WO2022146876A1

WO2022146876A1 - Cannula for perfusion system

Info

Publication number: WO2022146876A1
Application number: PCT/US2021/065109
Authority: WO
Inventors: Israel Jessop; Exal CISNEROS
Original assignee: Vascular Perfusion Solutions, Inc.
Priority date: 2020-12-30
Filing date: 2021-12-23
Publication date: 2022-07-07

Abstract

Various examples disclosed relate to a cannula for a perfusion system. The present disclosure includes cannulas configured to fluidly connect a heart to a perfusion system, where the cannula can help prevent or reduce the negative effects of aortic valve incompetence. For example, a flexible membrane (620), attached loosely to the end of the cannula (660), can be used. Such a membrane can respond to hydraulic pressure induced by retrograde fluid flow through the aortic valve (610) by folding over the leaking valve leaflets to seal off the retrograde flow.

Description

CANNULA FOR PERFUSION SYSTEM

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63/132,228, filed December 30, 2020, the contents of which are incorporated by reference in their entirety.

BACKGROUND

[0002] Perfusion includes the passage of fluid through the circulatory system or lymphatic system of an organ or tissue. In the human body, perfusion often refers to passage of blood through a capillary bed in tissue. Perfusion can allow for the delivery of oxygen, other dissolved gases, nutrients, and other items to the tissue. When tissue or an organ is not residing in the body, such as during transport of an organ for transplant, perfusion does not naturally occur and this can result in unwanted damage to the tissue or organ.

SUMMARY OF THE DISCLOSURE

[0003] The present disclosure provides a device, system and methods for perfusing an organ (or other tissue), making use of a cannula connection between the system and the organ. These cannulas can be used, for example, for an aortic connection to a heart. In some embodiments, the discussed devices, systems and methods can aid in efficient perfusion by reducing aortic valve incompetence when the organ is a heart. Thus, several concepts related to a cannula for addressing aortic valve incompetence are discussed herein: for example, a flexible corrugated type configuration, use of a pliable membrane to plug small openings between leaflets by draping aortic valve leaflets, occlusion of the left ventricular outflow tract, and direct cannulation of coronary arteries. [0004] Organs can be perfused during organ transport or transplant processes, research and diagnostics, and other ex -vivo organ treatments. During perfusion, the target tissue, such as a heart, is often attached to the perfusion system with a cannula. The cannula can be pushed down into the ascending aorta, using the inner lumen of the aorta to allow pumping of perfusate solution down the aortic root into the heart. In the aortic root, the aortic valve prevents regurgitation of perfusate into the left ventricle, and the resulting pressure buildup can push the flow of perfusate down to the right and left coronary arteries. However, effective coronary artery perfusion can be inhibited if the aortic valve is partially competent or not competent. That is, if the aortic valve allows some perfusate to flow straight into the left ventricle, the perfusate may bypass coronary circulation. This is often referred to as aortic valve incompetence or regurgitation. Aortic valve incompetence is highly variable in degree and occurrence, but can act as a limiting factor when perfusion systems are adopted for heart preservation.

[0005] The devices, methods, and systems discussed herein can address aortic valve incompetence in perfusion systems that are used to preserve or treat a heart outside the body, for subsequent transplantation, in a way that can accommodate valve incompetence without impeding normal coronary perfusion. Moreover, the devices, methods, and systems discussed herein can be used in a heart being perfused to address various degrees of aortic valve incompetence without impeding perfusion of hearts that do not exhibit aortic valve incompetence.

[0006] The devices, methods, and systems discussed herein can address aortic valve incompetence by plugging small openings between valve leaflets during retrograde aortic perfusion, in a relatively simple and inexpensive manner, without having to use balloon catheters, which could add complexity, traumatize tissue, and cause damage from vessel occlusion.

[0007] In an example, a perfusion system can include an oxygenator configured to be fluidly coupled with an oxygen source and configured to receive oxygen therefrom and to oxygenate perfusate; a perfusion pump operably coupled with the oxygenator and configured to circulate the perfusate through the oxygenator; a canister having a receptacle sized and shaped for receiving a target tissue; and a cannula fluidly coupling the perfusate pump and the target tissue, the cannula configured to introduce the oxygenated perfusate from the oxygenator to the target tissue in the canister, the cannula comprising a flow regulating element having a closed configuration and a deployed configuration, wherein in the closed configuration of the flow regulating element is configured to be advanced toward the target tissue, and in the deployed configuration the flow regulating element is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue.

[0008] In an example, a cannula can include a flow regulating element having a closed configuration and a deployed configuration, wherein in the closed configuration the flow regulating element is configured to be advanced toward the target tissue, and in the deployed configuration the flow regulating element is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue. The cannula can be for fluidly coupling a perfusion system to target tissue and configured to introduce perfusate from the perfusion system to the target tissue. In addition, the cannula may help anchor and support the target tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] In the drawings, which are not necessarily drawn to scale, like numerals may describe similar components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document. [0010] FIG. 1 illustrates a schematic drawing of a perfusion system that can incorporate a cannula, in an example.

[0011] FIG. 2 illustrates an exploded view of a cannula with a flexible elongated passage in an example.

[0012] FIGS. 3A-3B illustrate schematic diagrams of an aortic valve functioning normally in an example.

[0013] FIG. 4 illustrates an aortic valve with incompetence in an example.

[0014] FIGS. 5A-5B illustrate schematic diagrams of an example flexible membrane for use with a cannula in an example.

[0015] FIGS. 6A-6B illustrate schematic diagrams of an example flexible membrane for use with a cannula in an example.

[0016] FIGS. 7A-7C illustrate schematic diagrams of a method of attaching a flexible membrane in an example. [0017] FIG. 8 illustrates a schematic diagram of a cannula with a centrally supported flexible membrane in an example.

[0018] FIG. 9 illustrates a schematic diagram of a cannula with circumferential supports for a flexible membrane in an example.

[0019] FIG. 10 illustrates a schematic diagram of a cannula with a flexible membrane with rigid supports in an example.

[0020] FIG. 11 illustrates a schematic diagram of a cannula with a flexible with radial supports in an example.

[0021] FIGS. 12A-12B illustrate schematic diagrams of an expandable member cannula in an example.

[0022] FIG. 13 illustrates a schematic diagram of a bifurcated cannula in an example.

[0023] FIGS. 14A-14C illustrate schematic diagrams of a bifurcated cannula in an example.

[0024] FIGS. 15A-15C illustrate schematic diagrams of a bifurcated cannula with expandable members in an example.

DETAILED DESCRIPTION

[0025] The present disclosure describes, among other things, a cannula for a perfusion system, such as for connecting a target tissue to a source of perfusate. Once separated from a living body, organs, limbs and other vascularized tissues may be oxygenated, and metabolic waste products removed, to maintain viability of those tissues beyond the medically established cold ischemic time. Perfusion is a possible method to prolong organ viability outside the body. Perfusion systems can pump an oxygen-enriched liquid through the vasculature (e.g., arteries, capillaries, and veins) of tissue. Moreover, perfusion can deliver nutrient gas, such as oxygen, and metabolic substrates, such as glucose, to metabolically active cells and simultaneously remove metabolic waste gas, such as carbon dioxide.

[0026] Sometimes, in an example where the target tissue is a heart and when a heart is being transferred in a perfusion system, aortic valve incompetence can occur in the donor heart as it is being perfused and transferred. Aortic valve incompetence can occur when a heart valve doesn’t properly close. This can allow blood to flow backwards in the heart in a retrograde direction, instead of in the correct antegrade direction. If not addressed, the heart being transported may be in worse condition when delivered, or may be not useable because the perfusate does not flow properly into the coronary arteries to oxygenate the heart muscle.

[0027] Effective coronary perfusion of a heart can maintain a positive pressure differential between the coronary arteries via the aortic root compared to the ambient fluid pressure surrounding the heart in the canister or chamber in which the heart is perfused and transferred. Aortic root pressure can be accomplished, for example, by pressurizing the aortic root with perfusate fluid flowing from a cannula and relying on the aortic valve to seal off against retrograde perfusate flow across the aortic valve into the left ventricle.

[0028] When the aortic valve is competent, perfusate flow can be directed through the coronary arteries as intended. In cases where the aortic valve does not reliably prevent retrograde flow of perfusate through the left ventricle and atrium, a pressure differential between the aortic root and the fluid surrounding the outside of the heart may not be maintained sufficiently to drive perfusion through the coronary arteries, perfusing the heart.

[0029] FIG. 1 depicts an organ preservation system 100. The system 100 can include a head unit 110 with an oxygenator 112 with inlet 114 and outlet 116, a filter 118, a pump chamber 120 with inlet valve 122 and outlet valve 124, vent 126, a diaphragm 128, a three-way valve 130, perfusate lines 134 and 136, a canister 140, a base plate 150, and a cannula 160. The system 100 can be connected to an oxygen source 170 with oxygen lines 172, 174, 175, a pump pressure regulator 176, and a vent 178.

[0030] The system 100 can be used to circulate perfusate fluid through a target tissue or organ in the canister 140 to provide oxygen to the tissue. The perfusate fluid can be a perfusate, blood, saline, fluid specifically formulated for organ preservation or perfusion, or some other appropriate fluid for perfusion of an organ or target tissue in the canister 140. The fluid can be, for example, oxy gen-enriched fluid or blood-based fluid, to provide oxygen to the target tissue, organ, or limb. For example, the organ can be a heart, lung, kidney, or other vascular tissue requiring oxygenation while outside the body. The perfusion circuit can include, for example, tubing, piping, or hosing to carry the perfusate fluid between one or more fluid reservoirs, and the canister 140.

[0031] In system 100, the head unit 110 can house components for circulation of perfusate fluid and oxygen throughout the system 100. The head unit 110 can include the oxygenator 112, the filter 118, and the perfusion pump chamber 120, encapsulated by an optional housing (not shown). The head unit 110 can be connected to the canister 140, such as through the base plate 150. The cannula 160 may fluidly connect the head unit 110 to a cannulated organ or target tissue located in the canister 140 by allowing flow of perfusate therebetween. The oxygen source 170 can be in fluid communication with the head unit 110 to allow flow of oxygen, and allow for pressurization of the head unit 110 and the canister 140.

[0032] The head unit 110 can house the oxygenator 112, the filter 118, the pump chamber 120, and the three-way valve 130. The head unit 110 can include an optional housing for encapsulating or covering the components, such as a metallic, composite, or plastic material, for at least partially enclosing and protecting the components in the head unit 110. The head unit 110 can be shaped, sized, or arranged for optimal layout of the components in the head unit 110 while allowing for pumping of perfusate and oxygen through the system 100.

[0033] The oxygenator 112 can be configured to exchange oxygen and carbon dioxide in perfusate fluid. The oxygenator 112 can include a perfusate inlet 114 for incoming de-oxygenated perfusate from the canister 140, and a perfusate outlet 116, wherein outgoing oxygenated perfusate can exit the oxygenator 112. The oxygenator 112 can be secured within the head unit 110, such as to a base plate.

[0034] The oxygenator 112 can be fluidly coupled to the oxygen source 170. The oxygen source 170 can be an oxygen concentrator, an oxygen generator, tank of pressurized oxygen, or other appropriate oxygen source, such as a hook-up. The oxygen source 170 can provide oxygen to the organ preservation system 100 and provide a pressure gradient to the system 100 to induce flow of a perfusate fluid therethrough.

[0035] For example, the oxygen source 170 can be an oxygen concentrator that can filter surrounding air, compress that air to a specified density, and deliver purified oxygen in a pulsatile fashion, or in a continuous stream. Such an oxygen concentrator can be fitted with filters and/or sieve beds to remove nitrogen and other elements, gases, or contaminants from the air. In an example, the oxygen concentrator can include a pressure swing adsorption system, such as the Invacare® Platinum Mobile oxygen concentrator (Invacare Corporation, Elyria, OH). A pressure swing adsorption oxygen concentrator can leverage a molecular sieve to absorb gases and operate using rapid pressure swing adsorption to capture atmospheric nitrogen in minerals, such as zeolite, and subsequently vent that nitrogen, operating in a manner that is similar to a nitrogen scrubber. This can allow other atmospheric gases to exit the system, leaving oxygen as the primary remaining gas. Conventional oxygen concentrators can include an air compressor, the molecular sieve or alternatively a membrane, a pressure equalizer, and various valves and tubes to accomplish these functions. Other types or configurations of oxygen concentrators or oxygen sources are also envisioned herein.

[0036] In some cases, the oxygen source 170 can be an oxygen generator. In this context, an oxygen generator can produce molecular oxygen (O2 gas) by reaction of other chemical components. Examples of oxygengenerating chemical reactions can include thermal decomposition of chlorate or perchlorate salts, hydrolysis of potassium superoxide, enzyme (catalase)- mediated decomposition of hydrogen peroxide, electrolysis of water, or other appropriate reactions.

[0037] The pressure of the oxygen provided by the oxygen source 170 can be regulated by pump pressure regulator 176. The pressure can be about, for example, 75 mm Hg. The oxygen source 170 can be fluidly coupled to the oxygenator 112 through oxygen line 174 and three-way valve 130 to provide oxygen for oxygenation of perfusate running through the oxygenator 112 as will be discussed in greater detail below. Also waste gas can be vented out of the oxygenator at vent 178.

[0038] In the oxygenator 112, de-oxygenated perfusate fluid from the canister 140 can enter through the inlet 114. The perfusate can run up through the oxygenator towards the outlet 116. While perfusate is passed through the body of the oxygenator 112, the perfusate can be oxygenated. For example, the oxygenator 112 can be a hollow cylinder with a central lumen that the perfusate runs through. The cylinder of the oxygenator 112 can include one or more structures or components that allow for dissolution of oxygen within the perfusate. The oxygen and the perfusate within the oxygenator 112 can run in directions opposite each other, to create a counter-current flow. Such a countercurrent flow can increase the gradient and the oxygenation of the perfusate by diffusion of oxygen gas therein.

[0039] The filter 118 can be, for example, a plate filter across the outlet 116 of the oxygenator 112, so that oxygenated perfusate leaving the oxygenator 112 can be filtered for impurities before being cycled back towards the canister 140. The filter can be used leading into or out of the tissue canister 140 of the organ preservation system 100. The filter can include, for example, a particulate filter, a filter for removing contaminants in the perfusate fluid, a filter directed to chemicals or dissolved gases, or any other type of appropriate filter for treatment of the perfusate fluid. In any example of the portable oxygen source and perfusion system disclosed herein, multiple filters can be used. In some cases, a filter can be upstream of the tissue container of the organ preservation system 100 so as to filter the perfusate fluid prior to reaching the tissue or organ being perfused. In some cases, the filter can be downstream of the tissue container of the organ preservation system 100 so that fluid returning to the tissue container reservoir is filtered.

[0040] The oxygenated perfusate can flow out of the oxygenator 112 through the filter 118 into the pump chamber 120. The pump chamber 120 can have an inlet valve 122 and an outlet valve 124, which can be check valves. The diaphragm 128 in the pump chamber 120 can be de-pressurized to allow flow of the oxygenated perfusate into the pump chamber 120. The oxygenated perfusate can flow into the pump chamber 120 through the inlet valve 122, and fill the pump chamber 120 partially or fully. The oxygenated perfusate can remain in the pump chamber 120 until it is pumped out towards the canister 140.

[0041] The diaphragm 128, located in the pump chamber 120, can be pressurized to pump perfusate out of the pump chamber 120, through the outlet valve 124, and towards the target tissue in the canister 140 via line 136. Articulation of the diaphragm 128 can allow pumping of the perfusate out of the pump chamber 120. The valve 130 can be a controllable solenoid valve situated in the oxygen line 174 between the pump pressure regulator 176 and the oxygenator 112. The valve 130 is also between line 174 and diaphragm 128. Valve 130 may be fluidly coupled to the diaphragm 128.

[0042] The canister 140 can be a container for the target tissue or organ being perfused. For example, the canister 140 can contain the perfusate and a heart (or other organ or tissue), coupling with the head unit to form a sterile barrier around the organ, enclosing it within a fluid-tight container. The canister 140 can provide a sterile environment in which to transport and perfuse the target tissue and organ; the canister 140 can be filled with a perfusate liquid in which the target tissue or organ resides. The canister 140 can create a seal with the base plate 150, and be fluidly connected to the components of the head unit 110 through the cannula 160 and the base plate 150. The seal can be created by attachment mechanisms, such as threading, a snap fit, a press fit, O-rings, or other sealing attachments to allow for a liquid-tight seal.

[0043] The cannula 160 can allow for a cannula to fluidly connect the head unit 110 to the target tissue through the base plate 150. For example, where a heart is being transported and perfused, the cannula 160 can include a cannula that can fluidly couple the aorta of the donor heart to the output of the head unit, and also support the weight of the donor heart during transfer to the sterile surgical field. Examples cannulas that can address aortic valve incompetence are discussed below with reference to FIGS. 2-14B. Any of these cannulas may be used with any example of a perfusion system disclosed herein.

[0044] Other examples of perfusion systems are shown and discussed with reference to U.S. Appln. No. 63/118,497, which is herein incorporated by reference in its entirety.

[0045] FIG. 2 illustrates an exploded view of a cannula 200 with a flexible elongated passage. The cannula 200 can be configured to secure a heart to a perfusion system, such as system 100 discussed above, by way of the aorta 210, or it may be used with any other perfusion system. The cannula 200 can include an aortic connector 220, an elongate shaft 230, a converter 240, and an inner lid 250. [0046] The aortic connector 220 can be on a first end of the cannula 200, and the converter 240 can be on an opposing second end of the cannula 200. The aortic connector 220 can be designed with the outer diameter of the lower end matched to the inner diameter of the aorta 210 in the case of a heart target tissue. In the case of other types of organs or tissues, a different connector can replace the aortic connector to allow for a secure, fluid-tight connection for pumping of perfusate through the tissue or organ. The converter 240 can secure the cannula 200 to the perfusion system such as through the inner lid 250.

[0047] The elongate shaft 230 can be a flexible link between the bottom and top sections of the cannula 200 to accommodate the natural anatomical variations in aortic arch size and shape. This accommodation may help maintain valve competence by alleviating physiologically unnatural mechanical stresses on the valve structure which may predispose the valve to incompetence. The accommodation may also help address aortic valve incompetence by reducing unnatural stress in the aortic valve. The elongate shaft 230 can include a flexible portion having one or more corrugations. In some cases, the elongate shaft 230 can be a hose having crimping or a hose having scallops. The elongate shaft 230 can flex so that the cannula 200 and the heart, when connected to the perfusion system, are comfortably situated without inducing additional mechanical stresses in the aortic root structure. The convolutions, scallops, or crimps of the elongate shaft 230 facilitate flexibility of the connection while, critically, also preventing kinking of the inner lumen of the shaft.

[0048] FIGS. 3A-3B illustrate schematic diagrams of an aortic valve functioning normally in an example, while FIG. 4 illustrates an aortic valve with incompetence in an example. FIG. 3A shows a top view of an aortic root 300, while FIG. 3B shows a side view of the valve 310 in the aortic root 300. The aortic root 300 in FIGS. 3 A-3B includes aortic valve 310. The aortic valve 310 is divided into three valve leaflet junctures 312, 314, 316, which form a seal between the leaflets where the three leaflets come into mutual apposition. The three valve leaflet junctures 312, 314, 316 define three sinuses of Valsalva 318, 320, 322. The coronary arteries 315 connect to the aortic roots at two of sinuses of Valsalva 318, 320. [0049] Similarly, FIG. 4 depicts a top view of an aortic root 400, but the valve at the aortic root 400 in FIG. 4 is incompetent. The aortic root 400 can include aortic valve 410, leaflet junctures 412, 414, 416, sinuses 418, 420, 422, and coronary arteries 415. When a valve leaflet does not form a continuous line of physical contact with the adjacent valve leaflet, the aortic valve is incompetent, and fluid flows through any or all points where physical contact is discontinuous between the valve leaflet junctures 412, 414, 416. Fluid flowing through the valve bypasses the coronary arteries 415, shown by the arrows 405. [0050] Aortic valve incompetence during perfusion can be addressed, for example, by any of the cannulas discussed herein with reference to FIGS. 5A- 15C. For example, a flexible membrane, attached loosely to the end of the cannula, can be used. Such a membrane can respond to hydraulic pressure induced by retrograde fluid flow through the aortic valve by folding over the leaking valve leaflets to seal off the retrograde flow.

[0051] FIGS. 5A-5B illustrate schematic diagrams of a first example flexible membrane 520 for use with any cannula. FIG. 5A is a side view of an aortic root 500 with a flexible membrane 520, and FIG. 5B is a top down view. Shown in FIGS. 5A-5B are the aortic root 500, aortic valve 510, and a flexible membrane 520. The flexible membrane 520 can be tethered to a distal end of the cannula for insertion into the heart when the heart is placed in the perfusion system for transport. The flexible membrane 520 can be configured to cover aortic valve leaflets. The flexible membrane 520 can be configured to fold or drape over the valve leaflets and seal off retrograde flow. In some cases, the flexible membrane 520 can be configured to seal three valve leaflets.

[0052] The flexible membrane 520 can be suspended above the aortic valve 510. The aortic valve 510 itself can respond to retrograde flow of perfusate through the aortic valve 510. The change in pressure can induce the flexible membrane 520 to fold over contact points of the valve leaflets where leaking might be occurring. The flexible membrane 520 can be guided by the retrograde flow itself, and held in place by hydrostatic pressure once the leak has been sealed and pressure differential builds up.

[0053] FIGS. 6A-6B illustrate schematic diagrams of a second example flexible membrane 620 for use with a cannula 660 or any cannulas disclosed herein. FIGS. 6A and 6B are both side views of the aortic root 600. In FIG. 6A, the flexible membrane 620 is not engaged with the valve. In FIG. 6B, the flexible membrane 620 is engaged with the valve. The cannula 660 is shown in FIG. 6A and FIG. 6B connected to the flexible membrane 620. Also shown in FIGS. 6A-6B is the aortic valve 610.

[0054] In FIGS. 6A-6B, the flexible membrane 620 can be attached to the aortic cannula 660 in a manner that tethers the membrane 620 to the cannula 660, such that it is initially suspended and spread loosely above the valve 610 prior to initiation of perfusate flow. This also allows the flexible membrane 620 to be retrieved along with the aortic cannula 660 at the time of cannula removal so that it is not left behind in the heart.

[0055] Shown in FIG. 6A, the flexible membrane 620 can be suspended by a single, central tether prior to initiation of perfusate flow. Shown in FIG. 6B, the perfusate flow can push down through holes 630 in the end of the cannula 660 to force the periphery of the flexible membrane 620 to drape over the valve 610 leaflets, while the center of the membrane 620 can remain tethered to the cannula 660. In this way, the perfusate flow can be directed to the coronary arteries, which are the remaining exit path from the pressurized aortic root 600 for perfusate.

[0056] The flexible membrane 620 can include a single or multiple connection points to the cannula 660. The flexible membrane 620 can be configured to be suspended above the aortic valve 610 when the one or more connection points are engaged. Where a single connection point is used, a central point of the flexible membrane 620 can be tethered to the cannula 660.

[0057] FIGS. 7A-7C illustrate schematic diagrams of a method of attaching a flexible membrane, such as those flexible membranes shown in FIGS. 5A-6B. In FIGS. 7A-7C, the aortic root 700, aortic valve 710, flexible membrane 720, cannula 760, and a heart 770 are shown.

[0058] The flexible membrane 720 can be attached to the end of the cannula 760 in a variety of ways, such as through the tether 730 and attachment points 732, 734, 736. For example, a central tether 730 can be used, alone or in combination with spot attachments such as points 732, 734, 736. These attachment points 732-736 can connect to a distal end of the cannula 760, for easy insertion and use with the cannula 760. Points 732, 734, 736 could also indicate positions for tether attachments such that the flexible membrane 720 is suspended below the end of the cannula by tethers, filaments or fibers, such as about 5 mm in length.

[0059] FIGS. 7A and 7B depict a top-down view of the aortic root 700 with a flexible membrane 720 coupled to cannula 760 (best illustrated in profile view in FIG. 7C). In FIG. 7A. the flow is not yet initiated, and in FIG. 7B, flow of perfusate is initiated, causing the flexible membrane to conform to the shape of the leaflet junctions of the valve. In this case, the tether 730 and the attachment points 732, 734, and 736 of FIGS. 7A and 7B stay attached to the cannula 760 (which is shown in profile in FIG. 7C), but the remainder of the flexible membrane 720 is free to stretch and drape over the aortic valve 710 as influenced by any retrograde flow of perfusate that may be present.

[0060] Shown in FIG. 7C, in some cases, the flexible membrane 720 can additionally include a sponge type element 775 extending from the cannula 760, such that the sponge type element 775 abuts the valve leaflets and aids the flexible membrane 720 in meeting the valve 710. FIG. 7C depicts the cannula 760 with attached flexible membrane 720 inserted into the aorta of the heart 770 to address aortic valve 710 incompetence. In FIG. 7C, flow of perfusate is indicated by the arrows from the cannula 760 into the aortic root 700. As indicated by the arrows, the flow will avoid leaking through the aortic valve 710 when the flexible membrane 720 is engaged, and instead go out the coronary arteries. In FIG. 7C, the flexible membrane 720 can be loosely attached to the optional sponge type element 775 at the end of the cannula 760, which gently presses the membrane 720 down against the sealing surfaces of the valve 710. This can allow for a more effective seal, and less aortic valve incompetence.

[0061] FIGS. 8-11 illustrate potential supports for use with a flexible membrane attached to the cannula. Like the flexible membranes discussed above, the variations discussed with reference to FIGS. 8-11 can address aortic valve incompetence by plugging small openings between valve leaflets during retrograde aortic perfusion, without having to use balloon catheters, which could cause tissue damage from vessel occlusion, and the membrane can be relatively inexpensive. [0062] In FIGS. 8-11, a pliable flexible membrane, attached to a cannula distal end, can be suspended proximal to the aortic valve. The flexible membrane can have slack such that if significant retrograde flow across the aortic valve occurs because of valve incompetence, the retrograde flow can pull the flexible membrane into the openings between valve leaflets, and seal the leak. The flexible membrane can then be held in place by the pressure differential across the membrane.

[0063] The flexible membrane can be secured to the cannula in a mechanically secure fashion to allow easy recovery after use, to prevent the flexible membrane from translating into the coronary ostia and occluding the coronary arteries, and to prevent the flexible membrane from being sucked into the left ventricle of the heart if gross aortic valve incompetence is present.

[0064] The flexible membrane can be made in a variety of geometric configurations, for example, a circular planar shape, a planar shape cut into a trilobe shape, a molded 3D tri-lobe shape, vertical curtains, or other appropriate shapes. Where a circular planar shape is used, the flexible membrane can have a smaller diameter than the inner diameter of the valve, to avoid occlusion of the coronary ostia. A tri-lobe shape can be made to fit over the three leaflets of the aortic valve. A molded 3D tri-lobe shape can, for example, be a tri-lobed shape with three ridges for the valve. Such a tri-lobed shape can be, for example, pinched and naturally biased to fold into a tri-lobed form. A vertical curtain shape can, for example, be held adjacent to the leaflet junctures.

[0065] Preferably, translation of the flexible membrane to undesired locations is prevented. For example, plugging of the coronary ostia, or movement away from a functional position, can be prevented with the use of one or more supports to direct the draping and location of the flexible membrane. Mechanical supports can allow for help in maintaining positioning of the flexible membrane, such as by mechanical supports attached to the cannula. Various geometric shapes of the flexible curtain and various types of supports are shown and discussed with reference to FIGS. 8-11.

[0066] FIG. 8 illustrates a schematic diagram of a flexible membrane 820 attached to cannula with a central support 865 used in aortic root 800. In FIG. 8, a single central support 865 is used with the circular planar flexible membrane 820 over the aortic valve 810. In FIG. 8, the central support 865 is situated over the center of the valve tricuspid junction to center the flexible membrane 820 suspended over the valve 810.

[0067] FIG. 9 illustrates a schematic diagram of a flexible membrane 920 with the cannula 960 with circumferential supports 965 used in aortic root 900. The flexible membrane 920 can be a circular drape that is held down in place by the three circumferential supports 965. The three circumferential supports 965 can be situated equidistant from each other around the circumference of the circular drape flexible membrane 920. The circumferential supports 965 can extend down into the leaflets’ sinus and help secured the flexible membrane 920 into place. In FIG. 9, the supports 965 are around the circumference of the flexible membrane 920, whereas in FIG. 8, the support 865 is a single central support.

[0068] FIG. 10 illustrates a schematic diagram of a flexible membrane 1020 with the cannula 1060 with rigid supports 1065 having a castellated edge. FIG. 10 shows a side view of the cannula 1060 with the flexible membrane 1020 both before deployment (dotted line) and after deployment (solid line). The flexible membrane 1020 can extend from the cannula 1060 to drape over the aortic valve 1010.

[0069] The cannula 1060 can include a plurality of rigid supports 1065, spaced apart along the distal end of the cannula 1060. The rigid support 1065, not attached to the flexible membrane 1020, can help avoid the flexible membrane 1020 folding back on itself, and help direct cannula perfusate flow into the membrane 1020. These rigid supports 1065 could be used in conjunction with any of the other supports discussed above.

[0070] FIG. 11 illustrates a schematic diagram of a flexible membrane 1120 with radial supports 1165 used with the aortic root 1100. Shown in FIG. 11, three radial supports 1165 can be used with a flexible membrane 1120 in the form of a curtain falling down from said supports. In this case, the three radial supports 1165 can be positioned on top of valve leaflet junctures, and hold the curtain of the flexible membrane 1120 atop and in alignment with said junctures. The flexible membrane 1120 can, in an example, be in a tri-lobed or tri-rigged form, that may naturally fold or be pinched into this shape. The supports 1165 can help hold the three portions of the flexible membrane 1120 adjacent the leaflet junctures.

[0071] FIGS. 12A-12B illustrate schematic diagrams of an expandable member cannula 1260, an alternative to the flexible membrane configuration discussed above. The expandable member cannula 1260 can be a cannula with an expandable member 1220 situated to occlude the left ventricular outflow tract (LVOT), sized and shaped for insertion through the aortic root 1200 to address aortic valve incompetence in the aortic valve 1210.

[0072] The expandable member 1220 can be attached to and extend from a distal end of the cannula 1260, and be configured for insertion through the aortic valve 1200 to rest below the valve leaflets in the LVOT. The expandable member 1220 can be capable of an expanded configuration and a collapsed configuration. In the collapsed configuration, the expandable member 1220 can be deflated and configured for insertion or removal through the aortic valve 1200. In the expanded configuration, the expandable member 1220 can be inflated. The expandable member 1220 can be configured to be inflated after insertion thereby preventing perfusate flow past the expandable member. In an example, the expandable member 1220 can be a balloon.

[0073] In some cases, the cannula 1260 can additionally include one or more attachment mechanisms or supports to help secure the expandable member 1220 near the aortic valve 1210. In some cases, the cannula 1260 can include a passage (e.g., an inflation lumen 1225) for access to and inflation of the expandable member 1220. In another embodiment, the inflation lumen 1225 can also function as the attachment mechanism to the cannula 1260, having a mechanism for adjusting the length of the attachment mechanism between the end of the cannula 1260 and expandable member 1220. The expandable member 1220 can be attached to the cannula 1260 by an attachment mechanism 1235. [0074] The expandable member 1220 configuration combines a concept of an LVOT occlusion balloon with the aortic cannula. In FIGS. 12A-12B, the expandable member 1220 can be attached to the cannula 1260 so that it can be passed down through the aortic valve 1210 in the collapsed configuration, and held in place by an attachment to the aortic cannula 1260. The expandable member 1220, once in place, can be inflated through a passage in the cannula 1260 to the expanded configuration. In the expanded configuration, the expandable member 1220 can form a seal against the walls of the LVOT, preventing retrograde perfusate flow into the left ventricle in the case of aortic valve incompetence. The expandable member 1220, which may be a balloon, can be expanded with a fluid such as saline, contrast media, combinations thereof, or other fluids including gases.

[0075] The use of the expandable member 1220 prevents retrograde perfusate flow, and addresses the competence of the aortic valve 1210. An attachment or tether between the expandable member 1220 and the cannula 1260 allows for placement of the expandable member 1220 without downward migration of the expandable member 1220 out of the LVOT towards the left ventricle. In some cases, the tension of the attachment or tether, or the length of the tether, can be adjusted after the cannula 1260 is inserted. In some cases, the expandable member 1220 can be tethered to a distal end of the cannula 1260, but inflation can be separate. In this case, inflation can be done, for example, by a lumen exiting the heart at the left atrium. In some cases, the expandable member 1220 can include a catheter shaft exiting through the cannula 1260 to allow for inflation.

[0076] In some cases, direct cannulation of the coronary arteries is preferred to cannulation of the aorta. FIG. 13 illustrates a schematic diagram of a bifurcated cannula 1360 for direct cannulation of the coronary arteries via an expandable member or compression fit. In this case, the cannula 1360 can include two arms 1320, each arm 1320 configured to engage a coronary artery 1315. Each of the two arms 1320 can, for example, include an expandable member 1321, such as a balloon, to engage the coronary arteries 1315.

[0077] With a bifurcated cannula 1360, the two separate arms 1320 for perfusion of the right and left coronary arteries 1315 can allow for direct perfusion of those arteries instead of through the aorta 1300. The two arms 1320 can be sealed against the inner walls of the coronary arteries 1315, such as by balloons or a compression fit, to mitigate the potential effects of aortic valve incompetence.

[0078] FIGS. 14A-14C illustrate schematic diagrams of an arm 1420 of a bifurcated cannula such as the one in FIG. 13 above, having a tapered member 1321 for engaging the coronary artery 1315. In FIG. 14 A, the arm 1420 is inserted into the opening (ostia) of the coronary artery 1415. In FIG. 14 A, the arm 1420 is inserted into the opening of the coronary artery 1415 with the tapered member 1421 having the smaller end first. In FIG. 14B, the tapered member 1421 has a larger end that is engaged with the inner walls at the opening of the coronary artery 1415 as the tapered member 1421 is inserted. In FIG. 14C, the tapered member 1421 is engaged against the inner surface of the coronary artery near the opening 1415 to allow sealing. In FIG. 14C, orifices 1423 in the cannula can allow for a diffuse flow pattern and prevent occlusion of arterial side branches.

[0079] The bifurcated cannula in FIGS. 14A-14C can allow for a seal, aside from the expansion of the cannula. The tapered ends of the tapered member 1421 can allow for insertion through the ostia, with the larger end making a sealing contact with the opening of the coronary artery without having an actively expanding member. In some cases, the tapered member used on the left coronary artery can be about 0.5 mm larger in average to accommodate for anatomical differences.

[0080] FIGS. 15A-15C illustrate schematic diagrams of a bifurcated cannula 1560 with either expandable or tapered members 1520 and a pressurization member 1525. In cannula 1560, the additional pressurization member 1525 can be an expandable member such as a balloon that can be inflated after insertion to secure the cannula 1560 and the smaller members 1520 on the arms of the bifurcated cannula 1560 and help anchor them in position. This figure makes reference with similar compression fittings to those seen in FIG. 14 for the cannula arms 1420. However, in FIGS. 15A-15C, the force used to press the compression structure 1521 against the coronary ostia opening is applied by the expandable element 1525.

Various Notes & Examples

[0081] Example 1 can include a perfusion system comprising: an oxygenator configured to be fluidly coupled with an oxygen source and configured to receive oxygen therefrom and to oxygenate perfusate; a perfusion pump operably coupled with the oxygenator and configured to circulate the perfusate through the oxygenator; a canister having a receptacle to receive a target tissue; and a cannula to fluidly couple to the oxygenator and the target tissue, the cannula configured to convey the perfusate from the oxygenator to the target tissue in the canister, the cannula comprising a flow regulating element having a closed configuration and a deployed configuration, wherein in the closed configuration the flow regulating element is configured to be moved toward the target tissue, and in the deployed configuration the flow regulating element is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue.

[0082] Example 2 can include Example 1, wherein the cannula comprises an elongate shaft connecting a first end and a second end, the first end configured to interface to the perfusion system and the second end configured to interface with the target tissue.

[0083] Example 3 can include any of Examples 1-2, wherein the elongate shaft comprises a flexible portion having one or more convolutions. [0084] Example 4 can include any of Examples 1-3, wherein the elongate shaft comprises a hose having crimping.

[0085] Example 5 can include any of Examples 1-4, wherein the elongate shaft comprises a hose having scallops.

[0086] Example 6 can include any of Examples 1-5, wherein the cannula further comprises a flexible membrane configured to cover one or more aortic valve leaflets and prevent fluid flow therethrough, the flexible membrane tethered to a first end of the cannula.

[0087] Example 7 can include any of Examples 1-6, wherein the flexible membrane further comprises one or more connection points for attaching the flexible membrane to the cannula.

[0088] Example 8 can include any of Examples 1-7, wherein the flexible membrane is configured to fold over the valve leaflets and seal off retrograde flow.

[0089] Example 9 can include any of Examples 1-8, wherein the flexible membrane is configured to seal an open area bounded by two or three valve leaflets. [0090] Example 10 can include any of Examples 1-9, wherein the flexible membrane is configured to be suspended above the aortic valve when the cannula is engaged with the target tissue.

[0091] Example 11 can include any of Examples 1-10, wherein a central portion of the flexible membrane is directly tethered to the cannula.

[0092] Example 12 can include any of Examples 1-11, wherein the flexible membrane is tethered to the cannula at a single point of attachment.

[0093] Example 13 can include any of Examples 1-12, wherein the flexible membrane is tethered to the cannula at multiple points of attachment.

[0094] Example 14 can include any of Examples 1-13, further comprising a sponge element adjacent a distal end of the cannula configured to urge the flexible membrane into contact with one or more of the valve leaflets.

[0095] Example 15 can include any of Examples 1-14, wherein the flexible membrane comprises at least one circumferential support to secure the flexible membrane to the valve leaflets.

[0096] Example 16 can include any of Examples 1-15, wherein the cannula further comprises one or more rigid supports configured to prevent a prolapse of the flexible membrane.

[0097] Example 17 can include any of Examples 1-16, wherein the cannula further comprises at least one draping support over which the flexible membrane is configured to drape.

[0098] Example 18 can include any of Examples 1-17, wherein the cannula further comprises a left ventricular outflow tract (LVOT) expandable member having an expanded configuration and a collapsed configuration.

[0099] Example 19 can include any of Examples 1-18, wherein the expandable member is a balloon.

[00100] Example 20 can include any of Examples 1-19, wherein the expandable member is attached to an end of the cannula and configured for insertion through the aortic valve.

[00101] Example 21 can include any of Examples 1-20, wherein the expandable member in the collapsed configuration is deflated and configured to be inserted or removed through the aortic valve. [00102] Example 22 can include any of Examples 1-21, wherein the expandable member is inflated in the expanded configuration.

[00103] Example 23 can include any of Examples 1-22, wherein the expandable member is configured to be inflated after insertion through the aortic valve, to prevent fluid flow across the aortic valve.

[00104] Example 24 can include any of Examples 1-23, further comprising an attachment mechanism configured to secure the expandable member within the cannula.

[00105] Example 25 can include any of Examples 1-24, wherein the attachment mechanism, is adjustable.

[00106] Example 26 can include any of Examples 1-25, wherein the expandable member is configured to be inflated through a lumen in the cannula. [00107] Example 27 can include any of Examples 1-26, wherein the cannula comprises at least two arms, each of the arms configured to engage with a coronary artery.

[00108] Example 28 can include any of Examples 1-27, wherein each of the two arms further comprises an expandable member coupled thereto, the expandable member being inflatable when the cannula is engaged against the target tissue.

[00109] Example 29 can include any of Examples 1-28, wherein each of the expandable members comprises a tapered end for engaging the coronary artery.

[00110] Example 30 can include a cannula for fluidly coupling a perfusion system to target tissue, wherein the cannula is configured to convey perfusate from the perfusion system to the target tissue, the cannula comprising a flow regulating element having a closed configuration and a deployed configuration, wherein the flow regulating element in the closed configuration is configured to be advanced toward the target tissue, and the flow regulating element in the deployed configuration is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue.

[00111] Example 31 can include Example 30, wherein the cannula comprises an elongate shaft connecting a first end and a second end, the first end configured to interface to the perfusion system and the second end configured to interface with the target tissue.

[00112] Example 32 can include any of Examples 30-31, wherein the elongate shaft comprises a flexible portion having one or more convolutions.

[00113] Example 33 can include any of Examples 30-32, wherein the cannula further comprises a flexible membrane configured to cover one or more aortic valve leaflets and prevent fluid flow therethrough, the flexible membrane tethered to a first end of the cannula.

[00114] Example 34 can include any of Examples 30-33, wherein the flexible membrane further comprises one or more connection points for coupling the flexible membrane to the cannula.

[00115] Example 35 can include any of Examples 30-34, wherein the flexible membrane comprises at least one circumferential support to secure the flexible membrane to the valve leaflets.

[00116] Example 36 can include any of Examples 30-35, wherein the cannula further comprises a left ventricular outflow tract (LVOT) expandable member having an expanded configuration and a collapsed configuration.

[00117] Example 37 can include any of Examples 30-36, wherein the expandable member is a balloon.

[00118] Example 38 can include any of Examples 30-37, wherein the cannula comprises at least two arms, each of the arms configured to engage with a coronary artery.

[00119] Example 39 can include any of Examples 30-38, wherein each of the two arms further comprises an expandable member coupled thereto, the expandable members being inflatable when the cannula is engaged against the target tissue.

[00120] Example 40 can include a method of perfusing tissue comprising: pumping oxygenated perfusate through a cannula to the tissue, the cannula configured to convey perfusate from an oxygenator to the target tissue in a canister, the cannula comprising a flow regulating element having a closed configuration and a deployed configuration, wherein the flow regulating element in the closed configuration is configured to be moved toward the target tissue, and the now regulating element in the deployed configuration is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue. [00121] Example 41 can include Example 40, wherein the cannula comprises an elongate shaft connecting a first end and a second end, the first end configured to connect to the perfusion system and the second end configured to interface with the target tissue.

[00122] Example 42 can include any of Examples 40-41, wherein the cannula further comprises a flexible membrane configured to cover one or more aortic valve leaflets and prevent fluid flow therethrough, the flexible membrane tethered to a first end of the cannula.

[00123] Example 43 can include any of Examples 40-42, wherein the cannula comprises a left ventricular outflow tract (LVOT) expandable member having an expanded configuration and a collapsed configuration.

[00124] Each of these non-limiting examples can stand on its own, or can be combined in various permutations or combinations with one or more of the other examples.

[00125] The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the inventive subject matter can be practiced. These embodiments are also referred to herein as “examples.” Such examples can include elements in addition to those shown or described. However, the present inventors also contemplate examples in which only those elements shown or described are provided. Moreover, the present inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

[00126] In the event of inconsistent usages between this document and any documents so incorporated by reference, the usage in this document controls.

[00127] In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” In this document, the term “or” is used to refer to a nonexclusive or, such that “A or B” includes “A but not B,” “B but not A,” and “A and B,” unless otherwise indicated. In this document, the terms “including” and “in which” are used as the plain-English equivalents of the respective terms “comprising” and “wherein.” Also, in the following claims, the terms “including” and “comprising” are open-ended, that is, a system, device, article, composition, formulation, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.

[00128] Method examples described herein can be machine or computer- implemented at least in part. Some examples can include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples. An implementation of such methods can include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code can include computer-readable instructions for performing various methods. The code may form portions of computer program products. Further, in an example, the code can be tangibly stored on one or more volatile, non- transitory, or non-volatile tangible computer-readable media, such as during execution or at other times. Examples of these tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.

[00129] The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations. The scope of the inventive subject matter should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMS What is claimed is:

1. A perfusion system comprising: an oxygenator configured to be fluidly coupled with an oxygen source and configured to receive oxygen therefrom and to oxygenate perfusate; a perfusion pump operably coupled with the oxygenator and configured to circulate the perfusate through the oxygenator; a canister having a receptacle to receive a target tissue; and a cannula to fluidly couple to the oxygenator and the target tissue, the cannula configured to convey the perfusate from the oxygenator to the target tissue in the canister, the cannula comprising a flow regulating element having a closed configuration and a deployed configuration, wherein in the closed configuration the flow regulating element is configured to be moved toward the target tissue, and in the deployed configuration the flow regulating element is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue.

2. The system of claim 1, wherein the cannula comprises an elongate shaft connecting a first end and a second end, the first end configured to interface to the perfusion system and the second end configured to interface with the target tissue.

3. The system of claim 2, wherein the elongate shaft comprises a flexible portion having one or more convolutions, a hose having crimping, a hose having scallops, or combinations thereof.

4. The system of claim 1, wherein the cannula further comprises a flexible membrane configured to cover one or more aortic valve leaflets and prevent fluid flow therethrough, the flexible membrane tethered to a first end of the cannula, and wherein the flexible membrane further comprises one or more connection points for attaching the flexible membrane to the cannula.

26

5. The system of claim 4, wherein the flexible membrane is configured to fold over the valve leaflets and seal off retrograde flow.

6. The system of claim 5, wherein the flexible membrane is configured to be suspended above the aortic valve when the cannula is engaged with the target tissue.

7. The system of claim 5, further comprising a sponge element adjacent a distal end of the cannula configured to urge the flexible membrane into contact with one or more of the valve leaflets.

8. The system of claim 4, wherein the flexible membrane comprises at least one support, the support comprising a circumferential support to secure the flexible membrane to the valve leaflets, a rigid support configured to prevent a prolapse of the flexible membrane, or a draping support over which the flexible membrane is configured to drape.

9. The system of claim 1, wherein the cannula further comprises a left ventricular outflow tract (LVOT) expandable member having an expanded configuration and a collapsed configuration, wherein the expandable member is attached to an end of the cannula and configured for insertion through the aortic valve.

10. The system of claim 9, wherein the expandable member in the collapsed configuration is deflated and configured to be inserted or removed through the aortic valve.

11. The system of claim 9, wherein the expandable member is configured to be inflated after insertion through the aortic valve, to prevent fluid flow across the aortic valve.

12. The system of claim 9, further comprising an adjustable mechanism configured to secure the expandable member within the cannula.

13. The system of claim 1, wherein the cannula comprises at least two arms, each of the arms configured to engage with a coronary artery, each of the two arms further comprising an expandable member coupled thereto, the expandable member being inflatable when the cannula is engaged against the target tissue.

14. A cannula for fluidly coupling a perfusion system to target tissue, wherein the cannula is configured to convey perfusate from the perfusion system to the target tissue, the cannula comprising a flow regulating element having a closed configuration and a deployed configuration, wherein the flow regulating element in the closed configuration is configured to be advanced toward the target tissue, and the flow regulating element in the deployed configuration is configured to prevent retrograde flow of the perfusate across a native valve in the target tissue.

15. The cannula of claim 14, wherein the cannula comprises an elongate shaft connecting a first end and a second end, the first end configured to interface to the perfusion system and the second end configured to interface with the target tissue, the elongate shaft comprising a flexible portion having one or more convolutions.