claims 14-21, wherein, Detect key defects in the region to be excluded from at least one of the 2D bright-field image and the 2D transillumination image.

23. The method according to any one of claims 14-22, wherein, The mathematical optimization technique is a metaheuristic simulated annealing probability technique.

Images