Abstract:
The invention relates to a metallic, nanoporous canister used to encapsulate cellular and/or biotherapeutic agents. The device is biocompatible and functions to wholly isolate a therapeutically active agent and/or cells therein. Their implantation, and survival in vivo, permits the local or systemic diffusion of their encapsulated cellular and/or biomolecular and therapeutics factors with the potential to promote repair of damaged or degenerated tissues in mammalian hosts, primarily humans.

Description:
FIELD OF INVENTION 
       [0001]    The invention relates to a metallic, nanoporous device used to encapsulate cellular and biotherapeutic agents. The device is biocompatible and functions to wholly isolate a therapeutically active agent and/or cells therein. Their implantation, and survival in vivo, permits the local or systemic diffusion of their encapsulated cellular and/or biotherapeutic factors with the potential to promote repair of damaged or degenerated tissues in mammalian hosts, primarily humans. 
       BACKGROUND 
       [0002]    The field of cellular and biotherapeutic agents research and development has provided novel, patient centric alternatives to resolving many chronic and costly disease conditions. Traditional pharmaceutical based therapies have yet to provide a cure for these often acquired and congenital conditions. These include the +100 autoimmune diseases affecting 50 million Americans (AARDA) such as Type 1 diabetes (T 1 D), Rheumatoid Arthritis (RA), Multiple Sclerosis (MS) and neurodegenerative diseases including Parkinson&#39;s and Alzheimer&#39;s disease. Typically for these disease states, cellular production of required biomolecular factors that direct normal physiological function are missing. Unfortunately, the unexplained destructive attack on normal cellular function by the body&#39;s own protective immune system is frequently the cause. 
         [0003]    As an example, the most costly of these is Type 1 diabetes, a disease where the body&#39;s immune system attacks and destroys insulin producing β-cells in the pancreas. This disease, most frequently diagnosed in children, affects nearly 3 million Americans who require $15 billion in annual care, including $1.8 billion spent on insulin. 
         [0004]    Cellular therapy offers the option of replacing lost or damaged cells with donor cells or stem cells capable of producing and secreting a steady supply of biomolecular factors. These biomolecular factors have the potential to restore lost or impaired physiological function within the mammalian host. For example, replacing lost islets of Langerhans has been shown to restore glucose transport in mammals with insulin-dependent diabetes. And dopaminergic neurons or neural stem cell-based therapy have been shown to reduce the effects of Parkinson&#39;s disease. 
         [0005]    Biotherapeutic agents, or biologics, represent another novel therapy option. These biomolecular substances are derived from living organisms, where living tissues are made or modified to create therapeutic compounds. Insulin, used to regulate blood sugars, was the first medicine produced using biotechnological methods. Many biologics have been subsequently developed to treat chronic illnesses like cancer, anemia, multiple sclerosis, and rheumatoid arthritis. Such biologics also have the potential to disrupt unwanted physiological events, as in potent cancer compounds or anti-infectious disease vectors. These therapeutic and living tissue-derived and active factors include but are not limited to proteins, peptides, genes, antibodies hormones, growth factors and neurotransmitters. 
         [0006]    Envisioned is a complementing site-specific delivery device such as a canister or tube platform with the potential for the long-term (&gt;12 months) controlled secretion of these living tissue derived, biologically active and cell-based therapeutic agents. 
         [0007]    A key to utilizing cellular and biotherapeutic agents is their transplantation into mammalian tissues. As a foreign biomaterial, they trigger the host&#39;s naturally protective immune system response, which compromises their ability to survive and function. Likewise, as living tissues, careful placement is required to avoid harmful side effects to the mammalian host. For example, current medical practice requires the patient to remain on life-long immunosuppressant drug therapy following the direct administration of foreign but therapeutic cells (e.g. injection) into an organ or tissue. This required concomitant therapy unfortunately carries significant risks including toxicity to both the host and the implanted cells and/or biotherapeutic agents. There is also the concern that certain cell types (e.g. pluripotent stem cells), although potentially therapeutic, carry the risk of differentiating and developing tumorogenicity. Additionally, blood-mediated inflammatory reaction (IBMIR) destroys a significant portion of cells when transplanted into the vascular system. 
         [0008]    The sustained function of therapeutic cells and biotherapeutic compounds, especially when they trigger an aggressive immune response, require a specialized delivery canister alternative. The present disclosure describes an implantable, canister-like “platform” for sustained biomolecular agent-based therapies. Envisioned are a variety of specialized implantable canisters for delivering cells and biotherapeutics in vivo that address the following requirements; (1) are biocompatible and well tolerated by the mammalian host, (2) protect the delivered materials from immune response and rejection; (3) establish an environment that supports targeted cellular function and biotherapeutic activity; (4) allow for the continuous diffusion of their specific biomolecular factors for treating disease conditions; (5) complement current medical practice associated with implantable devices (e.g. post-implant visualization, infection control, retrieval, mechanically and structurally robust, sterility, etc.). 
         [0009]    Likewise, such a device delivery can potentially obviate problems associated with current cell and biotherapeutics delivery canister-based approaches:
       1) The implantable device (e.g., canister) utilizes medical grade metal materials that are well tolerated by the body and are biocompatible. Metal device manufacturing is a mature technology and applied across a variety of implanted medical devices like pacemakers, orthopedic implants, cardiovascular stents, etc. Existing processes and treatments render these materials to be clean, passive, corrosion resistant, mechanically stable and biocompatible by way of processes such as chemical cleaning, etching, electropolishing and acid passivation. Specific metals are known to have a protective oxide layer that renders surfaces relatively inert. This results in modest surface charges that minimize protein deposition in situ, curtail monocyte and macrophage adhesion. The metals materials characteristic results in generally low levels of (acute) inflammation, thus minimizing aggressive fibrotic encapsulation resulting from chronic inflammation and foreign body response. Currently available cell and biotherapeutic devices are pouch-like macroencapsulation constructs. They are constructed from multilayered polymer materials. Such implanted polymers are known to trigger untoward inflammatory reactions, primarily because of impurities inherent with their manufacture (e.g. catalysts, binders, monomers, initiators). Of additional concern is the lingering toxicity of these manufacturing impurities and their effect on the encapsulated cellular and/or biotherapeutic agents and their secreted therapeutic factors;   2) The metallic implant device can be made into a variety of shapes and sizes, whose physical characteristics can be crafted to meet specific clinical therapeutic requirements while offering superior structural integrity. Delivery pouches constructed of polymeric materials are limited in the variety of possible constructs when compared to metal based designs. Their designs incorporate layered elements including microfiber filters, webbing, spacers, shims, etc., making them prone to splitting, fracture, buckling and ballooning. Additionally, polymeric macroencapsulation delivery pouches contain undesirable artifacts associated with their manufacture. These manufacturing defects, such as sharp edges, inconsistent layered materials deposition, and poor edge seals, can cause implant site irritation, resulting in untoward inflammation and aggressive tissue reaction. They are known to cause significant scar tissue formation (fibrosis) that envelops the device, making it nonfunctional. They are known to disfigure and often kind following their implantation.       
 
         [0012]    To the contrary, metals based medical device manufacturing processes have been refined and eliminate such artifacts. They can be manufactured as a single material construct, with defined wall and overall device thickness. As a single materials construct, there is no need for layered elements. Anatomically appropriate features (e.g. rounded features, increased surface area refinements) are easily incorporated into the superstructure. Additionally, the nature of metal materials in medical applications is well documented and understood in terms of strength, durability, resistance to corrosion and wear. Similarly designed polymer devices generally fall short with regard to these important features when placed in normal physiological stresses and conditions;
       3) Nanoscale through-porous manufacturing processes permit control over pore size, pore density and morphology. Tailored pore sizing is a key criterion for the continuous diffusion of specific biomolecular factors for treating disease conditions. These biomolecular factors, most of which are considered to be small molecules, must freely exit from the delivery canister, exiting into the surrounding tissues of the mammalian host. Likewise, this tailored porous dimension can withstand the host&#39;s cell-mediated immunity, mechanically blocking immunocytes and their secretory immunoglobulins (IgM and IgA) and macrophages accessing the canister content. Methods for manufacturing such tailored nanoscale porous structures in metal include electrochemical dealloying at the atomic level, nanoparticulate fusing resulting in porous morphologies between metal particles and/or nanophase templates derived from block-co-polymer and block-co-metals. These processes can be used singularly or in combination. Important to these modification processes is the necessity of bicontinuous morphology. This nanophase materials outcome allows for controlled biomolecular factor secretion, necessary for any closed-looped delivery where factor release (e.g. timing) is an important therapeutic variable;   4) Nanotechnology derived materials significantly change metal properties by controlling the atomic, molecular, and supramolecular levels of the canister. These nanophase porous metal manufactured materials, especially at the surface, offer several physiological benefits. Due to the presence of numerous nanostructures (e.g., proteins) in the body, cells are accustomed to interacting with surfaces that have a large degree of nanometer roughness. Despite this fact, many current synthetic polymer delivery pouches possess conventional (micron-sized) surface features only.       
 
         [0015]    It is well documented that manufactured materials with nanophase implant surfaces can:
       Alter implant surface energy; in certain scenarios, they act to camouflage (endothelialization) and in others, they selectively deter (retard inflammatory cells response).   Control initial protein adsorption and bioactivity   Promote cellular activity/growth while inhibiting infection and chronic inflammation   Provide increased drug loading and prolonged drug delivery       
 
         [0020]    In the specific application to the envisioned delivery canister, the incorporated nanophase porosity will lead to increased vascular endothelial cell proliferation, important for therapeutic factor uptake from the enclosed therapeutic agents. 
         [0021]    Internal to the canister, the large surface to volume ratio will optimize the exchange of nutrients, oxygen, and removal of waste metabolites, thus increasing the rates of factor release and responsiveness changes in the surrounding tissues. This approach—of utilizing defined nanophase regions within the same metal construct—would allow contained biomolecular factors to reside, via varied porosity, closer to the external, vascularized surface of the canister without having to greatly diminish the canister&#39;s wall thickness and thus maintaining the required structural integrity of the delivery canister. Such internal nanophase structures that provide for improved cell adhesion to the device super-structure would facilitate phenotypic control and cell survivability. 
         [0022]    External and at the canister to tissue interface, nanophase modified surface textures could be used to facilitate use of anti-inflammatory, antibiotic and anti-fibrotic compounds to retard immediate foreign body responses while allowing for surface only imbedded vascularization agents for enhanced biomolecular factor survival and their long-term function of secreted therapeutic agents. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0023]      FIG. 1  shows a perspective view of an embodiment of the finished implant device, in this view, a canister. 
           [0024]      FIG. 1A  shows a perspective view of the embodiment shown in  FIG. 1 , where the two shell members are opened. 
           [0025]      FIG. 1B  shows a cut away embodiment of the canister containing no internal raised structure. 
           [0026]      FIG. 1C  illustrates a microscopic view of a metallic material with the nanoporous biocontinuous through-porous membrane morphology incorporated into the super-structure of the canister. 
           [0027]      FIG. 2  shows an embodiment of a metallic material used to construct the invention showing a single nanoporous biocontinuous, through-porous membrane morphology structure. 
           [0028]      FIG. 2A  shows another embodiment of a metallic material used to construct the invention showing two interconnected layers of nanoporous, through porous membrane morphology structures. 
           [0029]      FIG. 3  shows another embodiment of the invention wherein the device is circular shaped having internal circular channels, wherein the channels are formed from a continuous, raised protrusion. 
           [0030]      FIG. 4  shows yet another embodiment of the invention wherein the device is square shaped having internal square channels, wherein the channels are separate from each other. 
           [0031]      FIG. 5  shows a nanoporous surface pattern to increase internal and/or external surface areas to which a nanophase through-porous porosity is then applied. 
           [0032]      FIG. 6  shows an alternative surface pattern to increase internal and/or external surface areas to which a nanophase through-porous porosity is then applied. 
           [0033]      FIG. 7  shows another surface pattern to increase internal and/or external surface areas to which a nanophase through-porous porosity is then applied. 
           [0034]      FIG. 8  shows yet another surface pattern to increase internal and/or external surface areas to which a nanophase through-porous porosity is then applied. 
           [0035]      FIG. 9  shows a different surface pattern to increase internal and/or external surface areas to which a nanophase through-porous porosity is then applied. 
           [0036]      FIG. 10  shows another surface that is configured to display composite bends to increase internal and/or external surface areas to which a nanophase through-porous porosity is then applied. 
           [0037]      FIG. 11  shows another surface pattern to increase external and/or surface areas to which a nanophase through-porous porosity is then applied. 
           [0038]      FIG. 12  shows a perspective view of the canister having a centrally located port to allow flushing or injection into the interior chamber of the canister. 
           [0039]      FIG. 13  shows a perspective view of the canister with a port system comprising an infusion tube used to allow flushing or injection into the interior chamber of the canister. 
           [0040]      FIG. 14  shows a perspective, cut-away view of the outer one-half of a protective metallic canister with its nanophase through-porous membrane and encasing an inner porous polymeric pouch with a port for injecting biotherapeutic and/or cellular agents. 
           [0041]      FIG. 15  shows an alternative of the canister with its nanophase through-porous membrane and having multiple sealed chambers and a plurality of ports. 
       
    
    
     DETAILED DESCRIPTION 
       [0042]    Definitions 
         [0043]    “Biocontinuous Morphology” refers to at least two regions, each of substantially uniform composition which differs from the other and each of which forms a continuous pathway from one surface of an article to another surface of an article. Thus, a biocontinuous morphology will have two continuous pathways or two sets of continuous pathways extending from one surface of the material to the other surface. 
         [0044]    “Metabolically Active” means cellular or biotherapeutic agents that produce therapeutic metabolites in a biologically relevant environment. 
         [0045]    “Nanoporous” means very small pores extending through a surface, and measured in increments of a millionth of a meter or as 10 −9  of a meter (abbreviated “nm”). 
         [0046]    “Nanoscale” and “nanophase” means measurements in increments in increments of a millionth of a meter or as 10 −9  of a meter (abbreviated “nm”). 
         [0047]    “Rigid” means stiff and not bending. 
         [0048]    “Through-porous membrane” means a semipermeable membrane, also termed a selectively permeable membrane, a partially permeable membrane or a differentially permeable membrane, is a type of biological membrane that will allow certain molecules or ions to pass through it by diffusion and occasionally specialized “facilitated diffusion” along with other types of passive transport and active transport. 
         [0049]    Nomenclature 
         [0050]      10  First Nanoporous Region 
         [0051]      120  Second Nanoporous Region 
         [0052]      100  Canister 
         [0053]      102  First Major Surface 
         [0054]      104  Second Major Surface 
         [0055]      106  Side Surface 
         [0056]      108  Port 
         [0057]      108   a  Extended Silicone Tube 
         [0058]      110  Internal Barrier 
         [0059]      112  Interior Chamber 
         [0060]      212  Internal Channel 
         [0061]      300  Canister 
         [0062]      308  Port 
         [0063]      400  Canister 
         [0064]      408  Port 
         [0065]      412  Internal Channel 
         [0066]      500  Nanoporous and Patterned Surface 
         [0067]      600  Nanoporous and Patterned Surface 
         [0068]      700  Nanoporous and Patterned Surface 
         [0069]      800  Nanoporous and Patterned Surface 
         [0070]      900  Nanoporous and Patterned Surface 
         [0071]      1000  Nanoporous and Patterned Surface 
         [0072]      1100  Nanoporous and Patterned Surface 
         [0073]      1400  Canister 
         [0074]      1402  Outer Metallic Canister 
         [0075]      1404  Inner Polymeric Pouch 
         [0076]      1406  Port 
         [0077]      1500  Canister 
         [0078]      1502  First Major Surface 
         [0079]      1504  Second Major Surface 
         [0080]      1506  Side Surface 
         [0081]      1508  First Sealed Chamber 
         [0082]      1510  Second Sealed Chamber 
         [0083]      1512  Third Sealed Chamber 
         [0084]      1514  Fourth Sealed Chamber 
         [0085]      1516  Fifth Sealed Chamber 
         [0086]      1518  Sixth Sealed Chamber 
         [0087]    A platform for cellular and biotherapeutic agent delivery in a mammalian host, primarily humans, utilizing an implantable metal canister is described herein. Such a cell and biotherapeutics delivery canister provides a suitable environment for the cells and biotherapeutics to survive and function (e.g. produce and secrete therapeutic bioactive factors) without adversely affecting the mammalian host recipient or impaired by normal immunoprotective response. 
         [0088]    The cell and biotherapeutics delivery canister construct is made of medical-grade metal(s). In its simplest configuration, it is a metallic canister composed of two identical cup-shaped halves to create a hollow chamber. The medical-grade metals are modified to contain a nanoscale through-porous and bicontinuous membrane morphology. The internal void chamber of the envisioned canister is accessed through an incorporated silicon septum or attached infusion tube built into the canister, also sealed with a silicon septum for needle injection. 
         [0089]    The metals material is processed in a way that to create a porous, membrane-like structure. This modification takes place at the nanoscale level. The nanoscale pore size is sized and exacted to control bioactive factor exchange and diffusion. Specifically, a tailored nanoscale, through-porous feature with bicontinuous morphology within the canister superstructure allows for highly controlled therapeutic factor diffusion, both in and out of the delivery canister. The pore sizes range from approximately 20 nm to 5000 nm with a wall thickness of 5 to 250 microns. The wall thickness can be varied to provide a balance between efficient diffusion and structural integrity of the implanted device. 
         [0090]    The incorporated and tailored membrane also precludes certain unwanted biomaterials from penetrating the implanted delivery canister and contacting its therapeutic agent contents. These include immunogenic factors (e.g. immune cells or immune agents). The pore sizes may range from approximately 20 nm to 5000 nm with a wall thickness of 5 to 250 microns. The wall thickness can be varied to provide a balance between efficient diffusion and structural integrity of the implanted device. 
         [0091]    Nanophase biofunctional surfacing of implanted devices has been shown to match the recognition ability of biological systems, especially microvascularization. As such, topographic patterns can be executed on the canister delivery surface to match proteins at the nanometer scale and cells at the micrometer scale. The pore size feature of the canister superstructure metal material will facilitate desired vascular tissue incorporation of the canister to aid in the survival and/or function of its contents. The pore sizes may range from approximately 20 nm to 5000 nm with a wall thickness of 5 to 250 microns. The wall thickness can be varied to provide a balance between efficient diffusion and structural integrity of the implanted device. 
         [0092]    The availability of vascular supply to the encapsulated therapeutic agents relates to their survival and function. A constant supply of oxygen, nutrients, and waste removal are required for nourishing the implanted cells and maintaining an optimal environment within the delivery canister for their longevity. In the case of therapeutic cells, a well-vascularized environment prevents death or damage through the effects of ischemia or hypoxia. The nanoscale texturing of the external surface of the delivery canister will encourage growth of vascularized tissue into the porous construct of the device. At the same time, scar tissue formation, triggered by a foreign body response, is mitigated. The desired ingrown vascular tissues also stabilize the implant canister, preventing its translocation into other body regions or tissues. 
         [0093]    Nanoscale texturing of the internal void surface of the canister device will encourage distribution of therapeutic contents within the canister to the outermost regions of the delivery canister. This will encourage more immediate access to the vascularized tissues resident to the outer surface of the canister device, resulting in a large surface to volume ratio associated with nanophase materials construction. 
         [0094]    The implanted delivery canister, having as well a nanoporous external surface, can be coated with an approved antibiotic compound to minimize infections. The porous surface texture of the delivery canister can be tailored at the nanoscale level for specific retention and release of such pharmaceutical agents. Representative antibiotics alone and in combination, include but are not limited to ampicillin, tetracycline, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, vancomycin, gentamicin, streptomycin, erythromycin, penicillin, amoxicillin, sulfonamides and derivatives and analogues thereof. 
         [0095]    The implanted cell and biotherapeutics delivery canister, having a nanoporous external surface, can be coated with approved antifibrotic drugs to inhibit the formation of unwanted fibrous tissues. The porous surface texture of the delivery canister can be tailored at the nanoscale level for retention and release of such pharmaceutical agents. Antifibrotic agents alone and in combination may include but are not limited to paclitaxel, everolimus, tacrolimus, rapamycin, and derivatives and analogues thereof. 
         [0096]    The implanted cell and biotherapeutics delivery canister, having a nanoporous external surface, can be coated with approved biological or pharmaceutical agents (e.g. growth factors) to stimulate tissue in-growth and angiogenesis. The porous surface texture of the delivery canister can be tailored at the nanoscale level for retention and release of such pharmaceutical agents. Such biological or non-biological agents, alone or in combination, stimulate tissue incorporation and angiogenesis include but are not limited to PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor), FGF-1 (fibroblast growth factor), endoglin, ephrin, plasminogen activators, angiogenin and derivatives and analogues thereof. 
         [0097]    Functionality of the envisioned cell and biotherapeutics delivery canister is also based on proper dimensions of the delivery canister as they relate to particular cells, biotherapeutic volumes and clinical indications. Overall canister thickness, individual canister wall thickness, contour, shape, and the ability to load and recharge are important to sustaining a therapeutic number of cells for their ongoing survival and effect. The delivery canister shape must be anatomically convenient and non-protruding while meeting patient comfort and aesthetic considerations. In addition to size and shape, the metal material can be finely finished to avoid sharp traumatic edges. There may also be a clinical need to ultimately remove the delivery canister. 
         [0098]    Another embodiment of the cell and biotherapeutics delivery canister includes multiple divided, internal chambers within the canister. These can either be connected or separate depending on septal or cell infusion tube access to the crafted, internal chambers. This embodiment would for example, facilitate the delivery of multiple biotherapeutic compounds where phased delivery is critical to therapeutic endpoints. This phased delivery would be dependent upon size of these internal chambers and location of sized nanoscale through-porosity. 
         [0099]    Specifically important to cell survival is the ability to control cell distribution within the canister as cell clustering can impact their survival. Cell quantities can be positioned and controlled within the chamber utilizing internally crafted structures such as interconnected channels. 
         [0100]    In all embodiments, the cells are loaded using needled injection through either a septum or self-sealing infusion tube that is designed for needle injection. In one embodiment, the septum is made of a self-sealing medical grade silicone. The septum is positioned to one side of the delivery canister, thereby facilitating manual palpation when implanted in subcutaneous tissues. Deeper tissue placement will utilize a defined tube length and a self-sealing tube with an access port that facilitates needle injection. This self-sealing tube can be brought to the exterior of the patient&#39;s body in conjunction with surgical placement and standard wound closure. 
         [0101]    The method for loading cells first requires fixating the cell and biotherapeutics delivery canister in the mammalian host body. As such, the nanoporous through-porous membrane of the delivery canister is infiltrated with vascular and connective tissues. Once the cell and biotherapeutics delivery canister is encapsulated in a vascularized collagen matrix, delivering a cell and/or biotherapeutic agent is executed via needle injection, either through the built-in silicon septum or through the self-sealing access tube, which is connected to the delivery canister. 
         [0102]    Throughout the disclosure, the terms cell and biotherapeutic infusion and cell and biotherapeutic transplantation are used interchangeably. 
         [0103]    A transplanted cell and biotherapeutics delivery canister for containing therapeutic cells and biotherapeutics in vivo, in a mammalian host, is provided. The envisioned implanted cell and biotherapeutics delivery canister comprises a nanoporous canister that can be configured to create a hollow void chamber that is accessed for cell and biotherapeutic loading by way of syringe injection. 
         [0104]    Metallurgists have specifically graded metals for clinical applications with enhanced characteristics that make them highly compatible within living tissues. Included in this list are medical-grade metals. Examples of such biomedical grade metals and alloys include stainless steel based alloys, cobalt-chromium based alloys, alloys and nickel-titanium based alloys. More recently platinum containing alloys have been perfected for intravascular applications. 
         [0105]    The porous canister is formed of a biocompatible medical grade metal material that elicits only a mild inflammatory response in the body. The nanophase porous exterior portion of a through-porous membrane stimulates microvascular vessels to enter the cell and biotherapeutics delivery canister and promotes a vascularized collagen matrix to envelop the device, while curtailing a significant inflammation of tissues surrounding the delivery canister. The pore size and density of the nanoscale porous canister through-porous membrane encourages the growth and maintenance of these healthy vessels, which relate to the survival and targeted function of the therapeutic agents (e.g. molecular factor diffusion) contained within the delivery canister. 
         [0106]    The required size of the porous canister depends on the optimal surface area-to-volume ratios for holding metabolically active agents in vivo and for ensuring their long-term survival within the vascularized void chamber(s). The number of chambers in the implanted delivery canister is determined by the volume and/or number of cells and/or biotherapeutics that are to be transplanted. The total volume of the cell and biotherapeutics delivery canister can be adjusted by increasing or decreasing the number of chambers and the optimum surface area-to-volume ratio of each individual chamber. The length, width and height of the chambers are also defined and manufactured to meet total therapeutic volume requirements. 
       Method of Using 
       [0107]    The cell and biotherapeutics delivery canister disclosed can be implanted using standard surgical techniques. Applied surgical implantation can occur at the following anatomical locations: subcutaneous, intraperitoneal including the omentum, intramuscular, intravascular, intraocular, intracerebral or other appropriate sites including the digestive tract, spinal cord area or any other organ as required to elicit a therapeutic factor from implanted cells or biotherapeutic agents. 
         [0108]    The loading procedure is a two-step process comprising a cell and biotherapeutics delivery canister being implanted and then followed by agent transplantation. After an in vivo incubation period during which the implanted cell and biotherapeutics delivery canister is infiltrated with a vascularized collagen matrix, the agent infusion step is then executed. The desired incubation period is generally thirty days to allow for angiogenesis and collagen infiltration of the porous canister. The incubation period may vary, depending on the extent of desired neovascularization and tissue formation. For example, the device may vascularize at different rates depending on the cell and biotherapeutics delivery canister material, dimensions, or coatings (e.g. antibiotic/antifibrotic coatings, growth factors, vascularizing agents etc.). There may be different vascularization rates pending locations in different body cavities and tissues. A clinically prepared expert can determine the appropriate incubation period while applying imaging tools that can help measure the extent of connective tissue deposition around and through the walls of the porous implanted canister. 
         [0109]    For the metabolically active agent step, the implantation site is generally identified and needle accessed following (subcutaneous) palpation or a small surgical incision for deep tissue access. Specifically, the clinican will identify the septum built into the surface of the delivery canister. The cell and/or biotherapeutic agent is then delivered via needle injection through the incorporated silicon septum or self-sealing infusion tubing (e.g. polyethylene tubing) or any other suitable material to deliver the therapeutic agents into porous chamber of cell and biotherapeutics delivery canister during the agent infusion step. The number of septum or infusion tubes in the delivery system may correspond to the number of porous chambers. Deep tissue placement and access will likely involve image-guided technology commonly used in other medical device implant procedures. As a metallic device, medically accepted imaging is readily enhanced. 
         [0110]    It is also envisioned that the delivery canister is placed along with the therapeutic agent using a single step and thus implanted together. The potential need exists for a biodegradable polymer coating for short-term containment of the encapsulated cell and biotherapeutic agent during such a singular implant procedure to control leakage loss of the molecular factors within the porous canister. 
       Construction 
       [0111]    A void and porous canister may be created, for example, by joining (e.g.welding) the top and bottom halves of the canister along an edge. This would result in the canister being a single void chamber for holding the desired therapeutic agent. Its overall dimensions will generally be defined by the volume requirements and targeted anatomical location. In most embodiments the preferred delivery canister will measure 2-10 cm in length, 2-8 cm in width and have a height of 0.5 mm-5 mm. 
         [0112]    Different iterations of this device include similarly parallel halves with patterned gross textures. These geometric patterns, such as wave patterns, circular divots or indents, ridges, grooves and other roughened or contoured surfaces would aid in increasing the desired maximum surface area for enhanced cellular and biotherapeutic factor exchange and vascularization. 
         [0113]    As an implantable medical device, the cell and biotherapeutics delivery canister is sterilized using standard techniques prior to implantation. These include ethylene oxide, gamma radiation, cold plasma or dry heat autoclaving. The type of sterilization method used is dependent on the canister material. The cell and biotherapeutics delivery canister may be packaged in a self-seal package or any other sterilizable package along with a sterility indicator strip. 
         [0114]    The disclosed delivery canisters can be used for transplantation of any cells, or a combination of cells, any biotherapeutic agent or combination of agents into a mammalian host body for providing therapeutic factors to the mammalian host for the treatment of a disease condition. Allogeneic, xenogeneic or syngeneic donor cells, patient-derived cells, including stem cells, cord blood cells and embryonic stem cells are appropriate for such transplantation. Living tissue derived and active factors include but are not limited to proteins, peptides, genes, antibodies hormones, growth factors and neurotransmitters. 
         [0115]      FIG. 1  shows an implantable canister  100  defining a first major surface  102 , second major surface  104  and a side surface  106 . A port  108  extends from the side surface  106 , allowing access to the interior chamber  112  for infusion or flushing.  FIG. 1A  shows the canister  100  prior to being sealed shut, including an interior chamber  112  formed by combining both the upper shell  110  and lower shell  114 .  FIG. 1B  shows the canister  100  with one the upper shell  110  cut away, showing the interior chamber  112 . In all embodiments, the major surfaces can be fitted and/or joined and/or welded along an edge of the joined top and bottom halves, creating a single delivery canister. 
         [0116]      FIG. 1C  corresponds to the area shown on the first major surface in  FIG. 1A  and illustrates a microscopic view of the nanoscale through-porous membrane structure  10  of the canister  100 .  FIG. 2A  illustrates a microscopic view of the s nanoscale through-porous metallic membrane material of the canister  100 ,  300   400 ,  1400 ,  1500  having a uniform or homogeneous nanoporous structure.  FIG. 2B  shows similarly illustrates a microscopic view of the metallic material of the canister  100 ,  300 ,  400 ,  1400 ,  1500  that is processed to possess an interconnected biocontinuous morphology which containing two distinct porous regions  10 ,  20 , each of substantially uniform composition which differs from the other and each of which forms a continuous pathway from one surface of an article to another surface of an article. 
         [0117]      FIG. 3  shows a cut away view of a canister  300  configured to have an internal curved, raised pattern formed by an internal barrier  212  to physically stabilize a biotherapeutic agent (not shown) encased within.  FIG. 4  similarly is a cut away view of an embodiment of a canister  400  having a squared shape with a plurality of raised internal barriers  412  to physically stabilize a biotherapeutic agent (not shown) held by the canister  400 .  FIGS. 3 and 4  are shown for purposes of illustration only and are not intended to be limiting as variations of shape and internal barrier configuration within a canister are infinite. 
         [0118]      FIGS. 5-11  illustrate exterior nanoporous surface treatment patterns  500 ,  600 ,  700 ,  800 ,  900 ,  1400 ,  1500  that could be formed into the exterior and/or interior surface (unnumbered) of the canister  100 ,  300 ,  400 ,  1400 ,  1500 . The purpose of the different exterior and/or interior nanoporous surface treatment configurations is to increase the surface area of the canister  100 ,  300 ,  400 ,  1400 ,  1500  to allow improved inflow and outflow which positively affects the output of cellular and/or biotherapeutic agents contained in the canister and diffused from the canister.  FIGS. 5 to 11  are shown for purposes of illustration only and are not intended to be limiting as surface treatment variations of canister surface are infinite. 
         [0119]      FIG. 12  illustrates the canister  100  being loaded through its port  108  with a biotherapeutic agent.  FIG. 13  similarly illustrates a canister  100  having an extended tube  108   a  between the canister  100  and the exterior of a patient&#39;s body to allow loading of biotherapeutic agent (not shown) following a deep body (e.g., abdominal) implantation. 
         [0120]      FIG. 14  is a view of a metallic nanoporous outer protective canister  1400  with an inner polymeric pouch  1404  constructed of a semi-permeable material and containing biotherapeutic agent (not shown). The outer protective canister  1400  is constructed of a nanoscale or microscale through-porous membrane to facilitate cellular or biotherapeutic agent diffusion. The polymeric pouch  1404  is provided fluid communication by means of extended silicone tube  1406 . 
         [0121]    In another embodiment, as shown in  FIG. 15 , the delivery canister  1500  is composed of multiple individual and independent chambers  1508 ,  1510 ,  1512 ,  1514 ,  1516 ,  1518 . Each individual and independent chamber is accessed through its own port  108 . Each independent chamber can have the same or varied nanophase through-porous membrane structure  10 ,  20  for controlled diffusion of various cellular or biotherapeutic agents, thus allowing sequenced delivery. 
         [0122]    Other embodiments of the cell and biotherapeutic delivery canister will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.