In-SITU surface treatment system that uses arterial pulsation to enhance hemocompatibility in endovascular devices

Abstract

The inventive concept relates to in-situ surface treatment systems and methods to actively and continuously supply negative charges to the surface of indwelling endovascular devices to maintain a non-thrombogenic surface without batteries or electronics. The in-situ surface treatment includes forming a piezoelectric-dielectrophoretic material, integrating the piezoelectric-dielectrophoretic material with the endovascular device, and employing arterial pulsation.

Description

IN-SITU SURFACE TREATMENT SYSTEM THAT USES ARTERIAE PULSATION TO ENHANCE HEMOCOMPATIBILITY IN ENDOVASCULAR DEVICESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. 119(e) to United States Provisional Patent Application Serial No. 63 / 568,094, filed March 21, 2024, entitled “IN-SITU SURFACE TREATMENT SYSTEM THAT USES ARTERIAL PULSATION TO ENHANCE HEMOCOMPATIBILITY IN ENDOVASCULAR DEVICES”, which is herein incorporated by reference in its entirety.Field of the Invention

[0002] The inventive concept relates to in-situ surface treatment systems and methods to actively and continuously supply negative charges to the surface of indwelling endovascular devices to maintain a non-thrombogenic surface using arterial pulsation for a long-term solution without batteries or electronics.Background of the Invention

[0003] Thrombogenic complications associated with indwelling endovascular devices (e.g., stents) are one of the critical concerns to be solved, especially for endovascular devices used in the treatment of small artery diseases in coronary, cerebral or peripheral locations. Despite advances in therapeutic strategies, including the utilization of drug-eluting stents (DES), lifethreatening complications, such as late thrombosis, continue to affect patients, leading to severe consequences such as heart attacks, strokes, and pulmonary embolisms. Thus, even though the disease treatment methods and biomaterials have shown notable scientific advances, small artery diseases, such as coronary, cerebral, and peripheral artery diseases, still represent a significant disease burden in the United States. Various surface treatment study outcomes have demonstrated their improved hemocompatibility by reducing the thrombosis associated with the implanted endovascular devices. However, in these technologies, the surface of an endovascular device should be treated prior to its delivery, which will be typically effective in the beginning stage after placement of the device in the body.

[0004] Unlike large vessels, it is a challenge to treat small artery diseases in coronary, cerebral or peripheral locations because the implanted vascular devices suffer from long-term hemocompatibility complications such as thrombosis, e.g., blood clots developed within the implanted device. Recent recommendations in the treatment of these diseases include an expanding role for vascular stents as an alternative to open surgery since they are minimally invasive and less risky. However, there are still relatively high percentages of life-threatening complications, including late-thrombosis, after stent procedures that lead to heart attack, stroke, pulmonary embolism, or amputation.

[0005] The artificial biomaterials used in implanted endovascular devices (e.g., stents) may provide a source for thrombosis and fibrosis in patients. While new drug-eluting and bioresorbable stents have shown improved outcomes, there are still fatal late thrombosis or nonuniform material degradation. One of the important factors is the “surface charge” of the stent material, which is directly related to the platelet-mediated thrombosis since activated platelets are among the first biological species to arrive at the site of stent and surrounding regions. Platelets that facilitate blood coagulation contain negatively charged phosphatidylserine- rich membrane surfaces, which have been postulated to reduce the platelet adherence to negatively charged surfaces. While there are many negatively charged surface treatment studies that have demonstrated an improved hemocompatibility with negative charges, the surface is effective only over the short term in the beginning stage due to its passive nature (i.e., charges gradually disappear).

[0006] To address these issues, there is a need for a novel platform technology, i.e., Piezoelectric -Dielectrophoretic System (PDS), to treat the surface of indwelling endovascular devices using arterial pulsation in-situ, which will be a new development in the endovascular device area. While there are various surface treatment techniques known to reduce thrombosis, no known techniques provide an active and continuous surface treatment for the indwelling endovascular device.

[0007] This inventive technology provides an active and continuous in-situ surface treatment system using piezoelectric materials to supply negative charges to generate a negatively charged surface, on the surface of an indwelling endovascular device, that repels platelet adherence utilizing the negatively charged nature of blood phospholipids, thereby reducing the risk of clot formation. The surface of indwelling endovascular devices maintains a non-thrombogenicsurface using arterial pulsation for a long-term solution without batteries or electronics. The inventive concept includes a novel technology to ameliorate or prevent endovascular device thrombus development, which will have a significant impact on patient quality of life, a profound impact on decreasing the mortality rate, and reduce the amount of health care dollars spent on the small artery disease treatments.SUMMARY OF THE INVENTION

[0008] In one aspect, the inventive concept provides an in-situ surface treatment system of an indwelling endovascular device that includes a surface of an indwelling endovascular device; a piezoelectric-dielectrophoretic material integrated with the indwelling endovascular device; and an arterial pulsation, wherein the treatment system is structured to provide a continuous supply of negative surface charges to the surface of the indwelling endovascular device, and wherein the surface treatment system is effective to reduce platelet adhesion and thrombosis absent a use of batteries or electronics.

[0009] The endovascular device can be selected from a vascular stent or strut.

[0010] The piezoelectric-dielectrophoretic material can be in the form of a thin film or sheet. In certain embodiments, the piezoelectric-dielectrophoretic material includes polyvinylidene fluoride. The polyvinylidene fluoride can be in a form of a layer. The polyvinylidene fluoride layer can be in a form of a sheet. The poly vinylidene fluoride layer can include a metallic layer applied to a surface of the polyvinylidene fluoride layer.

[0011] The piezoelectric-dielectrophoretic material can be effective to control adherence and / or motion of the platelets on the surface of the endovascular device.

[0012] The supply of negative surface charges can be generated at 1 ,2V to reduce platelet adherence to less than 2% of the surface area of the endovascular device.

[0013] In another aspect, the inventive concept provides a method of surface treating an indwelling endovascular device that includes obtaining an indwelling endovascular device, having a surface; treating the surface of the indwelling endovascular' device with a negative charge in-situ, that includes forming a piezoelectric-dielectrophoretic material; integrating the piezoelectric-dielectrophoretic material with the indwelling endovascular device; utilizing arterial pulsation; continuously supplying negative surface charges to the surface of theindwelling endovascular device; and reducing platelet adhesion and thrombosis absent a use of batteries or electronics.

[0014] The forming and integrating steps can be conducted prior to placement of the endovascular device into a patient body. In certain embodiments, the forming and integrating steps include one or more of a multiple thin film deposition and etching process.

[0015] In certain embodiments, the one or more of a multiple thin film deposition and etching process is selected from plasma-enhanced chemical vapor deposition, e-beam evaporation, liftoff method, and spin coating with conventional photolithography process.

[0016] In certain embodiments, the forming and integrating steps include depositing the piezoelectric-dielectrophoretic material onto the surface of the endovascular device, or forming a thin film comprising the piezoelectric-dielectrophoretic material and applying the thin film to the endovascular device. In certain embodiments, the piezoelectric -dielectrophoretic material is polyvinylidene fluoride and the endovascular device is selected from a vascular stent or strut.

[0017] In certain embodiments, the forming and integrating steps include forming the piezoelectric-dielectrophoretic material into a sheet, and applying the sheet to an outer surface of a vascular stent or strut. In certain embodiments, the vascular stent comprises a balloon catheter.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The following drawings are related to, and describe aspects or features of, the innovative concept.

[0019] FIG. 1A is a schematic that illustrates a piezoelectric sheet including a polyvinylidene fluoride (PVDF) layer and a silver layer applied to the outer surface(s) of the PVDF layer, in accordance with certain embodiments of the inventive concept.

[0020] FIG. IB is an image that shows a cross-sectional SEM image of the PVDF / silver piezoelectric sheet as shown in FIG. IA, in accordance with certain embodiments of the inventive concept.

[0021] FIG. 2A is a schematic that illustrates a endovascular device 1 including a balloon catheter inside of an expandable stent, and a PVDF sheet mounted over the stent, in accordance with certain embodiments of the inventive concept.

[0022] FIG. 2B is a schematic that illustrates the endovascular device 1, as shown in FIG. 2A, wherein the balloon is inflated, in accordance with certain embodiments of the inventive concept.

[0023] FIG. 3 is a plot that shows a voltage signal acquisition of a 6 mm diameter piezoelectric device producing (2.2 V + / - 0.3 V) at a pressure of 120 mmHg, in accordance with certain embodiments of the inventive concept.

[0024] FIG. 4 is a plot that shows a voltage signal acquisition of a 6 mm diameter piezoelectric device producing (3 V + / - 0.2 V) at a pressure of 140 mmHg, in accordance with certain embodiments of the inventive concept.

[0025] FIG. 5 is a plot that shows a voltage signal acquisition of a 6 mm diameter piezoelectric device producing (3.5 V + / - 0.5 V) at a pressure of 160 mmHg, in accordance with certain embodiments of the inventive concept.

[0026] FIG. 6 is a plot that shows a voltage signal acquisition of a 6 mm diameter piezoelectric device producing (4.5 V + / - 0.5 V) at a pressure of 180 mmHg, in accordance with certain embodiments of the inventive concept.

[0027] FIG. 7 is a plot that shows a voltage signal acquisition of a 6 mm diameter piezoelectric device producing (6 V + / - 1 V) at a pressure of 220 mmHg, in accordance with certain embodiments of the inventive concept.

[0028] FIG. 8 is a plot that shows a voltage (V) versus pressure (mmHg) relationship acquired from a piezoelectric film, in accordance with certain embodiments of the inventive concept.

[0029] FIGS. 9A and 9B show plots that depict blood pressure and voltage levels versus time, respectively; FIG. 9A illustrates the relationship between blood pressure and time, and FIG. 9B illustrates the output voltage produced by a piezoelectric film due to the large strain (i.e., highly stretchable condition) in a coronary artery tissue, in accordance with certain embodiments of the inventive concept.

[0030] FIGS. 10A, 10B, and 10C show the following scanning electron microscopy (SEM) images: FIG. 10A illustrates the stent surface before the blood clot formation test, FIG. 10B illustrates the stent surface with 1.5 + / - 0.32 V applied, showing a pristine surface without visible platelets or blood products in accordance with certain embodiments of the inventive concept, and FIG. 10C illustrates a control stent surface (i.e., without piezoelectric film) after 1.5 hours of exposure to whole blood, showing moderate to severe blood clot formation in accordance with the prior art.

[0031] FIG. 11 shows a plot of platelet aggregation versus voltage levels for control, 0.5 volt and 1 volt applied voltages, in accordance with certain embodiments of the inventive concept.DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0032] The inventive concept relates to a Piczoclcctric-Diclcctrophorctic System (PDS), including a piezoelectric-dielectrophoretic material or structure, to treat the surface using arterial pulsation actively and continuously for indwelling endovascular devices. This inventive technology provides an active and continuous in-situ surface treatment system using piezoelectric materials to supply negative charges to generate a negatively charged surface that repels platelet adherence utilizing the negatively charged nature of blood phospholipids, thereby reducing the risk of clot formation. Use of the inventive in-situ surface treatment system enhances the hemocapatibility of endovascular devices.

[0033] The negative charges and dielectrophoretic platelet motion produced via a piezoelectric material using arterial pulsation creates the indwelling device’s anti-thrombogenic surface long term. The unique design of a dual piezoelectric system effectively manipulates the platelet motion by altering the polarity of the electric field between the electrode and surface of the endovascular device, e.g., stent.

[0034] Without being bound by any particular theory, the inventive concept includes the piezoelectric material producing an electric field during the systole phase, whereby the platelets are repulsed from the negative to positive electrode side. In the diastole phase, the piezoelectric material produces an electric field altering the polarity, which drives the platelets to the opposite side. Accordingly, it is hypothesized that the platelets do not have sufficient time to adhere on the surface of the indwelling endovascular device, e.g., stent struts, with the human pulsation frequency, which implements an active biocompatible surface within the blood vessel.

[0035] Certain embodiments of the inventive concept include a PDS that may be designed via structural computational modeling and mechanics modeling. Other embodiments include forming or fabricating the PDS, and then integrating the PDS with an endovascular device, such as but not limited to a vascular stent. Fabrication of the PDS may include nano / microfabrication technologies, use of a thin film manufacturing processes, a multi-layer thin film deposition process and two-photon polymerization process. Further embodiments may include evaluating hemocompatibility of a PDS stent in vitro to assess potential thrombus formation, and evaluating the functionality of the PDS with the stent.

[0036] The inventive concept is applicable to a wide variety of endovascular devices wherein charged particles or blood products are controlled with a low-profile device, without bulkybatteries or complex electronic. The inventive concept provides an active and continuous surface treatment for the indwelling endovascular devices to reduce or preclude thrombosis (i.c., blood clots developed within the implanted devices).

[0037] The inventive concept provides the use of arterial pulsation for in-situ hemocompatible surface treatment via a PDS material that includes a film or sheet, in any indwelling endovascular devices. The inventive system actively and continuously supplies negative charges to the surface of endovascular devices using arterial pulsation. A nano / micro system produces negative surface charges through the compliance changes in the artery under pulsatile flow (i.e., artery expansion and relaxation). The invention uniquely utilizes the produced charges for active continuous in-situ surface treatment purposes without a battery.

[0038] In addition, the inventive concept provides a long-term solution to supply the desired charges to the surface of the endovascular device to maintain excellent hemocompatibility until complete reendothelialization. Existing surface treatment technologies for endovascular devices are passive and typically effective for initial anti-thrombogenic behaviors only. However, the inventive concept includes an active long-term hemocompatibility solution, which refreshes the endovascular device’s (e.g., stent’s) surface using the negative charges from the PDS.

[0039] Additionally, the inventive concept provides a highly innovative active surface treatment platform technology using a simple, low-profile, battery-less piezoelectric system that can be applied to almost every endovascular device. The inventive device includes thin films that are relatively simple, compact, and do not require bulky batteries or complex electronics. The inventive concept is effective to produce sufficient electric potential for “in-situ dielectrophoresis” to maintain a non-thrombogenic surface by controlling the motion of platelets in most indwelling endovascular devices. The inventive concept is suitable for use with a wide variety of endovascular devices including coronary artery and various peripheral artery stents, as well as cardiac valves or occluders. This inventive concept is also useful for smaller artery or cardiac applications for pediatric patients.

[0040] Thrombotic complications represent a challenge in small artery diseases and vascular' devices. In accordance with the inventive concept, in certain embodiments, the in-situ piezoelectric material-based surface treatment system generates negative surface charges at 1.2V to substantially reduce platelet adherence to less than 2% of the surface area of the vascular device.

[0041] In certain embodiments, following stent fabrication, a circular polyvinylidene fluoride (PVDF) thin film is attached to the surface of the stent scaffold. In other embodiments, a PVDF thin film is deposited on the surface of the fabricated stent scaffold.

[0042] In certain embodiments, a thin film piezoelectric integrated vascular stent is formed of a PVDF layer. The thickness of the PVDF layer can vary and in certain embodiments, the PVDF layer is about 50 um thick. The PVDF layer is metallized with a metal layer, e.g., a silver (Ag) layer, applied to the outer surface of the PVDF layer. The thickness of the silver layer can vary and in certain embodiments, the silver layer is 25 um thick. The PVDF / silver layered sheet is then mounted on a metal stent. The diameter of the metal stent can vary and in certain embodiments, the stent has a 3.2 mm diameter. FIG. 1A is a schematic that shows a PVDF layer, e.g., sheet, and a silver layer applied to the outer surface of the PVDF layer or sheet. FIG. IB is a cross-sectional SEM image of the PVDF / silver piezoelectric layer or sheet.

[0043] In certain embodiments, a rolled PVDF sheet is placed over a balloon expandable stent of a catheter; the piezoelectric signal is then applied following balloon inflation.

[0044] Further, in certain embodiments, the aforementioned PVDF may be substituted with a thin film composed of or including a polystyrene, e.g., polyaniline, poly thiophene, polypyrrole, and / or polyacrylamide.

[0045] FIG. 2A is a schematic that shows a endovascular device 1 in accordance with certain embodiments of the inventive concept. As shown in FIG. 2A, a balloon catheter 3 is positioned inside of an expandable stent 5. A PVDF sheet 7 is mounted, e.g., folded, over the balloon expandable stent 5. FIG. 2B is a schematic that shows the endovascular device 1 wherein the balloon is inflated. The piezoelectric signal is then generated following balloon inflation. The piezoelectric output is calibrated to correlate with blood pressure dynamics. In accordance with the inventive concept, the piezoelectric stent (PES) device, integrated with the high strength stent scaffold, generates fluctuating electrostatic charges that repel negatively charged phospholipids, thereby preventing the initiation of platelet aggregation.

[0046] According to the inventive concept, when a force is applied to the PVDF in a specific direction, it induces a polarization of the polymer molecules, leading to the generation of an electric charge. The orientation of the polymer chains and the resulting electric charge are influenced by the direction of the applied force. FIGS. 3 through 7 show voltage vs. time resultsat various pressure values, and FIG. 8 illustrates voltage vs. pressure results, according to various embodiments of the inventive concept.

[0047] In certain embodiments, a low-profile piezoelectric unit, e.g., material, is built via a multiple thin film deposition and etching process including plasma-enhanced chemical vapor deposition (PECVD), e-beam evaporation, lift-off method, and spin coating with a conventional photolithography process.

[0048] Further, in certain embodiments, electrode patterns are achieved via photolithography, thin film deposition and etching processes, then a thin PVDF layer, e.g., with 20% weight / volume, is spin coated, e.g., with the spin speed from 1000 to 3000 rpm, to create a film thickness of about 7-12pm, then poling is conducted. The PVDF thin film, e.g., that contains the electrodes on the same side, is released by eliminating SiO2 sacrificial layer using hydrofluoric acid (HF). Varied thickness through the length of the piezoelectric structure is created to tailor localized elastic deformation on the desired locations for the maximum production of charges with the smallest feasible dimensions that are fit within the stent struts.

[0049] In certain embodiments, the fabricated PDS is integrated onto a self-expanding nitinol stent using an established low-energy based laser and ultrasonic joining process (e.g., frequencies of 15-50kHz and true RMS power of 5O-15OOW is used to integrate these components without generating thermal damages on the devices). Next, the entire device is subjected to an oxidation process to create a uniform dielectric oxide layer covered surface by immersion in 30% H2O2 (e.g., for 5-15 hours at room temperature). This surface treatment process creates a uniform oxide layer, which provides an important role as a dielectric layer to create surface charges with the electric potential. The grown oxide layer’s quality may be quantified either by X-Ray Photoelectron Spectroscopy (XPS) or Energy Dispersive Spectroscopy (EDS). In certain embodiments, the fabrication yield of working devices is at least 90%.

[0050] In addition, the produced electrical potential through piezoelectric systems, e.g., materials, under periodic bending and unbending cycles is sufficient to create dielectrophoresis to control the motion of platelets in blood. The piezoelectric performance is further improved by constructing a 3D structure using an advanced two-photon 3D lithography process, which provides a higher multi-dimensional bending in thicker PVDF layers.

[0051] For certain embodiments, the platelet adhesion assay setup preparation includes the following steps:(i) Samples are prepared for testing: 0 volts (control sample), 0.5 volts, 1.2 volts, and 3 volts.(ii) Each sample is repeated three times for results repeatability and consistency.(iii) Sodium citrate is used as an anti-coagulant to reduce any rapid thrombogenic reaction that may take place on the samples at the beginning of the assay.(iv) The test lasts for three hours to achieve good platelet adhesion.The range of voltages required for the in-situ surface treatment varies. In certain embodiments, low voltage levels of 0.5, 1.2, and 3V are effective under a typical pulsatile blood flow environment to achieve the platelet adhesion at the negative side, as well as at the positive side.

[0052] In accordance with the inventive concept, stents elastically deform its shape radially with the arterial pulsation generating piezoelectric effect. An analysis using open-circuit voltage and may be analyzed using a mechanical bending of a piezoelectric cantilever beam structure (e.g., polyvinylidene fluoride (PVDF)) as below:V3j= oXx(d3 / ST))L, where, V;q is the open circuit voltage generated perpendicular’ to the strain direction, GXXis the stress occurring in the lateral direction, both d3jand sTare piezoelectric constants, and Li is the distance between the electrodes. An output pattern voltage may be calculated for the bending strain of 0.05 - 0.20% assuming wide range of blood pressures from 80 - 220 mmHg. Once the simulated results show the electrical potential in ± 4V ranges, the peak voltages (V) under the heart rate (beats / min) can be averaged.

[0053] A dielectrophoresis analysis may be followed to optimize design parameters to minimize the platelet adhesion to the stent surface. It is hypothesized that dispersed platelets in the blood under the non-uniform electric field (i.e., dielectrophoresis) will move to the positively charged surface generating non-adherence of platelets on the surface of the negatively charged dielectric layer via two piezoelectric units. The electrophoretic mobility (pe) is defined as described by:Me = ErE0( f|)where, eris the dielectric constant of the blood, so is the permittivity of free space, r| is dynamic viscosity of the dispersion medium, and is zeta potential. Since the double layer is relatively thin compared with the radius of the platelets, Debye length can be neglected.Force of dielectrophoresis (FDEP) will be:FDEP(CO) = KEmR ■ Re(fcM(co)) ■ VIEI2

[0054] The first term of this equation represents the size of particles, while the second and third terms express species and capture capability, respectively. Therefore, platelets as the primary blood products can reduce or prevent the adherence to the surface since the size of particles is the leading parameter for both attraction and repulsion in the presence of electric fields.

[0055] The primary piezoelectric unit produces an electric field during the systole phase, when the platelets are repulsed from the negative to positive electrode side. In the diastole phase, the secondary piezoelectric unit produces an electric field altering the polarity, which drives the platelets to the opposite side

[0056] Whereas particular embodiments of the inventive concept have been described herein for purposes of illustration, it will be evident to those skilled in the art that numerous variations of the details may be made without departing from the inventive concept as set forth in the appended claims.EXAMPLESExample 1

[0057] The inventive concept leverages piezoelectric materials to generate a negatively charged surface using arterial pulsation without any battery, actively and effectively repelling platelets adherence to prevent potential clot formation.

[0058] Low voltage levels at 0.5, 1.2, and 3V may be used for the in-situ surface treatment system.

[0059] An oxide covered nitinol material was tested with sodium citrated whole swine blood in an in vitro test setup. Platelet aggregation after 3 hours of blood exposure ranged from 3.0 ± 1.0 (0.5V) to 2.0 ± 1.0 (1.2V) platelets / 100 pm2. The relationship between electrical voltage and platelet adhesion demonstrated that applying 1.2V negative charges reduced platelet aggregation to less than 2% of the surface area evaluated.

[0060] A low-profile piezoelectric unit was also designed via numerical and computational analyses, considering typical arterial pulsation and radial deformation of the endovascular devices. Given the feasibility of achieving the low voltages, the pulsation based piezoelectric system provides a solution for reducing the platelet adherence in indwelling endovascular devices without the need for passive coating or batteries, which enhances the overall effectiveness of endovascular devices.Example 2

[0061] A thin film piezoelectric integrated vascular stent was designed to improve the hemocompatibility of the endovascular device. The device was built in the form of a 50 um thick PVDF layer, metallized with 25 um silver on each surface, mounted on a 3.2 mm diameter metal stent. The piezoelectric output was calibrated to correlate with blood pressure dynamics. The stent was deployed in a silicone tube simulating arterial dimensions, where hemocompatibility was tested by exposing it to ovine blood under controlled flow, with physiological pressures of 120 / 80 mmHg and flow rates of 100 mL / min for 1.5 hours. SEM was used to analyze platelet aggregation, and ex vivo studies with an ovine heart assessed thrombogenic reactions.

[0062] FIGS. 9A and 9B show plots that depict blood pressure and voltage levels versus time, respectively; FIG. 9A illustrates the relationship between blood pressure and time, and FIG. 9B illustrates the output voltage produced by a piezoelectric film due to the large strain (i.e., highly stretchable condition) in a coronary artery tissue, in accordance with certain embodiments of the inventive concept. To further evaluate the device’s performance, an ex vivo sturdy was conducted using an ovine heart model. Sodium citrated blood flow tubes were sutured to the coronary arteries, replicating physiological pulsatile flow, with the control bare metal stent, and a PE device tested in parallel hemocompatibility assays. Scanning electron microscopy (SEM) images captured after the completion of the assay, provided detailed comparison between the two stents. FIGS. 10A, 10B, and 10C show the following scanning electron microscopy (SEM) images: FIG. 10A illustrates the stent surface before the blood clot formation test, FIG. 10B illustrates the stent surface with 1.5 + / - 0.32 V applied, showing a pristine surface without visible platelets or blood products in accordance with certain embodiments of the inventive concept, and FIG. 10C illustrates a control stent surface (i.e., without piezoelectric film) after 1.5 hours ofexposure to whole blood, showing moderate to severe blood clot formation in accordance with the prior art.

[0063] The foregoing results successfully demonstrated the effectiveness of the PDS device in preventing thrombosis and platelet aggregation.

[0064] Conducting this example, included the following processes and procedures.

[0065] 1.) A vascular flow apparatus with a 3D small diameter artery model was developed and used to validate the performance of the inventive device’s working principle. The relationship between local strain changes and voltage produced via piezoelectric system under various arterial conditions was quantitatively evaluated using an in vitro test model.

[0066] 2.) In vitro short-term hemocompatibility tests using fresh whole ovine blood were conducted. Fresh whole blood (<4hr after the blood draw) was drawn from female sheep, as available, but sex or species variances of blood donors was expanded using a commercially available blood source (Sinclair bio-resources, MO). Prior to its introduction into the flow loop, a subset of the blood was mixed with CMFDA or quinacrine dihydrochloride to observe locations of surface adhesion on the PDS integrated stent after contact with fresh whole blood for 2 hours at 37°C. All luminal areas of the flow loop were treated with albumin solution to minimize potential pre-activation of blood.

[0067] 3.) Further detailed thrombotic deposition (the platelet morphology, the aggregation or clot formation) was observed by a scanning electron microscope (JSM 633F, JEOL). The amount of platelet deposition was also quantitatively assessed using an established lactate dehydrogenase assay (LDH Cytotoxicity Detection Kit, Sigma- Aldrich) that involved lysis of deposited platelets on the device surfaces. The primary metric is the quantity of deposited platelets and location of adhesion. The thrombotic deposition on the stent surface was directly compared with bare metallic stent controls and several other surfaces treated, including the struts coated with heparin, as well as commercially available drug eluting stent coated with sirolimus, paclitaxel, or everolimus. The anticoagulant setting was also adjusted by adding CaCh or the heparin concentration (6U, 3U and lU / mL) to observe the thrombotic deposition under various anticoagulant conditions. In vitro protein adsorption analysis for fibrinogen was performed and the amount using a micro-bicinchoninic acid assay was quantified.

[0068] 4.) The results were presented as the mean of n = 5 and the standard deviation. The sample and effective size for the power analysis was adjusted based on the preliminary results.Data was analyzed by one-way analysis of variance followed by a post hoc Newman-Keuls testing. Significant differences were considered to exist at p < 0.05. However, at least 75% reduction of the average deposited platelet amount vs. that of controls was considered as a successful PDS performance.

[0069] In addition, FIG. 11 shows a bar graph of platelet aggregation versus voltage levels for the control bare metal stent sample (0 volts), as well as the PE device with applied voltage of 0.5 volts and 1 volt. In the control sample, there was almost a constant amount of the platelets over the length of the sample, and moderate adhesion of the platelets over the control sample. In the PE device with applied voltage of 0.5 V sample, there was a clear gradient of platelet adhesion, e.g., more adhesion at the positive end, and less platelet aggregation when moving towards the negative side. In the PE device with applied voltage of 1 V sample, it also appeared to have consistent results as in the 0.5 volt sample. Thus, a voltage level of at least 0.5 volts was sufficient to achieve less platelet aggregation at the negative side. Further, it was found that platelet aggregation after 3 hours of blood exposure ranged from 3.0 + 1.0 (1 V) to 2.0 + 1.0 (3 V) platelets / 100 um2.

Claims

We claim:

1. An in-situ surface treatment system of an indwelling endovascular device, comprising: a surface of an indwelling endovascular device; a piezoelectric-dielectrophoretic material integrated with the indwelling endovascular device; and an arterial pulsation, wherein the treatment system is structured to provide a continuous supply of negative surface charges to the surface of the indwelling endovascular device, and wherein the surface treatment system is effective to reduce platelet adhesion and thrombosis absent a use of batteries or electronics.

2. The system of claim 1, wherein the endovascular device is selected from a vascular stent or strut.

3. The system of claim 1, wherein the piezoelectric-dielectrophoretic material is in a form selected from a thin film or sheet.

4. The system of claim 1, wherein the piezoelectric-dielectrophoretic material comprises poly vinylidene fluoride.

5. The system of claim 4, wherein the poly vinylidene fluoride is in a form of a layer.

6. The system of claim 5, wherein the polyvinylidene fluoride layer is in a form of a sheet.

7. The system of claim 6, wherein the poly vinylidene fluoride layer further comprises a metallic layer applied to a surface of the polyvinylidene fluoride layer.

8. The system of claim 1, wherein the piezoelectric-dielectrophoretic material is effective to control one or more of adherence and motion of the platelets on the surface of the endovascular device.

9. The system of claim 1 , wherein the negative surface charges are generated at 1 ,2V to reduce platelet adherence to less than 2% of the surface area of the endovascular device.

10. A method of surface treating an indwelling endovascular device, comprising: obtaining an indwelling endovascular device, having a surface; treating the surface of the indwelling endovascular device with a negative charge in-situ, comprising: forming a piezoelectric-dielectrophoretic material; integrating the piezoelectric-dielectrophoretic material with the indwelling endovascular device; utilizing arterial pulsation; continuously supplying negative surface charges to the surface of the indwelling endovascular device; and reducing platelet adhesion and thrombosis absent a use of batteries or electronics.

11. The method of claim 10, wherein the forming and integrating steps are conducted prior to placement of the indwelling endovascular device into a patient body.

12. The method of claim 10, wherein the forming and integrating steps comprise one or more of a multiple thin film deposition and etching process.

13. The method of claim 12, wherein the one or more of a multiple thin film deposition and etching process is selected from plasma-enhanced chemical vapor deposition, e-beam evaporation, lift-off method, and spin coating with conventional photolithography process.

14. The method of claim 10, wherein the forming and integrating steps comprise: depositing the piezoelectric-dielectrophoretic material onto the surface of the endovascular device, or forming a thin film comprising the piezoelectric-dielectrophoretic material and applying the thin film to the endovascular device.

15. The method of claim 14, wherein the piezoelectric-dielectrophoretic material is polyvinylidcnc fluoride and the endovascular device is selected from a vascular stent or strut.

16. The method of claim 14, wherein the forming and integrating steps comprise forming the piezoelectric-dielectrophoretic material into a sheet, and applying the sheet to an outer surface of a vascular stent or strut.

17. The method of claim 16 wherein the vascular stent comprises a balloon catheter.

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