Medical device

Abstract

The present invention provides an implantable medical device having: a flexible substrate (10); a delivery catheter (20) formed in the flexible substrate and having an inlet and an outlet at a proximal end of the device wherein the delivery catheter leads from the inlet to the outlet via a circuit at a distal end of the device; and a delivery hole formed in the delivery conduit, the delivery hole allowing fluid to flow from the conduit to the outside of the substrate. Aspects of the invention also provide a system for delivering a medicament to a patient and a controller (43) for an implantable medical device configured to deliver a medicament primarily by diffusion rather than convection. Further aspects of the invention provide methods of delivering an agent primarily by diffusion rather than to a flow to a patient.

Description

Technical Field

[0001] The present invention relates to a medical device. In particular, the present invention relates to implantable devices, such as those that interface with biological tissue (such as the brain) and / or are used to deliver therapeutic substances. Background Art

[0002] Neurological diseases such as Parkinson's disease, Alzheimer's disease and depression are estimated to affect hundreds of millions of people worldwide. However, despite this high unmet need, existing treatments for central nervous system diseases have very low success rates.

[0003] There are likely two main reasons for this low success rate. The first is an incomplete understanding of the brain, especially at the macroscopic level. The second is the difficulty in achieving consistent targeted delivery of therapeutic agents due to the blood-brain barrier (BBB) ​​and blood-cerebrospinal fluid barrier (Wolak et al., 2013). It is estimated that the BBB blocks approximately 98% of small molecule drugs and nearly 100% of large molecule drugs (Zhou et al., 2013).

[0004] Various attempts have been made to develop delivery methods that can overcome the BBB. One proposed approach is electrophoretic drug delivery, which allows dry delivery by allowing only drug molecules to pass through the membrane into the brain. However, this approach is limited to certain applications because the drug needs to be small and charged; this still makes it difficult to deliver larger amounts of drugs (Proctor et al., 2018).

[0005] Another proposed approach is "convection enhanced delivery" (CED), a technique that exploits increased fluid flow to increase the delivery of macromolecules and drugs throughout tissues. CED works by applying a local pressure differential to drive fluid flow through the tissue so that convective forces dominate diffusive transport. This allows drugs to bypass the BBB.

[0006] However, CED has a number of disadvantages. The diameter of the needles used typically ranges from a few hundred micrometers to a few millimeters, potentially triggering a foreign body reaction and making it susceptible to reflux. In addition, the pressure applied may damage the brain and cause edema. Summary of the invention

[0007] The present invention is directed to solving one or more of the above problems.

[0008] Aspects of the present invention are directed to providing devices that can mitigate or even eliminate foreign body reaction.

[0009] Aspects of the invention are directed to providing devices having mechanical properties that match those of the brain.

[0010] In general, aspects of the invention provide minimally invasive devices that are capable of delivering drugs to regions of the body, such as the brain, at a cellular scale, preferably primarily using diffusion as a delivery mechanism.

[0011] A first aspect of the present invention provides an implantable medical device having: a flexible substrate; a delivery catheter formed in the flexible substrate and having an inlet and an outlet located at the proximal end of the device, wherein the delivery catheter passes from the inlet to the outlet via a loop at the distal end of the device; and a delivery hole formed in the delivery catheter to allow fluid to flow from the catheter to the outside of the substrate.

[0012] Thus, the delivery conduit can form a closed fluid passage from the inlet to the outlet, wherein the fluid can only exit the conduit through the delivery apertures. Such a circulation type arrangement can allow for diffusion delivery (or at least primarily diffusion delivery) of the agent by diffusion of the agent from the fluid in the delivery conduit through the delivery apertures, rather than convective delivery of the delivered agent through one or more open-ended delivery conduits.

[0013] In particular, the arrangement of the device can allow a fluid containing the agent to circulate to and through the implanted region, where the molecules of interest can diffuse into the region surrounding the delivery aperture, but only a small portion of the fluid supplied to the delivery catheter actually exits the catheter. This can be contrasted with the alternative of forcing a volume of fluid to the distal end of a more standard "injection-type" delivery catheter, where all of the fluid delivered to the distal end is forced into the body region surrounding that end.

[0014] Preferably, the delivery aperture is formed at the distal end of the device.

[0015] The device may have multiple delivery conduits, each forming a loop. These conduits may be in fluid communication with each other (eg, sharing a common inlet and a common outlet between two or more conduits), or may have separate inlets and outlets, or a combination of these alternatives.

[0016] The device may be arranged to deliver any type of drug or medicament through the delivery aperture.

[0017] Preferably, the device is sized and configured to minimize or eliminate foreign body response. This may include the selection of materials from which the device is made. For example, sizing the device at the cellular scale has been shown to mitigate foreign body response and allow long-term implantation.

[0018] Preferably, not only the substrate but also the entire device, or at least the implantable / distal end of the device (eg the part intended to contact the target tissue) is flexible, which preferably includes the sensor. Such flexibility also helps to reduce foreign body reactions.

[0019] In specific embodiments, the device or its distal end may have a bend radius of no greater than about 2 mm, preferably no greater than 1.5 mm, and more preferably no greater than 1 mm. The bend radius is measured based on the internal curvature and is the minimum radius at which a component (in this case, the device) can be bent in at least one direction without damaging it. The bend radius defined herein refers to elastic deformation as opposed to plastic deformation, such that a device that is bent to a radius greater than the minimum bend radius under an applied force will at least partially return to its original shape when the applied force is removed. In other words, in these embodiments, the device of this aspect can be bent to an internal curvature of 2 mm, for example by rolling up when the device is configured for insertion into a patient, and then unfolded (e.g., rolled out) to an extended, less curved configuration (e.g., a substantially planar configuration), and still function exactly as it did prior to being bent.

[0020] The device may further include one or more sensors. One or more of the sensors may be formed on an outer surface of the flexible substrate. Alternatively or additionally, one or more sensors may be formed in the delivery catheter.

[0021] The sensor may include one or more electrodes.The sensor may be positioned proximate to the delivery aperture.

[0022] The sensors may be arranged to detect delivery of medicament from the device and / or to detect the condition of the patient, for example by monitoring brain activity.

[0023] Sensors in the delivery catheter may be arranged to monitor flow rate or pressure.

[0024] The sensor may be arranged to detect the presence of a biochemical substance.

[0025] There may be multiple sensors, which may be arranged for the same purpose or for different purposes. The sensors may be arranged to cooperate, for example so that the difference between the signals from two (or more) sensors provides relevant information. The multiple sensors may be arranged in an array, which may include regular spacing of sensors, and / or positions of sensors at known distances from each other and / or from the delivery aperture.

[0026] The sensor may be connected to the proximal end of the device via one or more conductors.

[0027] The device may have multiple delivery holes, each of which allows fluid to flow from the catheter to the exterior of the substrate. Multiple holes may be provided to allow fluids and molecules to flow from the delivery catheter to the exterior of the substrate (e.g., into a patient) at a variety of different locations, or to increase the contact area available for fluid and molecule transfer.

[0028] In certain embodiments, a plurality of said delivery holes are arranged close to each other.

[0029] In certain embodiments, the delivery apertures are arranged in multiple groups, with the apertures in each group being closer to each other than apertures in different groups.

[0030] Preferably, the one or more delivery holes are micron-sized. More preferably, the one or more delivery holes have a diameter between 1 μm and 50 μm, preferably between 5 μm and 10 μm. Where there are multiple delivery holes, these delivery holes may have the same size, but not necessarily.

[0031] One or more delivery holes can have a semipermeable membrane that allows molecules below a certain size to pass through the delivery hole while preventing molecules above the certain size from passing through the delivery hole. This can allow, for example, relatively small drug molecules to pass from the delivery catheter through the delivery hole to the patient while preventing larger molecules (e.g., proteins) from passing in the opposite direction. In other embodiments, the hole is not covered by any type of membrane.

[0032] The outer diameter of the delivery catheter is preferably between 1 μm and 500 μm, more preferably between 5 μm and 100 μm, more preferably between 5 μm and 25 μm.

[0033] The device is preferably configured for implantation through an incision with a diameter of less than 6 mm. This can enable the device to be used in minimally invasive surgery. The device can be collapsible / foldable / rollable to fit through an incision.

[0034] Non-exclusive specific applications of devices of this aspect include the delivery of neurotransmitters to study brain behavior and to treat very localized diseases such as epilepsy and Parkinson's disease.

[0035] A second aspect of the present invention provides a system for delivering a drug to a patient, the system comprising: an implantable medical device according to the first aspect above, including some, all or none of the optional and preferred features of that aspect; and a controller arranged to control the flow of fluid through a delivery catheter of the implantable device.

[0036] The system may further comprise a pump in fluid communication with the delivery catheter, wherein the controller is arranged to control the pump.The pump may be any known pump suitable for this purpose, such as an electro-osmotic pump or a peristaltic pump.

[0037] Preferably, the controller is arranged to control the flow of fluid through the delivery conduit such that the medicament leaves the delivery conduit through the delivery aperture primarily by diffusion rather than convection.

[0038] The system may further include a supply reservoir and a waste reservoir, wherein fluid is introduced from the supply reservoir to the inlet of the delivery conduit and fluid exiting the outlet of the delivery conduit is stored in the waste reservoir.

[0039] In a certain embodiment, the system has multiple supply reservoirs. The controller can then be arranged to control the supply reservoirs from which fluid is introduced into the inlet of the delivery conduit. For example, the supply reservoirs may contain different medicaments, and the controller is arranged to select the medicament to be delivered.

[0040] Alternatively or additionally, the supply reservoir may contain different concentrations of the same medicament.In such an arrangement, the controller may select the concentration of medicament to be supplied to the delivery catheter.

[0041] Alternatively or additionally, the supply reservoir may comprise a reservoir containing a concentrated solution of the medicament and the delivery solution and a controller arranged to control the relative proportions of fluid from each reservoir to control the concentration of medicament in the fluid introduced into the inlet.

[0042] Alternatively or additionally, one of the supply reservoirs may contain a neutral or cleaning solution to allow flushing or cleaning of the delivery tube prior to and / or after drug delivery.

[0043] The implantable device may include a sensor, and the controller may be arranged to receive a signal from the sensor and to control the flow of fluid through the delivery catheter based on the signal received from the sensor.

[0044] A third aspect of the present invention provides a controller for an implantable medical device, the controller comprising a processor and a memory storing instructions for the processor, the controller being configured to: control a pump to deliver an agent to a patient through the implantable device so that the agent circulates in the implantable device and leaves the implantable device primarily by diffusion rather than convection.

[0045] In order for the agent to circulate and leave primarily by diffusion, the controller may receive information, for example from sensors, about the flow rates at the inlet and outlet of the device. In a diffusion regime, the flow rates should be equal or approximately equal. In other embodiments, the pressure at the inlet and / or outlet may be measured (instead of, or in addition to, measuring the flow rate); for a diffusion regime, the pressure should preferably be the same or nearly the same as the pressure within the target tissue. In other embodiments, data from sensors implanted in the delivery zone may be used by the controller to determine and / or monitor the actual delivery of the agent to the patient.

[0046] Preferably, the controller is further arranged to: receive information from a sensor on the implantable device; and adjust control of the pump based on the information received from the sensor.

[0047] A controller may be used with an implantable medical device according to the first aspect above, the controller including some, all or none of the optional and preferred features of that aspect, but not necessarily.

[0048] A fourth aspect of the present invention provides a method for delivering a drug to a patient, the method comprising the following steps: implanting a delivery device having a flexible catheter and a delivery hole, wherein the flexible catheter is configured to allow fluid to flow from outside the patient to the implantation site and allow fluid to return from the implantation site, and the delivery hole has a drug for delivery in the fluid; and delivering the drug through the flexible catheter so that the drug leaves the delivery hole primarily by diffusion rather than convection.

[0049] The method may further include sensing the results of the delivery using a sensor positioned near the implantation site, and adjusting the delivery of the agent based on the results from the sensor.The sensor may be part of the delivery device.

[0050] Medications can be delivered to multiple sites through a single catheter.

[0051] Further aspects of the invention provide a method of treating a brain disease and a controller for an implantable medical device, the controller being configured to perform the method.

[0052] The method of this aspect includes the steps of receiving electrophysiological data from one or more sensors located in the patient's brain; identifying a transition or change in the data from the received data, the transition or change indicating a transition from a normal state to an abnormal state; and, if a transition is identified, controlling the delivery of an agent to the patient's brain via an implantable device located in the patient's brain.

[0053] A specific example of a brain disorder is an epileptic seizure. The method may use electrophysiological data to identify and distinguish an epileptic seizure or pre-seizure condition from normal brain activity, or may identify patterns in the data that indicate a transition from a normal state to a seizure state.

[0054] The method may also include controlling which drug is delivered and the concentration of the delivered drug, provided that the configuration of the device provides this possibility.

[0055] The method may include delivering a drug when an abnormal condition is identified to treat the condition. Alternatively or additionally, the method may include delivering a drug when a transition from a normal state is identified, thereby allowing preventive treatment to avoid the transition to an abnormal state, or to delay or ameliorate the effects of the transition, or to reduce the severity of the abnormal state.

[0056] Control of drug delivery may include controlling a pump connected to the implantable device. This may allow control of whether a drug solution is delivered and the flow rate of the drug solution.

[0057] The method may further comprise the step of receiving further electrophysiological data from the sensor and using the further data to identify when the patient has returned to a normal condition, or when the patient's condition has stabilized. The method may comprise the step of adjusting drug delivery accordingly, for example by stopping drug delivery.

[0058] Unless otherwise stated, any feature (including optional or preferred features) described in conjunction with one of the above aspects is also applicable in combination with the apparatus and system of any other above aspect.

[0059] According to a further aspect of the invention there is provided a method of treating the human or animal body comprising implanting a medical device or bioelectric implant according to any variation of the method of the above aspects. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] The present invention is described below by way of example with reference to the accompanying drawings, in which:

[0061] Figure 1 is a schematic diagram of an apparatus according to an embodiment of the present invention modeled by computational simulation;

[0062] Figure 2 shows the use of Figure 1 The described model performs time-dependent simulations of devices according to embodiments of the present invention;

[0063] FIG. 3 is a series of graphs showing the flow rate at different flow rates using the Figure 1 Comparison of various profiles simulated by the described model along the axial distance from the bore of the device;

[0064] FIG. 4 is a series of graphs showing Figure 1 Describe the model in which the amount of drug delivered changes as the parameters are varied;

[0065] Figure 5a and Figure 5b It shows about Figure 1 Plots of the effects of variations in hole geometry in the described model;

[0066] Figure 5c and Figure 5d is shown using about Figure 1 Model described, plots of the spatial distribution of the drug delivered from a tube with three holes after 1 second and 60 seconds, respectively;

[0067] Figure 6a and Figure 6bis a schematic diagram of a device according to an embodiment of the present invention when implanted in the brain;

[0068] Figure 7 is a schematic diagram of a system according to an embodiment of the present invention;

[0069] Figure 8 is a schematic diagram of a system according to another embodiment of the present invention;

[0070] Fig. 9 Steps in a method of manufacturing a device according to an embodiment of the present invention are shown;

[0071] Fig.10 shows steps in an alternative method of making a device according to an embodiment of the invention; and

[0072] Fig.11 A flow chart of a control system algorithm according to an embodiment of the present invention is shown. DETAILED DESCRIPTION

[0073] In order to analyze the operation of the device according to an embodiment of the present invention, a model of a U-shaped flexible microtube was designed, which had an inlet and an outlet outside the brain, and a small hole was provided in the middle of the tube to allow the drug circulating in the tube to diffuse into the extracellular space. Figure 1 A schematic diagram of the model is shown.

[0074] The inventors have performed computational simulations of the model to understand various aspects of the device operation. In particular, the simulations were used to: a) observe how the drug will be delivered by modeling and observing the concentration of the drug in the brain over time; b) determine whether it is possible to minimize the pressure exerted on the brain to achieve primarily diffusion-driven delivery; and c) observe the effects of using different drugs or different sizes or numbers of pores on the delivery process.

[0075] Using COMSOL Simulations were performed. All simulations were time-dependent and performed in 2D. 2D was chosen to simplify the simulations while allowing a better understanding of the transport mechanisms involved and to observe the effects of various parameters.

[0076] Mathematical model

[0077] The brain is very densely packed with cells, whether considering gray or white matter. The transport of molecules occurs primarily in the space between cells, called the extracellular space (ECS). This space, which accounts for about 20% of the total volume of the brain, can be described as a foam (form), in which the cells correspond to the gas phase and the ECS represents the water phase.

[0078] Given that the ECS is several orders of magnitude lower than the distances drugs travel, the brain can be considered a porous medium, so Darcy's law applies:

[0079]

[0080] where α is the porosity of the brain, ρ is the density, u is the velocity vector, p is the pressure, μ is the dynamic viscosity, and κ is the permeability.

[0081] The drug concentration over time is governed by the modified diffusion equation (Syková et al.):

[0082]

[0083] The first term on the left represents how the concentration C at a given location changes with time. The second term is the diffusion term, where D * =D / λ 2 . The free diffusion coefficient D is reduced by a parameter λ called tortuosity, which takes into account the geometry, dead space, obstacles, and binding occurring inside the ECS. The third term in the equation is the introduction term, which was set to zero in this simulation because introduction is included in the boundary conditions of the simulation. The fourth term represents convection driven by the corrected velocity vector, and the last term incorporates losses, clearance, and absorption. In this model, diffusing molecules can be permanently removed from the ECS through the BBB by entering cells, by binding to receptors, or by enzymatic degradation. These processes are generally proportional to concentration, so f(C) = k elim .C, where k elim is the elimination rate.

[0084] These equations describe two transport mechanisms, diffusion and convection. Diffusion is driven by concentration gradients, and convection is driven by pressure gradients.

[0085] Model Geometry

[0086] The optimal width of the tube was chosen to be 10 μm, which was considered small enough to reduce the footprint of the device while still allowing the delivery of large amounts of drug.

[0087] The distance from the tube inlet to the U-shaped portion and from the U-shaped portion to the outlet was set to 1 cm so that the total length of the tube was 2 cm.

[0088] The size of the holes was set to 10 μm, but the effect of smaller (5 μm) and larger (15 μm) holes was also studied. The effect of having several holes was evaluated by implementing tubes with 2 and 3 holes. In the case of 2 holes, they were placed at +45° and -45° around the middle horizontal axis. In the case of 3 holes, they were placed at +90°, 0° and -90° around the same axis.

[0089] To avoid any influence of boundary effects of the simulation model, the brain was defined as a surface area larger than the action distance of any drug in the time scale studied, so a circle with a radius of 20 mm was chosen.

[0090] Model parameters and assumptions

[0091] The interior of the tube was assumed to be filled with water and the brain tissue was treated as a porous medium. Other material parameters required for the simulation were taken from Zhan et al. and are shown in Table 1 below. Parameters set by the user or dependent on the drug being delivered are shown in Table 2 and are further described below.

[0092] symbol name Tube Brain tissue α Porosity 0.2 ρ <![CDATA[Density (kg / m 3 )]]> 1000 1000 μ Dynamic viscosity (kg / (ms)) <![CDATA[8.9×10 -4 ]]> <![CDATA[7.8×10 -4 ]]> κ <![CDATA[Permeability (m 2 )]]> <![CDATA[6.4×10 -15 ]]>

[0093] Table 1: Parameters of tubes and brain tissue

[0094] symbol name value FR Flow rate (nL / min) 3.0 ICP Intracranial pressure (Pa) 536 HS Pore ​​size (μm) 10 NH Number of holes 1 <![CDATA[D * ]]> <![CDATA[Diffusion coefficient (m 2 / s)]]> <![CDATA[10 -9 ]]> <![CDATA[C d ]]> Drug concentration (mM) 10 <![CDATA[k elim ]]> <![CDATA[Elimination rate (s -1 )]]> 0

[0095] Table 2: Simulation parameters

[0096] Flow rate: The flow rate used in the study was 3 nL / min. The effects of different flow rates were evaluated over a range of flow rates from 1 nL / min to 7 nL / min.

[0097] Pressure: The pressure in the brain, also known as intracranial pressure (ICP), varies widely. It depends on several aspects such as age, body position and clinical condition, and of course it differs between humans and other animals. For this study, the average ICP of 536Pa found in rats was chosen. However, the study can be easily translated to other ICPs. ICP is measured as pressure relative to atmospheric pressure, so the pressure at the tube outlet is set to zero.

[0098] Diffusion coefficient: The free diffusion coefficient depends on the molecule. It has been shown that parameters such as size, shape and flexibility have an influence, so it is difficult to predict the actual diffusion coefficient without measuring it. In addition, the diffusion coefficient in the ECS is anisotropic and depends on the location in the brain. In this study, a range of different diffusion coefficients in the ECS was tested, but they were assumed to be isotropic and constant in all simulated brain tissues. The range evaluated was between 10 -11 m 2 / s to 10 -9 m 2 / s, which includes both smaller molecules (such as ions) and larger molecules (such as proteins). For simplicity, the free diffusion coefficient is used, and the average curvature is used to perform the calculation.

[0099] Drug concentration: This is the concentration of the drug injected into the tube. In some studies, the effect of this parameter on the diffusion process was investigated. However, for simulations where this parameter was not varied, it was set to 10 mM.

[0100] Elimination rate: The elimination rate is also molecule dependent. In this study, 10 -4 s -1 Up to 10 -2 s -1 However, for simulations where this parameter was not varied, it was set to 0 to remove the effect of this parameter and allow for a better understanding of the transport mechanism in operation.

[0101] Simulation parameters: The boundaries of the brain were set to ICP with no-flux conditions. The tube walls were set to no-slip and no-flux conditions. The outlet of the tube was set to atmospheric pressure with a relative pressure of 0. The mesh was coarse but with a user-defined maximum element size of 2 μm on the curvature ("U") of the tube.

[0102] result

[0103] Concentration distribution and time dependence

[0104] The results of the simulation at a flow rate of 3 nL / min are shown in Figure 2. Although some of the drug diffuses through the pores into the ECS, most of the drug remains inside the tube.

[0105] Figure 2b The concentration profile along a horizontal line from a tube in the ECS is shown. The profile shows an exponential increase over time. The increase in concentration decreases gradually over time.

[0106] Figure 2c The amount of drug delivered to the brain in diffusion-driven mode at a flow rate of 3 nL / min is shown.

[0107] Effect of flow rate on conveying mechanism

[0108] The pressure exerted on the brain can be affected by many different parameters, such as the geometry of the tube and the viscosity of the fluid being injected. For example, reducing the width of the tube while maintaining the same flow rate will increase the pressure exerted.

[0109] However, for the purposes of the current simulation, the dimensions of the tubes are fixed and only the flow rate set at the tube inlet is varied. The flow rate is optimized to balance too high a pressure, which would cause convection-driven transport, and too low a pressure, which would cause backflow.

[0110] Figures 3a to 3e Shown are how a) concentration distribution, b) pressure distribution, c) velocity magnitude distribution, d) diffusion and convection flux magnitudes, and e) the amount of drug infused into the brain change at different flow rates. Figure 3a to Figure 3d shows that 60 seconds later along with Figure 2b Variations of the same horizontal line in Figure 3e The changes over time are shown.

[0111] Figure 3a The concentration profile is shown as a function of flow rate. Figure 3a It is shown that drug delivery through the device can operate in both diffusion and convection modes depending on the pressure regime / flow rate. Figure 3a A transition from a concave to a convex concentration profile (or exponential to inverted sigmoid) is shown from 1.0 nL / min to 7.0 nL / min, indicating a change in state from diffusion-driven to pressure-driven. At 3 nL / min, the profile has an exponential shape, but for 5 nL / min and 7 nL / min, the profile becomes like an inverted sigmoid curve.

[0112] These different concentration profiles can be viewed by Figure 3b At 3 nL / min, the pressure in the brain remains almost completely constant and is only a few Pascals above the initial pressure in the brain (dashed line). For higher flow rates, the pressure near the orifice increases by several hundred Pascals, effectively doubling the ICP by injecting only 7 nL / min into the tube.

[0113] exist Figure 3c In Figure 2, similar profiles can be seen when looking at velocity magnitude. In fact, the pressure gradient induces velocity and moves the drug towards lower pressure, which is the basis of the convective transport mechanism.

[0114] Figure 3d This is confirmed by , where the magnitude of the convective flux is compared to the magnitude of the diffusive flux. It can be seen that for higher flow rates, such as 5 nL / min or 7 nL / min, the convective flux is higher than the diffusive flux, which makes sense because there is a higher pressure gradient, such as Figure 3b This in turn explains the difference in concentration profiles, since it can be mathematically shown that convection-driven transport is characterized by an inverted S-shaped concentration profile, while diffusion-driven transport is characterized by an exponential-like profile.

[0115] When the flow rate is reduced even further, as exemplified by the 1 nL / min line, the pressure inside the tube becomes less than the pressure in the brain, which creates a backflow, and only a very small amount of drug is able to diffuse against the flow and enter the brain.

[0116] Figure 3eThe total amount of drug delivered to the brain over time is shown. The convection-driven mode has a higher total amount of drug delivered compared to the diffusion-driven mode. However, the diffusion-driven mode allows for local delivery of only small amounts of drug to specific areas of need, thus resulting in a more controlled and focused treatment.

[0117] Effects of drug dependence parameters on drug delivery over time

[0118] To understand the effect of different parameters on the delivery process, these parameters were adjusted and the amount of drug infused into the brain was recorded over time. The results are shown in Figures 4a to 4c , which show the effects of changing a) the diffusion coefficient, b) the implant concentration and c) the elimination rate, respectively. Figure 4d is a contour plot showing the amount of drug infused depending on the diffusion coefficient and elimination rate when the drug concentration is 10 mM.

[0119] Diffusion coefficient (D * ) from 1×10 -11 to 1×10 -9 change. Figure 4a shows that the amount of drug delivered increases with increasing diffusion coefficient. From Equation 2 above, it can be seen that the diffusion term is proportional to the diffusion coefficient. However, with D * From 1×10 -10 m 2 / s increased to 1×10 -9 m 2 / s compared to D * Multiply by 10, from 1×10 -11 m 2 / s increased to 1×10 -10 m 2 / s produced much smaller differences in the amount of drug injected. However, for D * For all choices, the shape of the curve is the same.

[0120] Figure 4b The changes in drug concentration (C d ). It can be seen that the total amount of drug in the brain is linearly proportional to the drug concentration in the tube.

[0121] The final drug dependence parameter considered is the elimination rate. Figure 4c The effect of varying this parameter is shown in Figure 1. The two higher ratios in this figure indicate that the amount of drug infused does not increase linearly, but converges to a steady-state amount. This steady state is reached when the amount of drug removed by absorption, loss, or clearance (represented by the elimination rate) is the same as the amount of drug delivered from the tube to the brain. Although the small elimination rate (k elim =1×10 -4 s -1) made little difference, and a further order of magnitude increase in elimination rate significantly reduced drug concentrations in the brain.

[0122] Figure 4d is a contour plot showing the amount of drug infused after 60 seconds of simulation for the combined values ​​of the diffusion coefficient (vertical axis) and elimination rate (horizontal axis). Figure 4a and Figure 4c , high diffusion coefficient and small elimination rate achieve the highest drug concentration, while the opposite combination achieves the lowest drug concentration.

[0123] Effect of pore size and number on the amount of drug delivered over time

[0124] Figure 5a and Figure 5b The amount of drug infused into the brain over time is shown for a) varying the size of the holes and b) varying the number of holes, respectively. Figure 5c and Figure 5d The spatial distribution of the drug for the tube with 3 holes after c) 1 second and d) 60 seconds is shown.

[0125] To investigate the influence of these factors, simulations were calculated for pores with widths of 5 μm, 10 μm, and 15 μm (the simulations were performed in 2D) and the amount of drug injected into the brain was plotted, as Figure 5a It should be noted that the amount of drug is not linearly proportional to the width of the pore, as doubling the size of the pore does not result in twice as much drug being infused into the brain. In addition, increasing the pore size from 5 μm to 10 μm has a greater effect on drug infusion than increasing the pore size from 10 μm to 15 μm. Figure 5b As shown, similar behavior is observed as the number of holes changes.

[0126] These results occur because the drug concentration gradient is distributed by different wells. Since the driving transport mechanism in diffusion-driven delivery is the concentration gradient, this results in slower delivery. For example, in the case of 3 wells, Figure 5c and Figure 5d It shows that even at the very beginning of the process three different circles can be observed ( Figure 5c ), but after a short time (and at least 60 seconds), such as Figure 5d As shown, the three circles fuse together to form one large circular distribution, thus forming only one large concentration gradient around all the pores rather than three separate gradients.

[0127] Summary of simulation results

[0128] When all elimination processes are inhibited, the amount of drug delivered increases linearly once the process reaches steady state (i.e. after about 1 minute). This is because the source of delivery, i.e. the concentration in the tube, remains nearly constant throughout the tube over time.

[0129] However, the concentration distribution does not increase linearly over time. This can be explained by the fact that the drug fills a 2D circular surface, not just a line. Therefore, over time, the concentration radius of the drug distribution increases in proportion to the square root of the total amount of drug, making the increase decrease over time.

[0130] The transport mechanism driving drug infusion can be dominated by diffusion or convection. At lower flow rates, the pressure applied to the brain is reduced, and since convection is caused by pressure gradients, its contribution to the transport mechanism is reduced. Therefore, below a certain flow rate, a diffusion-driven process can be achieved. Figure 4d It was shown that, using the modeled parameters, a flow rate of approximately 3 nL / min produced a diffusion flux magnitude that was greater than the convective flux magnitude.

[0131] This diffusion-dominated process can also be observed in the concentration profiles. Diffusion-driven delivery has an exponential-like shape, whereas convection-driven delivery has an inverted S-shaped curve (ie, it has higher concentrations extending further from the delivery site).

[0132] Conversely, reducing the flow rate too much will result in the pressure in the brain being higher than the pressure in the tube, causing backflow. Thus, there is an optimal range of flow rates that will produce diffusion-dominated delivery. However, the exact range will depend on, among other factors, the pressure in the brain, the geometry of the tube, and / or the drug being delivered.

[0133] The effect of changing the diffusion coefficient simulates the real-world effect of delivering drug molecules of different sizes. Larger molecules (such as proteins) will have a smaller diffusion coefficient and therefore be delivered more slowly, while smaller molecules, such as individual ions (such as sodium or potassium), have a larger diffusion coefficient and therefore result in a faster delivery process.

[0134] The nearly linear relationship between the diffusion coefficient and the total amount of drug delivered results from the choice of diffusion-driven mode and may be different at higher flow rates.

[0135] It has been demonstrated that changes in drug concentration have a linear effect on the amount of drug delivered, and this holds true over a wide range of drug concentrations. However, taking into account the elimination rate (for whatever biological reason, such as absorption, loss, or clearance processes) has a significant effect on the shape of the curve, where the amount of drug delivered converges to an equilibrium where as much drug diffuses out of the tube as is removed from the ECS. A higher elimination rate results in a faster convergence to a lower value.

[0136] It was found that changing the number of holes or increasing the size of the holes had no linear effect on drug diffusion. This was particularly true for increasing the number of holes and can be explained by the interaction of diffusion processes between the holes after an initial period of time, which results in one large distribution with a lower concentration gradient, rather than a separate circular distribution around each hole. If the spacing of the holes is significantly larger, this interaction can be avoided and a linear increase in delivery can be produced. This interaction can be used to allow a larger and more uniform distribution to be achieved while maintaining diffusion-driven delivery.

[0137] Overall, these simulations show that with reduced applied pressure and small delivery tubes, a diffusion-driven delivery pattern can be achieved in the brain. In the simulated geometries, particularly the 10 μm wide tube with a U-shaped geometry, most of the drug continues along the tube and is released to an outlet outside the brain. This enables any excessive pressure on the brain to be avoided. Adjusting the flow rate from these starting parameters allows diffusion-driven delivery to be achieved, but the exact flow rate to achieve this will vary, especially if the size of the tube, the drug, or the animal (or region of the animal) being treated is different.

[0138] Equipment and systems

[0139] Figure 6a and Figure 6b A schematic diagram of a device 10 according to an embodiment of the invention implanted in the brain is shown. Figure 6a Components of the device at the implantation or distal end are shown, with the structure of the device omitted for clarity. Figure 6b The entire device is shown with the distal end magnified to enable features to be seen.

[0140] Figure 7 and Figure 8 A schematic diagram of a system 1 according to an embodiment of the present invention is shown, the system 1 incorporating an apparatus 10 such as Figure 6a and Figure 6b Those in .

[0141] The device has a cylindrical delivery tube 20 forming a U-shape at the distal end of the device with inlet and outlet arms 21, 22 connecting the U-shaped end 23 to the proximal end of the device and to a supply of drug solution and a waste reservoir (not shown), respectively.

[0142] To allow implantation through a sub-centimeter incision, the delivery tube has an outer diameter of about 10 μm to 50 μm, and in a specific embodiment, has an inner diameter of 10 μm.

[0143] Near the U-shaped end 23, a plurality of holes 25 are formed in the delivery tube 20. Figure 6a and Figure 6bIn the example shown, the holes are provided in groups of a plurality of holes each, but it will be appreciated that the configuration of the holes and their spacing relative to one another may vary, for example as explained with respect to the simulations above.

[0144] In certain embodiments, a semipermeable membrane is formed over or in the aperture 25. The membrane can help permit smaller molecules (such as small molecule drugs) to diffuse from the interior of the delivery tube 20 to the exterior, while preventing larger molecules (such as proteins) from flowing back into the interior of the delivery tube from the area of ​​the body where the device is implanted. This can be useful because it avoids the need for overpressure in the delivery tube to prevent backflow, and can ensure that the primary delivery mechanism for the drug is diffusion rather than convection.

[0145] A plurality of sensing electrodes 30 are arranged near the U-shaped end 23 and the two arms 21, 22 of the delivery tube 20. These electrodes can be arranged to sense various local variables, such as drug concentration, brain activity. All sensors can be identical in nature, or different sensor uses (or the same sensor with different uses) can be provided. In some embodiments, the sensor can also be provided in the delivery tube 20 itself.

[0146] The sensor 30 is connected to the proximal end of the device by a conductor 32, which terminates in an electrical connection 34. The conductor 32 carries the output from the sensor to one or more processors, which are located at the proximal end of the device or may be located remotely from the device having a communication module that transmits the output (raw or processed) from the sensor to the processor.

[0147] If a plurality of sensors of the same type are provided, the sensors may be arranged to detect the effect or amount of drug diffusion from the delivery tube 20 .

[0148] At the proximal end of the device a pump 40 is connected to pump the drug solution from a supply reservoir 41 into the delivery tube 20. The pump may be any known pump suitable for this purpose, such as an electro-osmotic pump or a peristaltic pump.

[0149] The device can be arranged so that the pressure applied at the connection to the inlet arm is balanced with the pressure at the connection to the outlet arm. An outlet flow control unit 42 connected to the outlet arm can be used to provide this function. The outlet flow control unit can include one or more valves and may also include an additional pump. The processor 43 can control the valves and / or pumps to balance the pressure based on signals received from one or more sensors.

[0150] In certain embodiments (e.g., Figure 7 ), the outlet flow control unit 42 may also separate the contents of the outlet flow into one or more constituent components, which may be parallel to the waste output. Figure 8 As shown), the outlet flow control unit 42 does not separate the outlet flow and it is completely routed to waste.

[0151] This helps to ensure that the pressure in the delivery tube 20 remains constant and that drug delivery through the apertures 25 is diffusive (or predominantly diffusive) rather than convective.

[0152] In some embodiments, such as Figure 7 and Figure 8 As shown, more than one delivery reservoir 41 is provided and connected to the inlet arm 21 of the delivery tube 20. This can increase the flexibility and usefulness of the device. For example, in some embodiments, one delivery reservoir may contain a concentrated form of the drug, while a second delivery reservoir contains a transport solution. By individually controlling the flow from each reservoir (e.g., using a valve or an additional pump), the concentration of the drug solution supplied to the inlet arm 21 of the delivery tube can be controlled. In other embodiments, multiple delivery reservoirs can be provided, each containing a different drug to allow different treatments to be administered by a single device. Additional reservoirs can contain an inert solution that can be used to flush any remaining drug from the delivery tube between administrations.

[0153] Equipment Manufacturing

[0154] The device according to the embodiment of the present invention can be manufactured by various methods. A specific method for manufacturing the device according to the embodiment of the present invention is monolithic fabrication or mold manufacturing.

[0155] Reference below Fig. 9 and Fig.10 Two examples of the one-piece molding method are described.

[0156] In the first example, the steps are as follows Fig. 9 as shown, and as follows:

[0157] 1. Coat the carrier wafer (100) with a suitable photoresist or molding material (110).

[0158] 2. The coated wafer is patterned to create grooves corresponding to the areas for forming the integrated tubes.

[0159] 3. Conformal polymer deposition / coating of Parylene C(120) is then performed using techniques such as low pressure chemical vapor deposition. The thickness of the coating is sufficient to achieve a hermetic seal of the trench on the top side of the wafer.

[0160] 4. Define the metal electrodes (130) through a second photolithography process. Depending on the specific sensor application, this step may be replaced by another sensor fabrication option, which may include fabricating the sensor within a microfluidic conduit.

[0161] 5. Passivation of the sensor / electrode via another polymer coating (140).

[0162] 6. Etch the sensor contact area.

[0163] 7. Etch inlet and outlet holes in the microfluidic conduits.

[0164] 8. Etch out the outline of the device.

[0165] 9. Remove / dissolve the mold material (100) to release the device.

[0166] The PEDOT:PSS coating on the recording sensor surface (not shown) may be applied on the contacts via electropolymerization or some other technique.

[0167] The manufacturing processes do not have to follow the order shown.

[0168] In a second example, the microfluidic conduit has no juxtaposed sensor and the steps Fig.10 as shown, and as follows:

[0169] 1. Coat the carrier wafer (100) with a suitable photoresist or molding material (110).

[0170] 2. The coated wafer is patterned to create grooves corresponding to the areas for forming the integrated tubes.

[0171] 3. Conformal polymer deposition / coating of Parylene C(120) is then performed using techniques such as low pressure chemical vapor deposition. The thickness of the coating is sufficient to achieve a hermetic seal of the trench on the top side of the wafer.

[0172] 4. Etch inlet and outlet holes in the microfluidic conduits.

[0173] 5. Etch out the outline of the device.

[0174] 6. Remove / dissolve the mold material to release the device.

[0175] control

[0176] Fig.11 4 shows a flow chart of a control system algorithm according to an embodiment of the present invention. The initial steps (S1-S3) in the algorithm are the initialization of the device and the controller. The controller can be implemented by a hardware processor 43, such as Figure 7 and Figure 8The controller may be located near the proximal end of the device 20, or may be remotely located and communicate with the sensors 30, pump 40, and other components of the system and device to receive information and control the operation of the system and / or device. The remote connection of the controller may be any known type of wired or wireless connection.

[0177] The combination of sensor 30 and the ability to deliver medication through delivery tube 20 and aperture 25 allows the processor to communicate with and receive information from sensor 30 to control the delivery of medication through the delivery tube.

[0178] In some embodiments, the processor can process data from the sensor to determine a physiological condition of the body part in which the device is implanted (S4). For example, the sensor can record electrophysiological data that is processed by the processor. The data can be compared to one or more baseline data sets to determine whether an abnormality exists (S5). Alternatively, the data can be compared to previously acquired data to determine and identify a transition or change in the data, which can, for example, indicate a transition from a normal state to an abnormal state, or vice versa.

[0179] In one embodiment, the device is implanted in the patient's brain. In such an embodiment, the processor may be arranged to analyze electrophysiological data from the sensor to identify and distinguish an epileptic seizure or pre-seizure condition from normal brain activity. Alternatively or additionally, the processor may be arranged to identify patterns in the sensor data that indicate a transition from a normal state to an epileptic seizure state.

[0180] The processor may be arranged to control the delivery of the drug through the delivery tube 20 of the device 10 based on the sensor data and analysis of the data (S6). The processor may also be arranged to control which drug is delivered and the concentration of the delivered drug, where the configuration of the device provides this possibility (S6). This may include, for example, controlling valves between the various reservoirs and the inlet arm 21 of the delivery tube 20, and / or controlling different pumps that cause different fluids to flow into the inlet arm 21, and the ratio of the supplied fluids may be controlled.

[0181] For example, the processor may be arranged to deliver a drug when an abnormal condition is identified to treat the condition. Alternatively or additionally, the processor may be arranged to deliver a drug when a transition from a normal state is identified, thereby allowing preventive treatment to avoid the transition to an abnormal state, or to delay or ameliorate the effects of the transition, or to reduce the severity of the abnormal state.

[0182] The processor can control the delivery of the drug by controlling a pump connected to the delivery tube 20. This allows the processor to control the on / off state of the drug solution passing through the delivery tube and the flow rate of the drug solution.

[0183] The processor may also use data from the sensors to identify when the patient has returned to a normal condition (S9) or when the patient's condition has stabilized, and may be arranged to adjust the delivery of medication accordingly (S10).

[0184] In some embodiments, the sensor provides information about drug delivery to the processor (S6), and this information can be used by the processor to control the delivery of the drug (S8), for example, to reduce or stop delivery once a certain delivery level (e.g., concentration) is reached. Alternatively or additionally, the processor can use this information to determine whether the delivery of the drug is diffusion driven (e.g., by using multiple sensors to consider the delivery distribution of the drug) and adjust the pump accordingly (S7-S8).

[0185] In a specific embodiment, the device is arranged to be implanted in the brain, and the sensor and processor are arranged to identify and distinguish an epileptic seizure or pre-epileptic condition from normal brain activity. Upon identifying an epileptic seizure or pre-epileptic condition, the processor controls the pump to facilitate delivery of an anti-epileptic drug, thereby controlling the epileptic seizure. Upon detecting a return to normal brain conditions, the processor controls the pump to stop the delivery of the drug.

[0186] Material

[0187] Devices according to embodiments of the present invention can be used to deliver drugs to many different parts of the body. Although specific examples of using devices to deliver drugs to the human brain have been given above, the present invention is not limited to such uses. Further examples include use for delivering drugs to malignant tumors (e.g., pancreatic tumors). Others include nerve damage, local pain, or inflammation.

[0188] The material of the device, especially the distal end of the device, is selected to have good compatibility with the tissue in the area where the device will be implanted. In addition to using generally biocompatible materials (such as PDMS, polyimide, parylene), other important considerations for tissue compatibility are geometry and bending stiffness.

[0189] Regarding bending stiffness, the distal end of the device should ideally approximate the bending stiffness of the target tissue. The bending stiffness of human tissue varies greatly, ranging from about 10% for the brain to about 20% for the brain. -13 Nm / mm–10 -10 Nm / mm, to about 10 for muscle -2 Nm / mm, and then to 1000Nm / mm for bones.

[0190] Flexural stiffness is a combination of the geometry (primarily thickness) and Young's modulus of the material.

[0191] The foregoing description is merely exemplary in nature, and those skilled in the art will appreciate that modifications and variations to the disclosed embodiments are possible within the scope of the claims. The invention is defined by the claims.

[0192] References

[0193] [1] DJ Wolak, RG Thorne, Molecular pharmaceuticals, pp. 10.5: 1492-1504 (2013).

[0194] [2] J. Zhou et al, Proceedings of the National Academy of sciences, pp. 110.29: 11751-11756 (2013).

[0195] [3] AMMehta, AM Sonabend, JN Bruce, Neurotherapeutics, pp. 14.2: 358-371 (2017).

[0196] [4] IUKhan, CASerra, N.Anton, T.Vandamme, Journal of controlled release, pp.172(3), 1065-1074(2013).

[0197] [5] O. Lewis, M. Wooley, D. Johnson, A. Rosser, NU Barua, AE Bienemann, SSGill, S. Evans, Journal of neuroscience methods, pp. 259, 47-56 (2016).

[0198] [6]RHBobo,DWLaske,A.Akbasak,PFMorrison,RLDedrick,EHOldfield,Proceedings of the National Academy of Sciences,pp.91(6),2076-2080(1994).

[0199] [7]CMProctor,A.Slezia,A.Kaszas,A.Ghestem,I.Del Agua,A.-M.Pappa,C.Bernard,A.Williamson and GGMalliaras,Science Advances,P.eaau1291(2018).

[0200] [8] E. McGlynn, V. Nabaei, E. Ren, G. Galeote-Checa, R. Das, G. Curia, H. Heidari, Advanced Science, p.8(10),2002693(2021).

[0201] [9] CJ Bettinger, M. Ecker, TDY Kozai, GGMalliaras, E. Meng, W. Voit, MRS Bulletin, 45(8), 655-668(2020).

[0202]

[10] A.Di Stefano,P.Sozio,A.Iannitelli,LSCerasa,Expert Opinion onDrug Delivery,pp.6(4),389-404(2009).

[0203]

[11] A. Lecomte, E. Descamps, C. Bergaud, Journal of Neural Engineering, pp. 15(3), 031001(2018).

[0204]

[12] E. Sykova, C. Nicholson, Physiological Reviews, pp. 88.4: 1277-1340.(2008).

[0205]

[13] SWKuffler,DDPotter,Journal of Neurophysiology,pp.27.2:290-320(1964).

[0206]

[14] W. Zhan, C.-H. Wang, Journal of Controlled Release, pp. 271:74-87(2018).

[0207]

[15] J M.Czosnyka, JDPickard, Journal of Neurology, Neurosurgery & Psychiatry, pp. 75.6: 813-821 (2004).

[0208]

[16] W.Zhan,F.Rodriguez and Baena,D.Dini,Drug delivery,pp.26.1:773-781(2019).

[0209]

[17] MERice,GAGerhardt,PMHierl,G.Nagy,RNAdams,Neuroscience,pp.891-902(1985).

[0210]

[18] RGThorne,S.Hrabetova,C.Nicholson,Journal ofNeurophysiology,pp.3471-3481(2004).

[0211]

[19] R.Raghavan,MLBrady,MIRodriguez-Ponce,A.Hartlep,C.Pedain,JHSampson,Neurosurgical focus,p.20.4:E12(2006).

[0212]

[20] FTSun,MJMorrell,REWharen.2008,Neurotherapeutics,pp.5(1),68-74(2008).

[0213]

[21] B.Rosin,M.Slovik,R.Mitelman,M.Rivlin-Etzion,SNHaber,Z.Israel,E.Vaadia,H.Bergman,Neuron,pp.72(2),370-384(2011).

[0214] Latest snowflake snowflake snowflakes.

Claims

1. An implantable medical device having: Flexible substrate; a delivery conduit formed in the flexible substrate and having an inlet and an outlet located at a proximal end of the device, wherein the delivery conduit passes from the inlet to the outlet via a loop at a distal end of the device; and A delivery hole is formed in the delivery conduit to allow fluid to flow from the conduit to the exterior of the substrate.

2. The implantable medical device according to claim 1, wherein: The delivery aperture is formed at the distal end of the device.

3. An implantable medical device according to claim 1 or claim 2, further comprising a sensor.

4. The implantable medical device according to claim 3, wherein: The sensor is positioned proximate to the delivery aperture.

5. An implantable medical device according to any one of the preceding claims, wherein: There are a plurality of delivery holes, each delivery hole allowing fluid to flow from the conduit to the exterior of the substrate.

6. The implantable medical device according to claim 5, wherein: A plurality of the delivery holes are arranged close to each other.

7. The implantable medical device according to claim 6, wherein: The delivery apertures are arranged in a plurality of groups, with the apertures in each group being closer to each other than apertures in different groups.

8. An implantable medical device according to any one of the preceding claims, wherein: The delivery aperture or apertures are micron-sized.

9. The implantable medical device according to claim 8, wherein: The diameter of the delivery hole or holes is between 1 μm and 50 μm, preferably between 5 μm and 10 μm.

10. An implantable medical device according to any one of the preceding claims, wherein: At least one delivery aperture has a semipermeable membrane that allows molecules below a certain size to pass through the delivery aperture while preventing molecules above the certain size from passing through the delivery aperture.

11. An implantable medical device according to any one of the preceding claims, wherein: The outer diameter of the delivery catheter is between 1 μm and 100 μm, preferably between 10 μm and 50 μm.

12. An implantable medical device according to any one of the preceding claims, wherein: The device is configured for implantation through an incision having a diameter of less than 6 mm.

13. A system for delivering a medicament to a patient, the system comprising an implantable medical device according to any one of the preceding claims and a controller arranged to control the flow of a fluid through a delivery conduit of the implantable device.

14. The system of claim 13, further comprising a pump in fluid communication with the delivery conduit, wherein the controller is arranged to control the pump.

15. A system according to claim 13 or claim 14, wherein: The controller is arranged to control the flow of fluid through the delivery conduit such that the medicament exits the delivery conduit primarily by diffusion rather than convection through the delivery aperture.

16. The system of any one of claims 13 to 15, further comprising a supply reservoir from which fluid is introduced into the inlet of the delivery conduit and a waste reservoir in which fluid exiting the outlet of the delivery conduit is stored.

17. A system according to any one of claims 13 to 16, wherein: There are a plurality of supply reservoirs, and wherein the controller is arranged to control the supply reservoirs from which fluid is introduced into the inlet of the delivery conduit.

18. A system according to any one of claims 13 to 17, wherein: The implantable device comprises a sensor, and wherein the controller is arranged to receive a signal from the sensor and to control the flow of fluid through the delivery catheter based on the signal received from the sensor.

19. The system of any one of claims 13 to 18, further comprising an outlet control in fluid communication with the outlet, and wherein the controller is arranged to control the pressure in the delivery conduit using the outlet control.

20. A controller for an implantable medical device, the controller comprising a processor and a memory storing instructions for the processor, the controller being configured to: control a pump to deliver an agent to a patient through the implantable device so that the agent circulates in the implantable device and leaves the implantable device primarily by diffusion rather than convection.

21. The controller according to claim 20, wherein: The controller is further arranged to: receiving information from a sensor on the implantable device; and Control of the pump is adjusted based on information received from the sensor.

22. A method of delivering a medicament to a patient, the method comprising the steps of: implanting a delivery device having a flexible conduit configured to allow fluid to flow from outside the patient to an implantation site and to allow the fluid to return from the implantation site, and having a delivery aperture for delivering an agent in the fluid; and The agent is delivered through the flexible conduit such that the agent exits through the delivery aperture primarily by diffusion rather than convection.

23. The method of claim 22, further comprising sensing a result of the delivery using a sensor positioned near the implantation site, and adjusting the delivery of the agent based on the result from the sensor.

24. The method according to claim 23, wherein: The sensor is part of the delivery device.

25. The method according to any one of claims 22 to 24, wherein: The agent is delivered to multiple sites via a single catheter.

Images