The present invention relates in general to hollow fiber membranes
and specifically to polysulfone ultrafiltration hollow fiber membranes useful
The membrane art may be divided into microfiltration, ultrafiltration
and dialysis. Each of these categories involves specific criteria and hence skills
as evidenced by the following basic differentiation. Microfiltration may be defined
as the separation of particles; ultrafiltration as the separation of molecules,
primarily macromolecules; and dialysis as the separation of molecules in the ionic
range. Thus it is a general objective of the present invention to overcome the
specific problems encountered by the dialysis membrane art as enumerated below.
Dialysis primarily involves the migration of molecules across the
membrane by diffusion processes governed by a concentration gradient. In hemodialysis,
diffusion is passive and molecules are transferred from a region of high concentration
to a region of lower concentration. The rate of movement of each molecular species
is called its clearance. Clearance is directly proportional to the concentration
gradient, diffusion constant of the molecule, temperature, thickness of the membrane
and area of the membrane exposed to the fluid. In simple terms, the larger the
concentration gradient, the smaller and more spherical the molecule, the higher
the temperature, the thinner the membrane and the greater the membrane area exposed,
the more rapidly the molecules move, i.e. the higher the clearance. Accordingly,
it is a primary objective of the present invention to produce a high flux membrane
taking into consideration the aforementioned criteria.
Hydrodynamic flow, the bulk movement of the fluid through a porous
medium, is an additional factor to be considered in membrane filtration. In simple
terms, the rate of flow of fluid through a porous membrane is directly proportional
to the permeability or porosity of the medium, the pressure difference across the
membrane, and inversely proportional to the viscosity of the fluid. Thus, the greater
the porosity, the greater the pressure difference, and the less viscous the fluid
the greater the flow. The present invention again successfully addresses these
criteria in a novel and elegant manner.
A further prior art perceived problem to be overcome is fouling.
Fouling is the buildup of material on the surface of the membrane which leads to
clogging of the pores and hence decreased permeability.
Still a further obstacle to be overcome is concentration polarization,
the concentration of a solute near the membrane surface. Increased solute concentration
decreases flow rate.
In addition to the aforementioned problems, numerous additional problems
are encountered in the kidney dialysis arena. The synthetic membrane art attempts
to approximate the natural kidney ultrafiltration of the blood through the glomerular
capillaries to remove waste products. The flow through the dialyzer units must
be speedy to minimize concentration polarization but not so speedy as to cause
denaturation or lysis of the blood components.
The prior art has attempted to solve the aforementioned inherent
problems in various novel ways with varying degrees of success. Thus, for instance,
flow rates have been increased by the arrival of anisotropic membranes, which have
in contrast to earlier isotropic membranes, unequal pore openings on both sides
or surfaces of the membrane. Rates were further increased by the advent of hollow
fiber membranes which provide for a large filtration area per unit volume and efficient
laminar flow to reduce concentration polarization effects.
To assure biocompatibility, most hemodialysis membranes are made
of cellulose, however, synthetic membranes are available. Polysulfone membranes
are highly biocompatible and have as such been employed in the filtration industry.
However, primarily only in the microfiltration industry which as previously outlined
deals with a much different set of problems than the ultrafiltration industry and
more specifically the hemodialysis industry. While not to be construed to be a
comprehensive survey of the art, the following patents are nevertheless considered
illustrative of the polysulfone membrane art.
U.S. Patent No. 4,906,375 issued to Fresenius discloses:
"An asymmetric microporous wettable hollow fiber, consisting
essentially of an inner barrier layer and an outer foam-like supporting structure
said fiber comprising a hydrophobic first organic polymer in an amount equal to
90 to 99% by weight and 10 to 1% by weight of polyvinyl pyrrolidone which is produced
by the following steps:
a) wet spinning a polymer solution made up of a solvent, of 12 to 20% by weight
of the first said polymer and 2 to 10% by weight of the polyvinyl pyrrolidone,
said solution having a viscosity of 500 to 3,000 cps, through a ring duct of a
spinnerette having an external ring duct and an internal hollow core,
b) simultaneously passing through said hollow internal core a precipitant solution
comprising an aprotic solvent in conjunction with at least 25% by weight of a non
solvent which acts in an outward direction on the polymer solution after issuing
from the spinneret,
c) casting into an aqueous washing bath, said spinerette and the upper surface
of said washing bath being separated by an air gap, said air gap being to provided
that full precipitation of components will have occurred before the precipitated
polymer solution enters said washing bath thereby,
d) dissolving out and washing away a substantial portion of the polyvinyl pyrrolidone
and of the said solvent, to form a fiber having a high clearance rate according
to DIN 58352, of 200-290 ml/min for urea and 200-250 ml/min for creatinine and
phosphate, at a blood flow rate of 300 ml/min, for fibers having 1.25 m² of active
While this membrane has a high level of hydraulic permeability, and
does not incur an oxygen decrease, it leaches polyvinyl pyrrolidine (PVP) which
makes it less biocompatible. Morphologically speaking, the membrane has a uniform
microporous barrier layer which has a pore diameter of 0.1 to 2 microns.
HEMOFLOW by Fresenius AG is a sponge-like membrane having micropores
of about 6,000Å diameter on its outer surface and 500Å diameter pores on its inner
U.S. Patent No. 4,874,522 issued to Okamoto discloses:
"A hollow fiber membrane comprising a polysulfone hollow fiber
having on its inner surface a dense skin layer having no pores observable even
with a scanning electron microscope (SEM) of magnification of 10,000 on its outer
surface micropores having an average pore diameter of 500 to 5000Å at a fractional
surface porosity of 5 to 50%, and a microporous structure inside said membrane,
said membrane exhibiting properties which render it suitable for filtering body
fluids and having permeabilities of serum albumin and inuline of not more than
10% and not less than 50% respectively, and a water permeability of not less than
60 ml/mm Hg.m²Hr.
Notably, the hollow fiber structure of this invention is a sponge-like
structure having substantially no large cavities.
Given the aforementioned criteria and disadvantages of the prior
art, the task of the present invention can be simply stated to provide a novel
ultrafiltration hollow fiber membrane which more closely approximates actual kidney
filtration by taking into consideration all the heretofore mentioned criteria and
specifically providing for a mechanically strong biocompatible, i.e. no leaching;
high flux, high solute clearance, decreased leukopenia, apoxia and ceU lysis, and
decreased pyrogen admittance.
In accordance with the present invention, this task is accomplished
in an efficient and elegant manner by providing for a morphologically heterogenous,
hydrophobic polysulfone hollow fiber membrane comprising a sponge-like dense inner
surface permeable to molecules of less than or equal to 30,000 Daltons, said inner
surface having a fractional surface porosity from about 70 to about 80%; and an
outer surface having large pore sizes ranging from about 6 to about 16µm in diameter
and small pore sizes less than 500Å in diameter and a fractional surface porosity
ranging from about 20 to about 30%.
Fig. 1 is a cross-sectional electron microscopic photograph (magnification
111,300x) showing the morphologic heterogeneity of the inner and outer surface
of the hollow fiber membrane of the present invention.
Fig. 2 is a cross-sectional electron microscopic photograph at 20,000
magnification depicting the outer surface pores ranging from 6-16µm.
Fig. 3 is a cross-sectional electron microscopic photograph at 20,000
magnification depicting the inner surface sponge-like structure.
Fig. 4 is a planar electron microscopic photograph at 14,700 magnification
of the outer membrane surface.
Fig. 5 is a planar microscopic photograph at 111,300 magnification
depicting the less than 500A small outer membrane pores.
Fig. 6 is a schematic depiction of the hollow fiber manufacturing
In addition to the aforementioned general criteria, the Association
for the Advancement of Medical Instrumentation developed the American National
Standard for First Use Hemodialyzers in the purification of the blood by diffusion
and convection between the blood and a solution of chemicals through a semi-permeable
membrane. It set labeling and documentation requirements, performance requirement,
mechanical/structural integrity requirements, device cleanliness requirements
and requirements for materials.
Performance requirements incorporate ultrafiltration rate, solute
clearance, pressure drop across the hemodialyzer, blood compartment volume and
compliance, and residual blood volume. The ultrafiltration rate may not vary by
more than ±20% of the stated value. Solute clearance may not vary by more than
The pressure drop across the hemodialyzer value and the blood compartment
volume must be initially determined and again after two hours of perfusion if the
drop or volume varies by more than ±10% during the interval. The residual blood
volume is determined after rinsing the hemodialyzer and after perfusing the blood
compartment with blood at a hematocrit of 25%. The residual volume is to be determined
initially and after four hours of perfusion, if the pressure drop across the hemodialyzer
varies by more than ±10% during this interval.
Mechanically and/or structurally, hemodialyzers randomly selected
from production models which have passed all safety and quality control tests,
must withstand 1.5 times the maximum recommended positive operating pressure and
a negative pressure which is 1.5 times the recommended negative pressure, or 700mmHg,
whichever is less. The membrane must further be tested for blood leaks and shipping
and storage induced structural defects.
The hemodialyzer blood pathway must be sterile and non-pyrogenic.
If ethylene oxide is the sterilant, ethylene oxide residue in the blood pathway
may not exceed federal limits. The dialyzer material contacting the blood or dialysate
must not interact physically or chemically so as to significantly alter the safety
or integrity of the blood or the dialysate.
The present invention simply stated complies with the aforementioned
general membrane performance parameters and specific hemodialysis requirements
to provide a novel and useful hemodialysis high flux ultrafiltration membrane.
The novel hollow fiber membranes of the present invention are to be used in dialyzers.
While dialyzers are very well known in the art, a standard dialyzer comprises,
in simple terms, a housing with four parts. Two parts communicate with a blood
compartment and two with a dialysate compartment. The hollow fiber membrane separates
the two compartments. Specifically, blood flows into a chamber at one end of the
housing and then enters thousands of hollow fiber membranes tightly bound into
a bundle. While blood flows through the fibers, dialysis solution flows around
the outside of the fibers. Once the blood flows through the fibers, the blood collects
in a chamber at the opposite end of the cylindrical housing where it is returned
to the patient. The present invention offers a time efficient way to detoxity a
patient's blood in compliance with the safety, performance, and structural requirements
set forth by the Association for the Advancement of Medical Instrumentation.
The task is solved by providing for a morphologically heterogenous,
hydrophobic polysulfone hollow fiber membrane comprising a sponge-like dense inner
surface permeable to molecules of less than or equal to 30,000 Daltons, said inner
surface having a fractional surface porosity from about 70 to about 80%; and an
outer surface having large pores ranging from about 6 to about 16µm in diameter
and small pores less than 500Å, in diameter and a fractional surface porosity ranging
from about 20 to about 30%.
Figs. 1-5 clearly depict the membrane's novel morphology. Fig. 1 is
an electron micrograph, magnification 2,000x, illustrating a cross-sectional view
of the outer and inner surface of the membrane. Areas A and B are respectively
depicted in Figs. 2 and 3 at a greater magnification, namely 20,000x. Fig. 2 demonstrates
a strikingly uniform large pore size distribution. Fig. 3 offers a view of a dense
sponge-like pore structure present on the inner surface of the membrane. The specific
pore size is not discernible by presently available electron microscope magnifications.
However, permeability was measured via molecular weight filtration which showed
the dense sponge-like structure to have a molecular weight permeability of up to
and including 30,000 Daltons.
In addition to the various pores, Fig. 1 depicts finger-like projections
also referred to as large cavities or macrovoids, which are located between the
two membrane surfaces yet do not extend therethrough.
Fig. 4 offers a planar view of the outer membrane surface at a magnification
of 14,700x While the larger pores are readily discernible, smaller pores; i.e.,
ones less than 500Å, however, are also present. They are more clearly discerned
in Fig. 5 which offers 111,300x magnification.
Since hemodialysis is dependent on selective permeability, having
multiple pore sizes which allows for transport of particular molecular weight
blood components is highly advantageous. In addition, being able to produce uniform
distributions of varying pore sizes is likewise advantageous. Thus, it is postulated
that the aforementioned novel morphology is responsible for the membrane's high
flux and high small solute clearances as well as removal of a wide range of molecular
The present membrane is produced by a dry jet wet spinning process
using phase inversion. Specifically, the membrane process involves the following
steps as depicted in Fig. 6:
1. Casting solution preparation
2. Fiber spinning
7. Texturizing (optional)
8. Collecting the fibers
The casting solution preparation involves dissolving polysulfone in
a suitable solvent with a compatible polymer to form a spinning dope and/or casting
solution. By way of illustration and not limitation, suitable solvents are Di-methylformamide,
dimethylacetamide, 4-Butyrolactone and N-methyl pyrrolidone. N-methyl pyrrolidone
being particularly preferred.
Again by way of illustration and not limitation mention may be made
of polypropylene oxide, polyvinyl pyrrolidone, and polyethylene glycol having a
molecular weight ranging from about 200 to about 30,000; polyethylene glycol molecular
weight 600 being particularly preferred for the compatible polymer.
The casting and/or dope solution is prepared by mixing 15-30% by
weight of polysulfone, 30-65% by weight of solvent and 20-50% by weight of compatible
The following example of a casting solution show by way of illustration
and not by way of limitation the practice of this invention.
Ingredient % By Weight Polysulfone21% N-Methyl pyrrolidone39% Polyethylene glycol 60040%
The thus formed casting solution and a coagulant solution comprising
70-100% water and 0-30% N-Methyl pyrrolidone, preferably 100% water, is added to
the introducing container(1), depicted in Figure 6, and is pumped via pump(2) to
a spinnerette(3) having a double bore nozzle. The casting solution is then pumped
to the outer bore and the coagulant solution is pumped to the inner bore.
Next, the fibers(4) are spun. The main variables which need to be
controlled to obtain a consistent fiber are:
1. Dope composition
2. Dope viscosity
3. Spinning temperature
4. Dope pumping rate
5. Composition of the coagulants
6. Spinnerette distance from the coagulant bath
7. Interior medium flow rate
8. Coagulation temperature
9. Fiber draw rate
The following fiber spinning conditions are preferably followed to
arrive at the novel features of the present invention:
1.Casting solution viscosity @ 45°C 7,000-11,000 cps 2.Spin temperature30-80°C 3.Dope pump rate per fiber0.5-1.25 ml/min 4.Spinnerette distance from coagulation bath10-70 inches 5.Interior medium flow rate (water) per fiber0.5-1.25 ml/min 6.Coagulation temperature15-50°C 7.Fiber draw rate20-300 ft./min.
Under these spin conditions, the non-solvent replaces the solvent
at such a rate as to leave the heterogenous surface morphology depicted in Fig.
After the fibers are spun in accordance with the aforementioned parameters,
the fibers are collected into bundles and immersed in a quench bath or coagulation
bath(5) of water ranging from about 25 to about 40°C. After the quench bath the
fiber bundles are placed in a wash bath(6) from about 20 to about 80°C for about
10-20 minutes to remove excess solvents, etc. Thereafter, the fiber bundles are
immersed in a glycerinization bath(7) to fill the pores of the fiber membrane wall
with a hydrophilic solution fluid so as to enhance pore wetting. Excess fluid is
thereafter removed via drying by ovens(8). If the fibers are to be texturized,
which is preferable, they are placed in a texturizing apparatus(9) which imparts
a wave-like pattern onto the fibers. Lastly, the texturized fibers are collected
on a take-off wheel(10).
The fibers formed via the aforementioned process yield fiber dimensions
of 180-220 microns I.D. (Internal Diameter) and a wall thickness of 30-60 microns.
The thus produced fibers may be characterized as having high small solute clearance,
high flux and enhanced biocompatibility. The latter was determined by the lack
of acute systemic leukopenia and change in C3a in effluent blood at 10 minutes'
dialysis time when evaluated in a dialyzer comprising the novel hollow fiber membranes
having 1.3m² surface area.
Clinical safety was further tested by introducing abnormally high
levels; i.e. 12,5000 EU/ml of pyrogens, endotoxins, into the dialysate solution
and measuring their concentration in the blood and dialysate at 0, 1.5, 3 and 24
hrs. Table I illustrates that an insignificant amount of endotoxins entered the
blood in 3 hrs. It may therefore be infered that no pyrogen was admitted during
the three-hour period, an amount of time which is approximately equivalent to the
usual hemodialysis session.
It is hypothesized that the pyrogen admittance is decreased by the
hydrophobicity of the membrane which adsorbs pyrogens. This adsorption in turn
prevents an immune reaction making the membrane more biocompatible.
The hydrophobic nature of the present invention has still a further
advantage in that is causes blood proteins to coat the membrane surface thereby
decreasing the likelihood of an auto-immune response to the synthetic membrane
material by turning, in simple terms, a synthetic foreign object into a body part.
The prior art refers to the adherence of proteins as fouling; i.e., a coating of
the membrane surface and clogging of the membrane pores. The prior art as previously
mentioned, views this as a disadvantage to be overcome since the protein adherence
The present invention, in contrast, promotes coating of the membrane
surface, while at the same time preventing clogging of the pores and thereby decreased
diffusion. The pores are not clogged due to the limited permeability of the membrane,
namely, less than or equal to 30,000 Daltons.
Thus, contrary to the prior art, the present invention advantageously
provides for protein coating and hence biocompatibility without significantly affecting
the diffusive properties of the membrane.
Six prototype dialyzers, ethylene oxide sterilized, were studied in
six stable and consenting chronic dialysis patients while undergoing hemodialysis.
The dialyzer was found to be high flux with a QU=27.6 (transmembrane
pressure-34.3)mL/hr/mm Hg. r=0.833. The relationship of UF,QB, RB, QU
and hematocrit (Hct) were such that at QB=300mL/min, the minimum QU
required to prevent back filtration at any point in the dialyzer was 358 mL/hr
at Hct 25% and 1089 mL/hr at Hct 35%. Notably the QU
the minimum required to prevent back filtration.
When standardized at T=1.5 hrs., QU=15 mL/min, QD=500
mL/min and Hct 30%, the mean small solute whole blood dearances derived from Ro/A
(membrane resistance/total surface area) values in mL/min. were:
After 10 minutes of membrane exposure to blood, the systemic mean
white blood cell count fell 13.7 ± 4.0% and the mean plasma C3a changed from 447
± 205 to 397 ± 387 ng/ml, mean % change -21.1 ± 56.7%. C3a increased in only one
patient between systemic predialysis blood and effluent blood at 10 minutes and
decreased in five patients.
Clearances measured in vitro using aqueous solution at QB=300ml/min,
QD=500 ml/min, QF=10ml/min and at a temperature of 37°C are illustrated in Table
From the foregoing description, including the test data, it is evident
that the present invention provides for useful hollow fiber membranes having high
flux, high biocompatibility, high hydraulic permeability and high small solute
Since certain changes may be made without departing from the scope
of the invention as described herein, it is intended that all matter described
in the foregoing specification, including the examples, shall be interpreted as
illustrative and not in a limiting sense.
A morphologically heterogenous, hydrophobic polysulfone hollow fiber membrane
comprising a sponge-like dense inner surface permeable to molecules of less than
or equal to 30,000 Daltons, said inner surface having a fractional surface porosity
from 70 to 80%; and an outer surface having large pores from 6 to 16µm in diameter
and small pores less than 500Å in diameter and a fractional surface porosity from
20 to 30%.
A membrane according to claim 1, further comprising finger-like projections
inbetween said inner and outer surfaces.
A membrane according to claim 1 or 2 having an ultrafiltration constant from
30 to 55 mL/hr/mmHg.
A membrane according to claim 2 or 3, having a BUN clearance from 160 to 295
A membrane according to any one of the preceding claims, having a creatinine
clearance from 150 to 260 mL/min.
A membrane according to any one of the preceding claims, having a phosphate
clearance from 135 to 230 mL/min.
A process for manufacturing a heterogenous, hydrophobic polysulfone hollow
fiber, comprising the steps of:
(a) forming a casting solution comprising:
(i) 15-30% by weight polysulfone,
(ii) 30-65% by weight solvent, and
(iii) 20-50% by weight compatible polymer
(b) pumping said casting solution and a coagulant solution through separate
bores of a spinnerette to form fibers;
(c) dry-jet-wet spinning said fibers;
(d) submerging said fibers in a coagulation bath, in a wash bath and a glycerinization
(e) drying said fibers to remove excess fluid.
A process according to claim 7, wherein the casting solution has a viscosity
from 7,000 to 11,000 cps at 45°C.
A process according to claim 7 or 8, wherein 5 the coagulant solution comprises
70-100% water and 0-30% solvent.
A process according to claim 7, 8 or 9, wherein the fibers are spun at from
30 to 80°C.
A process according to any one of claims 7 to 010, wherein the fibers are spun
at a draw rate of from 6 to 90 m/min (20 to 300 ft/min).
A process according to any one of claims 7 to 11, wherein the coagulation bath
is at a temperature from 15 to 50°C.
A process according to any one of claims 7 to 12, wherein the wash bath is
at a temperature from 20 to 80°C.
A process according to any one of claims 7 to 13 wherein the spinnerette is
positioned from 0.25 to 1.7m (10-70 inches) from the coagulation bath.
A process according to any one of claims 7 to 14, wherein the casting solution
comprises, as solvent, di-methylformamide, di-methylacetamide, 4-butyrolactone
or N-methyl pyrrolidone.
A process according to claim 15, wherein the solvent is N-methyl pyrrolidone.
A process according to any one of claims 7 to 16, wherein the casting solution
comprises, as compatible polymer, polypropylene oxide, polyvinyl pyrrolidone, or
polyethylene glycol and has a molecular weight from 200 to 30,000.
A process according to claim 17, wherein the compatible polymer is polyethylene
glycol having a molecular weight of about 600.
A heterogenous hydrophobic polysulfone hollow fiber membrane comprising fibers
obtainable by the process of any one of claims 7 to 18.
A method for detoxifying human blood which comprises filtering said blood through
a dialyzer comprising a morphologically heterogenous, hydrophobic polysulfone
hollow fiber membrane comprising a sponge-like dense inner surface permeable to
molecules of less than or equal to 30,000 Daltons, said inner surface having a
fractional surface porosity from 70 to 80%; and an outer surface having large
pores from 6 to 16µm in diameter and small pores less than 500Å in diameter and
a fractional surface porosity from 20 to 30%.
A method according to claim 20 wherein the inner membrane surface is coated
with a thin layer of blood proteins.
Dialysis apparatus comprising means for filtering body fluid comprising one
or more morphologically heterogenous, hydrophobic polysulfone hollow fiber membranes
each comprising a sponge-like dense inner surface permeable to molecules of less
than or equal to 30,000 Daltons, said inner surface having a fractional surface
porosity from 70 to 80%; and an outer surface having large pores from 6 to 16µm
in diameter and small pores less than 500Å in diameter and a fractional surface
porosity from 20 to 30%; the membranes being fixed in a housing comprising an
inlet and an outlet for transmitting blood through the fibers and dialysis solution
around the outside of the fibers.