Piezoelectric shear-thinning material compositions, piezoelectric microgels and microbeads

Abstract

Disclosed herein are methods and compositions for defining a series of shear-thinning hydrogels that exhibit piezoelectric properties. The described piezoelectric materials can be injected into a target environment percutaneously or via a transcatheter vascular route for localized area stimulation of cells or tissues using wireless impulses as the actuation mechanism. These external stimuli trigger electrical or mechanical responses in the implanted piezoelectric material for medical interventions such as tumor ablation, drug delivery, electroporation, chemoelectroporation, nerve stimulation, wound healing, cardiovascular applications, and musculoskeletal pain management.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to implantable bioelectronic and piezoelectric materials for the treatment of medical conditions. [Background technology]

[0002] Implantable bioelectronics provide researchers with the ability to interface and communicate with the human body. These systems, including devices such as pacemakers, cardiac defibrillators, and electrodes, have been developed to stimulate tissues and organs with external stimuli or to collect information from patients for diagnostic purposes. Recent developments in implantable bioelectronics include growing interest in neurostimulation for the treatment of neurodegenerative diseases and injuries that can cause problems ranging from paralysis to dyskinesia. Furthermore, these and other implantable bioelectronics have shown promise as a method of pain management in chronic pain scenarios. Electrode materials have also been used in tumor treatment, ablating tumor cells by delivering electrical current or mechanical energy to the lesion. Further therapies using electrode materials include externally triggered drug release applications and systemic drug delivery therapies that increase the cells' susceptibility to drug penetration via electroporation. In the case of tumor cells, this process is called chemoelectroporation.

[0003] Implantable bioelectronics offer solutions to a variety of human conditions, but many have not been widely adopted due to issues related to electrode implantation (e.g., requiring invasive surgery), the physical burden of external hardware (e.g., electrodes and stimulation control devices), or tissue-electrode stiffness mismatches. Implantable electrodes require invasive surgery to implant the device at the desired location, which can result in long recovery times. Similarly, many metal-based electrodes face matrix stiffness mismatches, potentially causing discomfort and scarring for patients.

[0004] For example, externally applied electrodes can be uncomfortable for patients not only while wearing the electrodes but also during treatment, and the inconvenience of wearing visible wires and devices for extended periods of time. This discomfort is of greater concern with bioelectrode systems that require a wired power source that is implanted near the electrode and may require a follow-up visit for replacement, or that is placed outside the body but requires the patient to carry the wired power source with them during treatment.

[0005] Therefore, there is a need for biocompatible electrode materials that can be wirelessly powered and minimally invasively delivered to increase the clinical relevance of these types of treatments. Summary of the Invention

[0006] In some embodiments, the present disclosure provides implantable bioelectronic devices. In one embodiment, the present disclosure relates to a piezoelectric shear-thinning composition comprising piezoelectric nanoparticles, one or more polymers, and deionized water.

[0007] In one embodiment, the composition comprises about 0.1% to about 50% (w / w) piezoelectric nanoparticles. In one embodiment, the piezoelectric nanoparticles are selected from the group consisting of synthetic (laponite) and natural (bentonite, kaolinite, montmorillonite-smectite) nanoclays, quartz, zinc oxide nanoparticles, aluminum nitride.

[0008] In one embodiment, the composition comprises from about 0.5% to about 20% (w / w) of one or more polymers. In one embodiment, the polymer is selected from the group consisting of gelatin, collagen, chitosan, silk, polytetrafluoroethylene (PTFE), polylactic acid (PLA), poly(l)lactic acid (PLLA), poly(d)lactic acid (PLDA), cellulose, alginate, agarose, starch, polyvinylidene fluoride (PVDF), polyethylene glycol (PEG), lignin, keratin, and polyvinyl alcohol (PVA).

[0009] In one embodiment, the composition comprises a contrast agent selected from the group consisting of tantalum, tungsten, and iohexol. In one embodiment, the composition has a storage modulus (G') of about 1 kPa to about 40 kPa.

[0010] In one embodiment, the composition is administered transdermally or intravenously to a patient in need thereof, and then the administered composition is exposed to an external stimulus, whereby an induced voltage is provided by the composition. In one embodiment, the induced voltage of the composition is from about 0.01V to about 10,000V.

[0011] In one embodiment, the external stimulus is selected from an ultrasound stimulus, a radio frequency stimulus, and a microwave stimulus. In one embodiment, the composition provides an induced voltage when exposed to an ultrasonic frequency of about 20 kHz to about 20 MHz.

[0012] In one embodiment, the composition provides an induced voltage when exposed to a radio frequency of about 50 MHz to about 200 MHz. In one embodiment, the composition provides an induced voltage when exposed to microwave frequencies between about 300 MHz and about 300 GHz.

[0013] In one embodiment, the present disclosure relates to a plurality of piezoelectric microgels or microbeads, said microgels or microbeads comprising piezoelectric nanoparticles and one or more polymers.

[0014] In one embodiment, the microgel or microbeads have an average particle size of about 50 microns to about 1000 microns. In one embodiment, the microgel or microbeads comprise about 0.1% to about 50% (w / w) piezoelectric nanoparticles.

[0015] In one embodiment, the piezoelectric nanoparticles are selected from the group consisting of synthetic (laponite) and natural (bentonite, kaolinite, montmorillonite-smectite) nanoclays, quartz, zinc oxide nanoparticles, aluminum nitride.

[0016] In one embodiment, the microgel or microbeads comprise from about 0.5% to about 20% (w / w) of one or more polymers. In one embodiment, the polymer is selected from the group consisting of gelatin, collagen, chitosan, silk, polytetrafluoroethylene (PTFE), polylactic acid (PLA), poly(l)lactic acid (PLLA), poly(d)lactic acid (PLDA), cellulose, alginate, agarose, starch, polyvinylidene fluoride (PVDF), polyethylene glycol (PEG), lignin, keratin, and polyvinyl alcohol (PVA).

[0017] In one embodiment, the piezoelectric microgel or microbead further comprises a contrast agent selected from the group consisting of tantalum, tungsten, and iohexol. In one embodiment, the microspheres or microbeads are administered transdermally or intravenously to a patient in need thereof, and then the administered composition is exposed to an external stimulus, whereby an induced voltage is provided by the microspheres or microbeads.

[0018] In one embodiment, the induced voltage of the microgel or microbead is from about 0.01V to about 10,000V. In one embodiment, the external stimulus is selected from an ultrasound stimulus, a radio frequency stimulus, and a microwave stimulus.

[0019] In one embodiment, the microspheres or microbeads are exposed to an ultrasonic frequency of about 20 kHz to about 20 MHz, which provides an induced voltage from the microgel or microbeads.

[0020] In one embodiment, the microgel or microbeads provide an induced voltage when exposed to a radio frequency of about 50 MHz to about 200 MHz.

[0021] In one embodiment, the microgel or microbeads provide an induced voltage when exposed to microwave frequencies between about 300 MHz and about 300 GHz.

[0022] In one embodiment, the present disclosure relates to a method of treating cancer or cancerous lesions by ablation, the method comprising: (a) administering a therapeutically effective amount of a composition described herein or a microgel or microbeads described herein; and (b) applying an external stimulus to provide an induced voltage from the composition, microgel, or microbeads.

[0023] In one embodiment, the composition, microgel, or microbeads are administered by transcatheter delivery or transdermal injection. In one embodiment, the external stimulus comprises applying sonic energy from ultrasound or high intensity focused ultrasound to the area where the composition, microgel, or microbeads has been administered.

[0024] In one embodiment, the present disclosure relates to a method of neurostimulation, the method comprising: (a) administering a therapeutically effective amount of a composition described herein or a microgel or microbead described herein; and (b) applying an external stimulus to provide an induced voltage from the composition, microgel, or microbead.

[0025] In one embodiment, the present disclosure relates to a method for pain management, the method comprising: (a) administering a therapeutically effective amount of a composition described herein or a microgel or microbead described herein; and (b) applying an external stimulus to provide an induced voltage from the composition, microgel, or microbead.

[0026] In one embodiment, the present disclosure relates to a method for promoting wound healing, the method comprising: (a) administering a therapeutically effective amount of a composition described herein or a microgel or microbead described herein; and (b) applying an external stimulus to provide an induced voltage from the composition, microgel, or microbead.

[0027] In one embodiment, the present disclosure relates to a method of cardiovascular pacing, the method comprising: (a) administering a therapeutically effective amount of a composition described herein or a microgel or microbead described herein; and (b) applying an external stimulus to provide an induced voltage from the composition, microgel, or microbead.

[0028] In one embodiment, the present disclosure relates to a method of electroporation, alone or in combination with a chemotherapeutic agent, comprising: (a) administering a therapeutically effective amount of a composition described herein or a microgel or microbead described herein; and (b) applying an external stimulus to provide an induced voltage from the composition, microgel, or microbead.

[0029] In one embodiment, the external stimulus stimulates the controlled release of an encapsulated therapeutic agent, including a chemotherapeutic agent. [Brief explanation of the drawings]

[0030] [Figure 1A] 1 shows a flow diagram of a method for delivering piezoelectric-based bioelectronics, according to an exemplary embodiment of the present disclosure. [Figure 1B] 1 illustrates a piezoelectric-based bioelectronic implementation according to an exemplary embodiment of the present disclosure. [Figure 2] 1A-1C are diagrams of the piezoelectric effect in three compositions of piezoelectric-based bioelectronics including laponite, gelatin, and water, according to exemplary embodiments of the present disclosure. [Figure 3]1A-1C are diagrams of three compositions of piezoelectric-based bioelectronics based on Laponite, gelatin, and water, according to exemplary embodiments of the present disclosure. [Figure 4] 1A-1C are diagrams of three compositions of piezoelectric-based bioelectronics containing different amounts of tantalum contrast agent, according to exemplary embodiments of the present disclosure. [Figure 5] 1A-1C are graphical illustrations of the piezoelectric effect in compositions with varying amounts of tantalum contrast agent, according to exemplary embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0031] Detailed Description The term "a" or "an" refers to one or more of that entity; that is, it can refer to a plurality of referents. Accordingly, the terms "one," "one or more," and "at least one" are used interchangeably herein. Furthermore, reference to "an element" by the indefinite article "a" does not exclude the possibility that a plurality of elements are present, unless the context clearly requires that there is only one element.

[0032] Throughout this application, the term "about" is used to indicate that a value includes the variation of error inherent in the device or method used to determine the value or the variation that exists between samples being measured. Unless otherwise stated or clear from the context, the term "about" means within 10% above or below the reported numerical value (except when that numerical value is above 100% or below 0% of the possible values). When used in conjunction with a range or series of values, the term "about" applies to the endpoints of the range or each recited value in that series, unless otherwise specified. As used in this application, the terms "about" and "approximately" are used synonymously.

[0033] Unlike conventional implantable devices intended to provide electrical stimulation or other therapeutic and / or diagnostic value to a patient, the present disclosure describes methods of electrically stimulating devices, compositions, and / or materials that are delivered minimally invasively to enhance clinical relevance. Such devices are described interchangeably herein as "bioelectronic" devices composed of "bioelectronic" compositions or "bioelectronic" materials.

[0034] One method for generating electrical stimulation is through the use of piezoelectric materials. Piezoelectric materials are a class of materials that respond to mechanical stimuli (e.g., ultrasonic pressure) with an electrical charge or current. When an energy source, such as radio frequency or microwaves, is applied, the material undergoes mechanical deformation. This phenomenon can be harnessed by adjusting the frequency and amplitude of the energy source stimulating the piezoelectric material, resulting in an electrical or mechanical output directly at the site of the material. Until now, piezoelectric materials have been used as a means to wirelessly activate electronic devices through external stimuli, such as ultrasound, radio frequency, microwaves, and other tissue-penetrating stimuli. This property arises from the lack of symmetry in the central unit cell of piezoelectric crystals, which has been shown to result in non-uniform charge distribution in response to mechanical strain. Unfortunately, many of the most commonly used piezoelectric materials (e.g., lead zirconate titanate) have been excluded from medical practice due to toxic byproducts generated during their manufacture or degradation. Furthermore, industrial piezoelectric materials face size limitations, biocompatibility, and flexibility issues when repurposed for biological applications. This has led to increased research into lead-free piezoelectric materials, including polymers, composites, and nanostructured materials for piezoelectric-based bioelectronic devices.

[0035] The viscoelastic properties of hydrogels make them an attractive alternative to traditional metal electrode materials for bioelectronics. Therefore, hydrogel electrodes can integrate more closely with target tissues, reducing issues associated with mismatch. Hydrogels are typically soft materials with storage moduli within the range of human tissues and organs (<100 kPa), thus avoiding the scarring issues associated with metal electrodes due to their stiffness. Piezoelectric hydrogels utilize the hierarchical and / or chiral structures of natural or artificial biopolymers to form structures with low symmetry, generating the piezoelectric effect. While biologically derived materials, such as proteins, can exhibit piezoelectric effects, many of these biomaterials undergo chemical crosslinking, limiting their tunability and injectability. This hinders their ability to be delivered via minimally invasive approaches. Therefore, the compositions and / or materials described in this disclosure offer distinct advantages over conventional methods, as detailed below.

[0036] Compositions of the present disclosure: In some embodiments, the present disclosure provides bioelectronic compositions for creating injectable bioelectronics, thereby enabling minimally invasive medical intervention. The bioelectronic compositions of the present disclosure can be bioelectronic shear-thinning hydrogels. The bioelectronic compositions of the present disclosure use the piezoelectric effect as a means to be wirelessly energized by application of an external stimulus, such as ultrasound, radio frequency, microwave, or other tissue-penetrating stimulus.

[0037] The bioelectronic composition can be a mixture of a piezoelectric material, a carrier, and a solvent, for example, the mixture can include a wide range of piezoelectric materials at a concentration of 0.1% to 50%, a wide range of carriers at a concentration of 0.5% to 20%, and the balance solvent.

[0038] In some embodiments, the piezoelectric material can be, among others, laponite, charged nanosilicate, quartz, zinc oxide nanoparticles, and aluminum nitride. In some embodiments, the carrier can be a hydrogel. In some embodiments, the carrier can be at least one polymer such as, among others, gelatin, collagen, chitosan, silk, polytetrafluoroethylene (PTFE), polylactic acid (PLA), poly(l)lactic acid (PLLA), poly(d)lactic acid (PLDA), cellulose, alginate, agarose, starch, polyvinylidene fluoride (PVDF), polyethylene glycol (PEG), lignin, keratin, and polyvinyl alcohol (PVA). In one example, the carrier is a gelatin hydrogel.

[0039] In some embodiments, the composition may further comprise a contrast agent such as tantalum, tungsten, iohexol, omnipaque, or a similar agent. According to one embodiment, the bioelectronic composition is a shear-thinning composition. Shear-thinning is the non-Newtonian behavior of a fluid, where the viscosity decreases when stress is applied. In other words, when a certain force (i.e., shear) is applied to such a shear-thinning fluid, the fluid flows more easily. This allows the shear-thinning composition of the present disclosure to be delivered via catheter, transdermal, etc.

[0040] Furthermore, the bioelectronic composition may have mechanical properties similar to those of the tissue adjacent to the bioelectronic composition upon implantation. For example, the bioelectronic composition may have a storage modulus (G') of 1 kPa to 1 MPa. In some embodiments, the bioelectronic composition may have a storage modulus (G') of 1 kPa to 100 kPa. In some embodiments, the bioelectronic composition has a storage modulus (G') of 1 kPa to 40 kPa. As can be appreciated, the mechanical properties of the bioelectronic composition are determined, in part, by the predicted mechanical properties of the tissue expected to be adjacent to the implanted bioelectronic composition.

[0041] In some embodiments, the bioelectronic composition has a yield stress of about 1 Pa to about 200 Pa. In some embodiments, the bioelectronic composition has a yield stress of about 1 Pa to about 100 Pa. In some embodiments, the bioelectronic composition has a yield stress of about 2 Pa to about 50 Pa. In some embodiments, the bioelectronic composition has a yield stress of about 1 Pa to about 25 Pa. In some embodiments, the bioelectronic composition has a yield stress of about 1 Pa to about 10 Pa. In some embodiments, the bioelectronic composition has a yield stress of about 1 Pa to about 5 Pa. In some embodiments, the bioelectronic composition flows upon application of a pressure greater than the yield stress.

[0042] In one embodiment, the phase transition characteristics of a bioelectronic composition depend, among other things, on the ratio of components in the bioelectronic composition and / or the total solids content of the bioelectronic composition. The ratio of components (e.g., oppositely charged polymers and nanoparticles) can affect electrostatic interactions. The combination of the ratio of components and the total solids content determines the viscoelastic properties of the bioelectronic composition (e.g., the change in viscosity under shear rate and the degree of recovery / reversibility).

[0043] In some embodiments, the size and shape of a bioelectronic composition can be determined by the particular mixture of piezoelectric material, carrier, and solvent, among other components, taking into account the mechanical properties of the bioelectronic composition and its phase transition characteristics. At low shear rates, the composition behaves as a soft solid; above a respective shear rate threshold, the composition behaves as a viscous fluid. Such shear-thinning behavior can make the bioelectronic composition injectable. The solid can have a predetermined shape or can take the shape of the space in which it resides (i.e., the implantation space). In some embodiments, the bioelectronic composition can be defined by the volume into which the bioelectronic composition is introduced, recognizing that the size and shape of the bioelectronic composition can vary depending on the application. In some embodiments, the bioelectronic composition can be configured as microgels or microbeads. The microgels or microbeads can have the same composition as the larger bioelectronic composition or a different composition (e.g., excluding the solvent or adding additional components), but can have a size ranging from 50 μm to 1000 μm in diameter. Reducing the size of the microgels or microbeads allows them to penetrate capillaries ranging from 100 μm to 5 mm in diameter.

[0044] Methods of using the compositions of the present disclosure: Embodiments of the present disclosure provide injectable piezoelectric shear-thinning hydrogels as bioelectronic compositions for minimally invasive medical interventions. The bioelectronic compositions (also referred to herein as bioelectronic materials) can be implanted by various means, such as direct percutaneous injection or via a transcatheter vascular route. In one example, the bioelectronic composition can be delivered by direct percutaneous injection to a lesion (e.g., a tumor). In one example, the bioelectronic composition is delivered via a transcatheter vascular route (e.g., as an embolic agent).

[0045] Embodiments of the present disclosure describe the formation of piezoelectric microgels or microbeads based on bioelectronic compositions that are delivered to the treatment site transdermally via a catheter or by direct injection, allowing for deeper penetration.

[0046] Bioelectronic devices based on at least the bioelectronic compositions defined herein can be delivered directly to the treatment site via transcatheter delivery or transdermal injection. Once the bioelectronic device is delivered to the target area, it is stimulated via ultrasound, radio frequency, microwave, or other energy source to induce electrical current in the tissue to be treated. An externally positioned transducer can be used to deliver the ultrasound, radio frequency, microwave, or other energy field to the piezoelectric embolic material.

[0047] 1A shows a flow diagram of a method for delivering a bioelectronic device, a bioelectronic composition, and / or a bioelectronic material according to an exemplary embodiment of the present disclosure. For clarity, the method is described below with reference to a bioelectronic composition.

[0048] FIG. 1A is a flow diagram of a method 100 according to an embodiment in which a bioelectronic composition is delivered for therapeutic purposes. In step 101 of method 100, a bioelectronic composition is prepared. In some embodiments, the bioelectronic composition can be mixed such that the piezoelectric material is uniformly suspended within the carrier. This allows the mixture to be used to generate a known amount of charge or motion when activated by a mechanical or electrical impulse. Various techniques can be used to achieve this uniform suspension. In some embodiments, mechanical agitation (e.g., shaking and mixing) is used to create this uniform suspension. In other examples, a centrifuge or vortex mixer is used.

[0049] In some embodiments, the bioelectronic composition prepared in step 101 of method 100 can be configured for a variety of applications and dimensional constraints, including use as a microgel or microbead, as shown in Figure 1B. In some embodiments, the bioelectronic composition can be configured to be delivered into a lumen ranging from 50 microns to 10 millimeters in diameter.

[0050] In step 102 of method 100, a bioelectronic composition can be delivered to a treatment area. In some embodiments, the bioelectronic composition can be delivered via a delivery device, such as a needle or catheter, configured to deliver the mixture to the treatment site. In some embodiments, a needle can be advanced to the treatment site (e.g., percutaneous injection), or a catheter can be guided through the vascular system to a vein or artery at the vascular input to the treatment site.

[0051] In step 103 of method 100, a medical imaging technique such as magnetic resonance imaging (MRI), fluoroscopy, or ultrasound can be used to determine the location of the delivery device and / or the bioelectronic composition (if the bioelectronic composition includes a contrast agent) during advancement or injection in step 102 of method 100. Once correctly positioned, the mixture can be injected into the treatment site. During and after injection, localized deposition of the mixture, for example, in the tumor bed, can be identified. In the absence of a contrast agent in the bioelectronic composition, a piezoelectric material injected as part of the bioelectronic composition can be used to identify localized deposition based on feedback generated by the piezoelectric material in response to electrical or mechanical stimulation.

[0052] In step 104 of method 100, the piezoelectric material in the bioelectronic composition is excited to generate heat (by application of an electrical impulse, such as an RF impulse) or electricity (by application of a mechanical impulse, such as an ultrasound). The precise location of the bioelectronic composition at the treatment site allows the energy applied for excitation to affect only a localized area. In this way, an ultrasound impulse can be delivered to the bioelectronic composition to generate electricity and ablate an area near where the bioelectronic composition is delivered without damaging the tissue itself. Similarly, delivery of an electromagnetic impulse, such as an RF impulse, can cause mechanical deformation in the piezoelectric material, thereby heating and ablating tissue without damaging the tissue itself.

[0053] In some embodiments, the bioelectronic composition (i.e., the piezoelectric material therein) is excited according to the particular clinical outcome being sought. For example, in the case of solid cancer, the clinical outcome may be tumor ablation. In some embodiments, electroporation, with or without chemotherapy, for the treatment of cancer may be achieved by exciting the piezoelectric material in the bioelectronic composition. In some embodiments, excitation of the piezoelectric material in the bioelectronic composition may enable, among other things, nerve stimulation, pain management, wound healing, cardiovascular applications, and drug delivery. Such implementations of method 100 are described in further detail in the remainder of this disclosure.

[0054] In some embodiments, ultrasound frequencies of 20 kHz to 20 MHz, corresponding to commonly available therapeutic ultrasound, are applied externally. 2 to 100,000 W / m 2 Ultrasound intensities up to 100 MHz may also be used. For radiofrequency stimulation, frequencies between 50 MHz and 200 MHz may be used, corresponding to the range of frequencies classified as radiofrequency. For microwave stimulation, frequencies between 300 MHz and 300 GHz may be used.

[0055] In some embodiments, the application of the stimulus in the time domain is based on the given implementation. In other words, different applications of the methods described herein will benefit from different exposures to the stimulus. As an example, the stimulus may be a short pulse, a long pulse, or a combination thereof. Of course, such examples are not limiting and will depend on the particular desired result.

[0056] External stimulation of the bioelectronic composition can be achieved using external stimulation devices for near-cutaneous stimulation (less than 1 cm from the external stimulus) or deep cutaneous stimulation (up to 15 cm), depending on the frequency corresponding to the maximum penetration depth, allowing stimulation of the bioelectronic composition from about 0.01 cm up to about 25 cm from the surface of the skin.

[0057] In some embodiments, an external stimulus can induce a voltage of 0.1 V to 10,000 V within the bioelectronic composition. In some embodiments, the bioelectronic composition can be configured to be excited 2 to 100 times and remain in the body for at least 24 hours after delivery. The stimulation is related to the number of excitations and the residence time in the body, and can be determined according to the requirements of a particular implementation of the disclosed method. In one embodiment, the bioelectronic composition can be biocompatible, bioabsorbable, or a combination thereof. The resorption of the bioelectronic composition can be tailored to a particular application to provide a therapeutic effect over a desired period of time.

[0058] At 105 of method 100, excitation of the bioelectronic composition is monitored. Steps 104 and 105 of method 100 may be repeated until a satisfactory result is obtained. Such a satisfactory result may be determined, for example, by a medical professional. The satisfactory result may be a clinical result related to tissue ablation.

[0059] 2 is a diagram of an exemplary bioelectronic composition according to one embodiment of the present disclosure. In FIG. 2, the bioelectronic composition includes various amounts of Laponite (i.e., synthetic nanoclay), gelatin, and water. 5NC85 corresponds to 5 weight percent solids and 85% of the total solids are nanoclay, 6NC85 corresponds to 6 weight percent solids and 85% of the total solids are nanoclay, and 7NC85 corresponds to 7 weight percent solids and 85% of the total solids are nanoclay.

[0060] Figure 3 shows a graph of three bioelectronic compositions containing different amounts of Laponite, gelatin, and water. Voltage was generated within each bioelectronic composition by applying 20 kHz sonic energy using a commercially available sonic dismembrator. Excitation was applied in 15-second pulses every 20 seconds. The results show that the voltage measured within each bioelectronic composition increased over the period that sonic energy was applied.

[0061] Figure 4 is a diagram of an exemplary bioelectronic composition according to one embodiment of the present disclosure. In Figure 4, the bioelectronic composition contains varying amounts of laponite, gelatin, water, and tantalum as a contrast agent. The doped nanoclay composition is 7NC85, which corresponds to 7 weight percent solids and 85% of the total solids being nanoclay. From left to right in the image, it can be seen that tantalum increases from 0% to 20% to 30%, and the color of each bioelectronic composition roughly reflects this change.

[0062] Figure 5 is a graph of two bioelectronic compositions containing varying amounts of laponite, gelatin, water, and tantalum as a contrast agent. As can be seen, a voltage is induced within the bioelectronic compositions during application of 20 kHz acoustic energy.

[0063] In some embodiments, the bioelectronic compositions described herein can be used in the treatment of cancer and cancerous lesions, including, but not limited to, tumor ablation. In some embodiments, tumor ablation is initiated by a bioelectronic device containing an electrode through the delivery of an electric current or charge, heating of the tumor or lesion, and the application of mechanical energy, including sonic energy from ultrasound or high-intensity focused ultrasound. Typically, standard therapies for tumor treatment include direct resection of the lesion or chemical treatments, including chemotherapy. For tumors not amenable to tumor resection, additional treatments include thermal ablation (e.g., microwave ablation, radiofrequency ablation).

[0064] Each treatment has drawbacks, such as damage to non-tumor tissue surrounding the treatment site. For example, the presence of surrounding healthy tissue and important veins and ducts (e.g., portal vein, bile duct, etc.) can make it difficult for clinicians to accurately deliver ultrasound, radiofrequency, or microwave energy directly to the tumor at therapeutic levels. Delivering an injectable bioelectronic composition can focus ablative energy on the cancerous tissue and limit damage to surrounding tissue. Some methods include wireless electrical stimulation via external stimuli such as ultrasound, high-intensity focused ultrasound, or radiofrequency. The presence of piezoelectric-based bioelectronic compositions focuses these energy sources on the treatment area by either increasing the electrical conductivity of the area or by directing electrical current through it. Furthermore, the use of bioelectronic compositions allows for the use of subthreshold energy levels, where threshold is the point at which tissue damage essentially occurs.

[0065] In some embodiments, the bioelectronic composition can be used for electroporation. In this treatment, the electrical stimulation induced by the piezoelectric-based bioelectronic composition is large enough to increase the permeability of cell membranes. Clinical applications include the treatment of benign, premalignant, or malignant tumors. In some embodiments, this treatment can directly induce cell death via apoptosis, necrosis, necroptosis, and pyroptosis. In some embodiments, this treatment is used for chemoelectroporation, which is used in patients who do not respond or respond poorly to typical systemic chemotherapy or immunotherapy drug delivery. In this iteration, the bioelectronic composition helps deliver chemotherapeutic or immunotherapeutic drugs to the cytoplasm by introducing an electric current to facilitate drug entry into the cell membrane. This technique can further enhance drug delivery to the brain by helping to open the blood-brain barrier by disrupting tight junctions and / or facilitating cell-to-cell passage via vesicular transport.

[0066] In some embodiments, bioelectronic compositions can be used to non-invasively provide neural stimulation via electrical current in suborgan tissues. In some embodiments, bioelectronic compositions are used to target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neural activity and provide therapeutic benefits for a myriad of neuropsychiatric disorders. Targeted neural tissues include, but are not limited to, vagus nerve stimulation (used to treat rheumatoid arthritis and Crohn's disease), splenic nerve stimulation (used to treat endotoxemia), and sciatic nerve stimulation, among others. To this end, in some embodiments, electrical current is generated by an external stimulus (e.g., ultrasound).

[0067] In some embodiments, the bioelectronic composition can be used to aid in pain management. Transcutaneous electrical nerve stimulation has been used for many years to manage pain. In this method, electrodes are applied externally to deliver electrical stimulation, activating complex neural networks and thereby reducing pain. This external placement can make it difficult to target specific areas of pain for more accurate and precise treatment. Transcutaneous electrical nerve stimulation can treat pain directly at the treatment site. In this embodiment, a bioelectronic composition of the present disclosure is delivered transcutaneously to the treatment site, and external stimulation is applied to excite neural pathways, activating the descending inhibitory system and reducing pain.

[0068] In some embodiments, bioelectronic compositions can be used to aid wound healing. Electrical stimulation has shown promise in aiding and promoting wound healing in patients with chronic or diabetic wounds. Wounds contain endogenous electric fields that support cell migration after injury, and the strength of these fields has been shown to promote the migration of lymphocytes, fibroblasts, macrophages, and keratinocytes. In some chronic wounds, these electric fields are absent or disrupted, causing patients to not respond adequately to standard wound treatments. In response, researchers have investigated methods to promote and enhance wound healing by applying exogenous electric field stimulation via external electrodes. In accordance with the present disclosure, the piezoelectric-based bioelectronic compositions described herein can be used to introduce these exogenous electric fields, stimulate cell migration, and enhance the wound healing response.

[0069] In some embodiments, bioelectronic compositions can be used in cardiovascular applications. Cardiac pacemakers are implantable bioelectronic devices commonly used to pace cardiac signals using wired electronic devices. Cardiac pacemaker leads have been associated with adverse effects, such as lack of response to cardiac resynchronization therapy, infection, fracture, and dislodgement. As a result, a need has arisen for wireless cardiac pacing technology. This disclosure describes compositions capable of pacing cardiac rhythms through periodic stimulation of piezoelectric-based bioelectronic devices near or within the cardiovascular system. The ability to deliver bioelectronic compositions transvascularly within bioelectronic devices offers the added advantage of minimally invasive cardiac applications.

[0070] In some embodiments, bioelectronic compositions can be used to aid in the delivery of encapsulated drugs. In some embodiments, the drug is encapsulated within the bioelectronic composition, and drug release is responsive to the introduction of an external stimulus, such as ultrasound, radiofrequency, or microwave energy. This method of drug delivery is particularly advantageous for drugs that exhibit toxicity when delivered systemically, because drug delivery and release are targeted to a specific treatment site. Thus, this technology can aid in the administration of chemotherapeutic agents without many of the adverse effects of systemic administration.

[0071] In some embodiments, the bioelectronic composition is a composition described in U.S. Patent No. 10,034,958, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the bioelectronic composition is a composition described in U.S. Patent No. 11,083,780, the contents of which are incorporated herein by reference in their entirety.

[0072] Incorporation by Reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes, except that mention of any reference, article, publication, patent, patent publication, or patent application cited herein should not be construed as an admission or any suggestion that they constitute valid prior art or form part of the general common knowledge in any country in the world.

Claims

1. Piezoelectric nanoparticles comprising natural or synthetic nanoclay. one or more polymers selected from gelatin or collagen, and Deionized water 1. A piezoelectric shear thinning composition comprising:

2. The composition described in claim 1, comprising 0.1% to 50% (w / w) of the piezoelectric nanoparticles.

3. The composition of claim 1 , wherein the piezoelectric nanoparticles comprise the synthetic nanoclay.

4. The composition described in claim 3, wherein the synthetic nanoclay is laponite.

5. The composition of claim 1, comprising 0.5% to 20% (w / w) of said one or more polymers.

6. The composition of claim 1 , wherein the composition comprises gelatin.

7. The composition of claim 1 further comprising an imaging agent.

8. 8. The composition of claim 7, wherein the contrast agent is selected from the group consisting of tantalum, tungsten, and iohexol.

9. The composition of claim 7, wherein the contrast agent is tantalum.

10. The composition of claim 1, wherein the storage modulus (G') of the composition is from 1 kPa to 40 kPa.

11. 10. The composition of claim 1, wherein the induced voltage of the composition is 0.01V to 10,000V.

12. 12. The composition of claim 1 or 11, wherein the external stimulus is selected from ultrasound, radio frequency, and microwave stimuli.

13. 13. The composition of claim 12, wherein the composition provides an induced voltage when exposed to an ultrasonic frequency of 20 kHz to 20 MHz.

14. 13. The composition of claim 12, wherein the composition provides an induced voltage when exposed to a radio frequency of 50 MHz to 200 MHz.

15. 13. The composition of claim 12, wherein the composition provides an induced voltage when exposed to a microwave frequency of 300 MHz to 300 GHz.

16. a plurality of piezoelectric microgels or microbeads, Piezoelectric nanoparticles, including natural or synthetic nanoclays; and one or more polymers, including gelatin or collagen wherein the piezoelectric microgel or microbeads are for use in generating an induced voltage in a target area of ​​a patient by exposing the administered piezoelectric microgel or microbeads in the target area to an external stimulus.

17. 17. The piezoelectric microgel or microbeads according to claim 16, wherein the average particle size of the microgel or microbeads is 50 μm to 1000 μm.

18. A piezoelectric microgel or microbead as described in claim 16, comprising 0.1% to 50% (w / w) of said piezoelectric nanoparticles.

19. 17. The piezoelectric microgel or microbead of claim 16, wherein the piezoelectric nanoparticles comprise synthetic nanoclay.

20. The piezoelectric microgel or microbead of claim 16, wherein the synthetic nanoclay is laponite.

21. A piezoelectric microgel or microbead as described in claim 16, comprising 0.5% to 20% (w / w) of said one or more polymers.

22. 17. The piezoelectric microgel or microbead of claim 16, wherein the one or more polymers comprise gelatin.

23. 17. The piezoelectric microgel or microbead of claim 16, further comprising a contrast agent.

24. 24. The piezoelectric microgel or microbead of claim 23, wherein the contrast agent is selected from the group consisting of tantalum, tungsten, and iohexol.

25. The piezoelectric microgel or microbead of claim 23, wherein the contrast agent is tantalum.

26. 17. The piezoelectric microgel or microbead of claim 16, wherein the induced voltage of the microgel or microbead is between 0.01V and 10,000V.

27. 27. A piezoelectric microgel or microbead according to claim 16 or 26, wherein the external stimulus is selected from an ultrasonic stimulus, a radio frequency stimulus, and a microwave stimulus.

28. 28. A piezoelectric microgel or microbead according to claim 27, wherein an induced voltage is provided from the microgel or microbead when the microgel or microbead is subjected to an ultrasonic frequency of 20 kHz to 20 MHz.

29. 28. A piezoelectric microgel or microbead according to claim 27, wherein an induced voltage is provided from the microgel or microbead when the microgel or microbead is exposed to a radio frequency of 50 MHz to 200 MHz.

30. 28. A piezoelectric microgel or microbead according to claim 27, wherein an induced voltage is provided from the microgel or microbead when the microgel or microbead is exposed to a microwave frequency of 300 MHz to 300 GHz.

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