Specialized hollow fiber membranes for in-vivo plasmapheresis and ultrafiltration

[0002] In U.S. Pat. Nos. 4,950,224, 5,152,743, 5,151,082, 5,735,809 and 5,980,478 there are disclosed methods and apparatus for carrying out in-vivo plasmapheresis for separating plasma from other blood components within the body and blood vessels of the patient. The apparatus uses pumping means to create a trans-membrane pressure (TMP) and motivate the flow of fluid from within the in-vivo system, whereby blood plasma is pumped from the patient to a treatment means such as a dialyzer apparatus in which toxic metabolic waste in the plasma is removed. After the plasma is treated for removal of waste products, excess fluids, toxins, and/or other deleterious plasma proteins, the treated plasma is returned and reintroduced to the patients' blood stream. Such methods are referred to as plasma dialysis, ultrafiltration or blood purification. The methods and apparatus described in the aforesaid patents are incorporated herein by reference.

[0003] These methods of toxin removal from blood as taught by the above patents are unique and substantially superior from conventional means of hemodialysis as presently practiced for both acute and chronic kidney failure, primarily because removal of whole a blood from the patient's vasculature is eliminated from the procedure using plasma, or portions of the plasma instead. In conventional hemodialysis procedures hollow fiber membranes are used in the ex-vivo dialysis and hemofilter cartridges for blood purification. The blood is routed from the body through the center lumen of the hollow fibers in the cartridges and dialysate fluid is routed over the outside walls of the fibers within the cartridge cavity in counter-flow direction to blood flow. Thus, toxin diffusion and ultrafiltration are from inside the fiber lumen to a compartment outside the fiber walls where the ultrafiltrate and toxin-saturated dialysate are collected for further processing and/or disposal.

[0004] Conventional hollow fiber membranes commercially used for present hemodialysis, hemo-ultrafiltration, and dialyzer cartridges fabricated from proprietary and non-proprietary polymer compositions generally utilize two types of morphologies: symmetrical and asymmetrical. In a symmetrical composition, the basic morphology or cellular structure and porosity of the fiber wall is uniform from the inner lumen to the outside surface. In asymmetrical compositions, both morphology and pore structures vary from the inner lumen to the outer surface to meet the high pressure requirements of the filter cartridges in which the TMP inside the fiber lumen is high (100-300 mmHg) while the blood flow itself in the fibers is near stagnant (2-300 ml/min/7,000 fibers=0.042 ml/fiber). These commercial membranes generally also have poor structural strength, acceptable in an encapsulated device external to the body but which would not be acceptable for an in-vivo placement for safety reasons. Such conventional fiber membranes are not suitable for the demanding environment of the in-vivo, high blood flow (vena cava=2.5 1/min), low TMP (≦50 mmHg), and unencapsulated environment of plasma extraction devices described by the aforesaid patent applications.

[0005] The present invention is directed to specialized hollow fiber membranes having the function of separation of plasma or a portion of the plasma from blood and having the unique morphology, performance properties and materials biocompatible characteristics necessary for effective and optimal utilization for in-vivo vascular implantation as the operating element in catheter-based devices as described in the aforesaid patents and other such similar devices for the separation and extraction of plasma and plasma components from the blood. The ultrafiltrate (exudate) may be transported ex-vivo via a catheter lumen where it is discarded, or treated by cascade filtration means, dialysis (solute diffusion) means, or other methods known to the art, and returned to the patient via a separate lumen in the catheter.

[0006] The hollow fiber membrane of the invention is tubular in shape and generally circular in cross-section, having a coaxial inner lumen along the length of the fiber in its center. The wall volume of the fibers is asymmetrical with a variable morphology from the outer diameter to that of the inner diameter, having a higher mass density at the outer wall and a lower mass density at the inner wall. The fibers are designed to facilitate ultrafiltration with the permeate outside the fibers and the exudate inside the fibers. The inner lumen of all fibers in a fiber extraction assembly are in direct fluid communication with the access lumen of the catheter which provides means for transporting the exudate ex-vivo.

[0007] FIG. 1 is a schematic end view of a hollow fiber illustrating the membrane morphology structure having four zones;

[0008] FIG. 2 is a scanning electron microscopy (SEM) image of a cross-section of a portion of the fiber of the invention at 400 μm magnification showing four zones of the asymmetrical wall structure between the inner and outer fiber wall surfaces;

[0009] FIG. 3 shows a portion of a cross-section of a portion of the fiber at a magnification of 5,000 μm;

[0010] FIG. 4 is a SEM cross-section of Zones 1, 2 and 3 of the fiber shown in FIG. 2 at a magnification of 1,000 μm;

[0011] FIG. 5 is a SEM cross-section of Zones 3 and, 4 of the fiber shown in FIG. 2 at a magnification of 1,000 μm;

[0012] FIG. 6 shows a transverse view of the inner lumen wall of the fiber at a magnification of 5,000 μm; and

[0013] FIG. 7 is a graph illustrating the hollow fiber membrane sieving coefficient curves.

[0014] As illustrated in FIGS. 1-5, the features of the fiber wall of the membrane of the invention include a pore and void structure defined within frames or solid walls which form boundaries of the pores. The pores are voids of variable definitive sizes which permit passage of fluid through the fiber wall to the lumen and which pores obstruct the passage of components larger than the pore diameter. As illustrated particularly in FIG. 3, the pores are irregular-shaped voids bounded by solid frames to form irregular tortuous paths for irregular and regular-shaped solutes. The wall structure of the fiber from the outer surface to the lumen is a continuum with non-linear pore and void distribution. The resulting structure is a continuous change in mass density between the outer surface of the fiber and the inner lumen surface. Thus, it is convenient to describe these changes in mass density as sections of the wall area having an average nominal pore size, porosity and wall mass in terms of zones with macro functions.

[0015] In FIG. 1, the wall structure illustrated has four zone sections, each zone characterized by a different mass pore density based on the average nominal pore size in the respective zones. The section of Zone 1 is adjacent to the fiber outer surface or outer diameter. Zone 1 forms the fiber interface with the permeate blood flow and although being the thinnest zone contains the highest density of operationally controlling pores for the fiber membrane performance. Thus, Zone 1 has the principal effect in the filtration process for controlling the trans-membrane flux (TMF) which is dependent on pore size, porosity and virtual membrane thickness.

[0016] The section of Zone 2, while having some flux-controlling pores, is principally a structural member for providing strength to the fiber as well as acting as a conduit for exudate flow to the section of Zone 3. The latter is principally a structural member with expanded pores for reducing the hydraulic resistance and providing a fluid conduit to the lumen of the fiber, and thus, in the example, as shown, has little filtration function. The section of Zone 4 has very large voids and pores with very little solid structure, thereby having the primary function of a major reduction of hydraulic resistance through the membrane and defining the fiber inner lumen diameter surface.

[0017] FIG. 2 illustrates a cross-section of the fiber wall showing the structure of Zones 1-4 at 400 μm magnification. The fiber wall morphology demonstrates the continuum of expanding plurosity and open spaces from the virtual control pore size of Zone 1 adjacent to the outer fiber diameter to the very open and low-flow resistant structure in Zone 4 adjacent to the inner lumen wall.

[0018] FIG. 3, a cross-section of Zone 1 at a magnification of 5,000 μm, shows pores and their boundary solid wall frames and the high uniformity of pore geometry and diverse irregular shapes of the individual pore dimensions. It is this high uniformity of pore size and high porosity as well as the thinness of Zone 1 which produces the high separation efficiency and high TMF of the membrane.

[0019] FIG. 4 shows a cross-section of Zones 1, 2 and 3 at a magnification of 1,0001 μm to illustrate the transition of the high-density structure of Zone 1 in comparison to the more open densities of Zones 2 and 3, as well as the uniformity and continuity of fiber structure producing high tensile and elongation strength.

[0020] FIG. 5, also at a magnification of 1,000 μm, shows the structure of Zones 3 and 4 to illustrate the rapidly expanding open spaces and fluid communication channels which produce the lowered hydraulic resistance to flow of the exudate and results in a very high TMF as a finction of a very low TMP.

[0021] FIG. 6 is a 5,000 μm magnification of a transverse view of the inner lumen wall showing the highly open but contiguous nature of the structure at that site, facilitating fluid communication of the exudate from the flow through the fiber to the fiber lumen.

[0022] FIG. 7 illustrates a sieving coefficient curve to provide a measure of membrane performance in-situ in an operating environment. The sieving coefficient curves illustrated are determined or generated by measuring the amount of a series of specific solutes or proteins in exudate passed through the membrane by convection as a percentage of the amount of the permeate of the same solute or protein in the blood. The vertical axis of the chart illustrated is linear from 0 to 100% and the horizontal axis is semi-logarithmic in two scales; the first scale is expressed in pore size in μm; the second scale is expressed in the molecular weight of the solute in Daltons. Curve 10 of FIG. 7 represents the typical curve of a plasma extraction membrane with exudate performance in Areas A and B. Curve 11 shows the typical exudate performance of a hemofilter (ultrafiltration) membrane with exudate performance in Area B, wherein Areas A plus B plus C constitute all components of the blood. Thus, Curve 10 represents the typical sieving coefficient curve for membranes with pores in the 0.3 to 0.7 μm diameter size, as used in plasmapheresis while Curve 11 represents a typical sieving coefficient curve for membranes with pores in the 0.006 to 0.009 μm diameter size used for ultrafiltration.

[0023] The driving force for convective transport of the plasma fluid and solutes is the TMF equal to P_f×TMP (and linear below the critical flow limit) where P_fis the hydraulic permeability of the membrane, and:

[0024] P_f=(nπτ_p⁴)/(τμΔx) Where:

[0025] (n)=Porosity (number of pores/unit area)

[0026] (π)=3.14159

[0027] (r_p)=Pore radius (pore size)

[0028] (τ)=Tortuosity of path

[0029] (μ)=Viscosity of solution

[0030] (Δx)=Membrane thickness

[0031] It should be noted that the largest leverage to obtaining optimum TMF is the radius of the pores because it is raised to the fourth power. The next largest lever is the porosity or number of such point area and the effect of the pore radius which is multiplied by the porosity. Functional optimization for this application therefore also relies on achieving a tight standard deviation of pore radius in the effective zone of filtration as well as a high density of such pores in the primary filtration zone of the membrane. The relationship is also affected by temperature to the extent that temperature changes the value of the parameters including the viscosity of the solution.

[0032] The membranes of the present invention may be prepared using any suitable polymer fibers which will result in a hollow fiber membrane which meets the biocompatibility requirements' and properties of the invention. Such membrane materials and surfaces must be highly biocompatible and resist clotting, protein adhesion and detrimental interaction with immune system components. The structural strength of the hollow fiber membranes must be high enough to safely withstand implantation as well as the hydraulic and physical perturbations existing in the vena cava environment. Thus, the functional convection extraction efficiency of such hollow fibers must be suitable to meet clinical treatment requirements in the smallest possible size in order to fit within the vena cava without stress. The membranes also must be designed with a morphology optimize for blood flow on the outside of the fiber and ultrafiltrate on the inner lumen of the fiber. A number of potentially suitable polymer fiber membrane materials are described in the aforesaid patents including fibers produced from polyurethane, polypropylene, polyethersulfone, polycarbonate, nylon, polyimide and other synthetic resins known to those skilled in the art A preferred polymer is polysulfone membrane, and more preferably a polysulfone modified with a polyethylene oxide-polyethylene glycol copolymer. Such polysulfone fibers are produced in the presence of polymer dopes, core fluids, and coagulation fluids using processes including membrane spinning methods which achieve the desired product. Examples of such additive materials used in the polymerization process, spinning process and/or fiber membrane production include polyvinyl pyrrolidone, N-methyl pyrrolidone, dimethyl acetomide, dimethyl sulfoxide, and mixtures of two or more such materials. Such polysulfone fibers have been found to have the least detrimental characteristics that influence protein membrane interaction such as crystallinity, ionic groups, hydrogen bonding groups and hydrophobic sites. The specific method used for producing the aforesaid polymers as well: as the processes and parameters during the manufacture are known to those skilled in the art. The general specifications and variation range of parameters for the hollow fiber membranes for medical applications within the scope of the present invention are as follows:

[0033] Examples of medical applications for which the hollow fiber membranes of the present invention may be used include the following: therapeutic apheresis applications including plasma exchange, cascade protein separation by filtration, cascade protein removal or modification by adsorption cartridge, cryogenic modification, or chemical adaptation; fluid management application or congestive heart failure both acute and chronic; tissue engineering applications including online generation of media for bioreactor from xenogenic, allogenic, and autogenic sources; continuous renal replacement therapy (CRRT) for both acute and chronic kidney failure; edema prevention therapies for MODS (multiple organ dysfunction syndrome); cytokine removal or modification in therapy for septic shock or SIRS (systemic inflammatory response syndrome); plasma extraction from peritoneal ascites; intermittent hemodialysis (IS)) or hemodiafiltration; and ARDS (acute respiratory distress syndrome) therapy by reduction of pulmonary edema and physiological pulmonary dead space.

[0034] Additional uses for the specific membranes of the present invention as well as those covered in the aforesaid U.S. patents incorporated herein by reference will be evident to those skilled in the art.