System and method for improved heart perfusion

Abstract

Provided is a system and method for improving ex vivo heart perfusion in a working mode or a resting mode configuration and for improving in vivo heart perfusion. The system can reduce myocardial energy consumption in a working mode configuration by unloading the perfusate in the left ventricle using a left ventricular assist pump (LVAD) that is synchronized with cardiac function of a heart. Disclosed methods achieve or simulate physiological coronary perfusion in a resting mode configuration, without perfusing the left ventricle, by artificially generating aortic pressure that may be synchronized with cardiac function.

Description

SYSTEM AND METHOD FOR IMPROVED HEART PERFUSIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application Serial No. 63 / 613,942 filed December 22, 2023, the contents of which are incorporated by reference.TECHNICAL FIELD

[0002] The present disclosure relates to organ preservation devices, ventricular assist devices, artificial hearts, artificial heart lungs, and extracorporeal membrane oxygenation devices.

[0003] More particularly, the disclosure relates to systems and methods of heart perfusion and related techniques including ex vivo heart perfusion and related techniques and in vivo heart perfusion and related techniques.BACKGROUND

[0004] Conventionally, progress and developments have been made for devices and methods for assisting the function of the heart. Representative examples of those developments and progress are found in ex vivo heart perfusion (EVHP) as well as in vivo heart perfusion.

[0005] Ex vivo heart perfusion (EVHP) may be used to maintain a heart in a functioning state while outside of a body such as for heart transplants, heart preservation, or research. This can be accomplished using specialized systems that simulate real physiological conditions of the heart. As discussed herein, ex vivo refers to instances in which the heart is located outside of the body. In vivo refers to instances in which the heart is located inside of the body.

[0006] Conventional techniques for EVHP may include placing the heart into various “modes” for preservation or research purposes while the heart is outside of a body. For instance, in a “resting mode,” a heart may be placed into a state in which the heart does not actively pump blood though the left atrium and left ventricle as it would while functioning normally in vivo. Instead, while in a conventional resting mode, the coronary arteries are perfused, through the aorta, with an oxygenated solution, such as blood or another preservation fluid, under low pressure. This helps to ensure that the heart is preserved in a metabolically low-demand state, which can be desirable when transporting or storing the heart ex vivo for extended periods of time.

[0007] A “working mode” may refer to a mode in which the heart is actively pumping blood or other fluid such as perfusate through left ventricle as it would in vivo. This mode allows for functional evaluation of the heart. For instance, this mode may allow medical professionals to assess cardiac function, such as heart rate, stroke volume, contractility, and various other parameters of the heart ex vivo. These tests may help to determine or predict a heart’s ability to function in vivo, which can be critical for evaluating a heart for a possible transplant. Sustaining a heart ex vivo in a conventional working mode can cause increased myocardial energy consumption due to increased cardiac workload. Increased myocardial energy consumption of a heart ex vivo may lead to shorter preservation times and overall undesirable results.

[0008] Therefore, it can be desirable to improve conventional ex vivo heart perfusion techniques, including functionality, efficiency, or preservation rate associated with conventional resting mode and working mode techniques.BRIEF SUMMARY

[0009] According to a first aspect, an ex vivo heart perfusion system includes an organ chamber configured to hold an ex vivo heart and a liquid perfusate, wherein the heart is cannulated at least at the aorta, the left atrium, and the left ventricle, to facilitate perfusion of the heart, a membrane oxygenator configured to oxygenate the perfusate. The system also includes a reservoir located beneath the organ chamber to receive a portion of the perfusate from the organ chamber, an afterload pump configured to receive a portion of perfusate from an output of the reservoir and to pump the portion of the perfusate from the reservoir to the membrane oxygenator, a preload pump configured to receive a second portion of perfusate from the output of the reservoir and to pump the second portion of perfusate from the reservoir to the left atrium to perfuse the left atrium, and a left ventricular assist device (LVAD) pump configured to pump a portion of perfusate from the left ventricle to a location along an aortic outflow path.

[0010] According to a second aspect, disclosed is a method of performing ex vivo heart perfusion (EVHP) with an EVHP system. The method includes perfusing a left atrium of a heart with a volume of a perfusate, operating an afterload pump to draw a first portion of the perfusate from an organ chamber, wherein the organ chamber is configured to support the heart and collect at least a portion of the perfusate flowing from the heart, operating an oxygenator to oxygenate the perfusate flowing from the afterload pump, wherein the oxygenated perfusate is recirculated throughout acircuit to perfuse the heart, and operating an LVAD pump to draw at least a portion of perfusate from a left ventricle of the heart.

[0011] According to another aspect, an ex vivo heart perfusion system may include an organ chamber configured to hold an ex vivo heart and a liquid perfusate, wherein the heart is cannulated at least at the aorta, to facilitate perfusion of the coronary arteries of the heart, a membrane oxygenator configured to oxygenate the perfusate, a reservoir located beneath the organ chamber to receive a portion of the perfusate from the organ chamber, an afterload pump configured to receive a portion of perfusate from an output of the reservoir and to pump the portion of the perfusate from the reservoir to the membrane oxygenator, and a preload pump configured to receive a second portion of perfusate from the output of the reservoir and to pump the second portion of perfusate from the reservoir to the aorta to facilitate perfusion of the coronary arteries of the heart, wherein the preload pump is configured to simulate physiological coronary perfusion by synchronizing the operating of the preload pump with at least one physiological function of the heart.

[0012] In other aspects, the system may further comprise an LVAD pump for simulating physiological coronary perfusion by synchronizing the operating of the LVAD pump with at least one physiological function of the heart.

[0013] Yet in further aspects, an in vivo heart perfusion system includes a left ventricular assist device (LVAD) pump configured to pump a portion of perfusate from a left ventricle cannula to a location along an aortic outflow path, at least one sensor including a left ventricular pressure monitoring sensor having a left ventricular pressure monitoring line, and a processor comprising machine-readable instructions, wherein when executed by the processor, the machine-readable instructions are configured to: transmit the ON command to the LVAD pump upon determining that the left ventricular pressure has reached a trigger value, the LVAD pump is operated in the first state for the first length of time.

[0014] In other aspects, the in vivo or ex vivo heart perfusion systems may utilize any physiological function of the heart to operate or synchronize the LVAD pump. In certain embodiments, a physiological function may be left ventricular pressure, ECG, peripheral arterial pressure, pulse oximeter waveforms, or any other waveform information associated with heart.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 illustrates a schematic diagram of an ex vivo heart perforation system configured to operate using a conventional resting mode technique.

[0016] FIG. 2 illustrates a schematic diagram of an ex vivo heart perforation system configured to operate using a conventional working mode technique.

[0017] FIG. 3 illustrates a schematic diagram of an exemplary ex vivo heart perforation system according to a first embodiment.

[0018] FIG. 4 illustrates a close up cut-away view of various cannulated portions of the heart, including a left ventricle unloading root.

[0019] FIG. 5 illustrates a schematic diagram of the ex vivo heart perforation system of FIG. 3 configured to operate in an exemplary LVAD mode.

[0020] FIG. 6 is a graphical illustration diagramming the behavior of selected operative parameters during specific stages of an example implementation of the ex vivo heart perforation system of FIG. 3, configured to operate in an exemplary LVAD mode.

[0021] FIG. 7 is an exemplary logic diagram according to an implementation of the ex vivo heart perforation system of FIG. 3, configured to operate in an exemplary LVAD mode.

[0022] FIG. 8 illustrates a schematic diagram of the ex vivo heart perforation system of FIG. 3 configured to operate in an exemplary modified resting mode, according to a first embodiment.

[0023] FIG. 9 illustrates a schematic diagram of the ex vivo heart perforation system of FIG. 3 configured to operate in an exemplary modified resting mode, according to a second embodiment.

[0024] FIG. 10 illustrates another schematic diagram of an exemplary ex vivo heart perforation system.

[0025] Fig. 11 illustrates a schematic diagram of an exemplary in vivo heart perforation system according to a third embodiment.DETAILED DESCRIPTION

[0026] Donor hearts must be preserved ex vivo prior to transplant into a recipient. A common method for ex vivo preservation of donor hearts for a heart transplant is static cold storage, in which a heart’s coronary arteries are filled with myocardial protection fluid and stored in an ice box. When preserving a donor heart with cold storage techniques, the time limit for a safe heart transplant can be at little as four hours. Because of this, improved storage and preservation methodsare required for extended preservation of a heart ex vivo. There is also a need to establish accurate methods of testing ex vivo cardiac function prior to transplanting a donor heart into a recipient.

[0027] Ex vivo heart perfusion (EVHP) may be used for improved preservation and evaluation of donor hearts in cardiac transplantation medicine. Typically, to accomplish EVHP, a harvested heart (or a donor heart) is separated from the lungs at the left atrial position, leaving the left atrial area open. Conventional techniques used for performing EVHP include configurations for resting mode and working mode.

[0028] As discussed above, conventional resting mode configurations may reduce myocardial energy consumption compared to conventional working mode configurations. But because there is no left atrial inflow in a resting mode configuration, the aortic pressure waveform is not generated by the heart, and thus coronary perfusion in conjunction with the aortic pressure waveform is not achieved as it is in vivo. This too may also affect the preservation of cardiac function of a heart ex vivo. In a resting mode, lactate levels may be utilized as a metabolic marker for graft quality. However, the utility of lactate might be limited based on its relatively low sensitivity, especially for hearts donated after circulatory death. Thus, to overcome these limitations, the working mode was developed. Nonetheless, there may still be some drawbacks associated with the conventional working mode.

[0029] In a working mode configuration, the left atrium is perfused, which may simulate normal cardiac function. Namely, perfusate is provided to the left side of the heart, allowing mechanical assessment of left heart function during EVHP. Most conventional working mode systems utilize a two-chamber working mode in which perfusate is provided to the left atrium (LA) and ejected from the left ventricle (LV). Some studies suggest that EVHP in a working mode may result in better functional preservation of the heart as well as a lower rate of apoptosis compared to the resting mode. Additionally or conversely, perfusing a heart in working mode may compromise preservation rates by shortening the amount of time the heart can be preserved ex vivo due at least in part to the increased myocardial energy consumption compared to resting mode. Therefore, for at least these reasons, it may be desired to improve the conventional resting and working modes.

[0030] The embodiments described herein improve ex vivo heart perfusion (EVHP). For instance, the present disclosure provides systems and methods in which myocardial energy consumption may be decreased in a working mode configuration. The disclosure also provides systems and methods in which physiological coronary perfusion can be achieved in a resting modeconfiguration. In other words, the present disclosure relates to improvements of both conventional resting mode and working mode configurations for ex vivo heart perforation techniques.

[0031] For instance, embodiments disclosed herein may reduce myocardial energy consumption in a working mode configuration. To accomplish this, the disclosed techniques may improve or assist cardiac contraction by unloading perfusate from the left ventricle at the start of systole using a left ventricular assist pump (LVAD), thereby reducing myocardial energy consumption from preloading. This technique may be referred to herein as “LVAD mode.”

[0032] Moreover, it is understood that conventional resting mode techniques (such as the Langendorff perfusion technique) do not cause cardiac output because there is no inflow of blood or perfusate into the left atrium. Therefore, physiological aortic pressure does not occur, and the associated perfusion to the coronary arteries is also non-physiological. This may be undesirable. Provided herein are systems and methods in which physiological coronary perfusion in a resting mode configuration can be achieved. In an embodiment, physiological coronary perfusion is achieved without perfusing the left ventricle by providing a system that artificially generates aortic pressure that may be synchronized with a heartbeat or other cardiac function of a heart. This may be achieved in the absence of cardiac output, thereby enhancing the effect of preserving mechanical cardiac function. Those skilled in the art will readily appreciate the advantages that may be achieved using the improved methods disclosed herein.

[0033] FIG. 1 illustrates a system 100 in which an ex vivo heart 10 is perfused using a conventional resting mode configuration. The system 100 includes an ex vivo heart 10, an afterload pump 102, an oxygenator 104 such as a membrane oxygenator, and an organ chamber 106 to capture a perfusate liquid 108. The heart 10 may be cannulated at least at the aorta using an aortic cannula 12. The system 100 can further include various fluid transport lines 110, 112, 114 configured to transport a volume of perfusate 108 throughout the system 100. The arrows illustrate an exemplary direction of flow for the perfusate 108 throughout the system 100 when operating in a conventional resting mode configuration.

[0034] As discussed, when operating according to a conventional resting mode, the coronary arteries of the heart 10 are perfused with the perfusate 108, through the aorta at the cannula 12. The perfusate 108 may be pumped from the afterload pump 102 to the oxygenator 104 via line 114. From the oxygenator 104, the perfusate 108 can travel through the line 110 into the aorta of the heart 10 via the cannula 12. The perfusate 108 may be pumped at a low pressure such that theperfusate 108 enters the aorta and travels to the coronary arteries of the heart 10. This helps to ensure that the heart 10 is preserved in a metabolically low-demand state, which can be desirable when transporting or storing the heart 10 ex vivo. Note, however, that physiological aortic pressure does not occur in this embodiment, and the associated perfusion to the coronary arteries is also non-physiological in the sense that perfusate flows counter-current to the normal blood flow through the heart operating in a working mode, such as in vivo.

[0035] The organ chamber 106 may hold the heart 10 and may further collect perfusate 108 flowing from the heart 10. In the current example for the resting mode configuration, perfusate 108 may enter the coronary arteries of the heart 10. When the perfusate 108 exits the heart 10, it may collect in the organ chamber 106 and may then exit the organ chamber 106 via the line 112 where it may enter the afterload pump 102.

[0036] The afterload pump 102 may be designed to simulate the resistance a heart encounters when pumping blood into systemic circulation. The afterload pump 102 can create controlled pressure or resistance downstream of the heart 10, effectively mimicking physiological conditions of a vascular system (e.g., afterload conditions). Moreover, the afterload pump 102 may circulate blood or perfusate 108 from the organ chamber 106 to the oxygenator 104 and / or further along the EVHP system 100.

[0037] The oxygenator 104 oxygenates the perfusate 108 so that it can effectively perfuse the heart muscle. In working modes discussed below, the oxygenator 104 can serve as an effective artificial lung oxygenating the perfusate during a physiologic flow of the perfusate that simulates an operative heart in vivo. The oxygenator can be a membrane oxygenator that facilitates the exchange of oxygen and carbon dioxide by passing deoxygenated blood or perfusate 108 through a semi-permeable membrane, where oxygen diffuses into the perfusate while carbon dioxide is removed. It may also add heat to the perfusate 108 to simulate normal temperature of blood in vivo. In the context of ex vivo heart perfusion, the oxygenator 104 ensures that the blood circulating through the perfusion circuit (e.g., system 100) is oxygenated to physiological levels, mimicking the oxygen conditions of in vivo systemic circulation. This oxygenated blood or perfusate 108 is then supplied to the coronary arteries to sustain myocardial metabolism, maintain cardiac functionality, and preserve the heart 10 for transplantation or research.

[0038] It should be appreciated that the system 100 is shown for illustrative purposes only and is not intended to limit the scope of the disclosure to the specific configuration depicted. That is,the system 100 may include additional components, modifications, or features that are commonly employed in the industry or would be understood by a person of ordinary skill in the art to be equivalent or advantageous for performing a resting mode EVHP procedure.

[0039] FIG. 2 illustrates a system 200 in which a heart 10 is perfused using a conventional working mode configuration. The system 200 may be similar to the system 100 in all aspects except as noted herein. Therefore, the disclosure for the system 100 may be equally applicable to the system 200 and similar reference numerals incremented by 100 will be used to describe similar features.

[0040] The system 200, like the system 100, includes an ex vivo heart 10, an afterload pump 202, an oxygenator 204 (which can be a membrane oxygenator), and an organ chamber 206 to capture a perfusate liquid 208. The system 200 can further include a chamber 220, a windkessel 222, and a preload pump 224. Ideally, the chamber 220 and the windkessel 222 are placed at a higher elevation than the organ chamber 206.

[0041] The combination of the chamber 220 (also referred to as a compliance chamber) and the windkessel 222 may be configured to replicate the compliance and resistance of an arterial system, thereby providing phy siologically-relevant conditions for the heart during perfusion with an EVHP system, such as the system 200. It may smooth pulsatile flow generated by the heart or EVHP system to mimic energy absorption and release characteristics of the arterial tree in vivo. In short, the windkessel 222 may modulate the flow and pressure of the blood or perfusate 208 to maintain hemodynamic stability within the perfusion circuit and can simulate realistic vascular resistance. This can ensure accurate functional assessment while protecting the heart from excessive fluctuations.

[0042] The preload pump 224 can be configured to regulate the flow of perfusate 208 into the heart's left atrium, via the cannula 14, simulating the in vivo flow of blood to the heart 10. By controlling the volume and pressure of the perfusate 108 entering the left atrium, the preload pump 224 can establish filling conditions necessary for proper cardiac function and may further simulate a physiologically relevant preload. The preload pump 224 may be configured and controlled for adjusting preload levels, allowing the system 200 to simulate varying physiological or pathological conditions. As discussed herein, preload may refer to the volume or pressure of blood (or perfusate 208) that is delivered to the heart's left atrium or ventricle to mimic the conditions before contraction (sometimes referred to as diastolic filling).

[0043] In the conventional working mode configuration, the heart 10 may be further cannulated at the aorta using an aortic cannula 12, in addition to at the left atrium via the left atrium cannula 14 discussed above. The system 200 can further include various fluid transport lines 210, 212, 214, 216, 218, 220 configured to transport a flow of perfusate 208 throughout the system 200. The arrows illustrate an exemplary flow of perfusate 208 throughout the system 200 when operating in a conventional working mode configuration.

[0044] As discussed above, in a working mode configuration, the left atrium is perfused, via the cannula 14, to simulate normal cardiac function. In this configuration, the left ventricle may dilate with increased perfusion to the left atrium, thereby increasing end diastolic volume (EDV). Additionally, myocardial contractility, during systole, may also increase with EDV, according to Frank- Starling's law. In a conventional working mode, mechanical cardiac function can be assessed by measuring changes in intraventricular pressure and volume relative to controlled left atrial pressure or EDV. But working mode may compromise preservation by shortening the amount of time the heart can be preserved ex vivo due to the increased myocardial energy consumption.LVAD MODE

[0045] Turning to FIG. 3, an exemplary embodiment of an improved EVHP system 300 is shown. The EVHP system 300 may be similar to the EVHP systems 100 and 200 except as noted herein. Accordingly, similar reference numerals increased by 100 over those in FIG. 2 may denote similar or corresponding features between the embodiments. Therefore, the disclosure for the systems 100 and 200 may be equally applicable to the system 300 except as noted herein. It should also be appreciated that the EVHP system 300 may be configured to operate in any of the “modes” disclosed herein. By way of example, the system 300 may be configured to operate in a conventional resting mode, a conventional working mode, an LVAD mode, a modified resting mode, or any other suitable EVHP mode or technique.

[0046] The EVHP system 300 may include an ex vivo heart 10, an afterload pump 302, an oxygenator 304, and an organ chamber 306 to capture a perfusate liquid 308. The system 300 may further include a chamber 320, a windkessel 322, a preload pump 324, and a reservoir 336. Ideally, the chamber 320 and the windkessel 322 may be placed at a higher elevation than the organ chamber 306 to achieve proper pressure balance in the system 300. The reservoir 336 may belocated at a lower elevation than the organ chamber 306 to receive perfusate 308 from the organ chamber 306. The afterload pump 302 and / or the preload pump 324 may also be located at an elevation lower than the organ chamber 306. In some embodiments, the afterload pump 302 and / or the preload pump 324 may be located at an elevation even lower than the reservoir 336. The perfusate 308 may be any suitable oxygenated solution, such as blood or another preservation fluid. In some embodiments, the perfusate 308 may be a combination of fluids such as blood and STEEN solution. In a particular example, the perfusate may be a combination of 1,600 mL autologous whole blood and 2,000 mL STEEN solution.

[0047] The system 300 may further include a left ventricular assist device (LVAD pump) 330, a left ventricle inflow cannula 16, and corresponding perfusate line 332 connecting the inflow cannula 16 to an input of the LVAD pump 330. The LVAD pump 330, afterload pump 302, and the preload pump 324 may be a rotary blood pump, a centrifugal pump, or any other suitable pump or device. The output of the LVAD pump 330 may feed the perfusate line 334 while in fluid communication with the aortic cannula 12 and the chamber 320. As discussed below in more detail, LVAD pump 330 may assist left ventricle unloading, which may reduce myocardial energy consumption while operating in a working mode configuration.

[0048] FIG. 4 illustrates a close-up, cut-away view of the heart 10 in the system 300. As illustrated, the heart 10 may be cannulated at the aorta using an aortic cannula 12, at the left atrium using a left atrium cannula 14, and at the pulmonary artery using a pulmonary artery cannula 18. Also illustrated is an inflow cannula 16 that is inserted into the left ventricle of the heart 10 via the left atrium. In the embodiment illustrated in FIG. 4, the superior vena cava 20 and inferior vena cava 22 are occluded (closed off), but it should be appreciated that they may also be cannulated for various procedures.

[0049] The heart 10, may be a human heart with the standard anatomical structures of a normal human heart. For instance, the heart 10 may have a left ventricle 50, a left atrium 52, a right ventricle 54, and a right atrium 56. For brevity, the other standard anatomical structures of a heart will not be described herein in detail. Notably, the systems and methods described herein may also be applied to non-human hearts.

[0050] FIG. 5 illustrates the ex vivo heart perforation system 300 of FIG. 3 configured to operate in an exemplary “LVAD mode.” As disclosed herein, the LVAD mode may reduce myocardial energy consumption while operating in a working mode configuration, which may result in animprovement in preservation rate compared to conventional working mode and / or resting mode techniques. Moreover, by incorporating heart rate synchronization control technology of the LVAD pump 330 into the system 300, cardiac energy consumption associated with myocardial contraction during the working mode may be suppressed, and myocardial metabolic activity may be maintained. Therefore, cardiac function and preservation may be preserved in the LVAD mode compared to conventional resting mode and / or conventional working mode.

[0051] The arrows in FIG. 5 illustrate an exemplary flow of perfusate 308 through the system 300. The forceps 40 in the drawings represent locations in which the various flow lines are blocked, crimped, or flow of perfusate 308 is otherwise restricted. Moreover, the embodiment illustrated in FIG. 5 may operate in a similar manner compared to the conventional working mode illustrated in FIG. 2 except as noted herein. That is, the left ventricle may be suitably perfused using the preload pump 324. However, as discussed, when operating in the LVAD mode, the LVAD pump 330 may assist the left ventricle with unloading of perfusate 308 which may reduce myocardial energy. Namely, the LVAD pump 330 may extract perfusate 308 from the left ventricle and may pump the perfusate 308 to a location in the system 300 that is downstream of the aortic flow, thereby assisting the left ventricle in the discharge of perfusate 308. As will be discussed below in more detail, the LVAD pump 330 may be configured to match or synchronize with normal contraction of the heart 10. That is, various settings of the LVAD pump 330 may be configured to achieve desired characteristics associated with normal physiological function and timing of a heart. For instance, various settings of the LVAD pump 330 may include any of the following: timing of the LVAD pump ON command, length of time the pump is ON, length of time the pump is OFF, frequency of the pump, RPM of the pump, ramp up time, ramp down time, pulse configuration, and the like.

[0052] In an embodiment, the LVAD mode supports contraction of the heart 10 by a co-pulse synchronization of the LVAD pump 330. The LVAD mode may express or create a preload to the left ventricle in the diastolic phase in the same way as the conventional working mode. In the LVAD mode, however, the system 300 may further assist with unloading of the pressure and the volume of perfusate 308 in the left ventricle (LV) in the systolic phase. In other words, the LVAD pump 330 may assist the left ventricle in displacing the volume or a portion of the volume of perfusate 308 within the left ventricle.

[0053] The effects of preload on the heart 10 can be divided into the following distinct functions performed by an EVHP system during diastole and systole phases: Function 1) to fillthe left ventricle (LV) with perfusate via the left atrium (LA) during a diastole phase, and Function 2) to eject the perfusate during the systole phase. Here, the presence (+) or absence (-) of Function 1 may be described by “LA+” (LA loading) or “LA-” (LA unloading), respectively. Whereas, the presence (+) or absence of Function 2 (-) may be described by “LV+” (LV loading) or “LV-” (LV unloading). Conventional resting mode operates according to LA- and LV- (e.g., in this mode, the left atrium is not filled or directly perfused and the left ventricle does not eject blood or perfusate). Conversely, the conventional working mode may operate according to LA+ and LV+ (e.g., in this mode, the left atrium is filled or directly perfused and the left ventricle ejects blood or perfusate). However, by utilizing the LVAD pump 330 in the LVAD mode as described herein, Function 2 during systole may be exempted (either partially or fully) due to the assisted contraction of the heart 10 from the LVAD pump 330. Therefore, in the embodiment described herein, the LVAD mode may be defined as LA+, LV-. As discussed, the LVAD mode illustrated in FIG. 5 may preserve myocardial function better than conventional resting and working modes.

[0054] According to an embodiment, co-pulse heart rate synchronization control may refer to a method of control for the LVAD pump 330 in which the system modifies or tunes the operation of the LVAD pump 330 to align with the cardiac function of the heart 10. In additional to or alternatively, co-pulse heart rate synchronization may include increasing the speed of the LVAD pump 330 during cardiac systole. In a conventional co-pulse heart rate synchronization control, it is not clearly defined how many seconds of LVAD pump unloading is achieved based on the systolic start time.

[0055] In an embodiment, the “unloading” of the LVAD pump 330 may be defined as a maximum time of acceleration of an increase in left ventricular pressure located in the middle of an isovolumic systolic period. The isovolumic systolic period (IVSP), also known as the isovolumetric contraction phase, can be defined as a brief phase of the cardiac cycle that occurs during the systole when the ventricles are contracting but blood is yet to be ejected. During this period, the volume of blood in the ventricles remains constant, but pressure increases, because the heart valves are still closed. For instance, this may be a time period from the lowest left ventricular intraventricular pressure period to the highest left ventricular intraventricular pressure period during which end diastolic volume (EDV) is maintained. This period can be further defined as the start of the systolic phase (e.g., at time equals 0 seconds).

[0056] The co-pulse beat synchronization control may be implemented to maximize the unloading flow rate of the LVAD pump 330 with the start of the systolic phase. In a specific example, the co-pulse beat synchronization control may be implemented to maximize the unloading flow rate of the LVAD pump 330 within ±100 ms of the start of the systolic phase. In other embodiments, the co-pulse beat synchronization control may be implemented to maximize the unloading flow rate of the LVAD pump 330 within ±300 ms of the start of the systolic phase. Yet in other embodiments, the co-pulse beat synchronization control may be implemented to maximize the unloading flow rate of the LVAD pump 330 within a certain predefined amount of time of any other suitable cardiac phase in order to synchronize the LVAD pump 330 with the cardiac functions of the heart 10. In other words, the unloading of the LVAD pump 330 may be timed with the isovolumic systolic period (IVSP) or any other measurable condition of the heart 10. As used herein, end-diastolic volume (EDV) is the total amount of blood in the ventricles of the heart at the end of diastole, the phase when the heart's chambers are relaxed and filled with blood just before contraction (systole). It represents the maximum volume of blood the ventricles may hold during the cardiac cycle.

[0057] By implementing co-pulse heart rate synchronization control, the LVAD pump 330 may reduce the cardiac systolic load of the heart 10 (e.g., stress placed on the heart 10 during systole, the phase of the cardiac cycle when the ventricles contract to eject blood into the circulation). Cardiac contractile load may be defined as the increase in left ventricular pressure during isovolumic contraction periods. Embodiments disclosed herein may reduce EDV, which can be caused by the activation of the LVAD pump 330 during the diastolic period. That is, the LVAD pump 330 may reduce the cardiac systolic load of the heart 10 by assisting with the ejection of blood from the left ventricle and / or by reducing EDV.

[0058] There may be a specific time range or target range to achieve both the reduction of the cardiac contractile load and reduction of EDV. This time period may be ±100 ms of the isovolumic systolic period (IVSP), as described above. The targeted time period may also coincide with the diastolic or systolic phases. In conventional heart rate synchronization control, the R wave of an ECG can be used as the trigger for driving an LVAD pump (e.g., to synchronize the pump with the heart). As discussed herein, the R wave is an upward deflection seen on an electrocardiogram (EKG or ECG) that represents the depolarization of the main mass of the ventricles. Synchronizing an LVAD pump with an R wave, however, does not rely on the heart rate synchronization controlmethod as discussed above and may be less accurate. Therefore, conventional heart rate synchronization control utilizing the R wave of an ECG may be less desirable compared to the method disclosed herein.

[0059] By way of example, synchronization of the LVAD pump 330 with R wave of an EKG may be inaccurate and undesirable because of lag time, start-up time, or delay in control of the LVAD pump 330. Specifically, if the unloading period or ON command for the LVAD pump 330 is triggered using the R wave of an EKG, the impeller of the pump may nonetheless miss the relevant period (e.g., the pump may not start in time). Said differently, it may take more time than the time difference from the R wave to the 0-second position (described above) until the impeller of the LVAD pump 330 starts rotating and intraventricular de-bleeding occurs by giving an ON command signal to the pump. That is, movement or control of the LVAD pump 330 may not be instantaneous, and there may be a non-zero lag time between the ON command to the pump and the actual start-up time of the pump. Therefore, in certain embodiments, a software that allows a user to visualize whether the target control (e.g., synchronization with the heart) is achieved may be utilized. Similarly, an interface may be provided to interact with a software platform to configure a phase delay for the pump start time in the ± time direction to achieve a targeted control of the LVAD pump 330. Other configuration settings may be controlled via the interface.

[0060] FIG. 6 is a graph 400 illustrating example behaviors of cardiac parameters during the cardiac pumping cycle, which may be referenced when configuring or analyzing the timing, synchronization, and / or other control parameters of the LVAD pump 330 of the system 300. More specifically, the graph 400 in FIG. 6 illustrates left ventricle pressure (LVP) 402 of a heart, LVAD pump motor voltage 404, LVAD pump speed 406, and LVAD pump flow 408, all as a function of time. The LVAD pump 330 may be powered on during the periods marked with “PumpOn=l” and may be powered off during the periods marked with “PumpOn=0.” The LVAD pump ON period may be denoted with 410 and the LVAD pump off period may be denoted with 412.

[0061] Alternatively, the PumpOn=l and PumpOn=0 states need not necessarily correspond to states of the LVAD pump 330 being activated and deactivated, respectively. Rather, these can correspond to the LVAD pump 330 being operated in a first state to generate a relatively higher flowrate and / or pressure of perfusate (cf. PumpOn=l in FIG. 6) compared to a second state in which the LVAD pump 330 is operated (i.e. it is not deactivated) to generate relatively lower flowrate and / or pressure (cf. PumpOn=0 in FIG. 6) compared to the first state. In either case, theLVAD pump 330 may be alternated between a first state (e.g. on / higher) and a second state (e g. off / lower) to synchronize the operation of the LVAD pump 330 with cardiac function of the heart 10. For instance, the first state may be a state in which the LVAD pump 330 is powered on, and the second state may be a state in which the LVAD pump 330 is powered off. Alternatively, the first state may be a state in which the LVAD pump 330 is operated at a first speed, first power, first volume output, etc. The second state may be a state in which the LVAD pump 330 is operated at a second speed, second power, second volume output, etc. Thus, it should be appreciated that although the LVAD pump 330 may be alternated between an ON or an OFF state, the LVAD pump 330 may also be alternated between various non-binary states. For instance, the LVAD pump may alternate between the first state in which the LVAD pump 330 operates at a high speed and a second state in which the LVAD pump 330 operates at a lower speed. Therefore, consistent with the discussion above concerning PumpOn=l or 0 in FIG. 6, although this disclosure describes various ON commands sent to the LVAD pump 330, it should be appreciated that sending an ON command to the LVAD pump 330 may comprise a command to transition from a low power state to a higher power state (e.g., from the second state to the first state, or vice versa). In some embodiments, the first state and the second state may coincide with diastolic and systolic phases of the heart 10. For example, the LVAD pump may transition to the first state at the start of the systolic phase of the heart 10 and may transition back to the second state at the start of the diastolic phase of the heart (or vice versa). In other embodiments, the first state and the second state coincide with other cardiac measurements of the heart 10.

[0062] The system 300 may be configured to send an ON command to the LVAD pump 330 upon the system 300 determining that a trigger condition is met. In the embodiment disclosed in FIG. 6, the LVP measurement may be used as the trigger condition such that the system 300 sends an ON command to the LVAD pump 330 upon determining that the LVP reaches a certain value (trigger value). For instance, the trigger value 414 may be predetermined or preconfigured. In other embodiments, the trigger value 414 may be adjusted in real-time to better synchronize the operation of the LVAD pump 330 with the cardiac function of the heart 10.

[0063] In the graph 400, the trigger value 414 is set at 40 mmHg of LVP. It should be appreciated that although 40 mmHg of LVP is illustrated in this example, other suitable pressure values or cardiac measurements may be used as a trigger condition. Moreover, the trigger value 414 may function such that an ON command is sent to the LVAD pump 330 once the applicablemeasurement reaches the trigger value 414 (e g., LVP = 40 mmHg). In certain embodiments, the ON command may be triggered only upon the measurement reaching the trigger value 414 from a value greater than the trigger value (e.g., ON command only triggered on a downward trend of LVP toward the trigger value 414). In certain cases, it may be undesirable to trigger the pump ON command on an upward trend of LVP, or non-suitable candidate waveform value. This will be discussed below in greater detail.

[0064] In other embodiments, a delay value may be configured such that an ON command is sent to the LVAD pump 330 once the LVP reaches the trigger value 414 and the delay value has elapsed. In other words, once the trigger condition is met, the system 300 may delay the ON command to the LVAD pump 330 until after the delay time has elapsed / passed. It should be appreciated that the delay value may be a time greater than, less than, or equal to zero. In the embodiment illustrated in FIG. 6, the delay value is set at 0 milliseconds. The delay value may be adjusted as necessary to synchronize the LVAD pump speed and / or flow with cardiac function of a heart (such as the heart 10).

[0065] Additionally, the trigger value 414 may be adjusted as necessary to synchronize the LVAD pump speed and / or flow with cardiac function of a heart (such as the heart 10). For instance, for an earlier ON trigger, the trigger value 414 may be increased so that the LVP reaches the trigger value 414 at an earlier point in time.

[0066] In other embodiments, the trigger value may be based on any measurable value of the system 300. For instance, the trigger value 414 may be based on a trigger candidate waveform of aortic pressure (AOP), left ventricle pressure (LVP), ECG, pulmonary artery pressure, or any other measurable value of combination of measurable values. The candidate waveform to be used by the system 300 may be selected by a user in a software such that a software and / or controller can generate a voltage signal to drive the LVAD pump motor based on the selected candidate waveform. In other words, although FIG. 6 illustrates the LVP as the candidate waveform, other suitable candidate waveforms may be used as a trigger for the LVAD pump ON command.

[0067] Other configurable values may include the period or length of time in which the LVAD pump 330 is powered on. For instance, the length of time in which a voltage or control signal is sent to the LVAD pump 330 may be referred to as “Length” as illustrated in FIG. 6. During this length of time, the controller may set “PumpOn=l”. In other words, once the trigger value 414 is reached, the controller may issue a pump ON command for a predetermined length of time. Thislength of time may be adjusted in real time by the user or automatically by the system 300 to better synchronize the pump operation with the cardiac function of the heart 10. The pump 330 may remain in an OFF state (PumpOn=0) until the LVP or other candidate waveform again reaches the pre-determined trigger value 414.

[0068] As discussed above, it may be desirable to filter out unwanted trigger conditions (e.g., conditions that trigger a pump ON command). For instance, the trigger value 414 may be reached for a first time as the LVP pressure decreases to the trigger value 414. However, the trigger value 414 may also be reached a second time on an upward trend of LVP (e.g., at 430). This may be undesirable. Or, additionally, if an arrhythmia of a higher frequency than the specified heart rate occurs, the trigger condition may be reached again or in multiple bursts. In some instances, this may occur during an already triggered ON period which may also be undesirable. In an embodiment, to reduce unwanted subsequent triggers or pump ON commands, the system 300 may be configured to ignore additional triggers during the pump ON period 410, or until the relevant pump ON period 410 has elapsed. Considering this, and because the pump 330 will not be triggered (e.g., or re-triggered) during the pump ON period, the length of the ON period 410 should be set shorter than one cardiac cycle of the heart 10 to achieve suitable heartbeat synchronization.

[0069] By way of background, problems can occur when the disclosed heartbeat-synchronized control is applied to EVHP. In EVHP, arrhythmia of the biological heart is common, and if arrhythmia occurs during the above-mentioned heartbeat-synchronized control, the LVAD pump 330 may also be driven irregularly in synchronization with it, which may cause a negative spiral that triggers further arrhythmia of the biological heart. To account for this, a trigger duration is set “length” or period 410. Even if a trigger condition is met again during the pump ON period due to a beating heart or arrhythmia, the trigger condition may be ignored during that period. This may help to mitigate or eliminate irregularities caused by such arrhythmia.

[0070] As discussed herein, configurable values of the system 300 may be set by a user, medical professional, or may be configured automatically in real time using suitable software or artificial intelligence. For example, a user can adjust the length of the pump on period 410 of the operating waveform or its phase shift parameter “Delay” on a software so that the maximum value of the target waveform (e.g., AOP or LVP) or its first-order derivative waveform or its second-order derivative waveform and the maximum value of the operating waveform (LVAD pump flow waveform) or its first-order derivative waveform match as closely as possible. Accordingly, whensuch waveforms are matched, it may be considered that the waveforms are synchronized such that the operation of the LVAD pump 330 is synchronized with the cardiac function of the heart 10. A user may further adjust, for example, a minimum voltage value “DiastV” or maximum voltage value “SysV” of the voltage signal sent to the LVAD pump 330 to adjust a magnitude of the operating waveform for the LVAD pump 330 (e.g., for the first state or the second state). It should be appreciated that further adjustments to the LVAD pump 330 may be made without deviating from the scope of this disclosure.

[0071] In other embodiments, a right ventricular assistance device (RVAD) also may be used in combination with the LVAD mode disclosed herein. A RVAD mode may operate in the same way as LVAD mode, except with the right atrium and right ventricle instead of the left atrium and left ventricle. That is, the RVAD mode may express the perfusate 308 in the same way as the conventional working mode in diastolic phase, but may unload the pressure and the volume in the right ventricle in the systolic phase. The effects on the heart can be divided into the following during diastole and systole: 1) to fill right ventricle with perfusate from the right atrium during diastole, and 2) to eject perfusate from right ventricle during systole.

[0072] A EVHP system, such as the system 300, may incorporate both LVAD and RVAD modes. A process to incorporate both LVAD and RVAD may include a priming step and a setting step. In this exemplary system, an RVAD, which may be a rotary blood pump or a centrifugal pump, may transmit perfusate from the systemic reservoir to the right atrium. RVAD mode may include a cannula leading to the right ventricle and another leading to a lung reservoir. RVAD mode may work as a bypass to increase effective ejection-fraction of the right ventricle to extrinsically pump perfusate out of the right ventricle and into the lung reservoir, thereby alleviating the right ventricle of some working burden on the heart. Right atrium contraction causes perfusate in the right atrium to empty into the right ventricle. The right ventricle contraction ejects perfusate therefrom into the right ventricle, and from there into a right ventricle afterload chamber. The right ventricle contraction causes cardiac output (CO), as discussed above with respect to LVAD mode, against the right ventricle afterload chamber. The right ventricle afterload chamber may adjust the pressure of perfusate, and then the adjusted perfusate is pumped into the lung reservoir. The perfusate in the lung reservoir is passed through an oxygenator and a filter. The oxygenated perfusate can be emptied into a preload chamber, where the pressure of the perfusate is adjusted to a pre-load pressure.

[0073] FIG. 7 illustrates an exemplary operational diagram 500 for the above-mentioned copulse control of the LVAD pump 330. For instance, at step 502, the system determines the mode of operation. The various modes may include conventional resting mode, conventional working mode, LVAD mode, modified resting mode type A, modified resting mode type B (the latter two as discussed below), or any other suitable EVHP mode.

[0074] At step 504, a user may input various control parameters for operation of the EVHP system 300 or 600. For instance, the trigger value 414 may be configured. Additionally, the desired ON period (i.e. length of time for PumpOn=l) for the LVAD pump 330 and the start delay may be configured. A user may further configure a minimum voltage value for a diastolic phase “DiastV” and maximum voltage value for a systolic phase “SysV” of the voltage signal to adjust the magnitude of the operating waveform of the LVAD pump 330 in the various operating states of the LVAD pump 330. As disclosed in FIG. 7, the “trigger” is a threshold to start sending a voltage to increase the LVAD pump speed. “SysV” is the value of voltage of the LVAD pump that determines the LVAD pump speed when PumpOn = 1. “DiastV” is the value of voltage of LVAD pump that determines the LVAD pump speed when PumpOn = 0, which in embodiments can mean that the LVAD pump is not active. “Length” is the length of time that the LVAD pump is in the ON state. “Delay” is the length of time before which the LVAD pump 330 enters the ON state after it is triggered.MODIFIED RESTING MODE

[0075] As discussed, it may be advantageous to mimic physiological conditions of a heart while performing ex vivo heart perfusion as doing so may increase preservation rate. In an embodiment, the above-mentioned heart rate synchronization control method performed in the LVAD mode can similarly be performed during a resting mode configuration to achieve physiological coronary perfusion. Doing so may generate or simulate heart rate-synchronized aortic pressure, thereby enhancing the effect of perfusion to preserve cardiac function in resting mode. This exemplary technique may be referred to herein as a “modified resting mode.” It should be appreciated that the co-pulse synchronization of modified resting mode may operate in a manner similar to what is described for LVAD mode except for the differences described herein.

[0076] For instance, in a resting mode, there is no left atrial inflow or preload as only the coronary arteries are perfused. Therefore, synchronization of a pump and the cardiac function of a heartcannot be performed by monitoring left ventricular pressure or aortic pressure, as discussed above for the LVAD mode. Instead, in the modified resting mode, an electrocardiogram (ECG or EKG) is used as the operating waveform. For example, the R wave of an ECG or EKG may be used as the waveform for triggering an ON command to the pump. Alternatively, if an electrocardiogram is difficult to obtain or if undesirable results are observed, a right ventricular pressure or a pulmonary artery pressure waveform may be used as the operating waveform.

[0077] FIG. 8 illustrates a first embodiment of the system 300 configured to operate in a modified resting mode (referred to herein a “modified resting mode type A”). In this configuration, the system 300 may operate in a similar manner compared to a conventional resting mode except one or more of the afterload pump 302, the preload pump 324, or the LVAD pump 330 may be used to simulate physiological coronary perfusion in a manner similar to the LVAD mode. Specifically, in this embodiment, the LVAD pump 330 may be utilized to simulate a physiological coronary waveform of the perfusate 308 entering the coronary arteries through the aorta and aortic cannula 12. To achieve this, the left atrium cannula 14 and the in-flow cannula 16 may be blocked off in a suitable manner (e.g., with forceps 40) so that perfusate 308 flowing through line 318 enters an input of the LVAD pump 330. From the output of the LVAD pump 330, the perfusate 308 may enter the aortic line 338 where at least a first portion of the perfusate 308 may flow into the aorta via the aortic cannula 12. A second portion of the perfusate 308 exiting the LVAD pump 330 may enter the chamber 320. Yet in other embodiments, the full volume of perfusate 308 exiting the LVAD pump 330 may enter the aorta. It should be appreciated that the afterload loop comprising the afterload pump 302, the oxygenator 304, the chamber 320, and the windkessel 322 may operate in a normal operating procedure as done on the conventional resting mode. In some embodiments, the preload pump 324 may also be operated in conjunction with the LVAD pump 330. Yet in other embodiments, the preload pump 324 may be unpowered. Further in other embodiments, a preload pump 324, may be excluded from the system 300 altogether.

[0078] FIG. 9 illustrates a second embodiment of the system 300 configured to operate in a modified resting mode (referred to herein as “modified resting mode type B”). In this configuration, the system 300 may operate in a similar manner compared to a conventional resting mode except one or more of the afterload pump 302, the preload pump 324, or the LVAD pump 330 may be used to simulate physiological coronary perfusion in a manner similar to the LVAD mode. Specifically, in this embodiment, the preload pump 324 may be utilized to simulate aphysiological coronary waveform of the perfusate 308 entering the coronary arteries through the aorta and aortic cannula 12. In this embodiment, flow to the LVAD pump 330 may be completely restricted or bypassed (e.g., by forceps 40) such that the LVAD pump 330 is not used. Here, the preload pump 324 may be used to simulate physiological coronary perfusion using co-pulse synchronization as discussed above.

[0079] Specifically, in this configuration, the perfusate 308 may enter the bypass line 340 to bypass the LVAD pump 330. From there, the perfusate 308 may enter the aortic line 338 where at least a first portion of the perfusate 308 may flow into the aorta via the aortic cannula 12. A second portion of the perfusate 308 exiting the preload pump 324 may enter the chamber 320. Yet in other embodiments, the full volume of perfusate 308 that exits the preload pump 324 may enter the aorta. It should be appreciated that the afterload loop comprising the afterload pump 302, the oxygenator 304, the chamber 320, and the windkessel 322 may operate in a normal operating procedure as with the conventional resting mode. In some embodiments, the preload pump 324 may also be operated in conjunction with the LVAD pump 330. Yet in other embodiments, the LVAD pump 330 may be excluded from the system 300.

[0080] Alternatively, the system 100 can be utilized for the “modified resting mode”. Then the pump 102 is performed in a manner similar to what is described for LVAD mode. That is, the MODIFIED RESTING MODE of the present disclosure is capable of being implemented without the afterload pump 302, the chamber 320, and the windkessel 322, as long as the pump 102 is performed in a manner similar to what is described for LVAD mode.CONTROL FUNCTIONS

[0081] FIG. 10 illustrates an exemplary EVHP system 600. The system 600 may be similar to the system 300 in all aspects except as noted herein. Therefore, the disclosure for the system 300 may be equally applicable to the system 600 and similar reference numerals, incremented by 300 over those in FIG. 3, will be used to describe similar features. It should also be appreciated that the EVHP system 600 may be configured to operate in any of the “modes” disclosed herein. By way of example, the system 600 may be configured to operate in a conventional resting mode, a conventional working mode, an LVAD mode, a modified resting mode, or any other suitable EVHP mode or technique.

[0082] The EVHP system 600 may include an ex vivo heart 10, an afterload pump 602, an oxygenator 604, and an organ chamber 606 to capture a perfusate liquid 608. The system 600 may further include a chamber 620, a windkessel 622, a preload pump 624, and a reservoir 636. Ideally, the chamber 620 and the windkessel 622 may be placed at a higher elevation than the organ chamber 606 to achieve proper pressure balance in the system 600. The reservoir 636 may be located at a lower elevation than the organ chamber 606 to receive perfusate 608 from the organ chamber 606. The afterload pump 602 and / or the preload pump 624 may also be located at an elevation lower than the organ chamber 606. In some embodiments, the afterload pump 602 and / or the preload pump 624 may be located at an elevation even lower than the reservoir 636.

[0083] The system 600 may include a left ventricular assist device (LVAD pump) 630, a left ventricle inflow cannula 16, a check valve 652, and corresponding perfusate line 632 connecting the inflow cannula 16 to an input of the LVAD pump 630. The output of the LVAD pump 630 may feed the perfusate line 634 while in fluid communication with the aortic cannula 12 and the chamber 620. As discussed below in more detail, LVAD pump 630 may assist left ventricle unloading, which may reduce myocardial energy consumption while operating in a working mode configuration.

[0084] The system 600 may further include a control system 650 that may be used to implement, monitor, or control various aspects of the systems 300 or 600. The control system 650 system may include a controller, a processor, and a memory operatively coupled to the processor. The controller can be configured to manage the overall operation of the system, including coordinating interactions between various components. The processor is configured to execute instructions stored in the memory to perform specific operations associated with the system's functionality. The memory includes a non-transitory, computer-readable medium that stores program code, operational data, and configuration settings useful for the controller and processor to execute the designated tasks. The memory may include volatile memory, such as random-access memory (RAM), and non-volatile memory, such as read-only memory (ROM), flash memory, or a hard disk drive (HDD). Together, the controller, processor, and memory operate to implement the methods and processes described herein, ensuring efficient execution of tasks while maintaining system stability and reliability.

[0085] In certain embodiments, the control system 650 can communicate information in a raw or a processed form to a server. It should be appreciated that the server can be local, remote, orcloud-based as part of a cloud computing environment. In various embodiments, the control system 650 or corresponding controller can exist as part of the server. In certain embodiments, the server can also include a database. The database can receive information from the server regarding sensor information, alerts, notifications, historic sensor information, user information, among other information. The database may be a standalone storage component or it may exist as part of the server.

[0086] A user device or human-machine-interface (HMI) may communicate with the control system 650 or the server. The user device may be, for example, a computer, or a mobile device such as a smartphone or tablet, a wearable device, among others. The user device may interact with an application or software operating on the server or control system 650. When executed, the application can interact with the user device to allow a user to view sensor information, view corresponding notifications or alerts, manipulate sensor information, or update configuration settings for various settings disclosed herein. The user device can provide a user interface that allows a user to interact with the application. It should be appreciated that in certain embodiments, the application may also exist locally on the user device or the control system 650.

[0087] The control system 650 may further include various monitoring systems, lines, probes, or sensors for monitoring various details and characteristics of the system 600. For instance, the control system 650 may comprise at least the following sensor inputs: an LVAD pump flow meter and corresponding LVAD pump flow monitoring line 660; an aortic pressure monitoring sensor and corresponding aortic pressure monitoring line 664; a left atrium pressure monitoring sensor and corresponding left atrium pressure monitoring line 666; an electrocardiogram monitoring line 668; a left vertical pressure monitoring sensor and corresponding left ventricle pressure monitoring line 670.

[0088] The control system 650 may comprise at least the following control outputs:LVAD pump control line 662;Pre-load pump control line 672;- After-load pump control line (not shown).

[0089] It should be appreciated that the control system 650 may be used, through the various inputs and outputs described above, to monitor and control various aspects of the systems 300 or 600. For instance, the control system 650 may be used to control the co-pulse synchronization of the LVAD pump 630 as described above with respect to the LVAD mode or modified resting modes. A user may configure the various settings using a user interface or user device that communicates with the control system 650.IN VIVO HEART PERFORATION (IVHP) SYSTEM

[0090] An exemplary embodiment of an in vivo heart perfusion (IVHP) system 700 is shown in Fig. 11. The IVHP system 700 may be similar to the systems 300 and 600 except as noted herein. Accordingly, similar reference numerals increased by 400 over those in FIG. 3 and similar reference numerals increased by 100 over those in FIG. 10 may denote similar or corresponding features between the embodiments. Therefore, the disclosure for the systems 300 and 600 may be equally applicable to the system 700 except as noted herein. It should also be appreciated that the IVHP system 700 may be configured to operate in any of the “modes” disclosed herein. By way of example, the system 700 may be configured to operate in a conventional resting mode, a conventional working mode, an LVAD mode, a modified resting mode, or any other suitable IVHP mode or technique.

[0091] The IVHP system 700 may include an in vivo heart 710, a left ventricular assist device (LVAD pump) 730, an outflow cannula 732 that pumps perfusate (blood) to the aorta and connecting the inflow cannula 16 to an input of the LVAD pump 730. The LVAD pump 730 may be a rotary blood pump, a centrifugal pump, or any other suitable pump or device. As already discussed above in more detail, LVAD pump 730 may assist left ventricle unloading.

[0092] The IVHP system 700 may further include a control system 750 that may be used to implement, monitor, or control various aspects of the system 700. The control system 750 system may include, as well as the control system 650 of the system 600, a controller, a processor, and a memory operatively coupled to the processor. The controller can be configured to manage the overall operation of the system, including coordinating interactions between various components. The processor is configured to execute instructions stored in the memory to perform specific operations associated with the system's functionality. The memory includes a non-transitory, computer-readable medium that stores program code, operational data, and configuration settingsuseful for the controller and processor to execute the designated tasks. The memory may include volatile memory, such as random-access memory (RAM), and non-volatile memory, such as readonly memory (ROM), flash memory, or a hard disk drive (HDD). Together, the controller, processor, and memory operate to implement the methods and processes described herein, ensuring efficient execution of tasks while maintaining system stability and reliability.

[0093] The control system 750 may comprise at least a left vertical pressure monitoring sensor and corresponding left ventricle pressure monitoring line 770, but may comprise any other types of sensors. For instance, the control system 750 may be configured to monitor and control the LVAD pump 730 based on any measurable physiological function or characteristic of a heart. In some embodiments, the control system 750 may monitor left ventricle pressure, ECG waveforms, aortic pressure, left atrium pressure, pulmonary artery pressure, or any other waveform or vital characteristics. It should be appreciated that the monitored physiological functions or characteristics of a heart may be utilized to determine the timing or start of cardiac systole. This may be similar to the EVHP systems described above. Additionally, various other measurable characteristics may be possible when perfusing a heart in vivo as monitoring may be possible non- invasively from outside of the body. In other embodiments, a combination of measurable characteristics or vitals may be utilized.

[0094] According to the configuration of the system 700 described in Fig. 11, a heart rate synchronization control that is identical or similar to the configuration described in Fig. 6 also for IVHP system 700.

[0095] The invention has been described with reference to the example embodiments described above. Modifications and alterations will occur to others upon a reading and understanding of this specification. Example embodiments incorporating one or more aspects of the invention are intended to include all such modifications and alterations insofar as they come within the scope of the appended claims.

Claims

CLAIMS1. An ex vivo heart perfusion system, comprising: an organ chamber configured to hold an ex vivo heart and a liquid perfusate, an oxygenator configured to oxygenate the perfusate; a reservoir located beneath the organ chamber to receive perfusate from the organ chamber; an afterload pump configured to receive a first portion of perfusate from an output of the reservoir and to pump the first portion of the perfusate to the oxygenator; and a left ventricular assist device (LVAD) pump configured to pump a portion of perfusate from a left ventricle cannula to a location along an aortic outflow path in-use.

2. The ex vivo heart perfusion system according to claim 1 , further comprising a preload pump configured to receive a second portion of perfusate from the output of the reservoir and to pump the second portion of perfusate to a left-atrium cannula to perfuse a left atrium of a heart in-use.

3. The ex vivo heart perfusion system according to claim 1, wherein control of the LVAD pump is synchronized with at least one physiological function of the heart.

4. The ex vivo heart perfusion system according to claim 3, wherein the LVAD pump is synchronized with at least one physiological function of the heart by alternating the LVAD pump between a first state and a second state, the LVAD pump is operated at a first power level in the first state and is operated at a second power level in the second state, the first power level being greater than the second power level, and the second power level optionally being a zero-power level.

5. The ex vivo heart perfusion system according to claim 4, wherein the system is configured to synchronize an ON command to the LVAD pump with a start of a systolic phase of a heart in- use by monitoring at least one characteristic of the heart indicative of the systolic phase, the ON command configured to operate the LVAD pump in the first state for a first length of time.

6. The ex vivo heart perfusion system according to claim 5, wherein the at least one characteristic is left ventricle pressure.

7. The ex vivo heart perfusion system according to claim 6, further comprising a processor comprising machine-readable instructions, wherein when executed by the processor, the machine- readable instructions are configured to: transmit the ON command to the LVAD pump upon determining that the left ventricle pressure has reached a trigger value, the LVAD pump is operated in the first state for the first length of time.

8. The ex vivo heart perfusion system according to claim 7, wherein the trigger value is a left ventricle pressure value between 35-45 mm Hg.

9. The ex vivo heart perfusion system according to claim 7, further comprising a configurable delay time, wherein the processor is configured to delay transmission of the ON command to the LVAD pump for a length of the delay time after determining that the left ventricle pressure has reached the trigger value.

10. The ex vivo heart perfusion system according to claim 7, wherein the processor is configured to prevent transmission of a subsequent on command to the LVAD pump while the LVAD pump is operating in the first state.

11. The ex vivo heart perfusion system of claim 1, further comprising an ex vivo heart received in said organ chamber, wherein a left ventricle of the heart is cannulated using the left ventricle cannula, the left ventricle cannula being in fluid communication with an input of the LVAD pump to facilitate pumping a portion of perfusate from of the left ventricle of the heart.

12. A method of performing ex vivo heart perfusion (EVHP) comprising: perfusing a left atrium of a heart with a volume of a perfusate;operating an afterload pump to draw a first portion of the perfusate from an organ chamber, wherein the organ chamber is configured to support the heart and collect at least a portion of the perfusate flowing from the heart; operating an oxygenator to oxygenate the perfusate flowing from the afterload pump, wherein the oxygenated perfusate is recirculated throughout a circuit to perfuse the heart; and operating an LVAD pump to draw at least a portion of perfusate from a left ventricle of the heart.

13. The method of claim 12, further comprising: operating a preload pump to draw a second portion of the perfusate from the organ chamber to the left atrium of the heart.

14. The method of claim 12, further comprising: synchronizing the operation of the LVAD pump with at least one physiological function of the heart.

15. The method of claim 14, wherein the LVAD pump is synchronized with the at least one physiological function of the heart by alternating the LVAD pump between a first state and a second state, the LVAD pump is operated at a first power level in the first state and is operated at a second power level in the second state, the first power level being greater than the second power level, and the second power level optionally being a zero-power level.

16. The method of claim 15, further comprising: monitoring at least one characteristic of the heart indicative of a systolic phase of the heart; and transmitting an ON command to the LVAD pump with a start of the systolic phase of the heart, wherein the ON command is a command to operate the LVAD pump in the first state at the first power level for a first length of time.

17. The method of claim 16, wherein the at least one characteristic is left ventricle pressure.

18. The method of claim 16, further comprising: detecting a trigger condition when a value of the least one characteristic reaches a trigger value; and upon detection of the trigger condition, transmitting the ON command to the LVAD pump.

19. The method of claim 18, further comprising: delaying the transmitting of the ON command for a length of time after detecting the trigger condition.

20. The method of claim 18, further comprising: upon detecting that the least one characteristic reaches the trigger value while the LVAD pump is operating the first state, blocking transmission of the ON command to the LVAD pump.

21. An ex vivo heart perfusion system, comprising: an organ chamber configured to hold an ex vivo heart and a liquid perfusate, an oxygenator configured to oxygenate the perfusate; a reservoir located beneath the organ chamber to receive perfusate from the organ chamber; an afterload pump configured to receive a first portion of perfusate from an output of the reservoir and to pump the first portion of the perfusate to the oxygenator; and a second pump configured to simulate physiological coronary perfusion by synchronizing an operation of the second pump with at least one physiological function of the heart.

22. The ex vivo heart perfusion system according to claim 21, further comprising a processor comprising machine-readable instructions, wherein when executed by the processor, the machine- readable instructions are configured to: synchronize the second pump with at least one physiological function of the heart by alternating the second pump between a first state and a second state, the second pump is operated at a first power level in the first state and operated at a second power level in the second state.

23. The ex vivo heart perfusion system according to claim 22, further comprising a processor comprising machine-readable instructions, wherein when executed by the processor, the machine- readable instructions are configured to: synchronize the second pump with at least one physiological function of the heart by alternating the second pump between a first state and a second state, the second pump is operated at a first power level in the first state and is operated at a second power level in the second state, the first power level being greater than the second power level.

24. An in vivo heart perfusion system, comprising: a left ventricular assist device (LVAD) pump configured to pump a portion of perfusate from a left ventricle cannula to a location along an aortic outflow path, at least one sensor including a left vertical pressure monitoring sensor having a left ventricle pressure monitoring line, and a processor comprising machine-readable instructions, wherein when executed by the processor, the machine-readable instructions are configured to: transmit an ON command to the LVAD pump upon determining that the left ventricle pressure has reached a trigger value, the LVAD pump is operated in a first state for a first length of time.

25. The in vivo heart perfusion system according to claim 24, wherein control of the LVAD pump is synchronized with at least one physiological function of the heart.

26. The in vivo heart perfusion system according to claim 25, wherein the LVAD pump is synchronized with at least one physiological function of the heart by alternating the LVAD pump between a first state and a second state, the LVAD pump is operated at a first power level in the first state and is operated at a second power level in the second state, the first power level being greater than the second power level, and the second power level optionally being a zero-power level.

27. The in vivo heart perfusion system according to claim 26, wherein the system is configured to synchronize an ON command to the LVAD pump with a start of a systolic phase of a heart in-use by monitoring at least one characteristic of the heart indicative of the systolic phase, the ON command configured to operate the LVAD pump in the first state for a first length of time.

28. The in vivo heart perfusion system according to claim 24, wherein the trigger value includes wave form that reflects a heart beat.

29. The in vivo heart perfusion system according to claim 28, wherein the trigger value is selected from the group consisting of left ventricle pressure, electrocardiogram, and pulmonary artery pressure.

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