So r ben t Membranes
November, 1978
Sorbent Membranes: Device Designs, Evaluations an,d Potential Applications Paul S. Malchesky, Wojciech Piatkiewicz, Warren G. Varnes, Lawrence Ondercin and Yukihiko Nose‘ INTRODUCTION In the use of sorbents for the extracorporeal treatment of body fluids, certain requirements must be met. The sorbent must be effective i n the removal of the solute(s) without depleting essential fluid components. Systems employing sorbents must be biocompatible, with no physical (particle release) or chemical toxic effects. Because of the wide range of biochemical abnormalities generally seen in the disease state, it m a y be necessary and, therefore, should be possible to use multiple sorbents or sorbents with other reactors. Attention must also be given to practical considerations, such as sorbent availability, ability to process the sorbent in device construction, sorbent sterilization and the cost of constructing the devices. With these criteria in mind, various schemes for the utilization of sorbents have been evaluated by the authors. The sorbent membranes of Enka (Wuppertal, Federal Republic of Germany) represent a unique scheme for the practical application of sorbents for the detoxification of body fluids.
ABSTRACT For the biomedical application of sorbents in extracorporeal circulation, the system must be free of particle release and must be biocompatible. In addition, because of the wide range of biochemical abnormalities generally seen in the disease state, the use of multiple sorbents should be possible. Based on these criteria, the Enka sorbent Cuprophan membranes have been selected for evaluation. Sorbent membranes are of two general types: sorption and sorption-dialysis. Coil, parallel plate and capillary designs have been constructed and tested employing sorption-dialysis charcoal membranes of film and hollow fiber configurations. The results have indicated potential advantages. By design, the sorbent membranes prevent direct interaction of the sorbent with blood cells a n d prevent particle release, making chronic applications safe. Devices employing sorbent fibers are particularly suited to select applications where higher sorbent contents are required or ultrafiltration is not desired. In a n effort to optimize the application of sorbents and the sorbent membranes with regard to the quantity of sorbent employed and the length of treatment, a general scheme for evaluation of sorbent systems h a s been established involving three phases: 1)equilibrium isotherm studies to determine the selectivity and capacity of the sorbent system for the solute, 2) kinetic studies to determine mass transfer properties of the sorbent system in the absence of fluid dynamic resistance and 3) device evaluation to determine overall mass transfer properties. Studies show that, i n device designs, it is possible to separate the effects of sorption and fluid dynamics a n d to design around the limiting parameters.
SORBENT MEMBRANES Various configurations of the sorbent membranes are available: 1) sorbent fiber (Cuprophan hollow fiber filled with sorbent in a matrix of Cuprophan), 2) sorbent dialyzing film in sheet and flat tube form
SORBENT FIBER
sorption, dialysis, membrane, Cuprophan, mass transfer, hemoperfusion
Ir
From the De,oartment o f Artificial Organs, Cleveland Clinic Foundation, 9500 Euclid Awe., Cleveland, Ohio, 44106, U.S.A.
SORSENT DIALYZING HOLLOW FIBER WITH CUPROPHANWALL ON INSIDE
This paper u a s presented, in part, at the “Hemoperfusion, Dialysate and Diafiltrate Purification” Symposium, September 11-13, 1978, Tutzing, Federal Replrbiic of Germany.
SORBENT DIALYZING FILM I I
11
SORBENT DIALYZING HOLLOW FIBER WITH CUPROPHAN WALL ON OUTSIDE ~~
FIG. 1. Schematic representation of various configurations of sorbent membranes.
367
Artificial Organs (bilayer of Cuprophan and sorbent in matrix of Cuprophan) and 3) sorbent dialyzing hollow fiber with the Cuprophan wall on either the inside or outside (Fig. 1). Various thicknesses and compositions of these materials have been produced. To date, two sorbent types have been incorporated into the membranes: activated charcoal and aluminum oxide. The manufacturer should be consulted for more information on the composition and general characteristics of these materials. By design, the sorbent membranes prevent particle release since the pore size of the Cuprophan wall is considerably smaller than the size of the sorbent particles encased (Fig. 2a). Previous studies have indicated no particle release.’ Blood cells and larger molecular species in plasma are prevented from direct contact with the sorbent by the interposing Cuprophan wall (Fig. 2b). The long history of Cuprophan use in dialysis has proven it to be an acceptable blood-contacting material. Studies o n
FIG.2a. Relative comparison of pore size of Cuprophan membrane and select substances.
Vol. 2, No. 4 animals1T2and in humans3 have been well tolerated and indicate no adverse effects. Molecular transport through the Cuprophan membrane is dictated by the permeability characteristics of Cuprophan. Because of the sorbent layer, the Cuprophan wall can be made thinner than those of conventional Cuprophan membranes. This preferentially enhances the transport of the higher molecular weight solutes. Riecently, a Cuprophan membrane with high flux properties h a s been used i n the production of the sorbent fiber membranes. This material further favors the transport of the higher molecular weight solutes. Overall transport properties of the sorbent membrane are strongly dependent on the sorbent and its characteristics. Studies on the important renal solutes, creatinine (MW 113 daltons) and uric acid CfMW 168 daltons) show that activated charcoal has a higher affinity for uric acid and, therefore, the charcoal sorbent membrane has a higher sorption capacity for this solute. Even though the molecular weight of uric acid is greater than that of creatinine, and lower transport is expected, with the sorbent membranes the transport of uric acid can be made comparable to or better t h a n the transport of creatinine, depending upon the quantity of charcoal emp1oyed.l Thus, the molecular spectrum of solute removal can be altered based upon the sorption properties. This may offer a unique advantage in the treatment of diseases that are accompanied by a wide range of biochemical abnormalities. To date, Enka sorbent membranes with individually encased sorbents have been evaluated. However, multiple sorbents may be mixed and encased in a unit membrane. Because of the configuration of the sorbent membranes, multifunctional transport processes may be conducted with the same membrane. For the film and hollow fiber designs, simultaneous sorption and dialysis or filtration may be carried out. Due to the nature of the membrane and sorbent, steam and gas sterilization are not applicable. Presently, for all in uivo studies, the sorbent membranes are sterilized by g a m m a irradiation. At recommended dosages there a r e no deleterious effects on the membranes.2
SORBENT MEMBRANE DEVICE DESIGNS The various forms of the Enka sorbent membranes make them readily adaptable to the conventional dialyzer designs. The flat film h a s been incorporated into parallel plate devices4 and coils.’i5 The hollow fiber with the Cuprophan layer on the inside (blood flow in the lumen) h a s been studied in standard hollow fiber devices.6 Because the thicknesses
FIG. 2b. Schematic of cross-sectional view of sorbent membranes.
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Sorbent Membranes
and diameters of these sorbent membranes differ from those of the conventional membranes, for the same overall device size the sorbent membrane device generally h a s a smaller surface area. The configuration of the sorbent membranes, particularly that of fibers, h a s dictated that designs different from the conventional fiber dialyzer designs be investigated. For the sorbent fiber, fluid flow must be over the fiber. The potted bundle design is unacceptable from a fluid dynamic point of view.7 A rectangular sorbent fiber plate design, in which fluid dynamics are more optimal, h a s been studied.' Devices utilizing the spindle-wound fiber839 have also been reported. The sorbent membrane hollow fiber with the Cuprophan layer on the inside has the disadvantage of exposing the sorbent layer to the flowing fluid (e.g., blood) a t the cut potted end. Utilizing the concept of blood flow over the fiber, the hollow fiber with the Cuprophan layer on the outside alleviates this concern. In this fiber, ultrafiltration is from the outside of the fiber to the inside. In addition, devices combining the sorbent and the sorbent dialyzing fibers may be produced whereby the degree of sorption and dialysis or filtration may be regulated.
sorbent system in the absence of fluid dynamic resistances and 3 ) device evaluation to determine overall mass transfer properties. While the testing schemes a r e applicable to all types of sorbent systems, sorbent fibers will be used as a n example. For isotherm studies,' known lengths of the fibers (typically 10-2000 cm, with the ends coated with a resin to prevent sorption i n the axial direction) are immersed in physiologic saline solution containing the solutes of interest. The solution pH is initially set at 7.4 a n d the temperature for the study is maintained a t 37°C. Jars containing the fibers and solution are rotated continuously. A jar of solution containing no fiber serves as a control. For sorbents such as activated charcoal, a 24-hour contact period has been established as an equilibrium time. Figure 3 shows a graph of creatinine sorption by the charcoal fiber CSM-251. The curve generated is of Type I or Langmuir sorption'o and can be represented mathematically by the Freundlich equation: x/m = KC1ln, where x/m is the amount of solute sorbed per u n i t weight of sorbent, C is the equilibrium concentration (for the present case taken a t 24 hours), and K (the value of x/m at the concentration of 1mg%) a n d n are constants for the sorbent fiber. In selecting sorbents, large K values are d e ~ i r a b l e . 1 .For ~ ~ solute-sorbent systems not following Langmuir sorption, the appropriate mathematical expression must be used. A practical expression of the transport property of a sorbent system, independent of fluid dynamics, is the mass transfer coefficient. Experimentally, the sorbent fiber (containing approximately two grams of sorbent) is attached to a support frame. This frame is placed into a container with physiologic
SORBENT MEMBRANE EVALUATION To optimize the application of sorbent membranes and sorbents, a general scheme for the evaluation of sorbent systems has been established consisting of three phases: 1) equilibrium isotherm studies to determine the selectivity and capacity of the sorbent system for the solutes of interest; 2) kinetic studies to determine the mass transfer properties of the
n = 2.43 K = 52.42 rng / gm
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FIG. 4. Creatinine m a s s transfer coefficient evaluation for fiber CSM-251 from plot of In (Ct - CCq)vs time.
FIG. 3. Creatinine isotherm for the charcoal fiber CSM-251.
369
I
Vol. 2, No. 4
Artificial Organs
saline solution a n d the solutes of interest. The solution pH is initially set at 7.4 and the temperature for the study is maintained at 37°C. The solution is stirred at a velocity predetermined to give maximal sorption, and sampling is done over a 24-hour period. Detailed mathematical analysis of the sorption process11 has yielded the following equation: Ct=(Cln - Ceq)e-hm Y t/V + c c ,
c
80
where Ct is the concentration in the sorbent at given time, t, Ci, is the initial concentration in volume, V, C,, is the expected solution concentration at infinite time, taken from the isotherm relationship (in this case the Freundlich equation), m is the mass of sorbent, y is a system parameter, a function of the sorbent p a r a m e t e r s (n, K, m ) a n d t h e i n i t i a l conditions (C,,, V), and h is the sorbent mass transfer coefficient. A plot of In (Ct-Ceq)vs t yields a slope of -hmy/V from which h may be obtained.Figure 4 shows a plot for fiber CSM-251. The sorbent mass transfer coefficient is a parameter analogous to the permeability of a membrane and represents the best transport possible with the given sorbent. In any device utilizing this sorbent, the presence of fluid dynamic resistances will cause transport to be less than ideal. Devices constructed with the sorbent fiber are evaluated in vitro under standard conditions. A known volume of physiologic saline solution, to which the test solutes are added, is recirculated through the device at a given flow rate for a set time period. The solution pH is initially set a t 7.4 and the b a t h volume is maintained at 37°C. The b a t h volume is continously stirred. At set intervals of time, bath and cartridge outlet samples are drawn and analyzed. Calculations are made of clearance, amount sorbed per unit weight of sorbent, mean clearance12 = V ln(Ct/C,)/(t-t,),where V is the volume of the bath, Ct is the solute concentration at time t, a n d C, is the concentration at a prior time, t,] a n d the overall mass transfer coefficient ( h o e Q (C,,-COut)/m { [(C1n+Cout)/2]-C~}where Q is the flow rate through the cartridge, C,n is the inlet concentration and Gout the outlet concentration of the device, m is the effective mass of sorbent, and Cs is the concentration in the sorbent equal to (x/mK)" for Langmuir-type sorption). Figure 5 shows a plot of overall mass transfer coefficient as a function of time for the rectangular plate fiber device containing sorbent fiber V-124. While clearance is a useful clinical parameter, other parameters a r e more useful in a n engineering analysis of the device. As a n example, the total resistance to transfer i n the device is the sum of the resistances due to fluid dyna-
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mics and the sorbent. Knowing the sorbent's resistance (the inverse of the sorbent mass transfer coefficient), the resistance due to fluid dynamics can be calculated. It is important in the design of devices a n d clinical methodologies that the limitation of the transfer process be identified. From the sorbent parameters (n and K for Langmuir-type sorption), the effective mass of sorbent can be calculated. This is important in analyzing for channeling or stagnation in a device.
APPLICATIONS Three basic schemes of operation with the sorbent membranes are possible: 1) sorption alone, 2) sorption plus filtration and 3) sorption plus filtration a n d dialysis. In removal of solutes alone, as in scheme one, using activated charcoal, the following are presently being considered: drug overdose applications, a n adjunct to dialysis (increased removal of solutes not effectively removed by dialysis), the regeneration of physiologic fluids (hemofiltrate, hemodialysis dialysate, peritoneal dialysis dialysate, plasma from plasmapheresis), a n d the experimental applications of extracorporeal blood treatment (for hepatic failure, schizophrenia and psoriasis). With additional sorbents, the spectrum of removal can be expanded. For the removal of solutes i n cases where fluid removal is also required, scheme two can be applied. This scheme is particularly attractive for the treatment of end-stage renal disease. Assuming all
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370
November, 1978
Sorbent Membranes
the appropriate sorbents or reactors can be encased, a dialysate-free artificial kidney for blood-contacting or peritoneal application should be possible. From the studies of systems requiring low volumes of dialysate with regeneration,13.14 a dialysate-free system appears possible, although not yet technically practical. Scheme three is presently a feasible scheme for the treatment of end-stage renal disease. Using activated charcoal, it is possible to increase the removal of the solutes sorbed. With combined sorption and dialysis, the removal of all solutes can be m a d e more comparable, t h u s more closely approaching the function of the natural kidneys. While this is not a n exhaustive list of the possible applications, the Enka sorbent membrane concept has provided investigators with a new tool that can be conveniently manipulated in the design of membrane, sorbent and device to achieve the desired goal.
References P. S., VARNES,W., PIATKIEWICZ, W., NOS;, Y. 1. MALCHESKY, Membranes containing sorbents for blood detoxification. Trans Am SOCArtif Intern Organs, 23:659, 1977. 2. MALCHESKY, P. S., PIATKIEWICZ, W., NAKAMOTO, S., NO&, Y. Haemoperfusion made safe with sorbent membranes. Proc Eur Dial Transplant Assoc, 1978 (in press). H. J., CASTRO,L. A., SAMTLEBEN, W. In vitro and 3. GURLAND, clinical evaluation of dialyzers with a double layer Cuprophan hollow fiber membrane containing different adsorbents. Proc ISAO, Tokyo, August, 1977 (in press). 4. GURLAND, H. J., CASTRO,L. A., SAMTLEBEN, W., FERNANDEZ, J. C. Combination of hemodialysis a n d hemoperfusion in a single unit for treatment of uremia. Proc Conf Nondialytic Management Uremia, Brooklyn, New York, March, 1978 (in press). D., TESSORE,V. 5. DENTI, E., WALKER,J. M., BRANCACCIO, Evaluation of novel sorbent systems for joint hemoperfusion. Med Instrum, 11:212, 1977. 6. CASTRO, L. A,, HAMPEL, G., GEBHARDT,R., FATEH, A,, GURLAND,H. J. Combination of hemodialysis and hemoperfusion in a single hollow fiber unit for treatment of uremia. Artificial Kidney, Artificial Lwer, and Artificial Cells. T.M.S. Chang, ed., Plenum Press, New York, p. 193, 1978. 7. AGISHI,T., OTA, K., NOS;, Y. Is hollow fiber occlusion due to maldistribution of blood? Proc Eur Dial Transplant Assoc, 1251, 1975. P. S., NOS& Y. The use of membranes a n d sor8. MALCHESKY, bents for blood detoxification: Cuprophan sorbent membranes. Artificial Kidney, Artificial Liver, and Artificial Cells. T.M.S. Chang, ed., Plenum Press, New York, p. 185, 1978. 9. BAND EL,^. Present directions in Cuprophan membranes for hernodialysis a n d hemofiltration. Presented i n discussion at 1977 Annual Meeting of the American Society for Artificial Internal Organs. Reprints available from Enka, Wuppertal, Federal Republic of Germany. S., DEMING,L. S., DEMING,W. E., TELLER, E. On 10. BRUNAUER, a theory of the van der Waals adsorption of gases. J Chem SOC,623723, 1940. W.. MALCHESKY. P. S.. VARNES.W. ONDERCIN. 11. PIATKIEWICZ. L., MAYEKAR,K:, NOSE),Y. A' standardized method for sor: bent evaluation. To be presented a t the American Institute of Chemical Engineering Meeting, Miami Beach, Florida, 1978. P. S., CASTINO, F., KOSHINO, I., SCHEU12. Nos& Y., MALCHESKY, CHER,K., NOKOFF,R. Improved hemoperfusion systems for renal-hepatic support. Kidney Int, 10S244, 1976. 13. GORDON,A., BETTER,0. S., GREENBAUM, M. A., MARANTZ, L. B., GRAL,T., MAXWELL,M. H. Clinical maintenance hemodialysis with a sorbent-based low-volume dialysate regeneration system. Trans Am SOC Artif Intern Organs, 17:253, 1971. S., SHIMIZU,K., MANJI,T., KOBAYA14. MAEDA,K., KAWAGUCHI, SHI, K., OHTA, K., SAITO, A,, AMANO,I., YOSHIYAMA, N., S., KOSHIKAWA,S. Ten-litre dialysate supply NAKAGAWA, system with adsorbents. Proc Eur Dial Transplant Assoc, 11:180, 1974.
SUMMARY The Enka sorbent membranes are designed to meet the requirements for t h e chronic extracorporeal treatment of body fluids with sorbents. The various configurations allow the construction of devices employing sorption alone, sorption plus filtration, or sorption plus filtration a n d dialysis. While conventional device d e s i g n s c a n be employed, novel schemes are being explored to take advantage of the special structural features of t h e sorbent membranes. A general scheme for the evaluation of sorbents and, in particular, the sorbent membranes allows optimal use of sorbents in practical device designs. While the potential applications include those of sorbents in general, the unique configuration of the sorbent membranes with the possibilities of using multiple sorbents a n d of combining sorption with other transport processes should expand the therapeutic capabilities.
371
November, 1978
Sorbent Membranes: Device Designs, Evaluations an,d Potential Applications Paul S. Malchesky, Wojciech Piatkiewicz, Warren G. Varnes, Lawrence Ondercin and Yukihiko Nose‘ INTRODUCTION In the use of sorbents for the extracorporeal treatment of body fluids, certain requirements must be met. The sorbent must be effective i n the removal of the solute(s) without depleting essential fluid components. Systems employing sorbents must be biocompatible, with no physical (particle release) or chemical toxic effects. Because of the wide range of biochemical abnormalities generally seen in the disease state, it m a y be necessary and, therefore, should be possible to use multiple sorbents or sorbents with other reactors. Attention must also be given to practical considerations, such as sorbent availability, ability to process the sorbent in device construction, sorbent sterilization and the cost of constructing the devices. With these criteria in mind, various schemes for the utilization of sorbents have been evaluated by the authors. The sorbent membranes of Enka (Wuppertal, Federal Republic of Germany) represent a unique scheme for the practical application of sorbents for the detoxification of body fluids.
ABSTRACT For the biomedical application of sorbents in extracorporeal circulation, the system must be free of particle release and must be biocompatible. In addition, because of the wide range of biochemical abnormalities generally seen in the disease state, the use of multiple sorbents should be possible. Based on these criteria, the Enka sorbent Cuprophan membranes have been selected for evaluation. Sorbent membranes are of two general types: sorption and sorption-dialysis. Coil, parallel plate and capillary designs have been constructed and tested employing sorption-dialysis charcoal membranes of film and hollow fiber configurations. The results have indicated potential advantages. By design, the sorbent membranes prevent direct interaction of the sorbent with blood cells a n d prevent particle release, making chronic applications safe. Devices employing sorbent fibers are particularly suited to select applications where higher sorbent contents are required or ultrafiltration is not desired. In a n effort to optimize the application of sorbents and the sorbent membranes with regard to the quantity of sorbent employed and the length of treatment, a general scheme for evaluation of sorbent systems h a s been established involving three phases: 1)equilibrium isotherm studies to determine the selectivity and capacity of the sorbent system for the solute, 2) kinetic studies to determine mass transfer properties of the sorbent system in the absence of fluid dynamic resistance and 3) device evaluation to determine overall mass transfer properties. Studies show that, i n device designs, it is possible to separate the effects of sorption and fluid dynamics a n d to design around the limiting parameters.
SORBENT MEMBRANES Various configurations of the sorbent membranes are available: 1) sorbent fiber (Cuprophan hollow fiber filled with sorbent in a matrix of Cuprophan), 2) sorbent dialyzing film in sheet and flat tube form
SORBENT FIBER
sorption, dialysis, membrane, Cuprophan, mass transfer, hemoperfusion
Ir
From the De,oartment o f Artificial Organs, Cleveland Clinic Foundation, 9500 Euclid Awe., Cleveland, Ohio, 44106, U.S.A.
SORSENT DIALYZING HOLLOW FIBER WITH CUPROPHANWALL ON INSIDE
This paper u a s presented, in part, at the “Hemoperfusion, Dialysate and Diafiltrate Purification” Symposium, September 11-13, 1978, Tutzing, Federal Replrbiic of Germany.
SORBENT DIALYZING FILM I I
11
SORBENT DIALYZING HOLLOW FIBER WITH CUPROPHAN WALL ON OUTSIDE ~~
FIG. 1. Schematic representation of various configurations of sorbent membranes.
367
Artificial Organs (bilayer of Cuprophan and sorbent in matrix of Cuprophan) and 3) sorbent dialyzing hollow fiber with the Cuprophan wall on either the inside or outside (Fig. 1). Various thicknesses and compositions of these materials have been produced. To date, two sorbent types have been incorporated into the membranes: activated charcoal and aluminum oxide. The manufacturer should be consulted for more information on the composition and general characteristics of these materials. By design, the sorbent membranes prevent particle release since the pore size of the Cuprophan wall is considerably smaller than the size of the sorbent particles encased (Fig. 2a). Previous studies have indicated no particle release.’ Blood cells and larger molecular species in plasma are prevented from direct contact with the sorbent by the interposing Cuprophan wall (Fig. 2b). The long history of Cuprophan use in dialysis has proven it to be an acceptable blood-contacting material. Studies o n
FIG.2a. Relative comparison of pore size of Cuprophan membrane and select substances.
Vol. 2, No. 4 animals1T2and in humans3 have been well tolerated and indicate no adverse effects. Molecular transport through the Cuprophan membrane is dictated by the permeability characteristics of Cuprophan. Because of the sorbent layer, the Cuprophan wall can be made thinner than those of conventional Cuprophan membranes. This preferentially enhances the transport of the higher molecular weight solutes. Riecently, a Cuprophan membrane with high flux properties h a s been used i n the production of the sorbent fiber membranes. This material further favors the transport of the higher molecular weight solutes. Overall transport properties of the sorbent membrane are strongly dependent on the sorbent and its characteristics. Studies on the important renal solutes, creatinine (MW 113 daltons) and uric acid CfMW 168 daltons) show that activated charcoal has a higher affinity for uric acid and, therefore, the charcoal sorbent membrane has a higher sorption capacity for this solute. Even though the molecular weight of uric acid is greater than that of creatinine, and lower transport is expected, with the sorbent membranes the transport of uric acid can be made comparable to or better t h a n the transport of creatinine, depending upon the quantity of charcoal emp1oyed.l Thus, the molecular spectrum of solute removal can be altered based upon the sorption properties. This may offer a unique advantage in the treatment of diseases that are accompanied by a wide range of biochemical abnormalities. To date, Enka sorbent membranes with individually encased sorbents have been evaluated. However, multiple sorbents may be mixed and encased in a unit membrane. Because of the configuration of the sorbent membranes, multifunctional transport processes may be conducted with the same membrane. For the film and hollow fiber designs, simultaneous sorption and dialysis or filtration may be carried out. Due to the nature of the membrane and sorbent, steam and gas sterilization are not applicable. Presently, for all in uivo studies, the sorbent membranes are sterilized by g a m m a irradiation. At recommended dosages there a r e no deleterious effects on the membranes.2
SORBENT MEMBRANE DEVICE DESIGNS The various forms of the Enka sorbent membranes make them readily adaptable to the conventional dialyzer designs. The flat film h a s been incorporated into parallel plate devices4 and coils.’i5 The hollow fiber with the Cuprophan layer on the inside (blood flow in the lumen) h a s been studied in standard hollow fiber devices.6 Because the thicknesses
FIG. 2b. Schematic of cross-sectional view of sorbent membranes.
368
Nouember, 1978
Sorbent Membranes
and diameters of these sorbent membranes differ from those of the conventional membranes, for the same overall device size the sorbent membrane device generally h a s a smaller surface area. The configuration of the sorbent membranes, particularly that of fibers, h a s dictated that designs different from the conventional fiber dialyzer designs be investigated. For the sorbent fiber, fluid flow must be over the fiber. The potted bundle design is unacceptable from a fluid dynamic point of view.7 A rectangular sorbent fiber plate design, in which fluid dynamics are more optimal, h a s been studied.' Devices utilizing the spindle-wound fiber839 have also been reported. The sorbent membrane hollow fiber with the Cuprophan layer on the inside has the disadvantage of exposing the sorbent layer to the flowing fluid (e.g., blood) a t the cut potted end. Utilizing the concept of blood flow over the fiber, the hollow fiber with the Cuprophan layer on the outside alleviates this concern. In this fiber, ultrafiltration is from the outside of the fiber to the inside. In addition, devices combining the sorbent and the sorbent dialyzing fibers may be produced whereby the degree of sorption and dialysis or filtration may be regulated.
sorbent system in the absence of fluid dynamic resistances and 3 ) device evaluation to determine overall mass transfer properties. While the testing schemes a r e applicable to all types of sorbent systems, sorbent fibers will be used as a n example. For isotherm studies,' known lengths of the fibers (typically 10-2000 cm, with the ends coated with a resin to prevent sorption i n the axial direction) are immersed in physiologic saline solution containing the solutes of interest. The solution pH is initially set at 7.4 a n d the temperature for the study is maintained a t 37°C. Jars containing the fibers and solution are rotated continuously. A jar of solution containing no fiber serves as a control. For sorbents such as activated charcoal, a 24-hour contact period has been established as an equilibrium time. Figure 3 shows a graph of creatinine sorption by the charcoal fiber CSM-251. The curve generated is of Type I or Langmuir sorption'o and can be represented mathematically by the Freundlich equation: x/m = KC1ln, where x/m is the amount of solute sorbed per u n i t weight of sorbent, C is the equilibrium concentration (for the present case taken a t 24 hours), and K (the value of x/m at the concentration of 1mg%) a n d n are constants for the sorbent fiber. In selecting sorbents, large K values are d e ~ i r a b l e . 1 .For ~ ~ solute-sorbent systems not following Langmuir sorption, the appropriate mathematical expression must be used. A practical expression of the transport property of a sorbent system, independent of fluid dynamics, is the mass transfer coefficient. Experimentally, the sorbent fiber (containing approximately two grams of sorbent) is attached to a support frame. This frame is placed into a container with physiologic
SORBENT MEMBRANE EVALUATION To optimize the application of sorbent membranes and sorbents, a general scheme for the evaluation of sorbent systems has been established consisting of three phases: 1) equilibrium isotherm studies to determine the selectivity and capacity of the sorbent system for the solutes of interest; 2) kinetic studies to determine the mass transfer properties of the
n = 2.43 K = 52.42 rng / gm
\
Slope= -0.137 Corr. coeff. = 0.993 r = 1.972 h= 56.1 rnl / hr-grn
a
0
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Iu 5
A
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9080.
____I/ ,//
0 n
n
70-
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60-
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CSM-251 7711-7) 8 I (1-7) n = 243 K = 52421ng/grn Corr Coeff = 0.98
Fiber: Ted
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FIG. 4. Creatinine m a s s transfer coefficient evaluation for fiber CSM-251 from plot of In (Ct - CCq)vs time.
FIG. 3. Creatinine isotherm for the charcoal fiber CSM-251.
369
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saline solution a n d the solutes of interest. The solution pH is initially set at 7.4 and the temperature for the study is maintained at 37°C. The solution is stirred at a velocity predetermined to give maximal sorption, and sampling is done over a 24-hour period. Detailed mathematical analysis of the sorption process11 has yielded the following equation: Ct=(Cln - Ceq)e-hm Y t/V + c c ,
c
80
where Ct is the concentration in the sorbent at given time, t, Ci, is the initial concentration in volume, V, C,, is the expected solution concentration at infinite time, taken from the isotherm relationship (in this case the Freundlich equation), m is the mass of sorbent, y is a system parameter, a function of the sorbent p a r a m e t e r s (n, K, m ) a n d t h e i n i t i a l conditions (C,,, V), and h is the sorbent mass transfer coefficient. A plot of In (Ct-Ceq)vs t yields a slope of -hmy/V from which h may be obtained.Figure 4 shows a plot for fiber CSM-251. The sorbent mass transfer coefficient is a parameter analogous to the permeability of a membrane and represents the best transport possible with the given sorbent. In any device utilizing this sorbent, the presence of fluid dynamic resistances will cause transport to be less than ideal. Devices constructed with the sorbent fiber are evaluated in vitro under standard conditions. A known volume of physiologic saline solution, to which the test solutes are added, is recirculated through the device at a given flow rate for a set time period. The solution pH is initially set a t 7.4 and the b a t h volume is maintained at 37°C. The b a t h volume is continously stirred. At set intervals of time, bath and cartridge outlet samples are drawn and analyzed. Calculations are made of clearance, amount sorbed per unit weight of sorbent, mean clearance12 = V ln(Ct/C,)/(t-t,),where V is the volume of the bath, Ct is the solute concentration at time t, a n d C, is the concentration at a prior time, t,] a n d the overall mass transfer coefficient ( h o e Q (C,,-COut)/m { [(C1n+Cout)/2]-C~}where Q is the flow rate through the cartridge, C,n is the inlet concentration and Gout the outlet concentration of the device, m is the effective mass of sorbent, and Cs is the concentration in the sorbent equal to (x/mK)" for Langmuir-type sorption). Figure 5 shows a plot of overall mass transfer coefficient as a function of time for the rectangular plate fiber device containing sorbent fiber V-124. While clearance is a useful clinical parameter, other parameters a r e more useful in a n engineering analysis of the device. As a n example, the total resistance to transfer i n the device is the sum of the resistances due to fluid dyna-
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Unit% Fiber*V-124 n = 3.290 K = 92.44 mgbm m= 31.52gm V = 35 liters
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Frc. 5. Overall mass transfer coefficient for device containing fiber V-124 as a function of time.
mics and the sorbent. Knowing the sorbent's resistance (the inverse of the sorbent mass transfer coefficient), the resistance due to fluid dynamics can be calculated. It is important in the design of devices a n d clinical methodologies that the limitation of the transfer process be identified. From the sorbent parameters (n and K for Langmuir-type sorption), the effective mass of sorbent can be calculated. This is important in analyzing for channeling or stagnation in a device.
APPLICATIONS Three basic schemes of operation with the sorbent membranes are possible: 1) sorption alone, 2) sorption plus filtration and 3) sorption plus filtration a n d dialysis. In removal of solutes alone, as in scheme one, using activated charcoal, the following are presently being considered: drug overdose applications, a n adjunct to dialysis (increased removal of solutes not effectively removed by dialysis), the regeneration of physiologic fluids (hemofiltrate, hemodialysis dialysate, peritoneal dialysis dialysate, plasma from plasmapheresis), a n d the experimental applications of extracorporeal blood treatment (for hepatic failure, schizophrenia and psoriasis). With additional sorbents, the spectrum of removal can be expanded. For the removal of solutes i n cases where fluid removal is also required, scheme two can be applied. This scheme is particularly attractive for the treatment of end-stage renal disease. Assuming all
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Sorbent Membranes
the appropriate sorbents or reactors can be encased, a dialysate-free artificial kidney for blood-contacting or peritoneal application should be possible. From the studies of systems requiring low volumes of dialysate with regeneration,13.14 a dialysate-free system appears possible, although not yet technically practical. Scheme three is presently a feasible scheme for the treatment of end-stage renal disease. Using activated charcoal, it is possible to increase the removal of the solutes sorbed. With combined sorption and dialysis, the removal of all solutes can be m a d e more comparable, t h u s more closely approaching the function of the natural kidneys. While this is not a n exhaustive list of the possible applications, the Enka sorbent membrane concept has provided investigators with a new tool that can be conveniently manipulated in the design of membrane, sorbent and device to achieve the desired goal.
References P. S., VARNES,W., PIATKIEWICZ, W., NOS;, Y. 1. MALCHESKY, Membranes containing sorbents for blood detoxification. Trans Am SOCArtif Intern Organs, 23:659, 1977. 2. MALCHESKY, P. S., PIATKIEWICZ, W., NAKAMOTO, S., NO&, Y. Haemoperfusion made safe with sorbent membranes. Proc Eur Dial Transplant Assoc, 1978 (in press). H. J., CASTRO,L. A., SAMTLEBEN, W. In vitro and 3. GURLAND, clinical evaluation of dialyzers with a double layer Cuprophan hollow fiber membrane containing different adsorbents. Proc ISAO, Tokyo, August, 1977 (in press). 4. GURLAND, H. J., CASTRO,L. A., SAMTLEBEN, W., FERNANDEZ, J. C. Combination of hemodialysis a n d hemoperfusion in a single unit for treatment of uremia. Proc Conf Nondialytic Management Uremia, Brooklyn, New York, March, 1978 (in press). D., TESSORE,V. 5. DENTI, E., WALKER,J. M., BRANCACCIO, Evaluation of novel sorbent systems for joint hemoperfusion. Med Instrum, 11:212, 1977. 6. CASTRO, L. A,, HAMPEL, G., GEBHARDT,R., FATEH, A,, GURLAND,H. J. Combination of hemodialysis and hemoperfusion in a single hollow fiber unit for treatment of uremia. Artificial Kidney, Artificial Lwer, and Artificial Cells. T.M.S. Chang, ed., Plenum Press, New York, p. 193, 1978. 7. AGISHI,T., OTA, K., NOS;, Y. Is hollow fiber occlusion due to maldistribution of blood? Proc Eur Dial Transplant Assoc, 1251, 1975. P. S., NOS& Y. The use of membranes a n d sor8. MALCHESKY, bents for blood detoxification: Cuprophan sorbent membranes. Artificial Kidney, Artificial Liver, and Artificial Cells. T.M.S. Chang, ed., Plenum Press, New York, p. 185, 1978. 9. BAND EL,^. Present directions in Cuprophan membranes for hernodialysis a n d hemofiltration. Presented i n discussion at 1977 Annual Meeting of the American Society for Artificial Internal Organs. Reprints available from Enka, Wuppertal, Federal Republic of Germany. S., DEMING,L. S., DEMING,W. E., TELLER, E. On 10. BRUNAUER, a theory of the van der Waals adsorption of gases. J Chem SOC,623723, 1940. W.. MALCHESKY. P. S.. VARNES.W. ONDERCIN. 11. PIATKIEWICZ. L., MAYEKAR,K:, NOSE),Y. A' standardized method for sor: bent evaluation. To be presented a t the American Institute of Chemical Engineering Meeting, Miami Beach, Florida, 1978. P. S., CASTINO, F., KOSHINO, I., SCHEU12. Nos& Y., MALCHESKY, CHER,K., NOKOFF,R. Improved hemoperfusion systems for renal-hepatic support. Kidney Int, 10S244, 1976. 13. GORDON,A., BETTER,0. S., GREENBAUM, M. A., MARANTZ, L. B., GRAL,T., MAXWELL,M. H. Clinical maintenance hemodialysis with a sorbent-based low-volume dialysate regeneration system. Trans Am SOC Artif Intern Organs, 17:253, 1971. S., SHIMIZU,K., MANJI,T., KOBAYA14. MAEDA,K., KAWAGUCHI, SHI, K., OHTA, K., SAITO, A,, AMANO,I., YOSHIYAMA, N., S., KOSHIKAWA,S. Ten-litre dialysate supply NAKAGAWA, system with adsorbents. Proc Eur Dial Transplant Assoc, 11:180, 1974.
SUMMARY The Enka sorbent membranes are designed to meet the requirements for t h e chronic extracorporeal treatment of body fluids with sorbents. The various configurations allow the construction of devices employing sorption alone, sorption plus filtration, or sorption plus filtration a n d dialysis. While conventional device d e s i g n s c a n be employed, novel schemes are being explored to take advantage of the special structural features of t h e sorbent membranes. A general scheme for the evaluation of sorbents and, in particular, the sorbent membranes allows optimal use of sorbents in practical device designs. While the potential applications include those of sorbents in general, the unique configuration of the sorbent membranes with the possibilities of using multiple sorbents a n d of combining sorption with other transport processes should expand the therapeutic capabilities.
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