Ultrasound (“US”)-based methods currently exist for remotely triggering release of a medical payload, such as drugs and diagnostic aids, from particles or devices implanted in a living tissue. Remotely-triggered payload release is desirable in supporting specific clinical goals, including, but not limited to examples such as:
release of medical payload only when the carrier is in a specific location (e.g., a tumor);
release of medical payload only at a specific time (e.g., at a particular step of a clinical procedure); or
release of medical payload only at particular concentration and/or quantity as determined by a clinical protocol.
Existing US triggering methods rely on a variety of effects, including:
thermal/mechanical effects based on US-induced cavitation, which causes localized heating due to vibration; and increased speed of diffusion and/or changes in localized medium properties which increase diffusion;
mechanical degrading/rupturing of carrier leading to payload release;
shape change of the carrier; and
Unfortunately, current methods suffer from a number of serious drawbacks. First, none of the current methods supports more than a subset of the following clinical requirements:
The ability to penetrate more than about 10 cm of tissue penetration depth (10 cm or greater, a limit for diagnostic US at frequencies of 7 MHz and up); and the ability to customize the depth of tissue at which release occurs.
Support for customizable US frequency ranges (KHz-MHz), for compatibility with existing medical US equipment, and to minimize invasiveness in tissue. For example, cavitation-based methods are typically most effective in the KHz range using High-Intensity Focused Ultrasound (HIFU), while polymer degradation methods are more effective in the KHz range and polymer conformation change methods are practical in the MHz range (diagnostic US).
Support for gradual payload release over a controllable time period; alternatively, support for an on-off switchable release functionality (rather than a single release pulse). In contrast, methods relying on degradation of a uniform polymer encasing the payload are by design irreversible and lack a gradual release functionality. Similarly, none of the described methods reliably support repetitive stop-treat-go cycles, namely gradual regimented payload release in the pre-set location.
Second, none of the existing methods supports individual control of multiple payload carriers in the same tissue region (i.e., releasing payload selectively from only specific carriers out of many carriers located within the same region exposed to the US trigger).
It would therefore be desirable to have implantable devices and methods thereof, which overcome the above restrictions of the current capabilities. This goal is attained by embodiments of the present invention.
According to various embodiments of the present invention, there is provided an implantable payload carrier device with at least one resonant element having a predetermined resonance frequency at an ultrasound frequency, to implement:
customizable tissue penetration depths;
support for customizable US frequency ranges;
gradual and on/off switchable and regimented payload release capabilities;
individual control of multiple payload carriers in the same tissue region; and
methods for use of the above devices.
Certain embodiments of the present invention rely on ultrasound (“US”) for remote triggering and navigation of carriers implanted in living tissue. Other embodiments combine ultrasound with other external physical stimuli, non-limiting examples of which include: electromagnetic fields, phenomena, and effects; and thermodynamic phenomena and effects, including both temperature and pressure effects.
The terms “carrier device” and “carrier” herein denote any object that is implantable in biological tissue, and is capable of carrying and releasing a medical payload into the tissue. The term “medical payload”, or equivalently the term “payload” used in a medical context is understood herein to include any substance or material, a combination of several relevant therapeutic materials, diagnostics or a combination of therapeutic and diagnostics. In certain embodiments of the present invention, a fluid payload is used; the term “fluid” herein denotes that the payload readily yields to pressure and is capable of flowing. In certain embodiments of the present invention, a solid payload is used; the term “solid” herein denotes that the payload yields to internal or external stimuli and can be released in the form of discrete particles. The term “device” (with reference to a carrier) herein denotes a carrier which is fabricated by known manufacturing techniques, including, but not limited to, 3D printing, molding, casting, etching, lithography, thin-film technologies, deposition technologies, and the like. The term “particle” (with reference to a carrier) herein denotes a carrier of up to macromolecular scale.
In various embodiments of the present invention, carrier devices are miniaturized for implantation in biological tissues. The term “miniaturized” (with reference to a carrier) herein denotes a carrier of small size, including, but not limited to: carriers of millimeter to centimeter scale; carriers of micrometer (“micron”) scale, referred to as “carrier micro-devices”; carriers of nanometer scale (including hundreds of nanometers), referred to as “carrier nano-devices”; and carriers of macromolecular scale, referred to as “carrier particles”. Not only are the carriers themselves of the size scales as indicated above, but the carriers' individual components are also of comparable scale.
In one embodiment, this invention provides a carrier device for implanting in a region of biological tissue to release a medical payload in the tissue, the carrier device comprising:
a cavity for containing the medical payload, wherein the cavity has an internal pressure;
a resonant element having a predetermined resonance frequency, and arranged so that the resonant element, when resonating at the predetermined resonance frequency, increases the internal pressure of the cavity and causes the medical payload to be released from the cavity into the tissue;
wherein the predetermined resonance frequency is an ultrasound frequency.
In one embodiment, the cavity is sealed by a flexible seal, which opens when the internal pressure exceeds a predetermined threshold value. In one embodiment, the flexible seal closes when the internal pressure is below the predetermined threshold value. In one embodiment, the cavity has a small hole through which the medical payload diffuses when the internal pressure exceeds a predetermined threshold value. In one embodiment, the medical payload stops diffusing when the internal pressure falls below the predetermined threshold value. In one embodiment, the resonant element is the cavity. In one embodiment, the resonant element is a flexible cantilever inside the cavity. In one embodiment, the resonant element is a membrane inside the cavity.
In one embodiment, the device further comprising at least one flexible cantilever attached to the outside of the carrier device, wherein the at least one flexible cantilever has a predetermined propulsion resonance frequency, and arranged so that the external flexible cantilever, when resonating at the predetermined propulsion resonance frequency, propels the carrier device through the biological tissue, and wherein the predetermined propulsion resonance frequency is an ultrasound frequency.
In one embodiment, this invention provides a method for releasing a medical payload in biological tissue, the method comprising:
selecting a carrier device containing the medical payload for implant in the biological tissue, wherein the carrier device includes a resonant element for releasing the medical payload, wherein the resonant element has a predetermined release resonance frequency, and wherein the predetermined release resonance frequency is an ultrasound frequency;
implanting the carrier device in the biological tissue; and
pulsing of ultrasound at the predetermined release resonance frequency, to release the medical payload in the biological tissue.
In one embodiment, the method further comprising: repeating the pulsing of ultrasound at the predetermined release resonance frequency, to repeat releasing the medical payload in the biological tissue.
In one embodiment, the carrier device further includes a propulsion resonant element for propelling the carrier device, wherein the propulsion resonant element has a predetermined propulsion resonance frequency, and wherein the predetermined propulsion resonance frequency is an ultrasound frequency, and where the predetermined propulsion resonance frequency is not the same as the predetermined release resonance frequency, the method further comprising: pulsing of ultrasound at the predetermined propulsion resonance frequency, to propel the carrier device through the biological tissue.
The subject matter disclosed may best be understood by reference to the following detailed description when read with the accompanying drawings in which:
For simplicity and clarity of illustration, elements shown in the figures are not necessarily drawn to scale, and the dimensions of some elements may be exaggerated relative to other elements. In addition, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.
Various embodiments of the present invention provide a carrier device containing a resonant element which actuates release of the carrier's payload. The term “resonant element” herein denotes any component or part of the carrier device which vibrates in response to physical stimuli and has a specific predetermined resonant frequency. Vibrational energy from a physical stimulus at or near the resonant frequency accumulates in the resonant element, which causes the amplitude of the vibrations to increase significantly at the resonant frequency. Physical stimulus that is not at or near the resonance frequency, however, does not accumulate in the resonant element, and thus the resonant element's response at or near the resonant frequency is an important characteristic of the resonant element. According to certain embodiments of the present invention, the resonance frequency of a resonant element of a carrier is referred to as the resonance frequency of the carrier itself.
According to these embodiments, the increased amplitude of vibration of the resonant element cause an increase in pressure of the payload, particularly in the case of a fluid payload, and the increased pressure in turn causes release of the payload from the carrier. Furthermore, according to these embodiments, the resonant frequency of the resonant element is predetermined to be in the range of ultrasound, so that the remote triggering of a particular carrier device to release the payload is accomplished by sending pulses of ultrasound tuned to the resonant frequency of the carrier device's resonant element.
In some embodiments of the present invention, a carrier device and its component parts are miniaturized. According to some embodiments, the diameter or actual length of the overall device is selected from: between 100 and 5,000 micrometers, between 10 and 100 micrometers, between 1 and 10 micrometers, between 200 and 1,000 nanometers, and any combination thereof. According to some embodiments, the diameter or actual length of the overall device is from 200 nanometers up to 5,000 micrometers.
In some embodiments of the present invention, a carrier device comprises a shape selected from elongated, axisymmetric, centrosymmetric, chiral, random and a combination thereof. In some embodiments of the present invention, a resonant element comprises a configuration selected from an elongated shape, a film, a wire, a string, a strip, a sheet, a plug, a membrane, flagellum, coil, helix, arm, joint and a combination thereof.
Following are detailed descriptions of some non-limiting embodiments, with reference to drawings thereof.
The embodiments shown in the above-referenced drawings and descriptions are non-limiting; other ultrasound-sensitive configurations are also possible in keeping with the present invention. In particular, one or more flexible mechanical components of different shapes and materials may be located at different positions inside the cavity relying on the principles describe above to achieve the effect of payload release.
According to embodiments of the present invention, the flexible mechanical components can be made of a variety of flexible materials, such as the polymer PET. Representative methods of fabrication include but are not limited to: template-assisted synthesis, as exemplified by direct or vertical laser writing; photolithographic etching and spinning techniques.
As a non-limiting example of a PET cantilever, choose the length to be 90 microns, the width and thickness to be 30 microns. With a Young modulus of 2×109/m2 and a density of 1.4 g/cm2, the resonant frequency is approximately 200 KHz (utilizing standard formulas for cantilever mechanical resonance orthogonal to cantilever length dimension). Appropriate adjustments of the geometrical parameters and material choice allow changing the resonant frequency by a factor of 100 or more, either up or down, easily covering the range of KHz to MHz as needed, which covers the frequency range of typical ultrasound pulses.
The selected resonance frequency F determines the possible penetration depth, and also enables the individual control of several carriers in a single region. As noted in the figures and in the corresponding descriptions above, each carrier can have a different resonant frequency, thus allowing individual activation of a single carrier by US pulses at specific frequencies.
While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
This application claims benefit of U.S. Provisional Patent Application Ser. No. 62/512,091, filed May 29, 2017, the priority date of which is hereby claimed.
Filing Document | Filing Date | Country | Kind |
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PCT/US2018/030949 | 5/3/2018 | WO | 00 |
Number | Date | Country | |
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62512091 | May 2017 | US |