Patent Application
20230293185
Stroke is a time-sensitive, medical emergency, a leading cause of serious, long-term disability, and the fifth leading cause of death (6% of all deaths) in Oklahoma in 2012. In the past two decades, endovascular therapy with Guglielmi detachable coils (GDCs) has become a well-received, minimally invasive technique for treating intracranial aneurysms (ICAs), also known as cerebral aneurysms. GDC-based embolization therapy, which aims at excluding the aneurysmal sac and neck from the cerebral circulation by means of complete and lasting occlusion, has been considered as an alternative to traditional surgical clip ligation associated with higher procedural mortality. However, recent studies have shown that there are still emerging clinical challenges in endovascular coil embolization, primarily aneurysmal recanalization and incomplete occlusion. In addition, more challenging clinical situations include the management and treatment of wide-necked aneurysms (with an unfavorable sack-to-neck ratio 1.0) and large aneurysms (diameter d>10 mm), due to their complex 3D geometry for achieving complete occlusion. Despite the tremendous evolution of embolic techniques for treating these problematic aneurysms, issues of their relatively low packing density (occupying only 26%-33% of the aneurysm's volume) and low complete occlusion rates (˜60%-70%) still remain elusive.
Shape memory polymer (SMP) has been successfully used for brain aneurysm treatment in animal studies. SMP-based medical devices have been developed for the purposes of clot removal, aneurysm occlusion, and vascular stenting. In particular, SMPs have been designed to achieve aneurysm occlusion using four different approaches with a thermal triggering mechanism for device deployment: (i) coating on platinum coils, (ii) SMP-based embolic coils, (iii) SMP foams coupled with metallic or polymeric stents, and (iv) SMP stents. However, no SMP device has been made available clinically that can completely solve the deficiencies of the GDC-based embolization therapy. The focus of the present disclosure is to address and resolve these clinical and technical challenges.
This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Several non-limiting embodiments of the present disclosure are hereby illustrated in the appended drawings. It is to be noted, however, that the appended drawings only illustrate several embodiments and are therefore not intended to be considered limiting of the scope of the present disclosure.
Before further describing various embodiments of the apparatus, compositions, and methods of the present disclosure in more detail by way of exemplary description, examples, and results, it is to be understood that the embodiments of the present disclosure are not limited in application to the details of apparatus, methods and compositions as set forth in the following description. The embodiments of the compositions and methods of the present disclosure are capable of being practiced or carried out in various ways not explicitly described herein. As such, the language used herein is intended to be given the broadest possible scope and meaning, and the embodiments are meant to be exemplary, not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting unless otherwise indicated as so. Moreover, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the disclosure. However, it will be apparent to a person having ordinary skill in the art that the embodiments of the present disclosure may be practiced without these specific details. In other instances, features which are well known to persons of ordinary skill in the art have not been described in detail to avoid unnecessary complication of the description. While the apparatus, compositions, and methods of the present disclosure have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the apparatus, compositions, and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the inventive concepts as described herein. All such similar substitutes and modifications apparent to those having ordinary skill in the art are deemed to be within the spirit and scope of the inventive concepts as disclosed herein.
The present disclosure is directed to shape memory polymer (SMP)-based devices for surgical treatment of an intracorporeal defect (e.g., a void or anomaly) such as (but not limited to) an intracranial aneurysm or fistula in a subject. In at least one non-limiting embodiment, the SMP device is a 3D-printed SMP material manufactured as tailored to specifically fit and thus occlude an intracranial aneurysm (ICA). The SMP device may be delivered to the defect via a catheter equipped with a heating mechanism wherein the SMP device is raised above its glass transition temperature as it is deployed, causing the SMP device to return to its permanent shape after the device has been deployed.
As noted above, prior GDC-based embolization treatment results in low packing density of the aneurysm's volume and unsatisfactory complete occlusion rates. In addition, the prior technology is not capable of completely stopping blood circulation in aneurysms in the long run; the patient may still suffer from stroke attack due to aneurysm rupture after medical surgery. Current SMP-based medical devices are manufactured without considering each patient's unique aneurysm geometries and pathological conditions, and are most commonly produced using the polymer casting method and thus have not fully solved the problems characteristic of GDCs. In order to improve the brain occlusion performance and to best optimize the medical device for a patient's unique condition, patient-specific 3D-printed SMP devices, based on the patient's particular aneurysm geometry, have been developed herein to improve the packing density of the aneurysm's volume and increase complete occlusion rates. The SMP devices of the present disclosure can achieve better occlusion by means of fully occupying the space of the aneurysm or other biomedical defect.
In one non-limiting embodiment, the SMP-based medical device comprises: (i) a patient-specific 3D-printed SMP device to occlude an intracranial aneurysm, (ii) a thermal deployment mechanism (such as, but not limited to, an electrothermal deployment mechanism or a photothermal deployment mechanism) to release the SMP device into the aneurysm, and (iii) a catheter for delivery of the SMP device into the patient's arterial system. The thermal deployment mechanism may include conductive wires (e.g., constructed of carbon fibers or other suitable heat conductive material) for generating heat to increase the temperature of the SMP device before releasing it into the patient's aneurysm. Once the temperature of the SMP device reaches the glass transition temperature, the material will start recovering its shape to the original design geometry. In at least one non-limiting embodiment, the SMP material has been formulated to have a glass transition temperature that is slightly above the normal human body temperature for the release of the SMP device in the brain tissue environment. The SMP device may be manufactured using additive manufacturing technology (e.g., 3D printing) and the patient-specific aneurysm geometries obtained from the patient's medical images, such as (but not limited to) a computed tomography (CT) or magnetic resonance imaging (MRI) scan. The SMP-based technology of the present disclosure is not limited to ICA or endovascular embolization, and, in fact, the desired mechanical performance and shape changing feature can be judiciously achieved to treat suitable intracranial defects or other biomedical applications, such as (but not limited to) Kyphoplasty surgery in spinal compressive fractures. In other non-limiting embodiments, the SMP-based technology of the present disclosure can be used for hemorrhage control, for example (but not by way of limitation) in battlefield situations, for wound dressing and healing, and as a foam scaffold for tissue repair and tissue engineering.
In at least certain non-limiting embodiments, the SMP device can be made using syringe extrusion-based 3D-printing (a.k.a., direct ink writing). In this method, the SMP pre-polymer is pre-cured and extruded from a syringe. In certain non-limiting embodiments, a photo-induced implantation process is used, wherein an infrared (IR)-based laser is used to generate heat to activate shape recovery of the SMP device locally during implantation. The IR light is absorbed by the SMP device so that the temperature of the SMP device will increase above its glass transition temperature. In at least certain non-limiting embodiments, the permanent shape of the SMP can be optimized by using combined computer simulations and additive manufacturing. For example, patient-specific CT images are used to reconstruct the 3D geometries of the defect (e.g., aneurysm). Through image-based computational modeling, the shape that can best fit into the defect will be calculated so that the final SMP shape will be the best fit for the treated defect. Once the desired permanent shape is determined, the SMP will be 3D printed so that the customized SMP-based device will be fabricated, packaged, and used for surgical operation.
In at least one non-limiting embodiment, the SMP device is made of a porous sponge (i.e., an open-cell material comprising pores) instead of a solid wire.
For example, the SMP (sponge) device can have a porosity in a range of from about 75% to about 85%, and, therefore, the volume can be compressed by about 80% to about 90% without fracturing the SMP structure. Compression may be done, for example, at a temperature about 10° C. above its glass transition temperature to ensure that no structural damage is induced in the SMP. When the compressed SMP sponge (now in its temporary shape) is cooled back to room temperature, the compressed (temporary) shape will be maintained. The compressed SMP sponge can be in a wire shape, which can then be inserted via a catheter for delivery. Once the catheter reaches the aneurysm during surgery operation, the compressed SMP is released out of the catheter, placed within the aneurysm, and heated, and then the SMP will autonomously recover its shape to fill the aneurysm's volume.
In certain non-limiting embodiments, the porous SMP device has an open-cell microstructure (e.g., having an average porous size in the non-limiting range of from about 50 μm to about 300 μm), so that blood can still flood into and saturate the sponge. Chemicals can be coated on the outer surface of the device and on the internal walls of pores in the device, and blood can be cured and caused to clot, so that the aneurysm is fully filled by bio-safe solid materials. In non-limiting examples, the inner walls of an open-cell porous SMP device can be coated with one or more chemicals that can cause blood coagulation, including hemostatic agents such as (but not limited to) chitosan, chitin, zeolite, and kaolinite; the fibrin precursor combination of fibrinogen, thrombin, factor XIII, and calcium; and the active ingredients in coagulants such as (but not limited to) CELOX™ (Medtrade Products Ltd, Crewe, UK), QUICKCLOT® (Z-Medica, LLC, Wallingford, CT), HEMCON® (Tricol Biomedical, Inc., Portland, OR), FastAct, BLEEDARREST® (Hemostasis, LLC, St. Paul, MN), QUICK RELIEF® (Biolife LLC, Sarasota, FL), AND TRAUMADEX® (Medafor, Inc., Minneapolis, MN) hemostatic products. The rapid blood coagulation can cause the solidification of voids in the porous SMP device, resulting in stiffened SMP foam and stopped blood flow into the aneurysms. The external surface of the porous SMP device can be coated with an anticoagulant, so that blood will not adhere thereto minimizing stiffening of the surface of the SMP device that could cut the wall of the aneurysm thereby causing rupture and internal blooding.
All patents, published patent applications, and non-patent publications referenced or mentioned in any portion of the present specification are indicative of the level of skill of those skilled in the art to which the present disclosure pertains, and are hereby expressly incorporated by reference in their entirety to the same extent as if the contents of each individual patent or publication was specifically and individually incorporated herein.
Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those having ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
As utilized in accordance with the methods and compositions of the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or when the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” The use of the term “at least one” will be understood to include one as well as any quantity more than one, including but not limited to, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or any integer inclusive therein. The term “at least one” may extend up to 100 or 1000 or more, depending on the term to which it is attached; in addition, the quantities of 100/1000 are not to be considered limiting, as higher limits may also produce satisfactory results. In addition, the use of the term “at least one of X, Y, and Z” will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z.
As used in this specification and claims, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
Throughout this application, the terms “about” and “approximately” are used to indicate that a value includes the inherent variation of error for the composition, the method used to administer the composition, or the variation that exists among the objects, or study subjects. As used herein the qualifiers “about” or “approximately” are intended to include not only the exact value, amount, degree, orientation, or other qualified characteristic or value, but are intended to include some slight variations due to measuring error, manufacturing tolerances, stress exerted on various parts or components, observer error, wear and tear, and combinations thereof, for example. The term “about” or “approximately”, where used herein when referring to a measurable value such as an amount, percentage, temporal duration, and the like, is meant to encompass, for example, variations of ±20%, or ±10%, or ±5%, or ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods and as understood by persons having ordinary skill in the art. As used herein, the term “substantially” means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance occurs to a great extent or degree. For example, the term “substantially” means that the subsequently described event or circumstance occurs at least 80% of the time, or at least 90% of the time, or at least 95% of the time, or at least 98% of the time.
As used herein any reference to “one embodiment” or “an embodiment” means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment. Further, all references to one or more embodiments or examples are to be construed as non-limiting to the claims.
As used herein, all numerical values or ranges include fractions of the values and integers within such ranges and fractions of the integers within such ranges unless the context clearly indicates otherwise. Thus, to illustrate, reference to a numerical range, such as 1-10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., and so forth. Reference to a range of 1-50 therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to and including 50, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., 2.1, 2.2, 2.3, 2.4, 2.5, etc., and so forth. Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series. Thus, to illustrate reference to a series of ranges, for example, a range of 1-1,000 includes, for example, 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150-200, 200-250, 250-300, 300-400, 400-500, 500-750, 750-1,000, and includes ranges of 1-20, 10-50, 50-100, 100-500, and 500-1,000. The range 100 units to 2000 units therefore refers to and includes all values or ranges of values of the units, and fractions of the values of the units and integers within said range, including for example, but not limited to 100 units to 1000 units, 100 units to 500 units, 200 units to 1000 units, 300 units to 1500 units, 400 units to 2000 units, 500 units to 2000 units, 500 units to 1000 units, 250 units to 1750 units, 250 units to 1200 units, 750 units to 2000 units, 150 units to 1500 units, 100 units to 1250 units, and 800 units to 1200 units. Any two values within the range of about 100 units to about 2000 units therefore can be used to set the lower and upper boundaries of a range in accordance with the embodiments of the present disclosure.
The term “pharmaceutically acceptable” refers to compounds and compositions which are suitable for administration to humans and/or animals without undue adverse side effects such as (but not limited to) toxicity, irritation, and/or allergic response commensurate with a reasonable benefit/risk ratio.
By “biologically active” is meant the ability of an active agent to modify the physiological system of an organism without reference to how the active agent has its physiological effects.
As used herein, “pure,” “substantially pure,” or “isolated” means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other object species in the composition thereof), and particularly a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80% of all macromolecular species present in the composition, more particularly more than about 85%, more than about 90%, more than about 95%, or more than about 99%. The term “pure” or “substantially pure” also refers to preparations where the object species (e.g., the peptide compound) is at least 60% (w/w) pure, or at least 70% (w/w) pure, or at least 75% (w/w) pure, or at least 80% (w/w) pure, or at least 85% (w/w) pure, or at least 90% (w/w) pure, or at least 92% (w/w) pure, or at least 95% (w/w) pure, or at least 96% (w/w) pure, or at least 97% (w/w) pure, or at least 98% (w/w) pure, or at least 99% (w/w) pure, or 100% (w/w) pure.
The terms “subject” and “patient” are used interchangeably herein and will be understood to refer an organism to which the compositions of the present disclosure are applied and used, such as (but not limited to) a vertebrate or more particularly to a warm-blooded animal, such as (but not limited to) a mammal or bird. Non-limiting examples of animals within the scope and meaning of this term include dogs, cats, rats, mice, guinea pigs, chinchillas, rabbits, horses, goats, cattle, sheep, llamas, zoo animals, Old and New World monkeys, non-human primates, and humans.
“Treatment” refers to therapeutic treatments, such as (but not limited to) for treating an intracorporeal (biomedical) defect. The term “treating” refers to administering the treatment (e.g., the SMP device) to a patient for such therapeutic purposes, and may result in an amelioration of the condition or disease.
The term “intracorporeal defect” as used herein will be understood to include (but not be limited to) intracranial defects and anomalies. Non-limiting examples of an intracranial defect include a void and an aneurysm. Non-limiting examples of an anomaly include a fistula.
The term “effective amount” refers to an amount of an active agent which is sufficient to exhibit a detectable biochemical and/or therapeutic effect, for example without excessive adverse side effects (such as (but not limited to) toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of the present disclosure. The effective amount for a patient will depend upon the type of patient, the patient's size and health, the nature and severity of the condition to be treated, the method of administration, the duration of treatment, the nature of concurrent therapy (if any), the specific formulations employed, and the like. Thus, it is not possible to specify an exact effective amount in advance. However, the effective amount for a given situation can be determined by a person of ordinary skill in the art using routine experimentation based on the information provided herein.
The term “ameliorate” means a detectable or measurable improvement in a subject's condition or a symptom thereof. A detectable or measurable improvement includes a subjective or objective decrease, reduction, inhibition, suppression, limit or control in the occurrence, frequency, severity, progression, or duration of the condition, or an improvement in a symptom or an underlying cause or a consequence of the condition, or a reversal of the condition. A successful treatment outcome can lead to a “therapeutic effect,” or “benefit” of ameliorating, decreasing, reducing, inhibiting, suppressing, limiting, controlling or preventing the occurrence, frequency, severity, progression, or duration of a condition, or consequences of the condition in a subject.
A decrease or reduction in worsening, such as (but not limited to) stabilizing the condition, is also a successful treatment outcome. A therapeutic benefit therefore need not be complete ablation or reversal of the condition, or any one, most or all adverse symptoms, complications, consequences or underlying causes associated with the condition. Thus, a satisfactory endpoint may be achieved when there is an incremental improvement such as (but not limited to) a partial decrease, reduction, inhibition, suppression, limit, control, or prevention in the occurrence, frequency, severity, progression, or duration, or inhibition or reversal of the condition (e.g., stabilizing), over a short or long duration of time (e.g., seconds, minutes, hours).
Certain non-limiting embodiments of the present disclosure are directed to a shape memory polymer (SMP) device that comprises an SMP material having a permanent shape, a temporary shape, and a glass transition temperature. When in the permanent shape, the SMP material has a specific three-dimensional (3D) geometry unique to a specific intracorporeal defect in a subject, such that the permanent shape of the SMP material will substantially conform to and fill a space in the specific intracorporeal defect in the subject when the SMP material is deployed into the specific intracorporeal defect at a temperature above the glass transition temperature of the SMP material.
In a particular (but non-limiting) embodiment, the intracorporeal defect is an aneurysm, such as (but not limited to) an intracranial aneurysm (ICA).
In a particular (but non-limiting) embodiment, the glass transition temperature is in a range from about 36° C. to about 46° C., such as (but not limited to) a range from about 37° C. to about 43° C.
In a particular (but non-limiting) embodiment, the 3D geometry of the permanent shape of the SMP material is obtained from computed tomography (CT) imaging of the specific intracorporeal defect in the subject.
In a particular (but non-limiting) embodiment, the SMP material is a 3D-printed SMP object.
In a particular (but non-limiting) embodiment, the SMP material is an open-cell material comprising pores, and the pores are coated with a blood coagulant.
In a particular (but non-limiting) embodiment, the SMP material has an external surface, and wherein at least a portion of the external surface is coated with a blood anticoagulant.
In a particular (but non-limiting) embodiment, the SMP material comprises Hexamethylene diisocyanate (HDI), N,N,N0,N0-tetrakis (hydroxypropyl) ethylenediamine (HPED), and Triethanolamine (TEA).
In a particular (but non-limiting) embodiment, the SMP material comprises a radio-opaque additive.
In a particular (but non-limiting) embodiment, the SMP material is a carbon nanotube (CNT)-SMP material.
Certain non-limiting embodiments of the present disclosure are directed to a method of treating an intracorporeal defect in a subject. The method comprises inserting any of the SMP devices disclosed or otherwise contemplated herein into the intracorporeal defect of the subject.
In a particular (but non-limiting) embodiment, the intracorporeal defect is an aneurysm, such as (but not limited to) an intracranial aneurysm (ICA).
Certain non-limiting embodiments of the present disclosure are directed to an SMP device delivery system that comprises any of the SMP devices disclosed or otherwise contemplated herein, wherein the SMP device is in its temporary shape. The SMP device delivery system also comprises a heating mechanism for raising the temperature of the SMP device to a temperature above the glass transition temperature of the SMP material before the SMP device is deployed into the specific intracorporeal defect of the subject.
In a particular (but non-limiting) embodiment, the heating mechanism is electrothermal.
In a particular (but non-limiting) embodiment, the heating mechanism is photothermal.
In a particular (but non-limiting) embodiment, the heating mechanism is heat resistive.
In a particular (but non-limiting) embodiment, the SMP device delivery system further comprises a catheter for delivery of the SMP device into the specific intracorporeal defect in the subject. In certain non-limiting alternatives of this embodiment, the heating mechanism comprises a portion of a terminal end of the catheter.
Certain non-limiting embodiments of the present disclosure are directed to a method of delivering an SMP device into an intracorporeal defect in a subject. The method comprises inserting any of the SMP delivery systems disclosed or otherwise contemplated herein into the subject to deliver the SMP device into the intracorporeal defect.
In a particular (but non-limiting) embodiment, the intracorporeal defect is an aneurysm, such as (but not limited to) an intracranial aneurysm (ICA).
Certain embodiments of the present disclosure will now be discussed in terms of several specific, non-limiting, examples. The examples described below will serve to illustrate the general practice of the present disclosure, it being understood that the particulars shown are merely exemplary for purposes of illustrative discussion of particular (but non-limiting) embodiments of the present disclosure only and are not intended to be limiting of the claims of the present disclosure. In particular, the present disclosure is to be understood to not be limited in its application to the specific experimentation, results, and laboratory procedures disclosed herein after. Rather, the Examples are simply provided as one of various embodiments and are meant to be exemplary, not exhaustive.
This work was focused on characterization of an aliphatic urethane-based SMP device. Twelve compositions of the SMP were synthesized, and their thermomechanical properties together with the shape recovery behavior were comprehensively investigated. Results showed that the SMPs experienced a significant decrease in the storage and loss moduli when heated above their glass transition temperature (32.3-83.2° C.), and that all SMPs were thermally stable up to 265° C. Moreover, the SMPs exhibited both composition-dependent stress relaxation and a decrease in the elastic modulus during cyclic loading/unloading. The shape recovery time was less than 11 seconds for all SMP compositions, which is sufficiently short for shape changing and recovery during embolization procedures. Several candidate compositions were identified which possess a glass transition temperature above normal human body temperature (37° C.) and below the threshold of causing tissue damage (45° C.). They also exhibit high material strength and low stress relaxation behavior, indicating their potential applicability to endovascular embolization of ICAs.
One form of SMP is an aliphatic polyurethane as synthesized using hexamethylene diisocyanate (HDI), N,N,N0,N0-tetrakis (hydroxypropyl) ethylenediamine (HPED), and Triethanolamine (TEA), and comprises two segments at the molecular level: (1) rigid and glassy segments which determine the permanent shape, and (2) amorphous segments which control the temporary shape. Currently, most biocompatible SMPs used for biomedical applications are thermally induced. When heated above the SMP's glass transition temperature (Tg), the amorphous segments of the SMP transition from a glassy state to a rubbery state, thereby allowing the polymer to be deformed under an external load. After cooling below Tg while under the external load, the temporarily compressed shape is obtained. When the temperature of the SMP increases above the Tg, the SMP then autonomously decompresses and returns to the original, programmed shape without external mechanical stimuli. Biomedical devices fabricated using SMPs can be introduced into a patient's body in a temporary, compressed shape and then be expanded on demand to their programmed shape. Since the shape recovery can be facilitated with a certain triggering mechanism, such as (but not limited to) increasing temperature, the release of the SMP device can be completed without additional complex surgical operations, but rather through a micro-catheter.
In this example, aliphatic urethane-based SMPs were synthesized and comprehensively characterized to investigate connections between the working temperature of the polymers and their mechanical behavior. Glass transition temperatures of each composition were identified using both the dynamic mechanical analysis (DMA) and the differential scanning calorimetry (DSC) tests. The thresholds for thermal degradation of each composition were determined using thermogravimetric analysis (TGA). Uniaxial cyclic and failure testing results were obtained and analyzed for differences in behavior among the different compositions.
Methods
Materials and SMP Synthesis
Hexamethylene diisocyanate (HDI, ≥99.0%), N,N,N0,N0-tetrakis (hydroxypropyl) ethylenediamine (HPED, ≥98.0%), and Triethanolamine (TEA, ≥99.0%) were purchased from Sigma-Aldrich and used as received for synthesizing the aliphatic urethane shape memory polymers. Twelve combinations of these three monomers were synthesized, with their respective SMP formulations given in Table 1.
The molar ratios for each batch were sourced from Wilson et al., (Wilson, et al., “Shape memory polymers based on uniform aliphatic urethane networks.” J. Appl. Polym. Sci. (2007) 106:540-551) with modifications to the second and last compositions. All measurement and mixing procedures occurred within a nitrogen-filled glovebox to avoid moisture contamination of the monomers (
In at least one non-limiting embodiment, the method comprises the steps of (i) measuring each of the monomers, (ii) mixing the monomers to form the polymer, (iii) disposing the mixture into the previously cast molds, and (iv) curing the mixture in the molds in a vacuum oven. Monomer weighing was performed using a Fisher brand motorized pipette filler (Thermo Fisher Scientific, Waltham, MA) and a digital scale (AWS-100, American Weigh Scales Inc., Cumming, GA). In brief, the HPED and TEA were measured in the same 100 mL glass beaker, while HDI was kept in a separate container until the stirring stage, where it was added to the mixture and stirred on a magnetic stirring plate. The mixture was stirred gently to avoid the introduction of gas bubbles into the liquid. Stirring continued until the mixture showed a sudden transition from translucent to uniformly clear. The time required to produce this transition increased as the ratio of HPED in the mixture decreased and the ratio of HDI increased (Table 1).
The procedures in Wilson et al., (op. cit.) suggested including an excess of 1-2% isocyanate (HDI). However, our early synthesis results were unsatisfactory, and the removal of this excess improved the success rate of our syntheses. A tendency of the mixtures to cure before degassing could take place, leaving large air bubbles in the resulting specimens, was also observed. Since the mixture of the monomers is an exothermic reaction, it was noticed that large batches of the mixture could generate adequate heat to act as a catalyst for the curing process. To avoid these scenarios, the size of each batch was limited to 16-18 g, and multiple small batches were mixed during a single synthesis procedure, rather than mixing the full volume all at once.
Once the mixture had sufficiently reacted, it was quickly removed from the glovebox, and the contents were poured into a set of silicone rubber molds—rectangular beams (45 mm×8 mm×1 mm) for glass transition-related characterizations and ASTM D638 Type V “dog bones” for uniaxial tensile mechanical testing (see below). Prior to the synthesis, two coats of mold release (Buehler 208186032) were applied to each specimen mold to minimize bubble generations due to any undesired interactions between the mixed monomers and the silicone rubber during curing. Then, specimen molds were placed in a vacuum oven (Being BOV-20), and five (5) vacuuming (−0.8 bar) and nitrogen purging steps were performed to create a nitrogen protected environment in the oven before degassing. A strong vacuum (−0.925 bar) was next induced using a vacuum pump for 10-12 minutes to remove gas bubbles trapped in the mixture (
When curing the SMP specimens, the procedure in Wilson et al. (op. cit.) was followed with several modifications. The specimens were kept at room temperature for one hour, and then the temperature was increased at a steady rate to 130° C., where it was kept for another hour. The heating rate of temperature was proportional to the glass transition temperature (Tg) of the specimen being cured, to ensure that each SMP had an equal curing time before reaching its Tg (Table 1). During the curing process, a slow loss of vacuum potentially caused by the pressure increase associated with the heating was observed. To maintain a consistent vacuum, the oven was resealed in intervals of an increase of 7.5° C., by reestablishing the vacuum (−0.4 bar) and quickly purging the system with nitrogen. Upon completion of the curing step, the SMP specimens were carefully removed from the molds and stored in a vacuum desiccator (Bel-Art Lab) to ensure no moisture contamination occurred before subsequent thermo-mechanical characterization experiments.
Characterization of the Synthesized SMPs
The mechanical properties of shape memory polymers vary according to temperature, especially regarding Tg. To characterize these temperature-dependent mechanical properties with various polymer compositions, a series of thermomechanical tests were conducted, including the dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and uniaxial tensile tests considering failure and cyclic loading conditions, to pinpoint the Tg of the SMP compositions and to better understand their thermally-dependent mechanical behaviors.
Dynamic Mechanical Analysis (DMA)
Dynamic mechanical analysis (TA Q800) was used to measure the mechanical properties of synthesized SMPs. The SMP beam specimens were heated under a nitrogen atmosphere from 20° C. to 120° C. at a heating rate of 5° C./min and in the tension mode with a cyclic frequency of 1 Hz. DMA studies revealed the significant mechanical and thermal properties of the samples, such as (but not limited to) storage modulus, loss modulus, and glass transition temperature.
Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)
Thermal analysis data were measured by both thermogravimetry (TA Q50, TA Instruments, New Castle, DE) and differential scanning calorimetry (TA Q20, TA Instruments). All measurements were performed under a nitrogen environment. In brief, the thermal degradation behavior of the samples was recorded with heating from room temperature to 600° C. at a rate of 10° C./min. An in-house MATLAB (MathWorks, Inc., Natick, MA) program was used to determine the onset temperature of thermal degradation, which was used as a reference for the ensuing DSC measurements. The program performed a linear regression on a section of each specimen's TGA curve below Tg and another linear regression of the region on the TGA curve between 90% and 85% mass. The intersection of these two lines was determined to be the threshold of thermal stability. DSC measurements were carried out by: (1) heating from 20° C. to 160° C. at a rate of 5° C./min, (2) cooling to 20° C. at 50° C./min, (3) maintaining for 3 min at 20° C., and then (4) repeating the above procedures. DSC studies revealed the significant thermal properties of the samples, such as (but not limited to) the glass transition temperature. All the DSC data presented in this study were from the second heating cycle.
Mechanical Testing of the SMPs
Before performing tensile and cyclic testing on the SMP “dog-bone” specimens, the overflow region was removed to produce a clean finish on both sides of the specimen and eliminate imperfections. The samples were polished using a custom designed and 3D-printed mount on a rotary polishing machine (LaboPol-5, Struers Inc., Cleveland, OH). Once polished, the width and thickness of the testing region were measured three times each and averaged. Tensile failure testing was conducted using a uniaxial tensile testing system (Instron 5969, Instron, Norwood, MA). Double-sided padded tape was applied to both sides of each gripping region before mounting to prevent slippage during testing.
Failure testing was conducted at 10° C. above the Tg of each specimen in a temperature regulated environment on the Instron device. The specimens were mounted in three steps. First, the base of the sample was clamped into the bottom set of grips and allowed to heat up to the temperature of the testing environment. Second, the top section was clamped into the top set of grips, and the distance between the two grips was measured with a digital caliper. After measuring the distance between the grips, the extension reading on the Instron was zeroed, and as the sample returned to testing temperature, the grip positions were adjusted to keep the measured load as close to zero as possible. Finally, both sets of grips were tightened to make up for the relaxation of the SMP past its Tg. Once the sample reached testing temperature and the measured load was returned to zero, the extension measured by the Instron testing machine was added to the previously measured length, and the extension was zeroed once again. This value was recorded as the initial length of the specimen. Upon starting the test, the specimens were subjected to a displacement of 2 mm/min until failure. Five failure tests were completed per specimen, and the best three were selected for characterization purposes based on relative consistency of the elastic modulus and failure stress values.
The procedures for cyclic testing closely resembled those for failure testing. Another set of “dog-bone” specimens were tested at 10° C. above Tg, and the same three step mounting procedures were exercised as previously mentioned. For the cyclic tests, each sample underwent three cycles of preconditioning at 25% of the failure strain as determined during failure testing. After the preconditioning step, the samples underwent ten loading and unloading cycles of the previously determined 50% failure strain. Both preconditioning and cycling steps were carried out at the same strain rate of 2 mm/min as the failure tests.
Quantification of Shape Recovery Capability
The shape recovery function of the synthesized SMPs was investigated by bending a straight beam sample at a 180° angle, then measuring the time required for full recovery at various temperatures. In brief, the initial bend was achieved using a 3D printed mold. The beam was heated above its glass transition temperature, and then placed into the mold, where the specimen could cool and maintain its shape at the desired angle. To measure the recovery time, a video camera was placed directly above a beaker of water on a hot plate. The bent sample was held with forceps on a ring stand and swiftly lowered into the heated water bath, where the SMP specimen was fully recovered. The video was analyzed frame by frame to determine the elapsed time between any two specific angles of 45, 90, 135, 165, and 180 degrees. This procedure was conducted using water baths at Tg, Tg+5° C., and Tg+10° C. for each sample. Three repeated recovery tests were conducted at each of the above temperature levels, resulting in a total of nine (9) recovery time measurements for each SMP composition.
Results
DMA Results
All SMP compositions showed a single steep transition in their shear storage modulus, each occurring at a different temperature threshold (
The compositions between SMP9 and SMP11 possess transition temperatures between normal human body temperature (37° C.) and the threshold of tissue damage (45° C., >4-5 minutes), providing a desirable Tg range for allowing the polymers to remain functional within the body without causing any tissue damage due to the heating associated with shape change triggering.
TGA Results
The TGA testing results (
DSC Results
The results of the DSC tests were used as a secondary means of determining the Tg of each SMP composition (
Uniaxial Tensile Testing Results
Under uniaxial tensile failure tests, the SMPs exhibited a sharp decrease in the failure stress and the failure strain from SMP1 to SMP3 and an increase in both failure stress and failure strain from SMP3 to SMP12 (
As for the uniaxial tensile cyclic tests, the SMPs showed a noticeable relaxation behavior under cyclic tensile testing. This can be seen in the representative specimen (
Shape Recovery Capability
The SMPs showed a consistent temperature dependence in their shape recovery behavior, an example of which is shown in
Overall Findings and Relevance to Endovascular Embolization Treatment for ICAs
The thermomechanical characterization of the aliphatic urethane SMPs provided a closer look at the shift in material properties that occurs as each SMP reaches its Tg. The DMA results showed a single sharp transition in the shear storage modulus for all compositions (
Moreover, uniaxial mechanical testing was conducted using the SMPs to determine their material strength and investigate how the strengths varied with composition. The failure test results demonstrated that higher values for both failure stress and strain occur in compositions with lower HPED contents, but the trend is nonlinear with significant variances at SMP3 (
Cyclic tensile testing was performed to investigate changes in the behavior of the SMP under repeated loading. The two major properties that were investigated were the elastic modulus and the peak stress value at 50% failure strain (Table 3). GDC-based coils are designed to be left in the body for the remainder of a patient's lifetime, so it is important that the SMP materials used for this endovascular embolization application will not relax over time, resulting in the aneurysm recurrence. One behavior that the cyclic testing revealed was a noticeable reduction in the peak stress, with most of the reduction occurring during the first few cycles. This stress reduction reached a maximum value of 26.9%±3.93% in SMP1 with respect to the first cycle, and the next highest values fell near the range of 8%-9% for SMPs 2-5. The relaxation behavior, which is not a desirable quality in the context of a permanent embolization device, was more pronounced for SMPs containing more HPED contents. The compositions containing large quantities of TEA exhibited less relaxation, reaching values as low as 1.15%±0.04% for SMP9 and 1.92%±1.36% for SMP11. In addition, the elastic modulus also varied with cyclic loading, but only during the first few cycles of the test. The elastic modulus values decreased sharply during the first cycle, but quickly reached a constant value around the third or fourth cycle (
Another important factor in designing an embolic device made from SMPs is the shape recovery behavior which occurs when the polymer transitions from a deformed state to its un-stressed state. The recovery tests conducted in this Example focused on the time required for the SMP to recover its shape. For endovascular embolization of ICAs, a short recovery time of the SMP-based device enables the device to avoid the prolonged heating of body tissues during device deployment. The recovery behavior of the SMPs was shown herein to be temperature dependent, speeding up as temperatures increased past the Tg. At Tg+10° C., no composition took more than 10.3 seconds to fully recover from a 180° bend.
In at least certain non-limiting embodiments, the SMP devices of the present disclosure include radio-opaque additives to make them visible under x-ray-based fluoroscopy so that physicians can pinpoint their location and orientation during device deployment. Without such additives, urethane-based shape memory polymers are typically invisible to radiographic imaging techniques. Examples of such radio-opaque materials include, but are not limited to, tantalum and bismuth (III) oxychloride.
Thermal energy can be supplied to the SMP devices via diverse activation techniques, many of which are based on the indirect delivery of thermal energy to the material. These methods include, but are not limited to, Joule heating with the addition of conductive inclusions, optical heating achieved using wavelength specific dyes and a matching laser light source, and magnetic stimulation of nanoparticles. Another activation technique uses chemical interactions to lower the Tg of the SMP below ambient temperature, triggering the shape memory effect. This effect occurs slowly in polyurethane SMPs, and quickly in hydrogels, when the materials are exposed to water.
The results indicate that in SMP compositions closer to SMP12, the decreases in both maximum stress and elastic modulus with cyclic loading were not as prominent. Since any changes in material properties of the device after implantation tend to be detrimental, the SMP compositions near SMP12 are more desirable in the context of endovascular embolization treatment for ICAs.
In this example, a highly porous carbon nanotube (CNT)-shape memory polymer (SMP) nanocomposite for the endovascular ICA treatment is presented. Pristine SMP foam is fabricated using a biologically safe and environmentally friendly sugar template method. A CNT-SMP nanocomposite foam is fabricated by infiltrating CNTs into pristine SMP foam in ethanol by ultrasonication. The porous nanocomposites are characterized to identify key parameters, such as (but not limited to) average pore size, density, porosity, and electrical resistivity. A resistive-heating mechanism can be used to trigger the shape recovery of the nanocomposites.
Materials
Chemicals were purchased from Sigma-Aldrich and used as received. Three monomers were used to synthesize the aliphatic urethane SMPs. The monomers used to synthesize SMP were: (i) Hexamethylene diisocyanate (HDI), (ii) N,N,N0,N0-tetrakis (hydroxypropyl) ethylenediamine (HPED), (iii) Triethanolamine (TEA). The molar composition ratio of the HDI, HPED, and TEA monomers was 1:0.05:0.6. Multi-walled carbon nanotubes (CNTs) (50-90 nm diameter, >95% carbon basis) improved the electrical conductivity of SMP nanocomposites. Ethanol was used as solvent to infiltrate CNTs into SMP foams.
Preparation of Solid SMP
To synthesize the solid SMPs, amounts of monomers of HPED, HDI, and TEA were measured and combined into a mixture which was mixed using a high-speed shear mixer for 3 minutes, and then cast into a “dog-bone” shape or rectangular molds for curing. The materials were degassed three times, and nitrogen was used to protect all the materials before and during curing using a vacuum oven. The temperature profile was first kept at room temperature for 60 minutes, followed by a ramp of 30° C. per hour up to 130° C., then followed by 1 hour at 130° C., and finally cooled back to room temperature naturally. The fully cured SMP samples were removed from the molds and saved for testing and characterization.
Preparation of SMP and Nanocomposite Foams
Porous and pristine SMP foams were synthesized using a sugar template assisted method. A sugar template was first manufactured by compressing a suitable amount of cane sugar (sucrose) into a silicon rubber mold. A slight amount of water was added to improve the formability of cane sugar. Once the sugar template was prepared, an appropriate amount of SMP monomers was measured and mixed by a high-speed shear mixer for 3 minutes, then the sugar template was merged into the mixed pre-polymer and kept in vacuum at −5° C. for 24 hours. The SMP monomers were fully cured following the heating procedure introduced above. The sugar template was dissolved in de-ionized water using a bath sonicator for 1 hour. The manufactured SMP foams were kept in a vacuum oven at 30° C. for 24 hours to fully eliminate all the humidity trapped in the SMP foams.
CNT-SMP nanocomposite foams were manufactured using the pristine SMP foam. An appropriate amount of CNTs was first dispersed in ethanol by mechanical shear mixing for 5 minutes and followed by bath sonication for 10 more minutes. Then a prepared SMP foam was submerged in the CNT-ethanol solution to infiltrate CNTs into the SMP foam using an ultrasonication bath. Finally, the open-cell CNT-SMP nanocomposite foams, with interconnected CNF network deposited on the porous wall, were dried and attained for testing. The detailed CNT concentration used during ultrasonication is shown in Table 4. CNT concentration in ethanol solution used in this Example was in the range of 0.001-0.006 g/ml. The sonication time was up to 50 minutes.
Experimental Characterization of Solid SMP
Dynamic mechanical analysis (DMA) was employed to determine the thermal transitions in the synthesized SMPs. Experiments were conducted using a TAQ800 dynamic mechanical analyzer. Rectangular beam samples were tested using tensile mode from 30° C. to 130° C. Differential scanning calorimetry (DSC) was employed to characterize the polymer's thermal properties, in particular to validate Tg. The comparison of Tg obtained from DMA and DSC can validate each other. Thermogravimetric analysis (TGA) tests were conducted to study the decomposition temperature and procedure of the synthesized SMP. The maximum allowable temperature of the SMP can be obtained from the TGA tests.
The characterization results of solid SMP are shown in
Experimental Characterization of Synthesized SMP and CNT-SMP Nanocomposite Foam
Microstructure and morphology of pristine SMP and CNT-SMP nanocomposite foam were characterized by field-emission scanning electron microscope (SEM). The pore size and size distribution of the pristine SMP foam were determined using commercial software ImageJ (NIH, Bethesda, MD) using five (5) SEM pictures.
The volume electrical resistivity of fabricated CNT-SMP nanocomposites was measured using the two-probe method. CNT-SMP nanocomposites were fabricated into cubic samples and clamped between two flat electrodes to measure the electrical resistance of the sample. The volume resistivity was calculated using Eqn. 1.
where R is the electrical resistance, A is the cross-section area of the sample, and l is the height of the sample.
Results
The mechanism of CNT infiltration is shown schematically in
The porosity of manufactured pristine SMP foam was calculated using Eqn. 2, where P is the porosity, df is the density of SMP foam, and ds is the density of solid SMP. The weight and dimensions of five cubic samples were measured to calculate the density of solid SMP and SMP foam. The average density of solid SMP was 1.172 g/cm3, and the average density of pristine SMP foam was 0.168 g/cm3. Therefore, the porosity of the SMP foam reported in this Example was 85.7%.
The shape recovery capability of pristine SMP foam is shown in
As noted, the electrical conductivity of the CNT-SMP nanocomposite foams was enhanced by infiltrating CNTs into the porous SMP microstructure in the ethanol solution using ultrasonication.
Actuation of shape recovery is necessary for the SMP in ICA applications due to complex biological system requirements. A Joule-heating based SMP actuation mechanism was developed. To validate the Joule-heating based triggering mechanism, an electrically conductive carbon wire was inserted into a cubic CNT-SMP nanocomposite sample. The sample surface temperature was measured when the electrical current was set at 0.05-0.2 A. Insufficient heat was generated, and the sample surface temperature was kept at temperature below the Tg of SMP when 0.05 A and 0.1 A current was applied, respectively (
These results demonstrate use of a highly porous CNT-SMP nanocomposite for the development of a novel SMP device to treat ICAs. As explained, the pristine SMP foam was first fabricated using a biologically safe sugar template, and then CNTs were infiltrated into the open cell foam using ultrasonication during nanocomposite fabrication. Uniform CNT distribution in the manufactured nanocomposites was validated by SEM microscopy. Both CNT concentration in ethanol solution and ultrasonication time are fabrication parameters that can be altered to vary the electrical properties of the compositions. The disclosed novel SMP nanocomposites exhibit good shape recovery capability triggered by the Joule-heating mechanism, recovering from the deformation of more than 50% compressive strain to their original shape within two minutes.
One non-limiting embodiment of the present disclosure is directed to a personalized SMP embolization device tailored to a patient's particular aneurysmal condition for treatment of an ICA. The SMP device is based on the specific geometry of the subject's aneurysm geometry. The device can be fabricated using additive manufacturing technology (e.g., 3D printing) to achieve a short preparation time before an operation/surgery. Image Data can be obtained, for example but not by way of limitation, via computed tomography (CT) or CT angiography (CTA). Semi-automatic image segmentation and 3D geometry reconstruction is used to investigate the patient-specific aneurysm environment (
The SMP compositions that can be used herein include, but are not limited to, the aliphatic urethane SMP compositions described elsewhere herein, such as (but not limited to) polyurethanes made from high molecular monomers in various molar ratios, including HDI, HPED, and TEA (
Cyclic uniaxial tensile tests were extensively carried out using ASTM D638 “dog-bone”-shaped specimens (length=9.5 mm, gauge width=3.2 mm, and thickness=2.4 mm) to determine the suitable mechanical strength and resistance. In brief, specimens were tested in a dual-column Instron system. Each specimen was clamped in the thermal chamber and kept at 10° C. above the Tg for 10-15 minutes before displacement-controlled cyclic tensile testing. Results demonstrated initial hysteresis corresponding to the residual stress; in addition, the results showed that once the SMPs have been fully stretched and relaxed for 3 cycles, the hysteresis characteristic becomes relatively insignificant (
where I1 is the first invariant of the right Cauchy-Green deformation tensor, C1 and λ are the material parameters denoting the strength of the polymer chains and their limiting network stretch, respectively. By implementing this constitutive model to a user material subroutine VUMAT in the FE software ABAQUS (Simulia, Dassault Systèmes) and formulating an inverse modeling-based parameter estimation pipeline, two model parameters for the synthesized SMP materials have been quantified based on nonlinear fitting to the measured mechanical data using the Levenberg-Marquardt algorithm (
Aneurysm Creation Model for In Vivo Small Animal Study
Aneurysm creation models in rabbits have been established as a useful means to evaluate the efficacy and performance of new endovascular embolization devices. An animal study was carried out using a modified elastase-induced aneurysm creation model (
Using the acquired retrospective patient's brain image data, image segmentation is performed for reconstructing a high-fidelity aneurysm geometry and the surrounding arterial vessel environment. Patient-specific FE models perform endovascular simulations for assessing the hemodynamics and biomechanics of the deployed embolic devices. The FE computational models are validated against the measured flow data from an in-house in vitro flow loop with a particle image velocimetry (PIV) system (
Image Segmentation & Geometry Reconstruction
By using the patient's acquired CT angiography (CTA) DICOM image data, semi-automatic image segmentation, based on the developed pipeline, is performed with the image segmentation software Amira (FEI Inc., Hillsboro, OR) to reconstruct high-fidelity 3D geometries of the patient arterial blood vessel and the aneurysm from each patient's brain image data (
FSI and Thermal-Mechanical FE Simulation Framework
The reconstructed parent blood vessel and aneurysm's geometries are imported to the FE mesh generation software Hypermesh (Altair Engineering, Troy, MI) to obtain the meshes of both the structural domain (parent arterial vessel wall and aneurysm wall) and the fluid and heat transfer domain (
Fabrication of Pristine SMP and SMP-Carbon Nanotubes (CNT) Based Embolic Devices with Shape Change Triggering Element
Synthesized SMP foams and balloons are compressed into thin wires as the embolic device during fabrication. The pre-compressed shape autonomously recovers to fit into the 3D geometry of the ICA once it is heated up to the programmable temperature. The design and manufacture of these embolic SMP devices is described in more detail below.
SMP Materials, Shape Change Triggering Mechanisms, and Embolic Device Forms for Endovascular Embolization Applications
In non-limiting embodiments, three general types of SMP materials are used in the fabrication/manufacturing process: 1) pristine SMP integrated with a photo-thermal activation shape changing mechanism (with shape changing activation thermal energy converted from laser source via laser dye); 2) SMPs infused with CNTs (CNT-SMP nanocomposites) integrated with an electro-thermal activation mechanism (with activation thermal energy converted from electrical energy via electrically conductive carbon nanotubes); and 3) photo-thermally activated SMP devices equipped with a laser-based activation mechanism (with an appropriate wavelength of laser delivered by embedded optical fiber). In addition, three embolic device forms are fabricated: 1) coils, 2) open-cell foams, and 3) thin-shell balloons.
In-Vitro Experiments
As noted above, SMP devices are manufactured based on a patient's brain image data by using a UV cured 3D-printing system and are then inserted into the aneurysm area (
In certain non-limiting embodiments, the SMP devices are constructed according to the design parameters shown in Table 5.
Further analyses were performed to characterize the presently disclosed SMP materials. The aliphatic urethane SMP devices used in this Example were fabricated using the same monomeric materials disclosed in the above experiments, i.e., HDI, HPED, and TEA, combined in a molar ratio of 1:0.05:0.6 (HDI:HPED:TEA). To synthesize the solid SMPs, appropriate amounts of monomers were first measured and mixed using a high-speed shear mixer for three (3) minutes and then cast into “dog-bone” or rectangular molds for curing. The materials were degassed three times, and nitrogen was used to protect all the materials before and during curing using a vacuum oven. The temperature profile was first kept at room temperature for 60 minutes, followed by a ramp of 30° C. per hour up to 130° C., then followed by 1 hour at 130° C., and finally cooled back to room temperature naturally. The fully cured SMP samples were removed from the molds and saved for testing and characterization.
SMP foams were synthesized using a sugar-assisted method. A sugar bar was first manufactured by compressing an appropriate amount of cane sugar (sucrose) into a silicon rubber mold. A slight amount of water was added to improve the formability of cane sugar. Once the sugar bar was prepared, appropriate amounts of the monomers were measured and combined and mixed by a high-speed shear mixer for 3 minutes. The sugar bar was then merged into the monomer mixture, and was kept in an ice bath in vacuum for 24 hours. The monomers were partially reacted, and the bar was post-cured following the heating procedure introduced above. The fully cured SMP/sugar bar was then merged in de-ionized water and kept in a bath sonicator for 1 hour to fully dissolve cane sugar. The manufactured SMP foams were kept in a vacuum oven at 30° C. for 24 hours to fully eliminate all the humidity trapped in the SMP foams.
Experimental Characterization of Synthesized SMP
Dynamic mechanical analysis (DMA) was employed to determine the thermal transitions in the synthesized SMPs. Experiments were conducted using a TAQ800 dynamic mechanical analyzer. Rectangular beam samples were tested using tensile mode from 30° C. to 130° C. Differential scanning calorimetry (DSC) was employed to characterize the polymer's thermal properties, in particular to validate the glass transition temperature (Tg). The comparison of Tg's obtained from DMA and DSC can validate each other. Thermogravimetric analysis (TGA) tests were conducted to study the decomposition temperature and procedure of the synthesized SMP. The maximum allowable temperature of the SMP can be obtained from the TGA tests.
Microscale Imaging Using SEM
Scanning electron micrography (SEM) imaging was employed to visualize the porous size distribution within the SMP foam. The SEM images were taken from two different layers of an SMP foam to investigate the average size of SMP at different locations.
Results
The shape memory functions of the synthesized SMPs were investigated. Each straight beam sample was first immersed into hot water (at 5-10° C. above the expected glass transition temperature), bent up to 180° to form a bended shape, then cooled back to room temperature while maintaining the bended shape. Then the SMP sample was placed back into hot water and the material restored to the initial straight form autonomously. SMP samples at different shapes are illustrated in
DMA tests were applied to evaluate the Tg of the SMP. As shown in
DSC testing results are shown in
Once the SMP solid samples were fully characterized, more detailed characterizations were carried out to understand the properties of the SMP foams. The fabricated SMP foams were examined using a SEM to measure the size of cells for evaluating the density and compression capability of the synthesized SMP foams. The SEM images were taken from two different layers of a single SMP foam sample. The typical SEM images are shown in
The shape recovery capability of the SMP foams was first obtained using a direct heating method. The SMP foam sample was first compressed and kept in a refrigerator at 5° C. to keep the deformed shape. Then the sample was placed on a hot plate with a surface temperature of 70° C. As shown in
Direct heating is not easy to implement, in particular for FDA approval. Therefore, a Joule-heating based approach was employed. As shown in
In certain non-limiting embodiments, the present disclosure is directed to an SMP device, such as (but not limited to) an SMP sponge, compressed into a wire or filament for delivery in a medical/surgical application by a catheter, and a method of such compression. As shown in
It will be understood from the foregoing description that various modifications and changes may be made in the various embodiments of the present disclosure without departing from their true spirit. The description provided herein is intended for purposes of illustration only and is not intended to be construed in a limiting sense, except where specifically indicated. Thus, while the present disclosure has been described herein in connection with certain embodiments so that aspects thereof may be more fully understood and appreciated, it is not intended that the present disclosure be limited to these particular embodiments. On the contrary, it is intended that all alternatives, modifications and equivalents are included within the scope of the present disclosure as defined herein. Thus, the examples described above, which include particular embodiments, serve to illustrate the practice of the present disclosure, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of particular embodiments only and are presented in the cause of providing what is believed to be a useful and readily understood description of procedures as well as of the principles and conceptual aspects of the inventive concepts. Changes may be made in the apparatus, formulations of the various components and compositions described herein, the methods described herein, or in the steps or the sequence of steps of the methods described herein without departing from the spirit and scope of the present disclosure.
This application is a continuation of U.S. Ser. No. 16/751,964, filed Jan. 24, 2020, now abandoned; which claims benefit under 35 USC § 119(e) of provisional application U.S. Ser. No. 62/796,876, filed Jan. 25, 2019. The entire contents of the above-referenced applications are hereby expressly incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62796876 | Jan 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16751964 | Jan 2020 | US |
| Child | 18318916 | US |
