Patent Application
20200087818
The disclosure generally relates to electrospinning of polymer fibers.
There is a wide range of medical treatments that require vascular grafts, for example surgical bypass for atherosclerosis of the major vessels, dialysis access in patients with end-stage renal disease, and pediatric congenital heart defects. Autologous tissue is the graft of choice in most surgical bypass procedures. When autologous tissue is not available in the patient, the next best option is the use of synthetic vascular grafts. See Hasan A, et al., (2014) Acta. Biomater., 10:11-25.
For the particular case of bifurcated vessels, surgeons can use commercial bifurcated synthetic vascular grafts, such as a) the GORE-TEX® Stretch Vascular Graft—Bifurcated (W. L. Gore & Associates, Newark, Del., USA), made out of stretched PTFE (commonly known as Teflon™), or b) the Vascutek® Gelsoft™ Bifurcate Grafts (Vascutek Ltd., Renfrewshire, Scotland, UK), based on polyester. However, these options are based on non-resorbable polymers and tubes of uniform dimensions. More limiting is when two tubular grafts have to be connected. Suturing at the roughly right angle connection is difficult and leaves the graft prone to failure at the suture site which is under high flow pressure. Current synthetic vascular grafts therefore present limitations, especially for cases involving vessels with bifurcations and small diameters. See Hasan A, et al., Acta. Biomater., 10:11-25 (2014).
The ideal bifurcated vascular graft would be tissue-engineered to better suit the patient. One limitation in achieving this goal is the limited availability of bifurcated tubular scaffolds based on resorbable materials.
While significant advances have been reported in the use of electrospinning for vascular grafts, both at in vitro and in vivo level, most of the work is limited to tubular shapes. See Hasan A, et al., Acta. Biomater., 10:11-25 (2014); Ingavle G C, et al., Tissue Eng. Part B Rev., 20:277-93 (2014); Rocco K A, et al., Tissue Eng. Part B Rev., 20:628-640 (2014). Zhang and Chang developed a method to build interconnected tubular structures with electrospun mats. Their method is based on guides for the electric field and removable scaffold mandrels. Zhang D, et al, Nano letters, 8:3283-3287 (2008).
The compositions and methods disclosed herein address these and other needs.
Disclosed herein is an apparatus for fabricating a branching structure, the apparatus comprising: a flexible, electrically conductive internal electrical field collector comprising a first collector end, a second collector end, a collector outer surface located between both collector ends, a collector longitudinal axis extending through the first collector end and the second collector end, and at least one articulating feature positioned between the first collector end and the second collector end, a compression and rotation mechanism in contact with the first collector end, and a continuously formed mandrel that can include branches, having a first mandrel circumference with a mandrel inner circumference larger than the collector outer circumference and positionable over the internal electrical field collector and a second mandrel located at sufficient distance outside the first mandrel to facilitate attraction of electruspun fibers.
Also disclosed is a method of making a branching graft, the method comprising:
providing a continuous, branched mandrel, wherein the branching mandrel comprises a first mandrel tubular shape that defines a first mandrel lumen extending along a first mandrel axis, and a second mandrel tube that defines a second mandrel lumen extending along a second mandrel axis, wherein the first mandrel axis creates an angle with the second mandrel axis, positioning the unbranched or branching mandrel on an elongated internal electrical field collector such that the internal electrical field collector extends through the primary (i.e., largest or longest object, i.e., the object with the primary axis for spinning) mandrel lumen, bending the internal electrical field collector away from a longitudinal axis extending through the first end of the electrical field collector and the second end of the electrical field collector, thereby rotating the unbranched or branched mandrel about the first mandrel axis and the second mandrel axis, coating the unbranched or branched mandrel in densely tangled fibers while rotating the internal electrical field collector about the longitudinal axis, thereby forming a branching graft around the branched mandrel, and removing the branched mandrel and the branched graft from the internal electrical field collector.
Further disclosed is a branching graft comprising: a graft wall formed of a single piece of continuous, resorbable material, the graft wall having a first graft tube that extends along a first graft axis and a second graft tube that extends along a second graft axis, wherein the first graft axis creates an angle with the second graft axis. Additional aspects and advantages of the disclosure will be set forth, in part, in the detailed description and any claims which follow, and in part will be derived from the detailed description or can be learned by practice of the various aspects of the disclosure. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain examples of the present disclosure and together with the description, serve to explain, without limitation, the principles of the disclosure. Like numbers represent the same element(s) throughout the figures.
The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s). To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. The following definitions are provided for the full understanding of terms used in this specification.
Disclosed are the components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular fiber is disclosed and discussed and a number of modifications that can be made to the fiber are discussed, specifically contemplated is each and every combination and permutation of the fiber and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of fibers A, B, and C are disclosed as well as a class of fibers D, E, and F and an example of a combination fiber, or, for example, a combination fiber comprising A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.
It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures which can perform the same function which are related to the disclosed structures, and that these structures will ultimately achieve the same result.
Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.
As used in the specification and claims, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an agent” includes a plurality of agents, including mixtures thereof.
As used herein, the terms “may,” “optionally,” and “may optionally” are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a composition “may include an second fiber” is meant to include cases in which the formulation includes a second fiber as well as cases in which the formulation does not include a second fiber.
Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed.
Disclosed herein is an apparatus for fabricating a branching structure, the apparatus comprising: a flexible, electrically conductive internal electrical field collector comprising a first collector end, a second collector end, a collector outer surface located between both collector ends, a collector longitudinal axis extending through the first collector end and the second collector end, and at least one articulating feature positioned between the first collector end and the second collector end, a compression and rotation mechanism in contact with the first collector end, and a continuously formed mandrel that can include branches, having a first mandrel circumference with a mandrel inner circumference larger than the collector outer circumference and positionable over the internal electrical field collector and a second mandrel located at sufficient distance outside the first mandrel to facilitate attraction of electruspun fibers.
Importantly, disclosed herein is the 3D printing of the outer surface of the mandrel or single object. The inner mandrel surface can also be 3D printed, but this is not a requirement. For example, one can put material inside the outer surface by any means. The outer surface can also be prepared by non-3D printing means. The 3D printed material can include conductive materials, which if used altogether, can improve the fabrication process. For example, the method can further comprise 3D printing the bifurcated mandrel prior to positioning the unbranched or branching mandrel on an elongated internal electrical field collector. Also disclosed is a method of removing the bifurcated mandrel from the formed unbranched or branching vascular graft.
In one embodiment, the first mandrel axis and the second mandrel axis meet at a reference point, and wherein the method further comprises aligning the origin of an electrospinning nozzle to the reference point.
The branching structure can be, for example, a bifurcated tubular structure. Bifurcation is one of three solutions disclosed herein. The other two are for anisotropic changes in wall shape (i.e., more complex than just change in diameter) and for changes in central axis direction. Taken together, these can allow for the electrospinning of a curving and possibly bifurcating tube that has a non-circular circumference. This can be applied to almost any shape as long as it can be spun about an axis. Examples include oblong, oval, angular, etc. The branches can include such structures as a bifurcation, trifurcation, etc. One of skill in the art will appreciate the various shapes that can be included.
The apparatus can continuously form single objects or a branching mandrels. The objects can solid, such as a solid circumference, or can have an open lattice structure. The compression and rotation mechanism can comprise a rod that extends along the collector longitudinal axis and contacts the first collector end. The compression and rotation mechanism can further comprise a stop that contacts the second collector end. The compression and rotation mechanism can also be capable of translational movement along a transverse axis of the internal electrical field collector.
Also disclosed herein is a method of making a branching graft, the method comprising: providing a continuous, branched mandrel, wherein the branching mandrel comprises a first mandrel tubular shape that defines a first mandrel lumen extending along a first mandrel axis, and a second mandrel tube that defines a second mandrel lumen extending along a second mandrel axis, wherein the first mandrel axis creates an angle with the second mandrel axis, positioning the unbranched or branching mandrel on an elongated internal electrical field collector such that the internal electrical field collector extends through the primary mandrel lumen, bending the internal electrical field collector away from a longitudinal axis extending through the first end of the electrical field collector and the second end of the electrical field collector, thereby rotating the unbranched or branched mandrel about the first mandrel axis and the second mandrel axis, coating the unbranched or branched mandrel in densely tangled fibers while rotating the internal electrical field collector about the longitudinal axis, thereby forming a bifurcated graft around the branched mandrel, and removing the branched mandrel and the branched vascular graft from the internal electrical field collector.
As the internal electrical field collector extends through the primary mandrel lumen, (i.e., largest or longest object, i.e., the object with the primary axis for spinning) the angle increases, and as the size of the branch increases, the control over the weave will decrease. However, the mandel can be rotated in various manners to accommodate for this.
Bending the internal electrical field collector can comprise activating at least one articulating feature on the internal electrical field collector. Bending the internal electrical field collector can also comprise compressing or stretching the internal electrical field collector along the main or a branch's longitudinal axis.
The length of the internal electrical field collector can change along the longitudinal or a branch's axis. Bending the internal electrical field collector can comprise translating the internal electrical field collector along a transverse axis extending perpendicular to the longitudinal axis.
In one embodiment, the length of the internal electrical field collector changes along the transverse axis. Bending the internal electrical field collector can comprise compressing or stretching the internal electrical field collector along a longitudinal axis and translating the internal electrical field collector along a transverse axis. Coating the mandrel in densely tangled to fully organized weave of fibers can further comprise depositing the fibers by an electrospinning process.
Disclosed herein is a branching graft comprising: a graft wall formed of a single piece of continuous, resorbable material, the graft wall having a first graft tube that extends along a first graft axis and a second graft tube that extends along a second graft axis, wherein the first graft axis creates an angle with the second graft axis.
In the claims herein, it is noted that the grafts can be for a variety of uses and purposes in the human body. Examples include, but are not limited to, tubular tracts such as the digestive tract, oropharyngeal tract, nasal tract, reproductive tracts, ventricular tracts, valvular structures along tubular tracts, vascular structures within and outside organs, tubular structures in other organs that include nervous, body humor transmitting or filtering, structural, or sensory tissues. Also disclosed are machine tubular structures for engine, heating, cooling, hydraulic, or other mechanical devices.
In one example, the first graft tube meets the second graft tube at an intersection point, and wherein the intersection point is devoid of sutures or adhesives. The first graft axis and second graft axis can be perpendicular, or can be non-perpendicular, and exist at any angle to each other, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, or more degrees with respect to each other.
One of skill in the art will appreciate that any material can be used, such as a continuous, porous mat of densely tangled fibers. The material can be electrospun, for example. The material can be polycaprolactone.
In one embodiment, the first graft tube comprises a first graft outer diameter and the second graft tube comprises a second graft outer diameter, wherein the first graft outer diameter and the second graft outer diameter differ by a factor greater than 10%, such as 20, 30, 40, 50%, or more.
The graft wall of the first graft tube can comprise a first graft thickness, the graft wall of the second graft tube comprises a second graft thickness, and wherein the first graft thickness and the second graft thickness differ by a factor greater than 10%, such as 20, 30, 40, 50%, or more.
With reference to
The continuously formed bifurcated mandrel 14 can have an open lattice structure 20. The compression and rotation mechanism 12 can comprise a rod 22 that extends along the collector longitudinal axis and contacts the first collector end 4. The compression and rotation mechanism 12 can further comprise a stop 24 that contacts the second collector end 6. The compression and rotation mechanism 12 can also be capable of translational movement along a transverse axis 26 of the internal electrical field collector 2.
With reference to
With reference to
With reference to
The fabrication device is typically constructed of materials which are not electrically conductive. Such materials avoid undesirable interference with the electrically conductive internal electrical field collector during the graft formation process (e.g., electrospinning process). Any solid, non-electrically conductive materials can be used which can provide the shape and utility of the fabrication device. For example, wood, plastic, composites, adhesives, cements, plasters, and other materials can be used. In some embodiments, the fabrication device is comprised of wood and/or plastic.
The electrically conductive internal electrical field collector can be comprised of one or more electrically conductive materials. For example, the electrically conductive internal electrical field collector can be comprised of metals, alloys, conductive gels, or other such materials. In some embodiments, the electrically conductive internal electrical field collector can be comprised of one or more metals such as silver, copper, gold, copper, or aluminum (e.g., aluminum foil). The electrically conductive internal electrical field collector can be comprised of a continuous material, or can be a collection of one or more materials packed in a regular or irregular arrangement (e.g., packed foil or a mesh of wires). During the process of making a bifurcated vascular graft, a voltage can be applied to the electrically conductive internal electrical field collector.
The fabrication apparatus contains at least one articulating feature positioned between the first collector end and the second collector end.
The fabrication apparatus further comprises a compression and rotation mechanism in contact with the first collector end.
The electrically conductive internal electrical field collector is positioned within at least a portion of the lumen of the continuously formed bifurcated mandrel. Thus, the mandrel contains a first mandrel tube with an inner diameter larger than the collector outer diameter and positionable over the internal electrical field collector. For example, the electrically conductive internal electrical field collector can be positioned on the inner luminal surface of the first mandrel tube. In some or further embodiments, the electrically conductive internal electrical field collector can substantially fill the lumen of the first mandrel tube. The mandrel further comprises a second mandrel tube extending away from the first mandrel tube at an angle. The electrically conductive internal electrical field collector can also be positioned on the inner luminal surface of the second mandrel tube. In some or further embodiments, the electrically conductive internal electrical field collector can substantially fill the lumen of the second mandrel tube.
The continuously formed bifurcated mandrel can have various forms of surface structure. In some embodiments, the bifurcated mandrel can have a continuous, closed structure. In some embodiments, the bifurcated mandrel can have openings within the structure. In some embodiments, the openings within the structure can be irregular, or alternatively, regular or repeating in pattern. In some embodiments, the bifurcated mandrel can have an open lattice structure.
The angle α can be any angle greater than zero degrees. In some embodiments, the angle α is from 1 degree to 90 degrees. In some embodiments, the angle α is from 10 degrees 10 degrees to 80 degrees, or from 30 degrees to 60 degrees. In some embodiments, the angle α is about 90 degrees such that the first graft axis and second graft axis are substantially perpendicular. In some embodiments, the angle α is less than about 90 degrees such that the first graft axis and second graft axis are non-perpendicular.
To further illustrate the principles of the present disclosure, the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compositions, articles, and methods claimed herein are made and evaluated. They are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their disclosure. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art. Unless indicated otherwise, temperature is ° C. or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of process conditions that can be used to optimize product quality and performance. Only reasonable and routine experimentation will be required to optimize such process conditions.
This example provides methods for the fabrication of resorbable, bifurcated vascular grafts by combining electrospinning and 3D printed mandrels that are patient-specific shapes, including bifurcations.
Conceptual Design.
The basic concept is the use of a directed electrical field and dynamic positioning of the construct, as shown in
Specific kinematics positioned the mandrel with respect to the direction of the electrospun fibers' flow.
The intended positioning system provided at least two degrees of freedom to rotate the mandrel in the A direction (around the xm machine axis), and, simultaneously, the device positioned the mandrel in the B direction (around the ym machine axis), as shown in
The combination of directed electrical field and dynamic positioning of the construct produced a semi-uniform mat of electrospun fibers on top of a bifurcated tubular mandrel.
Positioning Device.
The conceptual design was reduced to practice, including the positioning device shown in
Process Parameters
Scaffold Mandrel.
The mandrel was generated through Fused Modeling Deposition (FDM) with a Stratatys Fortus 400 machine and standard acrylonitrile butadiene styrene (ABS) material was used. The mandrel was designed with an open structure to facilitate electrical field flow. Internal diameters of 10.00 and 8.22 mm were used for the main tubular section and the T section, respectively. Wall thickness was about 1 mm.
Electrospinning Process.
The electrospinning solution was based on polycaprolactone (PCL) (at 10% w) and acetone, with stirring at 45° C. for 4 hrs. The solution was delivered with a syringe infusion pump (model KS 100 (KD Scientific Inc., Holliston, Mass.).
The power source had a maximum voltage of 20 kV and maximum current of 250 μA (model ES20P-5W, Gamma High Voltage Research Inc., Ormond Beach, Fla., USA). The specific electrospinning parameters used are listed in Table 1, including the positioning and rotation kinematics.
For the experimental design, only two variables were considered: whether the internal electric field collector was on or off, and the mandrel positioning in the B direction (Table 1). Five replications were used.
Characterization of Bifurcated Tubular Scaffolds
Qualitative Analysis.
The bifurcated scaffolds were analyzed via optical microscopy and SEM imaging. Overall density of electrospun membranes and scaffold integrity were evaluated for different process conditions.
Mechanical Properties.
Preliminary evaluation of mechanical properties was conducted for the bifurcated scaffolds. As shown in
A universal machine Instron 3365 (Norwood, Mass., USA) was used for indentation tests (5 N load cell and hexagonal rod with a flat end) and tension tests (1 kN load cell).
Table 1 shows a representative sample scaffold for each combination of variable parameters. From a qualitative point of view, there is a clear advantage in combining an internal electrical field collector with mandrel kinematics that combine rotation around xm machine axis (A direction, as defined in
Results for mechanical properties are shown in
Tension tests showed average maximum strengths of 2.74 MPa in samples with internal collector and indexing in B direction vs. 1.21 MPa in samples with internal collector and no indexing in B direction. The average scaffold membrane thickness was 170 mm vs. 150 mm, respectively.
Disclosed herein are a robotically controlled electrospinning fiber source and the electrical control of both the mandrel and the electrospun fiber source. The shape of the final scaffold corresponded well to the intended bifurcated tube (see Table 1). These results show that a user can maintain the use of internal electrical field collector and dynamic positioning of the mandrel to generate improved results.
Conventional tubular scaffolds have strengths in the range of 3 and 4 MPa in order to be considered adequate for in vivo testing as vascular grafts inside models. Nottelet B, et al., J. Biomedical Materials Research Part A, 89:865-875 (2009); de Valence S, et al., Biomaterials, 33:38-47 (2012). The resulting scaffolds disclosed herein showed maximum strengths over 50% of conventional tubular scaffolds with similar electrospinning materials.
Different mandrel and scaffold materials and process parameters can be tested, and more realistic shapes for the mandrel can be considered (as shown in
A combination of directed electrical field and dynamic positioning of the mandrel is disclosed herein to generate resorbable scaffolds with bifurcated tubular shapes. The approach produced a mat of electrospun fibers on top of a bifurcated tubular mandrel. Mechanical testing of the bifurcated scaffolds is reported, with maximum indentation force between 0.7 and 2.3 N. In tension tests, the scaffolds showed an average maximum strength of 1.21 MPa (no indexing condition) and 2.174 MPa (indexing in the B direction).
This example describes an electrospun bifurcated tubular scaffolds (EBTS) built by combining electrospinning and a dynamic positioning mechanism. The EBTS were made of polycaprolactone (PCL) using low and high-speed profiles for the positioning mechanism. Mechanical characterization was carried out in order to evaluate the EBTSs. Indentation tests of the bifurcated grafts showed an indentation force between 2.92 N (low-speed) and 4.29 N (high speed). Tension tests showed an average strength of 1.38 MPa with low speed profile and 2.34 Mpa with high speed profile.
The increase of rotational and translational speeds of the dynamic mechanism improves the electrospun fibers distribution and enhance EBTS mechanical strength. Environmental conditions for the experiments impacted EBTS material properties. Changes in room temperature and humidity can affect the viscosity of the PCL solution. Lower temperature and humidity can reduce the density of distribution of the electrospun fibers and cause a reduction of mechanical properties.
Publications cited herein are hereby specifically incorporated by reference in their entireties and at least for the material for which they are cited.
It should be understood that while the present disclosure has been provided in detail with respect to certain illustrative and specific aspects thereof, it should not be considered limited to such, as numerous modifications are possible without departing from the broad spirit and scope of the present disclosure as defined in the appended claims. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.
This application claims benefit of U.S. Provisional Application No. 62/471,568, filed Mar. 15, 2017, which is hereby incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2018/022746 | 3/15/2018 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62471568 | Mar 2017 | US |
