Patent Application
20240108864
The present disclosure relates generally to drug coated medical devices such as drug coated balloon catheters and optical imaging such as OCT, fluoresce, IVUS, and the like, and methods of diagnosis and treatment using drug coated medical devices and optical imaging.
Although introduction of drug-eluting stent (DES) in coronary artery disease improved the rate of in-stent restenosis compared to that when using bare metal stent (BMS), it is still occurs in 3 to 20% of patients and remains to be an issue after treatment. (Dangas et al., JACC, 2010; 56(23):1897-907) In DAEDALUS study, drug-coated balloon (DCB) showed its effectiveness and safety for in-stent restenosis in bare metal stent, while it showed its safety but not effectiveness for in-stent restenosis in drug eluting stent. (Giacoppo, et al., JACC, 2020; 75(21): 2664-2678)
Drug coating balloons have been developed as treatment options for cardiovascular disease, other peripheral artery diseases, and diseases involving non-vascular lumens such as, for example, asthma, chronic obstructive pulmonary disease (COPD), prostate cancer, benign prostatic hyperplasia and strictures in the urethra, esophagus, or sinus. Drug coated balloon catheters include those describe in U.S. Pat. No. 10,058,636 (catheter coated with Paclitaxel), U.S. Pat. No. 9,295,663 (catheter with Sirolimus), U.S. Pat. No. 10,668,188 (catheter with anti-inflammatory or anti-proliferative agents), and U.S. Pat. No. 10,987,451 (catheter coated with Paclitaxel).
There is a need to confirm whether effective transfer of drug from balloon surface to the vessel has occurred or not. There has been a concern of flaking of coating from balloon, which has been a major concern as the risk of thrombus. The drug coating lost in transit to vessel is a problem with DCB where 10% of drug may be lost before the target lesion is reached and 10% remain on the balloon after withdrawal. (Speck, U et al., Cardiovasc Intervent Radiol. 2018 October; 41(10):1599-1610.)
The method available to confirm proper treatment procedure of drug coated balloon has been to see if the balloon has dilated the stenosis lesion properly. This can be done by viewing the region using angiography, IVUS, and/or OCT or by confirming either the blood flow or physical opening of the vessel using FFR or angiography. However, each of these are useful for determining vessel dilation, not drug transfer. Accordingly, it would be desirable to provide a method for confirming the success or amount of drug transferred when using a drug coated balloon procedure.
Accordingly, it is an object of the present disclosure to provide medical devices and methods of use. In some embodiments, the medical device comprises an elongated tube; a balloon disposed over the elongate tube having at least one drug and at least one fluorescent agent on an outer surface of the balloon; an optical probe at the distal end of the elongate tube comprising an optical fiber configured to guide illumination light coming from a light source and an optical member configured for fluorescence imaging; and one or more detectors configured for fluorescence detection.
In some embodiments, the medical device comprises an elongated tube; a balloon disposed over the elongate tube having at least one drug and at least one fluorescent agent on an outer surface of the balloon; a probe at the distal end of the elongate tube, a first detector configured for fluorescence detection; and a second detector configured for detection of the structural imaging or physiological sensing. The probe of this embodiment is configured for fluorescence imaging, and for structural imaging or physiological sensing.
Methods of analysis using these medical devices are also contemplated. One such method comprises: inserting a catheter comprising an optical probe and a drug-coated balloon into a lumen, wherein the optical probe comprises an optical fiber configured to guide illumination light coming from a light source and an optical member configured for fluorescence imaging; and wherein the drug-coated balloon has a drug and a fluorescent agent on the outer surface of the balloon; expanding the drug-coated balloon in a region of the lumen to create a drug-transfer region of the lumen; detecting a fluorescence signal from the fluorescent agent in the drug-transfer region with the optical probe; correlating the fluorescence signal with a concentration of the drug transferred from the drug-coated balloon; and displaying information based on the concentration of the transferred drug.
In some of the medical devices and/or methods as described above, the structural imaging is optical coherence tomography (OCT) imaging or intravascular ultrasound (IVUS) imaging and/or the physiological sensing is fractional flow reserve FFR) and the second detector is configured for detecting pressure.
In some embodiments, the method provides for imaging at least a portion of the drug-transfer region of the lumen with the optical probe to obtain an image; and confirming or verifying dilation of the lumen and/or transfer of drug in the drug-transfer region with the image. The correlation of the fluorescence signal with a concentration of the drug may be uses a correlation factor obtained from ex vivo studies.
In some embodiments, the information based on the concentration of the transferred drug is information that compares the concentration of the drug transferred to a dose of the drug known to be sufficient for a treatment.
Further features of the present disclosure will in part be understandable and will in part be apparent from the following description and with reference to the attached drawings.
For the purposes of illustrating various aspects of the disclosure, wherein like numerals indicate like elements, there are shown in the drawings simplified forms that may be employed, it being understood, however, that the disclosure is not limited by or to the precise arrangements and instrumentalities shown. To assist those of ordinary skill in the relevant art in making and using the subject matter hereof, reference is made to the appended drawings and figures, wherein:
There are a number of balloon catheters for the expansion of a lumen and drug delivery on the market and in research. Any suitable balloon catheter to one of ordinary skill in the art may be used. The balloon catheter may include an inflatable balloon at the distal end of the catheter.
The drug is any therapeutic agent that may be administered by use of a balloon catheter. The drug may be an agent for the prevention and/or treatment of stenosis such as Sirolimus or Paclitaxel. More broadly, the drug may be therapeutic agent for prophylaxis or treatment of a vascular or nonvascular body lumen, such as with an anti-inflammatory or anti-proliferative drug. Additional additives for drug affinity, solvation agents, oils, lipids, etc. may also be included with the drug. An exemplary list of drugs is provided, for example, in U.S. Pat. No. 10,668,188.
The coating may also contain one or more excipients or carriers. An excipient may be preferentially added to aid in the transfer of the drug from the surface of the balloon to the tissue. The carrier can be selected for the speed and concentration of drug delivery from the balloon to the tissue in the lumen. Excipients, such as bio-degradable polymers, urea, and shellac into or onto which the drug is embedded can be used to optimize the release kinetics of the drug into the arterial tissue. Concentration of drug delivery may mean how much of drug is transferred to a unit area or the drug dose transferred to a predetermined area of the inner lumen where the balloon expands and touches.
The fluorescent agent 114 is any compound that fluoresces and is biocompatible. The terms dye, fluorescence dye, and fluorophore may be used instead of fluorescent agent. Examples of fluorescent agents are the Cy dyes, Alexa Fluor dyes, methylene blue and indocyanine green (ICG). There have been studies of uses of fluorescent agents for characterization of vessel tissue and one or more of these dyes are used. Some of the useful dyes include the following:
In some embodiments, the drug and fluorescent agent are co-encapsulated into a liposome, nanoparticle, or other moiety for controlled delivery. For example, sirolimus (rapamycin) and indocyanine green (ICG) were co-encapsulated into folate targeted thermosensitive liposomes. This was used to enhance tumor therapeutic and diagnostic functions. (See, for example, Pang X, Wang J, Tan X, et al. ACS Appl Mater Interfaces. 2016; 8:13819-13829.
In other embodiments, the drug and fluorescent agent are linked together through a linker, such a small molecule or peptide or a cleavable linker such as a self-immolative linker or a peptide-enabled linker. This enhances the effectiveness of the fluorescent agent as an indicator of drug transfer to the tissue since a proportional amount of dye is in contact with the drug moiety. (See, for Example, Lang et al., Journal of Pharmaceutical Analysis 10 (2020) 434-443). There are various drug-dye conjugates that may be used in conjunction with the present invention. Additionally, known conjugation chemistry may be adapted from some therapeutic modalities to accommodate the drug moieties used with balloon delivery.
In yet other embodiments the fluorescent agent may be included as part of a quenched complex, where two dyes are linked in such proximity that the fluorescence from them is quenched until they are separated (such as by an enzymatic cleavage in the region of interest).
The coating may be a direct coating on the balloon material. For example, the drug and dye may be dissolved in a carrier that is drop coated or dip coated onto the balloon surface and the carrier allowed to evaporate. The coating may be coating on a highly elastic wrap that is placed around the balloon (See, for example, Torsten, H, et al., European Cardiology 2010:6(4):40-4.)
Preferably, the coating will coat the balloon substantially evenly over the surface of the balloon that comes in contact with tissue upon inflation. As used herein, the term “substantially” is meant to allow for deviations from the descriptor that do not negatively affect the intended purpose.
The balloon catheter above contemplates the balloon inflation and drug delivery aspect of the present invention. An imaging catheter, either as a separate catheter or combined with the balloon, is also used in the present invention.
Imaging catheters and endoscopes have been developed to access to internal organs. In order to acquire cross-sectional images of tubes and cavities such as vessels, esophagus and nasal cavity, the imaging probe can be rotated in the lumen. In addition, the imaging probe can be simultaneously translated longitudinally during the rotation so that helical scanning pattern images are obtained and information along a longitudinal portion of the lumen is obtained. This translation is most commonly performed by pulling probe back towards proximal end and therefore referred to as a pullback.
In one or more embodiments, the optical probe (e.g., the probe 228 of the catheter 220) may comprise or include an optical fiber connector, an optical fiber, and an optical member disposed at or near the distal end of the optical probe. The optical member may be a lens. The optical fiber operates to deliver light to the distal lens. The distal lens operates to shape the optical beam and to illuminate light to the lumen and to collect light from the lumen efficiently. The double clad fiber may be used to transmit and/or collect OCT light through the core and to collect Raman and/or fluorescence light from sample (e.g., lumen or tissue) through the clad. The lens may be used for focusing and collecting light to and/or from the sample (e.g., lumen or tissue). The scattered light through the clad may be relatively higher than that through the core in a case or instance where a size of the core is smaller or much smaller than a size of the clad.
For optical coherence tomography (OCT) subsystem, the light source 332 operates to produce a light to the splitter 338, which splits the light from the light source 332 into a reference beam passing into the reference arm 334 and a sample beam passing into the sample arm 336. The beam splitter 338 is positioned or disposed at an angle to the reference mirror 340, the one or more detectors 342 and to the sample 348. The reference beam optionally goes through the phase shift unit 344 (when included in a system, as shown in the system 300), and the reference beam is reflected from the reference mirror 340 in the reference arm 3342 while the sample beam is reflected or scattered from a sample 348 through the PIU (patient interface unit) 346 and the catheter 320 and/or 330 in the sample arm 103. Both of the reference and sample beams combine (or recombine) at the splitter 338 and generate interference patterns. The output of the system 300 and/or the interferometer thereof is continuously acquired with the one or more detectors 342, e.g., such as, but not limited to, photodiodes or multi-array cameras. The one or more detectors 342 measure the interference or interference patterns between the two radiation or light beams that are combined or recombined. In one or more embodiments, the reference and sample beams have traveled different optical path lengths such that a fringe effect is created and is measurable by the one or more detectors 342. Electrical analog signals obtained from the output of the system 300 and/or the interferometer thereof are converted to digital signals to be analyzed with a computer, such as, but not limited to, the computer 350 (shown in FIG. S, respectively, discussed further below). The one or more detectors 342 measures visible and/or infrared light that is a fluorescence signal form the tissue. Optical filters may be used in the detector to detect the specified emission wavelength range for the fluorescent agent(s) 114 selected.
The light source 332 may include a plurality of light sources or may be a single light source. In one or more embodiments, the light source 332 may be a radiation source or a broadband light source that radiates in a broad band of wavelengths. In one or more embodiments, a Fourier analyzer including software and electronics may be used to convert the electrical analog signals into an optical spectrum. The light source 332 may include one or more of a laser, an organic Light-Emitting Diode (OLED), a Light-Emitting Diode (LED), a halogen lamp, an incandescent lamp, supercontinuum light source pumped by a laser, and/or a fluorescent lamp. The light source 332 may be fiber coupled or may be free space coupled to the other components of the system or systems discussed herein, such as, but not limited to, the system 300 or any other system discussed herein, etc.
In one or more embodiments, one of the one or more light sources 332 is an excitation light with a wavelength (e.g., any predetermined wavelength visible to infrared (IR)), for example, 0.633 um from a light source 332 and may be delivered to the tissue to through the catheter 320. The fluorescence light may be collected with the catheter (e.g., the catheter 320 of
In one or more embodiments, the one or more detectors 342 of the OCT sub-system may send the signal(s) to a computer system 350. This computer system 350 may include one or more data acquisition unit(s) or processor(s).
In
DCB with Fluorescent Material in the Coating
After the OCT/Fluorescence pullback step 506, the collected light is analyzed on the system. OCT light signal is processed as OCT data and the system displays the structural state of the vessel, showing the diameter of the vessel at the location of the procedure. The coated balloon was removed in previous step 504. Thus, the only fluorescence agent remaining in the vessel are the natural auto fluorescent material(s) in the vessel wall or the fluorescence agent included in the balloon coating and transferred to the vessel wall.
The fluorescence data is processed and information is displayed to the user. The process may include the distance correction of fluorescence value based on distance from the catheter to the wall from OCT data, as the fluorescence value is dependent on the distance from the source of fluorescence. The fluorescence data may be compared or compensated with correlation factor(s). One way to determine the correlation factor is using a predetermined fluorescence value from, for example, a lookup table that is used to correlate the in vivo fluorescence intensity with concentration of the fluorophore on the vessel wall. In other embodiments, experiments and measurement are performed to determine the coefficient of fluorescence measured with respect to the pressure of the pressing the drug coated material to the tissue. This experiment may be done with optimal drug and fluorescent agent concentration on the material to match the actual drug coated device. Alternatively, there is a separate experiment to measure the fluorescence intensity per given drug concentration with the fluorescence agent already pre-mixed. For example, in the case of the conjugate of fluorescent agent and drug, the fluorescent intensity versus the drug conjugate concentration may be measured. This data may, in turn, be correlated with the drug concentration transferred from the balloon to the vessel wall since the amount of fluorophore transferred from the balloon coating to the vessel wall is proportional to the transfer amount of the drug. Such information may be derived, for example, from an ex vivo study of drug transfer to a lumen or a mouse model of drug concentrations. While this embodiment is demonstrated with OCT, in some other embodiments, fluorescence but no OCT data is obtained during the pullback. The drug transfer can be determined using the fluorescence of the added fluorophore transferred off the balloon, the addition of OCT is useful for the information it provides regarding the physical characteristics of the vessel and is not necessary for determining drug transfer.
DCB Catheter with MMOCT Function
Spin without Pullback
While the embodiment described in
Another embodiment of the present invention uses IVUS for vessel imaging. As discussed above, IVUS can be used as the structural imaging modality in place of OCT for dilation confirmation after the procedure. On the probe 630 as shown in
Another embodiment of the present invention uses fractional flow reserve (FFR) for vessel dilatation confirmation by pressure measurement. The two pressure sensors are located distal and proximal to the balloon on the main balloon catheter and the pressure drop across the stenosis is measured before and after the balloon procedure. When the pressure drop across the stenosis is larger than 20%, the stenosis needs to be dilated and it is necessary to measure the pressure drop is decreased to confirm the success of balloon expansion after the procedure. (See George J. et al., Curr Cardiol Rev. 2015 August; 11(3): 209-219.)
Vascular tissue which has damages, inflammations, or disease shows auto-fluorescence, without any external fluorophores added. (See Hongki Yoo, et al. Nature Medicine volume 17, pages 1680-1684 (2011)). Thus, this information can be combined with the fluorescence signals as provided herein to include information about both the inflammatory or disease properties of the tissue and the transfer of drug to the same or similar tissue location. See, for example, U.S. Pat. Pub. 10,912,462, 10,952,616, 11,147,453, 10,674,985, and U.S. Pat. Pub. 2021/0407098. Thus, in some embodiments, two different fluorescence signals are separated based on spectra or wavelength range. The fluorescence tissue characterization based on auto fluorescence is done, for example, using 635 nm as excitation light and emitted light with a range between 650 and 900 nm as detected fluorescence. Alternative wavelength such as 780 nm may be used for excitation wavelengths of autofluorescense and 800 to 950 nm may be used for detection. A shorter wavelength range may be used for the fluorescence detection of drug coating transfer confirmation, using one of the combinations of the excitation and emission wavelength shown, for example, in Table 1 shown above. A laser with a wavelength close to the excitation wavelength is chosen and the band pass filter or similar component for the detection near the emission wavelength is used. The laser light of the fluorescent modality for excitation and emission is combined, separated and filtered in the optical combiner/beamsplitter in the PIU. The concentration of the dye in the coating may be adjusted for optimal detection with the bandwidth of the detection filter and the sensitivity of the detector. The two separate signals of fluorescence are used as drug transfer information (the shorter wavelengths) and as tissue characterization (the longer wavelengths for autofluorescense).
In the workflow of
In the workflow of
Unless otherwise discussed herein, like numerals indicate like elements. For example, while variations or differences exist between the systems/apparatuses, such as, but not limited to, the system 300, or the systems, catheters, and workflows provided herein. etc. (e.g., differences between the position(s) of the reference reflection 310 (and/or reference arm 304) depending on the OCT and/or fluorescence system or method being used), one or more features thereof may be the same or similar to each other, such as, but not limited to, the light source 302, the various catheters (310, 320, 330, 410, 630) or other component(s) thereof (e.g., the computer 350, etc.). Those skilled in the art will appreciate that the light source 302, the at least one detector 314 and/or one or more other elements of the system 300, may operate in the same or similar fashion to those like-numbered elements of one or more other systems. Those skilled in the art will appreciate that alternative embodiments of the system 300, the catheters, etc. and/or one or more like-numbered elements of one of such systems, while having other variations as discussed herein, may operate in the same or similar fashion to the like-numbered elements of any of the other systems (or component(s) thereof) discussed herein.
As aforementioned, hardware structure of an embodiment of a computer or console 1200 is shown in
The monitor or display 1209 displays the reconstructed image, and may display other information about the imaging condition or about an object to be imaged. The monitor 1209 also provides a graphical user interface for a user to operate a system for example when performing OCT, fluorescence, or other imaging technique(s) or performing an operation of the balloon. An operation signal is input from the operation unit (e.g., such as, but not limited to, a mouse device 1211, a keyboard 1210, a touch panel device, etc.) into the operation interface 1214 in the computer 1200, and corresponding to the operation signal the computer 1200 instructs the system to set or change the imaging condition, and to start or end the imaging. The light source 101 of an OCT sub-system and/or the light source 101 of a fluorescence sub-system as aforementioned may have interfaces to communicate with the computers 1200 to send and receive the status information and the control signals.
The present disclosure and/or one or more components of devices, systems and storage mediums, and/or methods, thereof also may be used in conjunction with various imaging probes. Such probes include, but are not limited to, the OCT imaging systems disclosed in U.S. Pat. Nos. 7,872,759; 8,289,522; and U.S. Pat. No. 8,928,889 to Tearney et al. and arrangements and methods of facilitating photoluminescence imaging, such as those disclosed in U.S. Pat. No. 7,889,348 to Tearney et al., as well as the disclosures directed to OCT and multimodality imaging disclosed in U.S. Pat. No. 9,332,942 and U.S. Patent Publication Nos. 2010/0092389, 2012/0101374, 2016/0228097, as well as in U.S. Pat. Nos. 10,578,422; 10,323,926; 10,558,001; 10,606,064; 10,674,985; 10,743,749; 10,782,117; 10,884,199; 10,895,692; 10,952,616; 11,147,453; and 11,175,126 and in U.S. Patent Publication Nos. 2019/0254506 2019/0313975; 2020/0126195; 2020/0256661; 2020/0345440; 2022-0040454; 2022-0042781; and 2022-0044428 each of which patents, patent publications and patent application(s) are incorporated by reference herein in their entireties.
Although the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure (and are not limited thereto). It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present disclosure. The scope of the following claims is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures and functions.
