US20180325646A1 - Inhibition of Platelet Absorption - Google Patents

Inhibition of Platelet Absorption Download PDF

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Publication number
US20180325646A1
US20180325646A1 US15/940,037 US201815940037A US2018325646A1 US 20180325646 A1 US20180325646 A1 US 20180325646A1 US 201815940037 A US201815940037 A US 201815940037A US 2018325646 A1 US2018325646 A1 US 2018325646A1
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Prior art keywords
graft
set forth
cardiovascular
cardiovascular graft
microns
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US15/940,037
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Luke David Burke
Martijn Antonius Johannes Cox
Aurelie Serrero
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Xeltis AG
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Xeltis Bv
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Application filed by Xeltis Bv filed Critical Xeltis Bv
Priority to US15/940,037 priority Critical patent/US20180325646A1/en
Assigned to XELTIS, BV reassignment XELTIS, BV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COX, MARTIJN ANTONIUS JOHANNES, SERRERO, AURELIE
Publication of US20180325646A1 publication Critical patent/US20180325646A1/en
Assigned to XELTIS AG reassignment XELTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: XELTIS BV
Priority to US17/183,543 priority patent/US11980535B2/en
Priority to US18/624,441 priority patent/US20240245498A1/en
Abandoned legal-status Critical Current

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Definitions

  • This invention relates to electrospun coatings, grafts or materials to inhibit thrombogenic effects.
  • Vascular disease involving blood vessels with a luminal diameter of 6 mm or less constitutes the majority of disease cases requiring clinical intervention.
  • the preferred intervention is vascular reconstruction or bypass surgery, utilizing either autologous vessels harvested from elsewhere in the patient or synthetic vascular grafts.
  • Such synthetic grafts are available in a range of dimensions and configurations and generally have a small set of medical polymers such as poly(tetrafluoroethylene) (PTFE) and Poly(etherterephthalate)(PET) in either woven or dendritic assemblies.
  • PTFE poly(tetrafluoroethylene)
  • PET Poly(etherterephthalate)
  • Hemostasis encompasses the myriad of biological processes by which bleeding from damaged tissues or blood vessels is stopped.
  • a primary mechanism of hemostasis is the activation and adhesion of circulating thrombocytes, also known as platelets.
  • released proteins cause platelets to “activate”, expressing adhesive structures at their surface and allowing them to bind to the injury site and begin to form a “plug” to prevent further blood loss.
  • activated platelets release further chemical signals to recruit and activate further circulating platelets in a cascade effect, these platelets may bind either to the injury site or to other activated platelets.
  • An intravascular thrombus results from a pathological disturbance of the hemostasis process.
  • platelet activation, adhesion and aggregation occur within a vessel due to turbulent flow, interactions between foreign materials and circulating platelets, release of signaling proteins from damaged vessel walls, or others.
  • an occlusion of the vessel occurs, limiting or completely preventing blood flow.
  • These conditions are exacerbated in vessels with low volumetric flow rates, typically below 600 mL/min. This is due to circulating platelets remaining in the vicinity of the growing thrombus for a longer time, as well as reduced shear stresses on adhered platelets due to reduced flow, reducing the potential for activated platelets to be removed.
  • the present invention advances the art by providing vascular grafts with highly reduced thrombogenicity.
  • a cardiovascular graft to reduce thrombogenic effects is provided for applications like a coronary bypass graft or an arteriovenous graft for dialysis access.
  • the cardiovascular graft has a tubular structure with an inner wall made out of a fibrous network of supramolecular compounds having hard-blocks covalently bonded with soft-blocks.
  • the hard-blocks has 2-ureido-4[1H]-pyrimidinone (UPy) compounds.
  • the hard-blocks could further include chain extenders at a range of 1 to 5, or even more preferred 1.5 to 3, for the chain extenders over the UPy compounds.
  • the soft-blocks are a biodegradable polyester, polyurethane, polycarbonate, poly(ortho)ester, polyphosphoester, polyanhydride, polyphosphazene, polyhydroxyalkanoate, polyvinylalcohol, polypropylenefumarate or any combination thereof.
  • the molecular weight of the soft-block ranges between 500 and 3000 Da.
  • the fibrous network is a bioresorbable electrospun non-woven fibrous network with fibers having an average fiber diameter of 1-10 microns.
  • the tubular structure has an inner diameter between 2-8 mm, and a wall thickness of 200-900 microns.
  • the inner wall has a thickness of at least 20 micrometers and pores with an average pore size between 5 and 10 micrometers.
  • the inner wall has pores with an average pore size between 5 and 8 micrometers and an average porosity ranging from 50 to 80%.
  • the tubular structure has an inner diameter between 3-6 mm and a wall thickness of 200-800 microns.
  • the tubular structure has an inner diameter between 4-8 mm and a wall thickness of 300-900 microns.
  • the tubular structure has an inner diameter of 5 mm or less.
  • the fibers having an average fiber diameter of 4-8 microns.
  • the fibers having an average fiber diameter of 4-6 microns.
  • the inner layer of the graft is hydrophobic, with a water contact angle of between 110 and 140 degrees.
  • the tubular structure has an outer wall reinforced by a braided structure, polymer strands, compounds or a combination thereof to provide resistance to prevent collapse of the cardiovascular graft.
  • the cardiovascular graft could include an ⁇ IIb ⁇ 3 inhibitor.
  • the cardiovascular graft could be provided in combination with oral, intravenous or other administration of an ⁇ IIb ⁇ 3 inhibitor.
  • FIGS. 1A-C show according to an exemplary embodiment of the invention SEM images (10,000 ⁇ times magnification) of platelet adherence and activation on supramolecular polymer (SP) micron and submicron electrospun fibers as compared to PTFE nonwovens.
  • FIG. 1A shows high magnification view of platelet adhesion and spreading behavior on SP electrospun fibres with average diameter of 4-6 ⁇ m.
  • FIG. 1B shows high magnification view of platelet adhesion and spreading behavior on SP electrospun fibres with average diameter of ⁇ 1 ⁇ m.
  • FIG. 1C shows high magnification view of platelet adhesion and spreading behavior on non-woven PTFE fibers with average diameter of ⁇ 1 ⁇ m.
  • FIGS. 2A-C show according to an exemplary embodiment of the invention platelet spreading on SP micron- and submicron-fibers as compared to PTFE nonwovens
  • FIG. 2A shows low magnification view of platelet spreading behavior on SP electrospun fibers with average diameter of 4-6 ⁇ m
  • FIG. 2B shows low magnification view of platelet spreading behavior on SP electrospun fibers with average diameter of ⁇ 1 ⁇ m
  • FIG. 2C shows low magnification view of platelet spreading behavior on non-woven PTFE fibers with average diameter of ⁇ 1 ⁇ m.
  • FIGS. 3A-C show according to an exemplary embodiment of the invention an analysis method of surface porosity in test materials after blood perfusion.
  • FIG. 3A Original SEM image
  • FIG. 3B Cropped, enhanced contrast image from “ FIG. 3A ”
  • FIG. 3C Binary image generated from “ FIG. 3B ”
  • FIG. 3B ImageJ automated thresholding to result in absolute black/white pixels from “ FIG. 3C ” showing a 27.35% total porosity.
  • FIG. 4 shows according to an exemplary embodiment of the invention the porosity decrease observed under SEM for test materials post blood perfusion due to platelet aggregation/spreading, expressed as a percentage of initial porosity
  • FIG. 5 shows according to an exemplary embodiment of the invention detection of activated ⁇ IIb ⁇ 3 in perfused blood from test surfaces.
  • FIG. 6 shows according to an exemplary embodiment of the invention SEM images at various magnifications of platelet adherence to electrospun SP material and PTFE non-woven materials with and without the addition of abciximab.
  • FIGS. 7A-C show according to an exemplary embodiment of the invention SEM images (250 ⁇ ) magnification of explanted samples from animals medicated with, FIG. 7A ) Heparin FIG. 7B ) Heparin & Aspirin, and FIG. 7C ) Heparin, Aspirin & Plavix.
  • FIGS. 8A-C show according to an exemplary embodiment of the invention angiography of 6 mm ( FIGS. 8A-B ) and 7 mm ( FIG. 8C ) carotid interposition grafts after 6 months implantation, arrows indicate Distal (top) and Proximal (bottom) anastomoses.
  • FIG. 9 shows according to an exemplary embodiment of the invention internal diameter of graft, measured immediately prior to distal anastomosis, for 6 and 7 mm carotid interposition grafts over 36 weeks.
  • FIG. 10 shows according to an exemplary embodiment of the invention data of incremental infusion versus pore size on a small diameter graft, showing that most of the pores range between 5 and 10 micrometers in size.
  • the average pore size for cardiovascular grafts according to this invention is different than observed or desired for pulmonary valves.
  • FIG. 11 shows according to an exemplary embodiment of that alignment of fibers enables the increase in fatigue resistance, expressed as the number of cycles until failure in an Accelerated Wear Tester (AWT) for a supramolecular polymer valve under aortic conditions according to ISO 5840.
  • AHT Accelerated Wear Tester
  • the invention relates to a cardiovascular graft with highly reduced thrombogenicity by having an electrospun mesh produced from supramolecular polymers (SP).
  • SP supramolecular polymers
  • the vascular graft is a non-woven mesh and/or large diameter fibers.
  • the invention also relates to a method to produce such grafts via electrospinning.
  • the invention further relates to the implantation of the vascular graft into the human body to allow vascular bypass/reconstruction, or repeated venous access for dialysis treatment, as well as other disorders of small-diameter blood vessels.
  • the inventors have demonstrated and describe herein unexpected platelet behavior on vascular grafts produced from SP. Platelet activation and adhesion were observed without significant spreading, aggregation or philopodia formation, in stark contrast with widely available “biocompatible” materials such as PTFE. Such outcomes prove that the material is ideal for small-diameter grafts where thrombosis and/or stenosis is a key concern. Moreover, the employed SP materials are bioabsorbable, and enable tissue infiltration and regrowth. This ensures that the risk of long-term remodeling, neo-intima formation and ongoing inflammatory response leading to stenosis of the vessel is greatly mitigated.
  • the cardiovascular graft to reduce thrombogenic effects is defined by a tubular structure with an inner wall made out of a fibrous network of supramolecular compounds having hard-blocks covalently bonded with soft-blocks.
  • the hard-blocks comprise 2-ureido-4[1H]-pyrimidinone (UPy) compounds.
  • the fibrous network is a bioresorbable electrospun non-woven fibrous network with fibers having an average fiber diameter of 1-10 microns.
  • the tubular structure has an inner diameter between 2-8 mm, and a wall thickness of 200-900 microns.
  • cardiovascular graft can be defined by the following structural aspects, either individually or in any combination, if applicable, thereof:
  • the supramolecular polymer (SP) referenced herein may comprise the ureido-pyrimidinone (UPy) quadruple hydrogen-bonding motif and a polymer backbone, for example selected from the group of biodegradable polyesters, polyurethanes, polycarbonates, poly(orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinylalcohol, polypropylenefumarate.
  • polyesters are polycaprolactone, poly(L-lactide), poly(DL-lactide), poly(valerolactone), polyglycolide, polydioxanone, and their copolyesters.
  • polycarbonates are poly(trimethylenecarbonate), poly(dimethyltrimethylenecarbonate), poly(hexamethylene carbonate).
  • polymers may be biodegradable or non-biodegradable polyesters, polyurethanes, polycarbonates, poly(orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinylalcohol, polypropylenefumarate.
  • polyesters are polycaprolactone, poly(L-lactide), poly(DL-lactide), poly(valerolactone), polyglycolide, polydioxanone, and their copolyesters.
  • polycarbonates are poly(trimethylenecarbonate), poly(dimethyltrimethylenecarbonate), poly(hexamethylene carbonate).
  • the morphology of the graft's luminal surface plays an important role in thrombogenic properties.
  • Experiments performed in vitro with human blood reveal that fiber diameter of the non-woven mesh is key, with larger diameter fibers of 4-6 ⁇ m being preferred over smaller fibers.
  • Samples of electrospun SP materials with various surface morphologies were coated onto PET sheets coated with indium tin oxide (ITO). These samples were exposed via a constant-shear rate flow cell to a perfusion of human blood containing 3.2% citrate to inhibit thrombin activation, allowing platelet behaviour to be specifically investigated. After 30 minutes of perfusion the flow cell was removed and the surface of the material was fixed using ethanol dehydration and characterised via scanning electron microscopy (SEM). Negative controls were performed on bare PET-ITO sheet and showed no significant platelet adherence. Positive controls were performed on collagen-coated PET-ITO and showed significant platelet cluster formation. All experiments were performed in triplicate, with multiple healthy blood donors.
  • ITO indium tin oxide
  • the electrospun SP meshes showed significantly reduced platelet activity as compared to market-available PTFE nonwoven materials. This effect was clearest on larger-diameter fibres, however reduced spreading was also apparent on submicron fibres, with morphology similar to PTFE nonwovens. SEM images of platelet adherence to the SP fibres and nonwoven PTFE are shown at high magnification (10,000 ⁇ ). Platelet adherence to fibres and activation is clearly observed, however aggregation and spreading of platelets is significantly reduced compared to PTFE nonwovens. Lower magnification (1000 ⁇ ) SEM images of all substrates are also shown, demonstrating the reduction in platelet spreading and aggregation over a greater area.
  • the UPy-based electrospun fibers show decreased platelet spreading and aggregation in human blood as compared to market available biocompatible materials with similar morphology.
  • the observed platelet behaviour is unusual and highly relevant for bioabsorbable devices intending to achieve tissue remodelling.
  • the presence of an activated platelet coating incites subsequent remodelling phases and re-epithelialization.
  • the presence of an active platelet layer is frequently accompanied by a severe thrombogenic response, leading to rapid occlusion of small-diameter conduits comprised of synthetic materials. Therefore, the demonstrated platelet response represents an ideal situation for the formation of neo-tissues over a bioabsorbable substrate, which is theorized to result in a wholly non-thrombogenic biological surface.
  • the nature of supramolecular chemistry allows a degree of flexibility in mechanical properties of synthesized polymers, allowing increased tunability of device properties to further improve blood response.
  • FIGS. 3A-C Quantification of the surface coverage of blood products on the test materials was based on analysis of decrease in total porosity of surfaces observed under SEM. Analysis was carried out using ImageJ software, the stages of which are outlined in FIGS. 3A-C .
  • the SEM image is prepared via cropping and contrast enhancement and conversion to a binary image (containing only black or white pixels”. This binary image is then analysed via ImageJ's “Threshold” feature, which counts the total number of black pixels within the image. This process is conducted on three characteristic SEM images of the sample surface before blood perfusion, and SEM images of the surface after blood perfusion and the change in porosity is reported.
  • FIG. 4 shows the decrease in porosity due to surface coverage by blood products for all material samples after perfusion over surface.
  • Abciximab an inhibitor of ⁇ IIb ⁇ 3
  • Abciximab an inhibitor of ⁇ IIb ⁇ 3
  • Blood was subsequently perfused over a sample material of electrospun non-woven SP material with fiber diameter of 4-6 ⁇ m using a controlled shear rate flow cell for 30 minutes as well as a sample of non-woven PTFE.
  • Post-flow the sample was fixed and imaged using Scanning Electron Microscopy, allowing direct visualization of platelet adherence.
  • the addition of Abciximab (ReoPro) resulted in greatly decreased platelet adhesion as compared to control ( FIG. 6 ).
  • the mechanism for this exaggerated effect is unclear, and is hypothesized to be driven by a dissimilarity in apparent surface charge density and/or associated hydrophobicity of SP electrospun material.
  • the surface charge density, or the electric charge possessed per unit area of material surface is known to effect the binding of proteins. This effect arises due to the charge distribution within these proteins leading to an attraction/repulsion effect from disparately/similarly charged surfaces, respectively.
  • materials showing a significant degree of surface roughness are likely to further exaggerate or compound this effect, as the total charge density increases at areas of curvature such as microscale protrusions from a flat surface as well as nano-scale roughness of these surfaces and protrusions.
  • chemotherapeutic agents such as abciximab
  • electrospun fibres and polymer coatings Due to the to apparent specific interaction between SP electrospun materials and glycoprotein inhibitors, particularly abciximab, a highly effective antithrombotic effect may be realized through this method.
  • the combination of bioabsorbable electrospun supramolecular constructs with abciximab or other compounds targeting glycoprotein IIb/IIIa inhibition is expected to be especially beneficial because the combination may allow the regeneration of body own tissue in applications such as coronary bypass grafts, for which this was not possible before.
  • chemotherapeutics include but not limited to incorporation into the electrospun fiber material, either covalently or else, absorbed at the fiber surface or included in a carrier material coated onto the non-woven surface. Yet another possibility would be to administer said chemotherapeutics, either orally, intravenously or otherwise. This could be done before, during or after the implantation of the cardiovascular graft.
  • FIG. 8 shows good patency of grafts prior to explantation at 6 month time point.
  • FIG. 9 shows the diameter of the distal anastomosis (most prone to thrombotic occlusion) over the course of the study to data.
  • a supramolecular polymer could be made using one of the recipes described in U.S. Provisional Application 62/611,431 filed on Dec. 28, 2017, which is herein included by reference for all that it teaches and to which this application claims priority.
  • supramolecular compounds are defined as hard-blocks covalently bonded with soft-blocks.
  • the hard blocks are based on UPy moieties.
  • the soft block is the backbone of the supramolecular compounds.
  • Polycarbonate (PC) was used as it showed surprisingly benefit for the purposes and objectives of this invention, especially compared to polycaprolactone.
  • the ratio between the soft block and the hard block has an influence on the material properties.
  • ratios of components within the hard block section has a tremendous impact on properties such as durability.
  • a specific combination of ratios within the hard block and length of the polymer used to form soft block that lead to enhanced mechanical properties (durability).
  • polycarbonate with a molecular weight range of 500-2000 Da provide enhanced durability and reduced fatigue compared to e.g. polycaprolactone.
  • the hard block is composed of the Upy component, a diisocyanate and a chain extender.
  • the ratio (R) within the hard-blocks for 2-ureido-4[1H]-pyrimidinone (UPy) compounds and chain extenders at a range of 1.5 to 3 for the chain extenders over the UPy compounds.
  • Telechelic hydroxy terminated polycaprolacton with a molecular weight of 800 g/mol (30.0 g, 37.5 mmol, dried under vacuum), 1,6-hexanediol (4.4 g, 37 mmol), and UPy-monomer (6.3 g, 37 mmol) were dissolved in dry DMSO (105 mL) at 80° C.
  • hexamethylene diisocyanate (18.8 g, 111.5 mmol) was stirred overnight at 80° C. The next day, the reaction mixture was cooled to 25° C.
  • Polymers made with polycarbonates with molecular weight varying from 500 to 3000 g/mol were synthetized in a similar manner as for XP1. The changes were made depending on the length of the polycarbonate and the desired ratio between the components. Molar ratio can be expressed as followed.
  • A polycarbonate
  • B chain extender
  • D Upy
  • C is always equal to 0.8 to 1.2 times the total molar amount of A plus B plus D.
  • Molar ratio B/D is noted R.
  • Table 1 provides a non-exhaustive list of examples of supramolecular polymers obtained according aforementioned instructions.
  • a feature that can for example influence durability is the alignment of the fibers within the scaffold.
  • the preferred fiber alignment is circumferential around an imaginary axis of the implant wherein the axis points in the direction of blood flow in case of a tubular implant.
  • Alignment defined as the linear elastic stiffness ratio between the preferred fiber direction and perpendicular to the preferred fiber direction was varied up to 8:1. While the example of FIG. 11 is based on the comparison of alignment in an electrospun supramolecular polymer heart valve, it is anticipated that the same principle will apply to cardiovascular grafts.
  • a supramolecular polymer (SP) material for example obtained as in one of the recipes infra, is dissolved to a concentration of 11.5 wt % in a solvent mixture of chloroform and hexafluoroisopropanol.
  • This solution is delivered via syringe pump to a blunt-ended stainless steel needle maintained at an electric voltage of between 5 and 10 kilovolts, resulting in an electrostatically-driven whipping jet.
  • This jet is attracted to a cylindrical collector charged to a negative voltage of between 1 and 4 kilovolts, resulting in the formation of a highly porous, fibrous non-woven coating.
  • removal from the collector device is achieved via separation with a soft-tipped spatula, resulting in an electrospun tubular graft with wall thickness of 0.5 mm.
  • the data described herein demonstrates an unexpected effect of the cardiovascular graft of this invention on the activation, adherence and spreading of platelets.
  • a quantifiable reduction in platelet-driven thrombus formation on cardiovascular graft as compared to known biocompatible synthetic polymers e.g. FIG. 4 : porosity reduction of 27% for electrospun SP materials and 59% for PTFE
  • FIG. 4 porosity reduction of 27% for electrospun SP materials and 59% for PTFE

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US10953139B2 (en) * 2017-12-28 2021-03-23 Xeltis Ag Electro-spun cardiovascular implant
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US20220023034A1 (en) * 2018-12-05 2022-01-27 Xeltis Ag Electrospun Suture Ring
US20220088283A1 (en) * 2019-01-23 2022-03-24 Antonio SALSANO Endovascular device for dysfunctional fistulas

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US11865014B2 (en) * 2017-08-14 2024-01-09 Globus Medical, Inc Surface treated medical implant devices
US10953139B2 (en) * 2017-12-28 2021-03-23 Xeltis Ag Electro-spun cardiovascular implant
US20220023034A1 (en) * 2018-12-05 2022-01-27 Xeltis Ag Electrospun Suture Ring
US20220088283A1 (en) * 2019-01-23 2022-03-24 Antonio SALSANO Endovascular device for dysfunctional fistulas
CN111303348A (zh) * 2020-01-22 2020-06-19 广东工业大学 一种光固化水性聚氨酯乳液及其制备方法和应用

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