Embodiments of the present disclosure relate to the field of membrane coatings for implantable medical devices, implantable medical devices having at least one surface coated with a membrane, and methods for inhibiting fibrotic capsule formation and the formation of vascular structures at a medical implant device site. Embodiments of the present disclosure also relate to implantable devices that provide enhanced vascularization with a host, and immune-isolated devices which provide for encapsulation of live cells.
Immuno-isolation devices designed for delivering a cellular medical therapy featuring an outer vascularizing membrane and an inner allogenic cell protective membrane are manufactured with relatively difficult and labor-intensive processes. The outer vascularizing membrane generally has a three-dimensional structure that is sufficiently open to allow cells to penetrate the membrane material. This is usually laminated or otherwise affixed to an inner immune-isolation membrane that has pores that are sufficiently large to allow biological macromolecules to freely diffuse across the membrane but prevent cells of the recipient from crossing the membrane. These membranes are typically manufactured separately, laminated together, and then affixed to an implantable medical device as part of an assembly process. The separate step by which the membranes are joined together is time consuming and difficult, and renders the membrane subject to pealing, delamination and decomposition. When such pealing or delamination occurs, the tissue surrounding the implant can react to the implanted medical device by creating local regions of fibrosis. If the implantable device contains living cells that produce a therapeutic product, the local fibrosis can lead to an environment that results in impairment of function of the encapsulated cells and possibly death of those cells. Therefore, a means of creating an outer vascularizing membrane in combination with an inner, denser immune-isolation layer that cannot delaminate or peal apart from the device would allow the development of a more stable and predictable implant with better function.
The implantable medical device field remains in need of coatings and/or membranes that overcome these and other limitations associated with multi-layer, laminated, membrane constructs.
The number of patients suffering from Type I and Type II diabetes is estimated to affect about 4.6% of the world's population. Pancreas transplantation and islet transplantation are known methods for treating diabetes. However, pancreas and islet transplantation into diabetic patients is limited to a small percent of patients who might benefit from either procedure due to the lack of available human pancreata or pancreatic islets. With the recent development of insulin secreting cells derived from human stem cells, there is a possibility of treating patients with insulin dependent diabetes through transplantation. However, such cells would be subject to rejection by the immune system of the recipient patient unless immunosuppressive drugs were administered to the patient for the rest of their life. Alternatively, insulin secreting cells could be provided with an immuno-isolating implantable device and placed in the diabetic patient to act as an insulin delivery source.
Accordingly, studies for improving the viability of islet cells and islet progenitor cells in a ported immune-isolated implantable device are being conducted.
Since the islet transplantation protocol was established, clinical islet transplantation has been regarded as a treatment method for treating type 1 diabetics. However, the low engraftment success of transplanted islet cells remains a major cause of failure of long-term blood sugar regulation. Upon implantation, it is necessary for islet cells to be successfully engrafted through revascularization and blood flow regulation within a few days after transplantation. However, transplanted islet cells are exposed to a state with low vascular density and insufficient oxygen conditions, making it difficult to achieve normal engraftment of islet cells and the ability to achieve regulated insulin secretion in the patient.
Currently, there are limited means and materials to effectively implement live cell containing immuno-isolation devices in vivo. Limitations associated with supply of adequate oxygen levels to encapsulated cells, sufficient nutrient levels to the encapsulated cells, insufficient vascularization of the implanted device and immune response to the implant, remain barriers to use of cell-containing implantable devices.
Embodiments of the present disclosure provide a single layer gradient membrane, such as a non-naturally occurring single layer polymeric or similar material gradient membrane, wherein the single layer gradient membrane comprises a gradually transitioning gradient of material density and pore sizes in the micron size range. The single layer gradient membrane is characterized by continuously variable and differing pore sizes throughout the thickness of the single layer gradient membrane (
As used herein, the terms “gradient” and “gradient membrane” relate to a polymeric or similar material membrane having an internal structure comprising gradually changing pore sizes. The pore sizes of the gradually changing pore sizes of the gradient membrane are in the micron size range. As used herein, the term “micron” is used in the singular and plural to refer to micrometer and/or micrometers.
Single component membranes of the present disclosure (i.e., single layer membranes with a non-laminated structure) are characterized by a continuous gradient of gradually transitioning pore size, from a tight or dense intertwined structure region (having relatively small pore size) to a more open or loose intertwined fiber network (having a relatively larger pore size). Progression from the inner structure/surface to the outer structure/surface of the membrane evidences a transition of gradient to a more open structural configuration. Likewise, the pores gradually transition from smaller to larger, such as from about 0.1 to about 1.0 micron at one surface (such as an inside surface), towards the outer surface of the membrane, having a membrane region comprising a gradient of pore size from about 2.0 to approximately 100 micron (or in some embodiments, from about 5 to about 15 micron) through the single layer, component membrane.
One of ordinary skill in the art will readily understand the term “pore size” as used herein. Additionally, one of ordinary skill in the art will understand and recognize different methods and devices for measuring and evaluating pore sizes. In some embodiments, pore sizes of embodiments of the present disclosure are evaluated, measured, and/or confirmed by the use of a bubble point test method or a scanning electron microscope.
Single layer gradient membranes of the present disclosure comprise various materials, including those deemed appropriate by a person skilled in the art for an implantable medical device. For example, membranes of the present disclosure are contemplated as being prepared from a polymeric material. In such embodiments, the single layer gradient membrane is prepared from such polymeric materials as: polysulfone, polyarylethersulfone (PAES), polyethersulfone (PES), cellulose ester (cellulose acetate, cellulose triacetate, cellulose nitrate), nanocellulose, regenerated cellulose (RC), silicone, polyamide (nylon), polyimide, polyamide imide, polyamide urea, polycarbonate, ceramic, titanium oxide, aluminum oxide, silicon, zeolite (alumosilicate), polyarylonitrile (PAN), polyethylene (PE), low density polyethylene (LDPE), polypropylene (PP), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyvinylchloride (PVC), polypiperazine amide, polyethylene terephthalate (PET), polycarbonate (PC), polyurethane, and any complex or mixtures thereof In particular embodiments, a single layer gradient membrane comprises of a polymeric material comprising polytetrafluoroethylene (PTFE). In certain preferred embodiments, PTFE is provided for at least a vascularizing layer of devices of the present disclosure. Additional materials are contemplated as being provided in membranes and implants of the present disclosure in addition to or in lieu of PTFE.
In some embodiments, a gradient membrane comprises an electro-spun polymeric membrane, such as an electrospun PTFE membrane that is applied directly to a surface, such as a surface of an implantable medical device. Implantable medical devices of the present disclosure are contemplated as comprising an internal chamber of live cells. No separate assembly steps are required to provide a protective layer/film to an internal chamber of an implantable medical device in which live cells may be contained, as the single layer gradient membrane is capable of protecting the cells from immune attack, while simultaneously permitting nutrient flow/oxygen to contained live cells, owing to the appropriate gradient pore size provided by the single layer gradient membrane. Single layer gradient membranes of the present disclosure also provide for a slightly larger pore size within the membrane region extending to the other surface (e.g., outer surface) of the single layer membrane, thus providing a surface suitable for vascularizing the outer surface of the implantable medical device in a host.
In various embodiments, single layer, gradient membranes are formed with phase inversion, interfacial polymerization, solution coating and/or phase deposition methods. These and other processes are described in Baker (Baker, R. Membrane Technology and applications. John Wiley & Sons, 2004), which is hereby incorporated by reference in its entirety.
In various embodiments, electrospinning is provided as a process to control fabricating a fibrous mat of changing and defined density in a single layer membrane construction.
It is an aspect of the present disclosure to provide materials and processes that provide for the elimination of delamination problems of prior fabricated techniques having a bi-layer membrane structure. In addition, the method by which the single layer, gradient membranes are prepared are preferable to other 2-step processes, that require a separate lamination and/or fusing step between two separately fabricated membranes, such as that described in U.S. Pat. No. 6,060,640, which is hereby incorporated by reference in its entirety.
In various embodiments, implantable medical devices are provided that comprise at least one surface upon which a single layer membrane material having a gradient structure is applied. The surface is contemplated as comprising the surface of an implantable medical device, such as an implantable device that has a lumen comprising living cells (e.g. stem cells). The gradient pore size of the single layer membrane permits the passage of desired molecules, such as nutrients in an in vivo environment, to move through the membrane and to encapsulated living cells in the lumen of an implantable medical device. The single layer gradient membrane also permits passage of molecules out of the lumen of an implantable medical device, such as a therapeutic product/agent that is contained in the lumen of the implantable medical device. In this manner, the gradient single layer membrane permits the implantable medical device to act in releasing therapeutic product/agents out of the implantable medical device and available for absorption in the patient.
In various embodiments, membranes are employed as coatings on any or all surfaces of an implantable medical device. Some surfaces of an implant device may be devoid of a membrane. For example, surfaces at which fibrotic mass formation is not a significant occurrence are contemplated as being devoid of membranes. Additional surfaces that are devoid of a membrane include, for example, surfaces at a sonic weld joint on an access port of an implantable medical device.
In one embodiment, a single layer gradient membrane to reduce overall fibrosis comprises pores having a size of about 0.1 to about 100 micron (or, from about 0.1 or about 5 micron to about 15 micron). In some embodiments, an implantable medical is provided that comprises a lumen comprising living cells. The single layer gradient membrane comprises a pore size that does not interfere with the passage of molecules (such as insulin produced by contained islet cells) out of a lumen chamber (having its own chamber lining), and out of the implantable medical device into the body. In this regard, the membrane is sufficiently thin so as to allow rapid diffusion of molecules out of the implantable medical device. As another example, a single layer gradient membrane is provided on some surfaces of a component of a multi-component implantable medical device and not on other surfaces.
In certain embodiments, implant systems are provided that comprise a surface having a single layer gradient membrane, such as a membrane comprising a polymeric material. By way of example, the polymeric material is contemplated as comprising PTFE, where the PTFE membrane comprises a gradient of pore sizes. This single layer PTFE gradient membrane is provided to the external surface of the implantable medical device system. The outer side (host vasculature inter-facing) of the PTFE gradient membrane enables cellular ingress (greater than 1 micron to about 15 micron), and the PTFE gradient membrane titrates down in relative pore size to an appropriate size that would prohibit cellular ingress (about 0.1 micron to about 1 micron) into the cell-containing inner chamber of the implantable medical device. The pore size of the PTFE gradient membrane renders the implantable medical device immuno-isolating for the implanted cells.
In further embodiments, implant systems comprise a surface with an electrospun PTFE gradient membrane combining immunoisolation and vascularization features as described above are provided. An electrospun PTFE multielement layer comprises relatively larger fibers, of a size sufficient to inhibit fibroblast layer formation. This feature may take the form of a final, outer gradient layer comprising multiple strands to form thick fibers of about 25 to about 200 micron in diameter. With such larger fibers randomly oriented on the outer surface of the gradient membrane, the layer serves as a surface to inhibit fibroblasts from forming a fused fibrotic layer.
In another aspect, a manufacturing process and/or method is provided for producing an implantable medical device comprising an immune-isolation chamber of live cells. In one embodiment, the method comprises a series of steps that provide for application of a single layer gradient membrane, such as an electrospun PTFE single layer gradient membrane, to a surface of the implantable medical device. The method can also provide a single step electrospun deposition process wherein a material, such as PTFE, is extruded onto a surface in a manner such as to create increasingly less dense and therefore larger pore size, regions in the single layer membrane plus a modification to the gradient membrane that will form large diameter (about 25 micron to about 200 micron) randomly oriented fibers on the surface of the gradient pore membrane that assist in preventing the formation of tight layers of fibroblasts in the host tissue region close to the implantable medical device/tissue interface.
In some embodiments, methods of the present disclosure do not require, and advantageously eliminates an assembly step for sealing two separate component membrane layers together. Prior constructs required a separate step of this nature to achieve the fabrication of a membrane coating having varying pore size. The present single layer gradient membranes are absent a sharp demarcation zone within the membrane separating areas or regions of differing pore size.
Various embodiments of the present disclosure contemplate the provision of membranes of the present disclosure on an implantable device. The outer membrane region of the membrane may be further defined as having a surface that is closest to the exterior of the membrane, and would be expected, in some embodiments, to interface with the in vivo environment of an animal or human when provided on the surface of an implantable medical device. The inner membrane region of the membrane is further defined as having a surface that is closest to the interior of the membrane, and in some embodiments forms an interface with a surface or an internal lumen of an implantable medical device. Such an internal lumen would be designed to contain living cells or a therapeutic agent. A transitional gradated membrane region resides between the inner membrane region and outer membrane region in some embodiments of the present disclosure.
In some embodiments, the inner membrane region comprises a gradient of relatively smaller pore size, such as a gradient of from about 0.1 to about 1 micron pore size. In some embodiments, the outer membrane region is characterized as a having a gradient of relatively larger pore size, such as a gradient of from about 2 micron to about 100 micron (or about 5 to about 15 micron). In this embodiment, the transitional gradient membrane region between the inner and outer region is characterized as having a gradual gradient of pore size of between about 1 micron at an interface closest to the inner membrane region, and about 5 micron at an interface closest to the outer membrane region.
In some embodiments, a single layer electrospun gradient membrane is provided that further includes a gradient membrane region having a pore size of between about 15 and about 50 micron at a region closest to an interface with the outer membrane region as described above, or alternatively a gradient pore size of up to about 190 micron.
In some embodiments, the membrane is further defined as a single layer immuno-isolation electrospun PTFE gradient membrane, the single layer membrane comprising gradient individual membrane regions within the single layer, one membrane region having a graduated pore size of about 0.1 to about 1 micron, a membrane region having a pore size of about 2 micron to about 100 micron (or about 15 micron), and a transitioning membrane region there between having a gradient pore size of about 5 micron to about 50 micron (or alternatively between about 5 micron to about 15 micron).
The single layer membrane can be constructed to further include an outer layer comprising a woven or non-woven layer. This outer layer may or may not be attached to the single layer gradient membrane. This layer may comprise a non-woven polyester fiber mesh, or be fabricated to include thicker fibers comprising a non-woven mesh. The outer layer would comprise a pore size greater than about 200 micron. In some embodiments, the outer layer comprises randomly dispersed strands of electrospun polymeric material, such as PTFE, or a non-woven immune-compatible material as polyester.
In another embodiment, an immuno-isolation implantable medical device is provided that comprises a surface having thereon the single layer immuno-isolation electrospun gradient membrane as described herein. This single layer immuno-isolation electrospun gradient membrane may comprise electrospun PTFE, and the single layer immune-isolation electrospun gradient membrane will comprise an inner and an outer membrane region having a gradient pore size. The membrane regions, for example, may comprise a first innermost PTFE membrane region having a gradient pore size ranging from between about 0.1 to about 1 micron, an outer gradient PTFE membrane region having a pore size ranging from about 5 micron to about 50 micron (or about 5 to about 15 micron), and a transition region having a gradual gradient pore size of about 1 micron to about 15 (or 10) micron.
In some embodiments, an immuno-isolation implantable medical device is provided that comprises an inner lumen, and the inner lumen comprises a population of live cells or therapeutic agents. By way of example, the live cells may comprise human cells, such as islet cells, naturally occurring primary cells, cell lines, genetically engineered cells, stem cell derived cells, or a combination thereof.
In some embodiments, the single layer gradient membrane is provided over the entire surface of an implantable medical device.
In yet another embodiment, a method of manufacture of a single layer immuno-isolation electrospun gradient membrane comprising a polymeric material is provided. This single layer immuno-isolation electrospun gradient membrane comprises membrane regions having a gradient pore size produced in a single layer by an electrospinning process, wherein a single membrane layer is created having several gradient membrane regions of different pore size so as to create a continuous and gradual gradient of increasing pore size through the single layer membrane. In one embodiment, the single layer will have an inner membrane region having a gradient pore size of about 0.1 to about 1 micron, an outer membrane region having a gradient pore size of about 5 micron to about 50 (or alternatively about 5 micron to about 15 micron); and a transition membrane region there between having a gradient pore size of about 5 micron to about 40 micron (or alternatively about 5 micron to about 10 micron).
The single layer immuno-isolation electrospun gradient membrane preferably comprises a relatively thin thickness. In some embodiments, the thickness of the single layer gradient membrane is between about 20 micron and 150 micron or any subrange between 20 and 150 micron. The single layer immuno-isolation electrospun gradient membrane does not comprise an abrupt demarcation between the various gradient inner and outer membrane regions or at the interface with the transition membrane region. The continuous gradient of pore size though out the single layer gradient membrane structure presents superior and more uniform diffusion properties, and facilitates a more predictable and steady release of therapeutic agents and compounds that may be included within a lumen of an implantable medical device comprising the single layer gradient membrane. Such features present significant advantages and avoids the problems associated with prior implantable structures, such those structures described in U.S. Pat. No. 6,060,640.
In various embodiments, the present disclosure provides implantable devices having a number of improved characteristics and features. In some embodiments, an implantable device is provided that possesses a unique configuration that facilitates a maximization of surface area available for vascularization by a host animal. The configuration of the implant device, in some embodiments comprises a multi-component structure, comprising one or more individual element members and a hub and/or a manifold, wherein the individual pod elements are in communication with the hub and/or manifold. In this regard, means are provided that permit multiple of the individual element members of the device to communicate with at least one common component of the device, such as a hub or a manifold. In this manner, and where the individual member element comprises an internal lumen, access to the lumen of each individual element member and the hub and/or manifold is provided.
Implant devices of the present disclosure comprise unique configurations and may be implanted in a manner that optimizes the number of devices per unit area of a surgical site in a patient. The configuration of the implantable device can be optimized to the shape and size of a particular surgical site into which it is being inserted into a patient, such as to closely pattern the surgical insertion site created by a blunt tissue dissection. The design of the individual element members of the implantable device also permits enhanced access to the interior lumen areas of the element members, making the device readily available to addition of an agent of interest suitable for delivery to a host, such as a therapeutic agent, or alternatively, to the loading of a live cell population to the lumen.
In various embodiments, implantable devices of the present disclosure comprise a manifold having a means to provide communication from one or more element members (i.e. immuno-isolation devices) to a hub of the device. The means to communicate between the manifold and an element member may be implemented to selectively transfer oxygen, therapeutic agents, nutritional agents, electrical signals, electrical power or multiple combinations thereof to the element member. In certain embodiments, communication means from the manifold to the element member(s) comprise a tube or catheter to supply gas or liquids to the element member, such as specifically to a lumen of an element member. This connecting communication means may also be utilized as part of the implant device to connect electrical wires or circuit leads to transmit electrical signals or power, or to communicate combinations of materials to the lumen of the element member.
In some embodiments, the hub or central portion of an implant comprises a component within which the implant device may house an oxygen generator, pump for therapeutic agents or nutritional agents, reservoir(s), electronics, power supply or combinations thereof, and to communicate to element members via the manifold.
The manifold and hub of implant devices of certain embodiments impart a number of distinct functions to the device. For example, the manifold provides a pathway to communicate between the element member (immuno-isolation device) and a hub. The hub, in some embodiments, provides a structure in which functional elements of the implant device may be housed. In some embodiments, the implant device comprises both a manifold and a hub, and the manifold is in communication with the hub. Configurations of the device implant are also provided where an element member is in communication with more than one hub and a (or more than one) manifold, such as through one or more connection means between the manifold and the lumen of an element member. In some embodiments, the implant device will comprise element members having multiple access ports and lumens.
In some embodiments, the hub and/or manifold comprises a surface which comprises a vascularizing material. By way of example, such a vascularizing material may comprise an immune-isolating membrane, for example, a 5 μm nominal pore size expanded PTFE membrane. This membrane serves to reduce the inflammatory response of a host once the implant device is provided under the skin (subcutaneously) in the animal.
The advantages of the presently disclosed immune-isolation implantable devices include a maximization of surface area presented by the device available for vascularization by a host. In particular, implantable devices or portions thereof that comprise an immuno-isolation device present surface area that may be vascularized by the host when implanted. This structure maximizes vascularization of the device as a whole in the animal. Implantable devices of the present disclosure comprise at least one manifold and a hub, the manifold being in communication with one or more pod members. Pod members comprise at least one lumen providing a communication pathway. In some embodiments, each lumen comprises at least one distinct chamber within the lumen.
In some embodiments, pod elements of the present disclosure are (i) tapered at the proximal end to minimize the overlap of multiple implant devices in communication with the manifold, (ii) tapered at one end to enable multiple pod elements having a lumen to be implanted with at least one cross-section surface of the pod element (and the lumen contained therein) to be in contact with the in vivo host environment upon implantation, at a single surgical site, (iii) tapered at one end to minimize the distance from any adjacent pod member, (iv) shaped to have an overall shape that is similar to that created by a common blunt surgical instrument during an implantation procedure, (v) shaped to optimize and minimize the length of the communication means (such as a tube or catheter) that is provided to establish access and/or communication between the manifold and a pod member, or two or more pod members implanted in a single surgical site.
The multi-component implantable device may be further described as an immuno-isolation device. In some embodiments, each pod member comprises a tapered end having at least one access port in communication with at least one lumen of a pod. The taper enables multiple devices to be implanted (i) in a stack one-on-top-the-other configuration, (ii) edge to edge in a fan configuration, (iii) overlapping to expose a portion of the top and bottom to the in vivo environment of the host. At least one proximal port of each pod member may be in communication with a manifold, so as to provide access of the manifold to the lumen of each pod member. Other ports can be located at each element member of the immune-isolation device. These additional ports may be used to facilitate additional access to the lumen of the pod member. The individual pod members and their internal volumes are filled with an identified amount of desired cells or therapeutic agents. The desired cell population, for example, may comprise cells that are designed to secrete a therapeutic product. By way of example, the cells may comprise a population of cells enriched for islet cells capable of secreting insulin through the membrane of the lumen and into the in vivo environment of the host, in response to circulating glucose levels in the host. Alternatively, the chambers may be empty and a drug may be introduced through injection or pumping into a hub for distribution to the multiple attached chambers.
In various embodiments, one or more pod members of immuno-isolation devices of the present disclosure comprise an electro-chemical or optical sensor provided in communication with the hub and the manifold. Communication means of the manifold including, but not limited to, electrical wiring, pumps, and other features, are operable to transmit power, a pre-pulse signal, a measurement signal, and/or oxygen to and from the sensor. A pre-pulse signal is contemplated at least in embodiments comprising electro-chemical sensors to initiate a measurement. Devices of the present disclosure comprising one or more pod members and porous membranes provide means to transport fluids or agents from vascular structures adjacent to a device surface to the encapsulated sensor.
Alternatively, one or more lumens of the present disclosure are operable to disperse one or more therapeutic agents to a host. For example, a lumen of pod may be provided with an active agent, such as an active biological agent, insulin, Factor VIII, Factor IX, HGH hormone, or proteins from the hub via the manifold. The active agent will then be released through the lumen of the pod of the implant device and be rapidly dispersed through the vascular structures formed surrounding the implant device.
In the above manner, and through an interconnection of the pod ports, the immune-isolation device implanted into the soft tissue of an animal, such as a human, may also be configured to communicate with other implanted immune-isolation devices, device manifolds, catheters, or other desired materials through one or more of the available device pod ports.
In one embodiment, an immuno-isolation membrane is provided that comprises an inner region and an outer region. The inner region and the outer region each comprise pores with a pore-size gradient from the inner region to the outer region. The inner region comprises a pore size of between about 0.1 micron and about 1.0 micron, and the outer region comprises a pore size of between about 3.0 micron and about 15 micron.
In various embodiments, methods of forming and manufacturing membranes and devices are provided. In one embodiment, a method of manufacturing an immuno-isolation membrane comprising an inner membrane region, an outer membrane region, and a transition gradient region there between. The method comprises steps of depositing an electrospun inner membrane region, wherein the inner membrane region comprises a porous structure with pore sizes of between 0.1 micron to 1.0 micron; depositing an electrospun outer membrane region, wherein the outer membrane region comprises a porous structure with pore sizes of between 2.0 micron to 50.0 micron; and wherein the inner membrane region and the outer gradient membrane region are formed with a continuous pore size gradient devoid of lamination or welding between the regions.
In one embodiment, an implantable medical device operable for subcutaneous implantation in an animal is provided wherein the device comprises a hub comprising an internal void, and at least one pod in communication with the hub. The pod comprises an inner cavity operable to receive at least one of cells, a gas and a therapeutic agent. An immuno-isolation member is provided adjacent to and exterior to the inner cavity. A vascularizing membrane is provided adjacent to and exterior to the immuno-isolation member. The hub and the pod are provided in communication with one another by at least one channel extending between the internal void of the hub and the inner cavity of the at least one pod.
In one embodiment, an implantable medical device is provided that is operable for subcutaneous implantation in an animal. The device comprises a hub with an internal void, and at least one pod in communication with the hub. The pod comprises an inner cavity operable to receive at least one of cells, a gas and a therapeutic agent. An immuno-isolation member is provided adjacent to and exterior to the inner cavity, and a vascularizing membrane provided adjacent to and exterior to the immuno-isolation member. The vascularizing membrane comprises an inner region and an outer region, the inner region and the outer region each comprise pores, and a pore-size gradient is provided from the inner region to the outer region. The inner region comprises pore sizes of between about 0.1 micron and about 2.0 micron, and the outer region comprises pore sizes of between about 2.0 micron and about 20 micron. The hub and the pod are provided in communication with one another by at least one channel extending between the internal void of the hub and the inner cavity of the pod.
Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
Reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.”
As used herein, “about” means within a statistically meaningful range of a value or values such as a stated concentration, length, molecular weight, pH, sequence identity, time frame, temperature or volume. Such a value or range can be within an order of magnitude, typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The allowable variation encompassed by “about” will depend upon the particular system under study, and can be readily appreciated by one of skill in the art.
Typically, implantable immuno-isolation medical devices suitable for carrying a chamber of live cells are constructed with a vascularizing membrane and are assembled using two separate layers made separately, and then joined together (
By contrast,
Advantageously, and according to methods of the present disclosure, a single layer membrane 2 is constructed that allows for cell penetration to a certain extent and which is not prone to delamination. Embodiments of the present disclosure provide a single layer with a first gradient region that allows for vascularization, and a second gradient region (an inner region) providing for a more tightly woven electrospun membrane (such as a PTFE membrane). Such single layer membrane of varying porosity with a gradient of pore sizes are contemplated as being formed in-place on an implantable medical device including, but not limited to, those shown and described herein.
In certain embodiments, a single layer gradient membrane is constructed separately and then provided to a desired surface of an implantable medical device during manufacture of the implantable medical device, such as by application of a sheet of a pre-fabricated single layer gradient membrane as described herein to the desired surface or surfaces. Notably, the present single layer gradient membranes do not have an abrupt transition zone within the membrane, as is characteristic of other bi-membrane systems.
Electrospun membranes of the present disclosure serve as a single component embodying immunoisolation and vascularization features and comprise a thickness of at least about 20 micron and not more than about 200 micron. In some embodiments, at least two membranes are contemplated as being provided and welded together in a manner that creates or defines an interior cavity that is operable to receive therapeutic agents including, but not limited to cells. The surface of the membrane 2 facing or provided adjacent to the interior cavity comprises tightly intertwined fibers that create pores from about 0.1 micron to about 1 micron. A continuous transition in gradient is provided from this tight intertwined structure to a more open or loose intertwined fiber network and as one progressed from the inner structure to the outer surface, and the transition is to a more and more open structure in a gradual gradient. Likewise, the pores gradually transition from about 0.1 to about 1 micron at the inner surface 6 facing the lumen to between about 5 and 50 micron, and preferably of about 10 to about 15 micron towards the outer surface of the membrane 4.
In certain embodiments, an implantable medical device having multiple components is provided wherein one of the components, for example, a lumen chamber suitable for containing a population of live cells (e.g., stem cells or other desired material) having an immune-isolating membrane, may be processed to include the single layer gradient membrane described herein over all or a portion of the implantable medical device. Such would provide surfaces suitable for enhancing vascularization to the implantable medical device in vivo. A sonic welding technique may be used, for example, to apply and secure the single layer gradient membrane to the surfaces of the implantable medical device. In various embodiments, electrospun membranes are provided that comprise strand 8 sizes of about 5 micron or less, 5 micron pore sizes and a preferred thickness of between about 5 and 1,000 micron, and more preferably of about 15-90 micron. A gradient is provided wherein a pore size of a membrane is between approximately 5 to 15 micron proximal to an outer portion of the membrane, and decreases to about 0.4 micron or less at an inner portion of the membrane.
Preferred methods for creating a side seal or peripheral of the device include but are not limited to ultrasonic welding, heat sealing, over-molding, gasket compression, compression, silicone, glue, spin welding, laser welding, and various combinations thereof. In some embodiments, polyethylene inserts are provided, which are melted and driven into a perimeter or periphery of the device to create a seal around the pod. In some embodiments, the side or peripheral seal also secures the ports 22, 24, 26 to the pod 21. U.S. Pat. No. 5,545,223 to Neuenfeldt et al. discloses devices and methods for sealing implants, and is hereby incorporated by reference in its entirety.
As shown in
In various embodiments, a pod 21 with an internal volume or void comprises a peripheral seal formed by one or more of ultrasonic welding, heat sealing, over-molding, gasket compression, compression, silicone, glue, spin welding, and laser welding. In various embodiments, the outer porous structure 30 comprises a porous surface area over at least about 20% of the surface area of the structure 30. The vascularizing structure 32 comprises a porous structure with pores of between approximately 0.1 μm to 50 μm in diameter. The immune barrier 34 comprises a porous structure with pores of less than approximately 1.0 μm in diameter. The inner cavity 36 comprises a void to house or receive cells, tissues, therapeutic agents, oxygen, sensors, nutrients, pumps, electronics, electrical connectors, or combinations thereof.
As shown and described with respect to
Although interior void members 46 are described as comprising a void or lumen, it will be recognized that these regions are contemplated as receiving materials and may not necessarily comprise a “void” upon complete assembly of the device. The interior void members 46a, 46b, 46c are contemplated as comprising cells, gas, and/or various therapeutic agents. Additionally, in some embodiments, one or more of the interior void members 46a, 46b, 46c are contemplated as comprising or receiving one or more of a pump, a sensor (e.g. oxygen sensor), power storage (e.g. a battery), and electronics (e.g. a controller). The foregoing is true for lumens and interior voids of various embodiments of the present disclosure and is not limited to the embodiment of
Implantable devices of the present disclosure, including that shown in
The fan-like configuration of the implantable device 50 of
In the case of cellular therapies, the pod(s) 21, 51 of an implantable device of the present disclosure are provided with cells that secrete therapeutic molecules intended to treat a disease condition in the patient. Those cells may be primary, natural cells obtained from human donors, an immortalized cell line derived from a specific human tissue, a human cell line derived from tissue that does not produce any therapeutic molecule but has been genetically engineered in the laboratory to secrete a specific protein or stem cell derived tissue in which stem cells have been converted to a specific tissue in the laboratory.
By way of example, in the case of primary tissue that occurs naturally in the body, one might fill the interior volume 36 of a pod with parathyroid tissue harvested from a human donor thereby providing parathyroid hormone to individuals suffering from parathyroid insufficiency.
In various embodiments, it is contemplated that implants of the present disclosure comprise various internal structures and features. For example, and as shown in
In the case of a cell line, devices of the present disclosure are contemplated as being filled with cells maintained in culture at repositories such as the American Type Culture Collection that express therapeutic proteins. Fibroblast cell lines may be used as a generic cell type for genetic engineering where one or more genes might be inserted by genetic engineering methods to create cells that secrete proteins necessary to treat diseases. Examples include cells engineered to produce Factor IX for a form of hemophilia or erythropoietin for patients with anemia secondary to kidney disease. It is now possible to direct the maturation of stem cells along the pathway to specific cell types. For example, stem cells can be manipulated in the laboratory to convert to pancreatic cells such as B-cells that secrete insulin. Such cells may be loaded into the interior volume 36 of the pods 21 to provide a treatment for diabetes.
The examples set forth above are provided to give those of ordinary skill in the art a complete disclosure and description of how to make and use the embodiments of the methods for prediction of the selected modifications that may be made to a biomolecule of interest, and are not intended to limit the scope of what the inventors regard as the scope of the disclosure. Modifications of the above-described modes for carrying out the disclosure can be used by persons of skill in the art, and are intended to be within the scope of the following claims.
It is to be understood that the disclosure is not limited to particular methods or systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, other embodiments are within the scope of the following claims.
This Continuation application claims priority to U.S. patent application Ser. No. 17/279,474, filed Mar. 24, 2021, which is a national stage application under 35 U.S.C § 371 of and claims the benefit of PCT Application No. PCT/US19/52728, filed Sep. 24, 2019, which claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 62/736,244, filed Sep. 25, 2018, and U.S. Provisional Patent Application Ser. No. 62/735,697, filed Sep. 24, 2018, the entire disclosures of which are hereby incorporated by reference.
Number | Date | Country | |
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62736244 | Sep 2018 | US | |
62735697 | Sep 2018 | US |
Number | Date | Country | |
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Parent | 17279474 | Mar 2021 | US |
Child | 17876302 | US |