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WO2025065018A1 - Conduits vasculaires avec microcanaux pour réduire la perte de cellules endothéliales - Google Patents

Conduits vasculaires avec microcanaux pour réduire la perte de cellules endothéliales Download PDF

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Publication number
WO2025065018A1
WO2025065018A1 PCT/US2024/048021 US2024048021W WO2025065018A1 WO 2025065018 A1 WO2025065018 A1 WO 2025065018A1 US 2024048021 W US2024048021 W US 2024048021W WO 2025065018 A1 WO2025065018 A1 WO 2025065018A1
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WO
WIPO (PCT)
Prior art keywords
microchannels
substrate
vascular conduit
synthetic vascular
endothelial cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/US2024/048021
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English (en)
Inventor
JR. John F. LADISA
Brandon J. TEFFT
Adam J. TELEGA
Robert P. Mccarthy
Hilda JURKIEWICZ
Alexander RASKIN
Alexander Armstrong
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Medical College of Wisconsin
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Medical College of Wisconsin
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Publication of WO2025065018A1 publication Critical patent/WO2025065018A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A61F2002/0081—Special surfaces of prostheses, e.g. for improving ingrowth directly machined on the prosthetic surface, e.g. holes, grooves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A61F2002/0086—Special surfaces of prostheses, e.g. for improving ingrowth for preferentially controlling or promoting the growth of specific types of cells or tissues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1698—Blood oxygenators with or without heat-exchangers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3653—Interfaces between patient blood circulation and extra-corporal blood circuit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0244—Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2207/00—Methods of manufacture, assembly or production

Definitions

  • Blood-contacting devices such as vascular conduits
  • vascular conduits carry strict biocompatibility and hemocompatibility requirements for safe and efficacious clinical use.
  • Small-caliber vascular conduits e.g., less than 6 mm diameter
  • thrombosis thrombosis
  • neointimal hyperplasia neointimal hyperplasia
  • restenosis This presents challenging clinical scenarios for patients requiring coronary bypass, peripheral stenting, hemodialysis access, and extracorporeal membrane oxygenation (ECMO), among others.
  • ECMO extracorporeal membrane oxygenation
  • Synthetic vascular grafts are used to treat vascular disease when autologous grafts are unavailable, but are highly thrombogenic. Synthetic vascular conduits are not safe to use in small-caliber applications. A living layer of endothelial cells is widely considered to be critical for safe and efficacious small-caliber vascular conduits to avoid thrombosis and help balance the vascular response to physiologic wall shear stress. However, excessive wall shear stress produced by circulating blood results in detachment and loss of seeded endothelial cells from conduit surfaces. The ability to maintain a viable endothelial cell layer in synthetic grafts when exposed to physiological wall shear stress (e.g., the frictional force due to flowing blood) remains challenging.
  • physiological wall shear stress e.g., the frictional force due to flowing blood
  • the present disclosure addresses the aforementioned drawbacks by providing a synthetic vascular conduit that includes a substrate composed of a biocompatible material and having formed therein a plurality of microchannels.
  • the plurality of microchannels form a pattern that reduces wall shear stress on endothelial cells deposited within the plurality of microchannels.
  • the method includes forming a substrate from a biocompatible material.
  • a plurality of microchannels is formed in the substrate according to a microchannel pattern that optimizes at least one of total surface area protected from wall shear stress or endothelial cell migration distance between microchannels. Endothelial cells are seeded in the plurality of microchannels.
  • FIG. 1 illustrates an example substrate for forming a synthetic vascular conduit, in which a plurality of microchannels are formed for containing endothelial cells.
  • FIG. 2 shows a cross-section of an example synthetic vascular conduit having microchannels with a rectangular cross-section that have been seeded with endothelial cells.
  • FIG. 3 shows a cross-section of an example synthetic vascular conduit having microchannels with a semicircular cross-section.
  • FIG. 4A shows an example CAD model of the unmodified fluid domain within a parallel plate flow chamber.
  • FIG. 4B shows an example CAD model of a parallel plate fluid chamber in the fluid domain with added microchannels.
  • FIGS. 5A-5B show an example simulation of flow in the parallel plate flow chamber without channels. Simulations revealed streamlines (FIG. 5A) and rendered velocity (FIG. 5B) of the parallel plate flow chamber model without the channels to obtain baseline values.
  • FIGS. 6A-6C show an example simulation of flow in the parallel plate flow chamber with microchannels having a 60 pm channel radius.
  • the computational fluid dynamics (CFD) results show that with the addition of channels, the fluid flow within the parallel plate flow chamber is minimally disturbed and creates pockets of low velocity and wall shear stress to protect endothelial cells from being w ashed out, thereby giving them an opportunity' to establish on the graft and allowing them to migrate out from the channels to the surrounding surfaces.
  • FIG. 7A shows a side view of velocity streamlines showing how cells within the microchannel (inset) are shielded from physiologic wall shear stress.
  • FIG. 7B show's a botom- up view of wall shear stress values for regions outside the microchannels (14.63 dyn/cm 2 ) and within the microchannels (0.57 dyn/cm 2 ).
  • FIG. 8 is a flowchart seting forth the steps of an example method for manufacturing a synthetic vascular conduit according to some aspects of the present disclosure.
  • FIG. 9 illustrates an example process for electrospinning a substrate.
  • FIG. 10 is a photograph and scanning electron microscope image of an example vascular conduit substrate electrospun from polyurethane.
  • FIG. 11 A shows an example of a 3D printed stamp for imprinting microchannels into a substrate.
  • the scale bar in FIG. 11 A indicates 500 pm.
  • FIG. 11B shows an imprinted microchannel pattern formed in an electrospun polyurethane substrate.
  • the scale bar in FIG. I IB indicates 500 pm.
  • FIG. 12 illustrates example stamp paterns that can be used to form semicircular microchannels (round peak stamp) or rectangular microchannels (square peak stamp).
  • vascular conduits and methods for their use and manufacture are constructed to have patterned microchannels on the blood-contacting surface of the vascular conduits to protect seeded endothelial cells from wall shear stress.
  • the synthetic vascular conduits described in the present disclosure remain patent long term and can be used without administration of anti-platelet agents. This can be achieved by lining the luminal surface of the vascular conduit with functional endothelial cells, which naturally inhibit thrombosis and neointimal hyperplasia to maintain patency under physiological conditions.
  • the endothelial cells are seeded into the paterned microchannels, which reduce wall shear stresses on the endothelial cells. By reducing exposure of the endothelial cells to these physiological wall shear stresses, the disclosed vascular conduits can provide significantly improved endothelial cell retention as compared to existing vascular conduits.
  • the vascular conduits described in the present disclosure can be used for a variety of potential clinical applications for an endothelialized surface. Surgically implanted conduits may be useful for bypass of small caliber arteries (e.g., coronary heart disease and peripheral artery disease) as well as reconstruction of small caliber vasculature in pediatric patients (e.g., congenital heart disease). Additionally or alternatively, the vascular conduits can be formed into self-expanding stent-grafts or covered stents. As an example, these self- expanding stent-grafts can be based on the hyperelastic properties of nitinol, which can be preseeded with endothelial cells.
  • ex vivo conduits may be useful for applications including extracorporeal membrane oxygenation (ECMO).
  • ECMO extracorporeal membrane oxygenation
  • the vascular conduits described in the present disclosure have several advantages over existing vascular conduit designs.
  • the disclosed vascular conduits are straightforward to implement because they do not involve extra processing steps to coat or otherwise modify a biomaterial surface. They also do not involve extra processing steps to stimulate the adhesion strength of cultured endothelial cells.
  • the disclosed vascular conduits can be safer than existing vascular conduit approaches because the disclosed vascular conduits have improved adhesive characteristics of the biomaterial substrate such that adhesion of undesirable cell types, including platelets and inflammatory cells, is reduced (e.g., the disclosed vascular conduits do not promote non-specific adhesion of the undesirable cell types). Additionally, the disclosed vascular conduits do not require molecular modifications to endothelial cells, which may otherwise have unforeseen effects on cell behavior, including oncogenesis.
  • the disclosed vascular conduits can be combined with existing approaches (e.g. fibronectin coating, wall shear stress preconditioning) to achieve synergistic enhancement of cell retention.
  • existing approaches e.g. fibronectin coating, wall shear stress preconditioning
  • vascular conduits described in the present disclosure overcome these challenges by utilizing local microchannels optimized in a way that shields endothelial cells from washing away in response to physiologic wall shear stress levels, thereby leading to improved endothelial cell retention when imposed on graft materials.
  • a vascular conduit 10 generally includes a substrate 12 having a blood-contacting surface 14.
  • a plurality of microchannels 16 are formed in the blood-contacting surface 14 of the substrate 12.
  • Endothelial cells 18 are seeded into the microchannels 16 (e.g., as shown in FIG. 2).
  • the microchannels 16 are designed to maximize the total surface area protected from wall shear stress and/or to minimize the distance over which endothelial cells 18 need to migrate to repopulate unprotected regions of the substrate 12.
  • the microchannels 16 may have a rectangular cross section (as illustrated in FIG. 2), a semi-circular cross section (as illustrated in FIG. 3), or any other suitable polygonal cross section or other arbitrary cross sectional shape.
  • the microchannels 16 may have a width of about 120 pm.
  • the microchannels 16 may have a width within a range of 100-140 pm, such as a width of 100 pm, 105 pm, 1 10 pm, 115 pm, 120 pm, 125 pm, 130 pm, 135 pm, 140 pm, or so on.
  • the microchannels 16 may have a depth of about 60 pm.
  • the microchannels 16 may have a depth within a range of 40-80 pm, such as a depth of 40 pm, 45 pm, 50 pm, 55 pm, 60 pm, 65 pm, 70 pm. 75 pm. 80 pm. or so on.
  • the microchannels may also have an inter-channel spacing of about 60 pm.
  • the microchannels 16 may have an inter-channel spacing within a range of 40-80 pm, such as an inter-channel spacing of 40 pm, 45 pm, 50 pm, 55 pm, 60 pm, 65 pm, 70 pm, 75 pm, 80 pm, or other such inter-channel spacing that allows for endothelial cells to proliferate and migrate from the channels (e.g., over a distance of 20-40 pm, such as ⁇ 30 pm) in order to replace cells that are lost in the inter-channel regions of the substrate 12.
  • the end result is a vascular conduit 10 capable of establishing and maintaining a confluent endothelium over the entire blood-contacting surface 14 of the substrate 12.
  • microchannel patterns widths, depths, helicities, orientations, spacings, etc., can be used to maximize the total surface area protected from wall shear stress and to minimize the distance over which endothelial cells need to migrate to repopulate unprotected regions.
  • the substrate 12 may be composed of polyurethane.
  • the polyurethane may be electrospun polyurethane, for example.
  • the substrate may be composed of other biocompatible materials, including expanded polytetrafluoroethylene (ePTFE), polyethylene terephthalate (PET), small intestinal submucosa, and so on.
  • the microchannels 16 may be formed in the substrate 12 using a variety of manufacturing techniques, including stamping, additive manufacturing (e.g., 3D printing), laser etching, photolithography, microfabrication, and so on.
  • potential applications for the vascular conduits 10 include vascular grafts for bypass surgery, vascular reconstruction, and hemodialysis access.
  • Other applications include transcatheter procedures with stented conduits for reconstruction of peripheral veins, arteries, bypass grafts, and hemodialysis access fistula and grafts as well as exclusion of aneurysms, dissections, and other vascular anomalies.
  • Other applications include ex vivo conduits for ECMO.
  • the parameters of channel number, depth, helicity, and angle relative to the primary flow direction were varied to arrive at 25%, 50%, and 75% of the area exposed to sub-physiologic wall shear stress (e.g., ⁇ 5% of Poiseuillean wall shear stress), which are contemplated to avoid washout of endothelial cells.
  • CFD simulations may be used optimize these parameters and to identify favorable combinations for use in a parallel plate flow chamber.
  • the patterned flow domain for each simulation was exposed to a wall shear stress of 15 dyn/cm 2 to create physiological conditions.
  • the simulation process may optimize microchannel dimensions and spacing using a wall shear stress-based cost function.
  • the geometry of the parallel plate flow chamber differs from that of a conduit, local wall shear stress shielding via channels is maintained regardless of the conduit shape since the global wall shear stress (i.e., 15 dyn/cm 2 ) is selected to mimic in vivo conditions.
  • a parallel plate flow chamber is placed atop a layer of endothelial cells seeded onto a synthetic graft material (i.e., a substrate of a vascular conduit).
  • a synthetic graft material i.e., a substrate of a vascular conduit.
  • the computer-aided design (CAD) model of the unmodified fluid domain within the parallel plate flow chamber 42a is shown in FIG. 4A, and the CAD model of a parallel plate fluid chamber 42b in the fluid domain w ith added microchannels 46 is shown in FIG. 4B.
  • Microchannels 46 were added to the base of the CAD model to assess how they altered the fluid dynamics.
  • FIGS. 5A-5B show an example simulation of flow" in the parallel plate flow chamber 42a without channels. Simulations revealed streamlines (FIG. 5A) and rendered velocify (FIG. 5B) of the parallel plate flow chamber model without the channels to obtain baseline values.
  • FIGS. 6A-6C show an example simulation of flow' in the parallel plate flow chamber 42b with microchannels 46.
  • the microchannels 46 were designed to have a 60 pm channel radius.
  • the CFD results show that with the addition of microchannels 46, the fluid flow within the parallel plate flow chamber 42b is minimally disturbed and creates pockets of low velocity and wall shear stress to protect endothelial cells from being washed out, thereby giving them an opportunity to establish on the graft and allowing them to migrate out from the microchannels 46 to the surrounding surfaces.
  • FIG. 7A shows a side view of velocity streamlines showing how cells within the microchannel (inset) are shielded from physiologic wall shear stress.
  • FIG. 7B shows a bottom-up view of wall shear stress values for regions outside the microchannels (14.63 dyn/cm 2 ) and within the microchannels (0.57 dyn/cm 2 ).
  • SEM scanning electron microscopy
  • DAPI 4,',6- diamidino-2-phenylindole
  • the cell seeded substrates can then be assembled into a parallel plate flow chamber (GlycoTech Corp, Gaithersberg, MA).
  • Phosphate buffered saline (PBS) can be passed through the chamber via syringe pump at a flow rate of 0.79 mL/min to achieve a wall shear stress of 15 dyn/cm 2 .
  • Fluorescence microscopy can again be performed to measure cell density after 1 hour of flow to determine percentage of endothelial retention.
  • FIG. 8 a flowchart is illustrated as setting forth the steps of an example method for manufacturing a synthetic vascular conduit according to some aspects of the present disclosure.
  • the method includes forming a substrate for the vascular conduit, as indicated at step 802.
  • the substrate may be formed using a variety of manufacturing techniques, such as electrospinning, additive manufacturing, or the like.
  • the substrate may be composed of a suitable biocompatible material, including polyurethane, ePTFE, PET, small intestinal submucosa, and so on.
  • the substrate may be formed by fabricating electrospun fluorinated polyurethane grafts (e.g., those illustrated in FIG. 9).
  • an electrospinner that creates a charged nanofiber of fluorinated polyurethane graft material was used to spin a substrate onto a rigid former, such as a microscope slide. After the substrate is electrospun, it may be removed from the rigid former, or the microchannels may be formed in the substrate (i.e., in step 804 below) before the substrate is removed from the rigid former.
  • forming the substrate may include forming the substrate into a desired shape for its use or deployment.
  • the substrate may be formed into a tubular shape for insertion in a blood vessel, or the like.
  • the substrate may be formed into a stent-graft.
  • polyurethane is electrospun onto a rotating mandrel to achieve 4 mm diameter conduits to be rolled around 3D printed patterns to imprint the microchannel pattern onto the surface.
  • Conduits can be reinforced with clinical-grade vascular grafts or stents to enable surgical and transcatheter applications, respectively.
  • Photograph and SEM images of an example polyurethane vascular conduit manufactured using electrospinning are shown in FIG. 10.
  • a plurality 7 of microchannels are then formed in the substrate, as indicated at step 804.
  • the substrate may be formed using an additive manufacturing process (e.g.. 3D printing).
  • the substrate can be constructed such that build material is not deposited where the microchannels are to be located. In this way, the additively manufactured substrate will have the plurality of microchannels inherently formed therein.
  • the microchannels may be formed in the substrate by stamping, laser etching, photolithography, microfabrication, or the like.
  • a stamping process may be used to imprint the microchannel patterns using a suitable stamp.
  • the stamp may include a 3D printed stamp using an ultra-high-definition 3D printer to fabricate stamps for imprinting a microchannel pattern in the substrate.
  • An example of a 3D printed stamp is shown in FIG. 1 1A. and a resulting imprinted microchannel pattern formed in an electrospun polyurethane substrate is shown in FIG. 1 IB.
  • the scale bars in FIGS. 11 A and 1 IB indicate 500 pm.
  • FIG. 12 illustrates example stamp patterns that can be used to form semicircular microchannels (round peak stamp) or rectangular microchannels (square peak stamp). Example specifications for the stamp patterns are shown in Table 1 below.
  • the plurality of microchannels are formed according to a set of desired characteristics that will maximize the total surface area on the substrate that is protected from wall shear stress and/or minimize the distance over which endothelial cells need to migrate to repopulate unprotected regions of the substrate.
  • the plurality of microchannels may, therefore, be formed with patterns, widths, depths, helicities, orientations, spacings, etc., that achieve these desired characteristics.
  • Endothelial cells are then seeded onto the patterned surface of the substrate, as indicated at step 806.
  • endothelial cells can be seeded onto the patterned surface of the substrate at a density of 2. O x 10 5 cells/cm 2 and allowed to adhere overnight.
  • a vascular conduit can be gravitationally seeded by rotating an endothelial cell suspension (1.0 x 10 6 cells/cm 2 ) at six revolutions per hour for two hours. Cells are allowed to adhere overnight.

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  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Vascular Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
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  • Dermatology (AREA)
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  • Prostheses (AREA)

Abstract

Des conduits vasculaires synthétiques sont construits de manière à présenter des microcanaux à motifs sur la surface de contact avec le sang des conduits vasculaires. Les cellules endothéliales sont ensemencées dans les microcanaux. Les microcanaux à motifs protègent les cellules endothéliales ensemencées d'une contrainte de cisaillement de paroi, augmentant la rétention de cellules endothéliales dans les conduits vasculaires dans des conditions physiologiques. Les microcanaux sont modelés pour optimiser la surface totale protégée contre le stress de cisaillement de paroi et/ou la distance de migration des cellules endothéliales entre les microcanaux.
PCT/US2024/048021 2023-09-21 2024-09-23 Conduits vasculaires avec microcanaux pour réduire la perte de cellules endothéliales Pending WO2025065018A1 (fr)

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US202363584304P 2023-09-21 2023-09-21
US63/584,304 2023-09-21

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060085063A1 (en) * 2004-10-15 2006-04-20 Shastri V P Nano- and micro-scale engineering of polymeric scaffolds for vascular tissue engineering
US20070154511A1 (en) * 2003-06-25 2007-07-05 Shastri Venkatram P Retention of endothelial cells on vascular grafts
US20180228960A1 (en) * 2014-10-02 2018-08-16 Cardiac Assist, Inc. Va ecmo with pulmonary artery ventilation
US20190223996A1 (en) * 2016-09-30 2019-07-25 Vascutek Limited A vascular graft
US20200237494A1 (en) * 2009-10-28 2020-07-30 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Bioerodible Wraps and Uses Therefor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070154511A1 (en) * 2003-06-25 2007-07-05 Shastri Venkatram P Retention of endothelial cells on vascular grafts
US20060085063A1 (en) * 2004-10-15 2006-04-20 Shastri V P Nano- and micro-scale engineering of polymeric scaffolds for vascular tissue engineering
US20200237494A1 (en) * 2009-10-28 2020-07-30 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Bioerodible Wraps and Uses Therefor
US20180228960A1 (en) * 2014-10-02 2018-08-16 Cardiac Assist, Inc. Va ecmo with pulmonary artery ventilation
US20190223996A1 (en) * 2016-09-30 2019-07-25 Vascutek Limited A vascular graft

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ESCH MANDY B., POST DAVID J., SHULER MICHAEL L., STOKOL TRACY: "Characterization of In Vitro Endothelial Linings Grown Within Microfluidic Channels", TISSUE ENGINEERING PART A, MARY ANN LIEBERT, INC., US, vol. 17, no. 23-24, 1 December 2011 (2011-12-01), US, pages 2965 - 2971, XP093295690, ISSN: 1937-3341, DOI: 10.1089/ten.tea.2010.0371 *

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