U.S. patent application number 11/105140 was filed with the patent office on 2005-10-27 for devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in blood products.
This patent application is currently assigned to RenalTech International. Invention is credited to Brady, James A., Davankov, Vadim, Norris, Frank M., Pavlova, Ludmila, Quartararo, Peter J. JR., Salsberg, Jamie A., Tsyurupa, Maria, Winchester, James F..
Application Number | 20050239041 11/105140 |
Document ID | / |
Family ID | 29731508 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050239041 |
Kind Code |
A1 |
Brady, James A. ; et
al. |
October 27, 2005 |
Devices, systems, and methods for reducing levels of
pro-inflammatory or anti-inflammatory stimulators or mediators in
blood products
Abstract
Devices, systems, and methods reduce levels of pro-inflammatory
or anti-inflammatory stimulators or mediators in blood by selective
adsorption. The devices, systems, and methods are useful in
situations where abnormal levels of or unregulated or excessive
interaction among pro-inflammatory or anti-inflammatory stimulators
or mediators occur, or during events that do induce or have the
potential for inducing abnormal production of pro-inflammatory or
anti-inflammatory stimulators or mediators. The devices, systems,
and methods serve to prevent, control, reduce, or alleviate the
severity of the inflammatory response and disease states that are
associated with abnormal levels of or unregulated or excessive
interaction among pro-inflammatory or anti-inflammatory stimulators
or mediators.
Inventors: |
Brady, James A.; (South
Hampton, NY) ; Winchester, James F.; (New York,
NY) ; Davankov, Vadim; (Moscow, RU) ;
Tsyurupa, Maria; (Moscow, RU) ; Pavlova, Ludmila;
(Moscow, RU) ; Norris, Frank M.; (New York,
NY) ; Quartararo, Peter J. JR.; (New York, NY)
; Salsberg, Jamie A.; (New York, NY) |
Correspondence
Address: |
RYAN KROMHOLZ & MANION, S.C.
POST OFFICE BOX 26618
MILWAUKEE
WI
53226
US
|
Assignee: |
RenalTech International
|
Family ID: |
29731508 |
Appl. No.: |
11/105140 |
Filed: |
April 13, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11105140 |
Apr 13, 2005 |
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10032802 |
Dec 21, 2001 |
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11105140 |
Apr 13, 2005 |
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09832159 |
Apr 10, 2001 |
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11105140 |
Apr 13, 2005 |
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09829252 |
Apr 10, 2001 |
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Current U.S.
Class: |
435/2 |
Current CPC
Class: |
B01J 20/321 20130101;
A01N 1/02 20130101; A61M 1/169 20130101; A61M 1/3679 20130101; B01J
20/261 20130101; A61M 1/1686 20130101; A61M 1/3486 20140204; A61M
1/3681 20130101; B01J 20/3272 20130101; A61M 1/34 20130101; A61M
1/16 20130101; A01N 1/0226 20130101; A61M 1/28 20130101; B01J
20/327 20130101; A61M 1/1696 20130101; A61M 1/3403 20140204; B01D
39/04 20130101; A61M 1/281 20140204; B01J 20/3293 20130101; A61M
1/1678 20130101; A61M 1/1698 20130101; A61M 1/284 20140204; B01J
20/26 20130101 |
Class at
Publication: |
435/002 |
International
Class: |
A01N 001/02 |
Claims
We claim:
1. A blood processing system comprising a blood component product
harvested from the blood drawn from an individual, a container
sized to receive the blood component product, and a device
communicating with the container to remove cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood component product.
2. A system according to claim 1 wherein the blood component
product includes a red blood cell component.
3. A system according to claim 1 wherein the blood component
product includes a platelet component.
4. A system according to claim 1 wherein the blood component
product includes a white blood cell component.
5. A system according to claim 1 wherein the blood component
product includes a plasma component.
6. A system according to claim 1 wherein the device includes an
adsorption medium to remove cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators.
7. A system according to claim 6 wherein the adsorption medium is
characterized by a Biocompatibility Index of not greater than
14.
8. A system according to claim 7 wherein the Biocompatibility Index
is not greater than 7.
9. A system according to claim 1 or 2 wherein the device includes
an adsorption medium to remove cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators, the
adsorption medium comprising a polymeric material.
10. A system according to claim 9 wherein the polymeric material
comprises particles prepared by polymerization or copolymerization
of a monomer selected from a group consisting of styrene,
ethylstyrene, .alpha.-methylstyrene, divinylbenzene, di isopropenyl
benzene, trivinylbenzene, and alkyl methacrylate.
11. A system according to claim 9 wherein the polymeric material
comprises particles formed from crosslinked polystyrene-type resins
having a surface modified to minimize activation of blood
complement system.
12. A system according to claim 9 wherein the polymeric material
comprises particles formed from a porous hydrophobic divinylbenzene
copolymer having a surface modified to include surface exposed
functional groups selected from the group of polymers of
2-hydroxyethyl methacrylate, N-vinylpyrrolidine,
N-vinylcaprolactame and N-acrylamide.
13. A system according to claim 9 wherein the polymeric material
comprises particles formed by polymerization of aromatic divinyl
compounds or their copolymerization with aromatic monovinyl
compounds in the presence of porogens or mixtures of porogens with
properties close to those of .theta.-solvents.
14. A system for collecting a blood component product comprising
means for processing the blood drawn from an individual into a
blood component product, a storage container, means for collecting
the blood component product in the storage container, and means for
removing cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the blood component
product before, during, or after its collection in the storage
container.
15. A system according to claim 14 wherein the blood component
product includes a red blood cell component.
16. A system according to claim 14 wherein the blood component
product includes a platelet component.
17. A system according to claim 14 wherein the blood component
product includes a white blood cell component.
18. A system according to claim 14 wherein the blood component
product includes a plasma component.
19. A system according to claim 14 wherein the means for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators includes an adsorption medium to remove
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators.
20. A system according to claim 19 wherein the adsorption medium is
characterized by a Biocompatibility Index of not greater than
14.
21. A system according to claim 20 wherein the Biocompatibility
Index is not greater than 7.
22. A system according to claim 14 wherein the device includes an
adsorption medium to remove cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators, the
adsorption medium comprising a polymeric material.
23. A system according to claim 22 wherein the polymeric material
comprises particles prepared by polymerization or copolymerization
of a monomer selected from a group consisting of styrene,
ethylstyrene, .alpha.-methylstyrene, divinylbenzene, di isopropenyl
benzene, trivinylbenzene, and alkyl methacrylate.
24. A system according to claim 22 wherein the polymeric material
comprises particles formed from crosslinked polystyrene-type resins
having a surface modified to minimize activation of blood
complement system.
25. A system according to claim 22 wherein the polymeric material
comprises particles formed from a porous hydrophobic divinylbenzene
copolymer having a surface modified to include surface exposed
functional groups selected from the group of polymers of
2-hydroxyethyl methacrylate, N-vinylpyrrolidine,
N-vinylcaprolactame and N-acrylamide.
26. A system according to claim 22 wherein the polymeric material
comprises particles formed by polymerization of aromatic divinyl
compounds or their copolymerization with aromatic monovinyl
compounds in the presence of porogens or mixtures of porogens with
properties close to those of .theta.-solvents.
27. A method for collecting a blood component product comprising
the steps of processing the blood drawn from an individual into a
blood component product, collecting the blood component product in
a storage container, and removing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the blood component product before, during, or after its collection
in the storage container.
28. A method according to claim 27 wherein the blood component
product includes a red blood cell component.
29. A method according to claim 27 wherein the blood component
product includes a platelet component.
30. A method according to claim 27 wherein the blood component
product includes a white blood cell component.
31. A method according to claim 27 wherein the blood component
product includes a plasma component.
32. A method according to claim 27 wherein the removing step
includes use of an adsorption medium to remove cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators.
33. A method according to claim 32 wherein the adsorption medium
comprises a polymeric material.
34. A method according to claim 33 wherein the polymeric material
comprises particles prepared by polymerization or copolymerization
of a monomer selected from a group consisting of styrene,
ethylstyrene, .alpha.-methylstyrene, divinylbenzene, di isopropenyl
benzene, trivinylbenzene, and alkyl methacrylate.
35. A method according to claim 33 wherein the polymeric material
comprises particles formed from crosslinked polystyrene-type resins
having a surface modified to minimize activation of blood
complement system.
36. A method according to claim 33 wherein the polymeric material
comprises particles formed from a porous hydrophobic divinylbenzene
copolymer having a surface modified to include surface exposed
functional groups selected from the group of polymers of
2-hydroxyethyl methacrylate, N-vinylpyrrolidine,
N-vinylcaprolactame and N-acrylamide.
37. A method according to claim 33 wherein the polymeric material
comprises particles formed by polymerization of aromatic divinyl
compounds or their copolymerization with aromatic monovinyl
compounds in the presence of porogens or mixtures of porogens with
properties close to those of .theta.-solvents.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of co-pending patent
application Ser. No. 10/032,802 filed 21 Dec. 2001. This
application is also a continuation-in-part of co-pending U.S.
patent application Ser. No. 09/832,159, filed Apr. 10, 2001, and
entitled "System for Treating Patient with Bacterial Infections,"
which is incorporated herein by reference. This application is also
a continuation-in-part of co-pending U.S. patent application Ser.
No. 09/829,252, filed Apr. 10, 2001, and entitled "Method of
Treating Patient with Bacterial Infections," which is also
incorporated herein by reference. This application claims, under 35
U.S.C. .sctn. 120, the benefit of the filing date of copending U.S.
patent application Ser. No. 09/294,224, filed Apr. 19, 1999, and
entitled "Method for Removing Beta-2 Microglobulin from Blood,"
which is a continuation-in-part of U.S. patent application Ser. No.
08/902,727, filed Jul. 30, 1997 (now U.S. Pat. No. 5,904,663).
FIELD OF THE INVENTION
[0002] This invention relates to devices, systems, and methods for
removing targeted proteins or toxins from the blood, blood
products, or physiologic fluids.
BACKGROUND OF THE INVENTION
[0003] In animals, an inflammatory response occurs when tissues are
injured by bacteria, trauma, toxins, heat, or other agents, which
can be collectively referred to as "Inflammatory Agents." The
nature and character of a given inflammatory response is regulated
by the complex interaction of a variety of pro-inflammatory or
anti-inflammatory stimulators or mediators, which are synthesized
and released by tissue. Known species of pro-inflammatory or
anti-inflammatory stimulators or mediators include, but are by no
means limited to, cytokines, nitric oxide, thromboxanes,
leukotrienes, platelet-activating factor, prostaglandins, kinins,
complement factors, superantigens, monokines, chemokines,
interferons, free radicals, proteases, arachidonic acid
metabolites, prostacyclins, beta endorphins, myocardial depressant
factors, anandamide, 2-arachidonoylglycerol, tetrahydrobiopterin,
and chemicals including histamine, bradykinin, and serotonin. The
discovery of new (i.e., previously unrecognized) species of
pro-inflammatory or anti-inflammatory stimulators or mediators
occurs almost daily.
[0004] The nature and intensity of inflammatory responses differ,
depending on the site which has been invaded, and on the character
of the Inflammatory Agent(s), and the interaction of
pro-inflammatory or anti-inflammatory stimulators or mediators
involved.
[0005] The inflammatory response, when regulated and localized, is
beneficial. However, if not regulated and generalized, the
inflammatory response can cause significant tissue injury and even
death.
[0006] For example, cytokines are a class of proteins produced by
macrophages, monocytes, and lymphocytes in response to viral or
bacterial infection, as well as in response to T cell stimulation
during an immune response. Cytokines are normally present in very
low concentrations in the blood or tissues.
[0007] The structures and activities of cytokines have been the
subject of many studies. It has become apparent that cytokines
possess a wide spectrum of immunological and non-immunological
activities. It is also apparent that cytokines affect diverse
physiologic functions, such as cell growth, differentiation,
homeostasis and pathological physiology. It is clear that cytokines
have multiple biological activities and interact with more than one
cell type. Cytokines are also known to be capable of stimulating
their own synthesis, as well as the production of other cytokines
from a variety of cell types. This phenomenon is called the
"cytokine cascade."
[0008] Cytokine cascades are associated with systemic changes
arising from infection and tissue injury and, in this context, they
serve a myriad of biological functions. For example, various
cytokines, categorized as the interleukins (IL), interferons (IF),
and tumor necrosis factor (TNF), are produced during immune and
inflammatory responses. These cytokines beneficially control
various aspects of these responses. In this situation, the cytokine
cascade mediates normal host defense responses, cell regulation,
and cell differentiation.
[0009] However, it has been observed that the function of cytokine
production can become disordered. This can lead to the presence of
larger than normal concentrations of cytokines. When the cytokine
cascade becomes disordered, there can be a rapid extension and
amplification of the intended localized host response in such a way
that only one or a few initiating stimuli trigger the eventual
release and participation of scores of host mediators. Although a
number of features of the host response assist in fighting off
invasion, an overly robust or poorly modulated endogenous response
can rapidly accelerate to produce other profound alterations in
host homeostasis at the cellular, tissue, and systemic levels. As a
result, cytokine expression in a region of the body where tissues
or organs are legitimately subject to bacterial infection or an
immune response challenge, can, when disordered, lead to unwanted
destruction of healthy tissue elsewhere in the body. Larger than
normal concentrations of certain cytokines can cause disease and
other deleterious health effects, some of which can be lethal.
[0010] For example, a disordered cytokine cascade that leads to the
increased presence of the cytokines IL-1 and TNF can, alone or in
combination, cause a state in animals clinically identical to
"septic" shock. It is recognized that septic shock arises due to
the individual, combined, and concerted effects of a large number
of cytokines. It is a condition inflicting more than 450,000
Americans every year. Cytokine-induced septic shock can be brought
about by infection by a variety of microorganisms, including not
only bacteria but also viruses, fungi, and parasites. Septic shock
can also be initiated by host response to invasion in general, such
as by cancer or as a result of major surgery or trauma. Septic
shock is a potentially lethal cytokine-mediated clinical
complication against which there is no generally effective
therapeutic approach.
[0011] One of the best studied examples of cytokine-induced septic
shock is the case of infection by gram-negative bacteria. It is
believed that the appearance of bacterial endotoxins, such as
lipopolysaccharide (LPS), in the host bloodstream leads to the
endogenous production of a variety of host factors that directly
and indirectly mediate the toxicity of LPS. These host-derived
mediators include many now well-recognized inflammatory cytokines,
as well as endocrine hormones, in addition to a number of other
endogenous factors such as leukotrienes and platelet activating
factor. Among the interacting factors that together comprise the
cytokine cascade, the cytokine TNF alpha is believed to be the most
important identified to date. During the ensuing cytokine cascade,
the mediators that appear early in the invaded host are thought to
trigger the release of later appearing factors. Many of the
cytokine mediators not only exert direct functions at the targeted
tissues, but also at other local and remote tissues, where
subsequent responses to other mediators produced during the cascade
occur, and so on. The result, if unchecked, can be a multifaceted
pathological condition, which is characterized most prominently by
deleterious hemodynamic changes and coagulopathy leading to
multiple organ failure and, often, to death.
[0012] Multiple attempts have been made and still many others are
currently underway to block specific mediators of this response.
These attempts have been relatively unsuccessful. Therapy aimed at
single mediators cannot effectively attenuate the entire response.
Furthermore, it is the duration rather than the intensity of
inflammation that correlates best with outcome, in that the longer
the duration of over-expression of proinflammatory cytokines the
higher the mortality. Systemic inflammation results in organ injury
which results in the prolongation of the inflammatory response and
thus, more organ injury.
[0013] Less lethal but just as profound physiologic effects can
occur as a result of abnormal production of certain cytokines,
without the presence of exogenous bacterial toxins. As one example,
cytokine TNF-alpha has been found to be an anti-tumor cytokine. As
a result, TNF-alpha has been expected to be useful as an antitumor
agent. However, it has been discovered that TNF-alpha is identical
with cachectin, which is a cachexia-inducing factor. The disordered
production of TNF-alpha has also been correlated with, not only
septic shock, but the incidence of rheumatoid arthritis, adult
respiratory distress syndrome (ARDS), the severity of viral
hepatitis, myocardial ischemia, and the inhibition of myocardial
contraction. Also, TNF has recently been shown to be involved in
initiating the expression of human immunodeficiency virus in human
cells that carry latent virus, which could be a contributing factor
in the expression of latent AIDS virus in certain individuals.
Furthermore, a correlation between the TNF level in the blood and
blood pressure has also been observed. As TNF levels increase,
blood pressure decreases, which can lead to serious complications
such as kidney failure.
[0014] It has also been observed that TNF-alpha also has an
activity of stimulating production of other types of cytokines,
such as IL-1, etc. It is known that the cytokine IL-1 is an
important agent for inducing and transmitting the systemic
biological response against infection and inflammation. IL-1
induces the usual, desirable responses observed in inflammation in
general, such as fever, increase of leukocytes, activation of
lymphocytes, induction of biosynthesis of acute phase protein in
liver. It also known that this cytokine has a strong antitumor
activity.
[0015] However, when IL-1 is produced in abnormally larger amounts,
it may contribute to the severity of chronic inflammatory diseases,
such as rheumatoid arthritis. Thus, the abnormal activation of
various cytokines such as the interleukins (IL) and tumor necrosis
factor (TNF) is believed responsible for the tissue damage and pain
that occurs in various inflammatory conditions like rheumatoid
arthritis. In rheumatoid arthritis, levels of TNF, IL-1, IL-6 and
IL-8 increase dramatically and can be detected in the synovial
fluid. The cytokine cascade induced by expression of these
cytokines results in depressed lipoprotein metabolism as well as
bone and cartilage destruction.
[0016] As another example, the cytokine IL-6 plays an important
role in antibody production in B cells. The cytokine IL-6 also is
an important factor in body systems, e.g., the hematopoietic
system, nervous system, and the liver, as well as in immune system.
For example, IL-6 is effective for inducing proliferation and
differentiation of T cells, inducing the production of protein at
acute phase by acting on hepatic cells, and promoting the growth of
cells in bone marrow.
[0017] However, it has also been observed that there is a
correlation between the abnormal secretion of IL-6 and various
disease states, e.g., autoimmune diseases, such as
hypergammaglobulinemia, chronic articular rheumatism, and systemic
lupus erythematosus; the abnormal state of polyclonal B cells, as
well as in the development of the abnormal state of monoclonal B
cells such as myeloma cells; Castleman's disease accompanied with
tumor of the lymph nodes, for which the cause is unknown; primary
glomerular nephritis; and the growth of mesangial cells.
[0018] As yet another example, in bacterial infections, cytokines
such as IL-8 act as a signal that attracts white blood cells such
as neutrophils to the region of cytokine expression. In general,
the release of enzymes and superoxide anions by neutrophils is
essential for destroying the infecting bacteria. However, if
cytokine expression causes neutrophils to invade, for example, the
lungs, release of neutrophil enzymes and superoxide anion can
result in the development of adult respiratory distress syndrome
(ARDS), which can be lethal.
[0019] Despite their diverse and myriad functions, all cytokines
share one common feature. They are all within a narrow size and
molecular weight range of 8 to 28 kilodaltons. This size
characteristic is extremely important for the clearance of
cytokines from the blood. In this range, cytokines are effectively
cleared by the liver and also the kidney, which clears all proteins
below 50 kilodaltons in size. An imbalance between cytokine
production and cytokine removal can cause damage to the liver and
kidney.
[0020] In disease states where the kidney has failed--which is
often the case in septic shock--hemodialysis or hemofiltration
membranes are used as substitutes for the glomerular membrane of
the kidney. However, artificial membranes are severely limited in
their ability to clear cytokines from the blood due to their
inadequate porosity. In fact, the predominant mechanism by which
these membranes remove cytokines in clinical practice is not
filtration, but rather nonspecific surface adsorption (J. Am Soc
Nephrol 1999 April; 10(4): 846-53, Cytokine removal during
continuous hemofiltration in septic patients, De Vriese A S,
Colardyn F A, Philippe J J, Vanholder R C, De Sutter J H, Lameire N
H). Typically these membranes have 0.5 to 2 square meters of
surface area available for adsorption that becomes saturated within
the first 30 to 90 minutes of treatment (Biomaterials 1999
September; 20(17):1621-34, Adsorption of low molecular weight
proteins to hemodialysis membranes: experimental results and
simulations, Valette P, Thomas M, Dejardin P).
[0021] It is therefore clear that pro-inflammatory or
anti-inflammatory stimulators or mediators, such as cytokines but
by no means limited to cytokines, have the potential for both
desirable physiologic results and undesirable physiologic results,
depending upon the robustness and modulation of a particular
inflammatory response. There is a need for straightforward and
biocompatible devices, systems, and methods that serve to reduce or
otherwise modulate levels of pro-inflammatory or anti-inflammatory
stimulators or mediators in instances where abnormal levels of or
unregulated or excessive interaction among such materials exist or
can be expected to arise.
SUMMARY OF THE INVENTION
[0022] A detrimental inflammatory response, such as may occur,
e.g., in the continuum from early sepsis to septic shock, or
ischemia reperfusion, allograft rejection, chemical/biologic
warfare casualties, has traditionally been viewed as a condition in
which the local inflammatory response has become generalized and
uncontrolled. Immune effector cells, especially neutrophils,
possess potent cytotoxic capacity and when unchecked, this response
can cause significant tissue injury.
[0023] However, while this traditional view is true, these intense
inflammatory response conditions may also be viewed as a syndrome
of immune suppression. Immune effector cells become dysfunctional
and are no longer capable of normal immune surveillance. Such a
condition results in increased susceptibility to recurrent
infection, prolonged inflammation and continued tissue injury. This
condition can be referred to as "immuno-paralysis" and can be
easily demonstrated. When either intact septic animals or whole
blood taken from septic patients is exposed to an inflammatory
stimulus (e.g. endotoxin) the normal host response is severely
inhibited.
[0024] From this perspective, therapy aimed at reducing an
inflammatory response by targeting removal of some of the
pro-inflammatory stimulus may not restore normal immune
responsiveness and thus, may not improve outcome. Instead, a more
desirable immune modulating strategy is to use a biocompatible
adsorption medium to selectively adsorb a broader spectrum of
pro-inflammatory or anti-inflammatory stimulators or mediators,
which may include but is not neccesarily limited to cytokines, and
to thereby restore immunologic stability, rather than
indiscriminately inhibiting or stimulating one or another
component. Such a strategy counters the immunologic instability of
sepsis and other intense inflammatory response conditions by
reducing the number, and thus the activity, of a wide array of both
pro- and anti-inflammatory molecules. Such a strategy would
"auto-regulate" itself, such that as one component of the response
increased so too would the effect on that component. Finally, the
desirable strategy might well be limited in its effect to the
circulating pool of mediators rather than influencing the tissue
levels where their activity may be beneficial.
[0025] The invention provides devices, systems, and methods for
reducing levels of cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators in the blood,
desirably whole blood, or blood products, or physiologic fluids in
situations where abnormal levels of or unregulated or excessive
interaction among such stimulators or mediators occur, or during
events that do induce or have the potential for inducing abnormal
production of or unregulated or excessive interaction among such
stimulators or mediators. The devices, systems, and methods serve
to prevent, control, reduce, modulate, or alleviate the severity of
many physiologic conditions and disease states that are associated
with abnormal levels of or unregulated or excessive interaction
among pro-inflammatory or anti-inflammatory stimulators or
mediators.
[0026] One aspect of the invention provides devices, systems, and
methods for removing cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators from the blood,
desirably whole blood, which are of use in acute situations where
abnormal levels or unregulated or excessive interaction among such
stimulators or mediators are present in individuals experiencing
infection, or individuals experiencing an immune response. In such
situations, the devices, systems and methods serve to modulate the
inflammatory response by removing at least some of these
stimulators or mediators from blood circulation, even as such
stimulators or mediators are being produced by the individual to
fight off the infection or invasion. This aspect of the invention
serves to prevent an overly robust endogenous response, such as
occurs, e.g., during septic shock. The devices, systems, and
methods can be used alone or in combination with other forms of
treatment targeted to the treatment of the bacterial infection
and/or immune response.
[0027] Another aspect of the invention provides devices, systems,
and methods for removing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the blood, desirably whole blood, which are of use in situations
where abnormal levels of or unregulated or excessive interaction
among such stimulators or mediators are or may be present, or which
involve events that do induce or have the potential for inducing
abnormal production of or unregulated or excessive interaction
among such stimulators or mediators in certain "at risk"
individuals undergoing or about to undergo surgery, e.g., for
treatment of burns or cardiac conditions; or for organ
transplantation or reconstructive surgery, or other episodes
involving ischemia-reperfusion injury. Other like situations, where
abnormal levels of or unregulated or excessive interaction among
such stimulators or mediators are or may be present, or which
involve events that do induce or have the potential for inducing
abnormal production of or unregulated or excessive interaction
among such stimulators or mediators, include certain "at risk"
individuals who have experienced trauma, such as burns, or "the
crush syndrome." In such situations, the devices, systems, and
methods serve to reduce the population of such stimulators or
mediators by removing at least some of such stimulators or
mediators from the blood circulation. This aspect of the invention
also serves to modulate the inflammatory response by removing at
least some pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood circulation, even as such stimulators or
mediators are being produced by the individual in response to the
surgery or trauma. This aspect of the invention serves to prevent
an overly robust endogenous response, to prevent, e.g., septic
shock or other conditions that may occur.
[0028] Another aspect of the invention provides devices, systems,
and methods for removing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the blood, desirably whole blood, which are of use in situations
where abnormal cytokine levels are present in certain "at risk"
individuals, whose chronic disease states are caused by or
otherwise correlate with increased inflammatory activity. Such
disease states include, e.g., rheumatoid arthritis; or lung disease
such as emphysema or asthma; or pulmonary failure; or adult
respiratory distress syndrome (ARDS); viral hepatitis; or
myocardial ischemia; or autoimmune disease; AIDS; or as a result of
accidental or intentional exposure to biological or chemical
agents, such as anthrax. In such situations, the devices, systems,
and methods serve to reduce the population of cytokines or or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators by removing such stimulators or mediators from the blood
circulation. This aspect of the invention serves to treat a given
disease condition by lessening the abnormal population of cytokines
or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators, which is known or suspected of
contributing to severity of the disease condition. The devices,
systems and methods can be used alone or in combination with other
treatment modalities for the disease condition.
[0029] Another aspect of the invention provides devices, systems,
and methods for removing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the blood, which are of use in other events that do induce or have
the potential for inducing production of such stimulators or
mediators due to extracorporeal blood processing, handling, or
storage. These events can lead to an incidental or "obligatory"
activation of the immune system due to subjecting the blood to
extracorporeal treatment, pumping, or storage, e.g., for
centrifugal or membrane blood separation; or for hemodialysis or
hemofiltration; or for oxygenation. This obligatory activation of
the immune system can activate production of cytokines or or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators in the blood as it undergoes extracorporeal treatment,
handling, or storage. The increased presence of cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators in the treated, handled, or stored blood or blood product
can, upon re-infusion, generate an incidental inflammatory response
in the recipient's system, or at least can contribute to an
incidental abnormal level of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators in
the recipient. In such events, the devices, systems and methods
serve to reduce the population of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators by
removing such stimulators or mediators from the treated, handled,
or stored blood or blood product. This aspect of the invention
serves to prevent incidental inflammatory response conditions or
disease states as a result of otherwise beneficial blood treatment,
handling or storage, by lessening the population of cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators present in the re-infused blood or blood product.
[0030] The devices, systems, and methods that embody features of
the invention also make it possible to restore a normal balance
between pro-inflammatory stimulators or mediators and
anti-inflammatory stimulators or mediators. For example, during a
cytokine cascade, pro-inflammatory cytokines are typically
generated in larger numbers in proportion to anti-inflammatory
cytokines. In situations where abnormal cytokine levels exist, the
removal of cytokines according to the invention will tend to remove
more pro-inflammatory cytokines than anti-inflammatory cytokines,
and thereby aid in maintaining a more normal balance between the
two.
[0031] Another aspect of the invention provides devices, systems,
and methods for removing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
physiologic fluids. For example, spent peritoneal dialysis solution
can carry cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators. Systems and methods
exist for regenerating spent peritoneal dialysis solution withdrawn
from a patient, by removing waste and uremic toxins from the spent
solution, as well as introducing electrolytes and buffering
materials into the spent solution. In this way, fresh peritoneal
dialysis solution can be recreated, obviating the need for bagged
replacement solutions. In such situations, the devices, systems,
and methods that embody this aspect of the invention remove
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from the peritoneal dialysis solution,
before, during, or after solution regeneration. This aspect of the
invention serves to prevent incidental inflammatory response
conditions or disease states as a result of exchange of spent
peritoneal dialysis solution with regenerated peritoneal dialysis
solution.
[0032] As another example, organs harvested for transplantation,
e.g., kidney, liver, or heart, are typically stored for period of
time in a suitable preservation solution until transplantation
takes place. Storage of the organ in preservation solution can lead
to the generation of cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators, which accumulate in
the preservation solution. In such situations, the devices,
systems, and methods that embody this aspect of the invention
remove cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the preservation
solution during organ storage and/or before transplantation of the
organ occurs. In this way, the invention serves to prevent or at
least ameliorate inflammatory response conditions or disease states
as a result of organ transplantation.
[0033] As yet another example, body fluids that are removed from
and then recycled back to the body during a given treatment
modality can carry cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators, or cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators can be generated as a result of such treatment
modalities. Treatment systems and methods exist for removing and
recycling such fluids, e.g., lymphatic fluid, synovial fluid,
spinal fluid, or cerebrospinal fluid. The devices, systems, and
methods that embody this aspect of the invention can be used in
association with such treatment modalities, to remove cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators from the body fluids before, during, or after primary
treatment.
[0034] In preferred embodiments, the devices, systems, and methods
remove cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the blood by
selective adsorption. Desirably, the selective adsorption medium is
characterized by a biocompatibility index that reflects a
negligible production of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators in
the blood as a result of exposure to the medium. Thus, the
adsorption medium, which beneficially serves to remove cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators from the blood, does not itself produce an offsetting
result of generating additional cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators
.
[0035] Other features and advantages of the inventions are set
forth in the following specification and attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is a schematic view of a system for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from the blood in acute or chronic or
other "at risk" situations;
[0037] FIG. 2 is a schematic view of a system for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from the blood during an extracorporeal
blood processing procedure, such as blood separation, dialysis,
hemofiltration, or extracorporeal oxygenation;
[0038] FIG. 3 is a side section view of a unitary, extracorporeal
device containing an adsorption medium for removing cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators from the blood;
[0039] FIG. 4A is a side view of an exchangeable device that can be
coupled to a conventional intravenous blood access catheter for the
purpose of removing cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators from the blood;
[0040] FIG. 4B is a side view of the exchangeable device shown in
FIG. 4A after being coupled to a conventional intravenous blood
access catheter for the purpose of removing cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood;
[0041] FIG. 5 is a side section view of an intravenous catheter
having a wall that is impregnated with an adsorption material that
removes cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the blood;
[0042] FIG. 6 is a side section view of an intravenous catheter
having an integrally formed chamber containing an adsorption medium
that removes cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the blood;
[0043] FIG. 7 is a side view of an indwelling catheter having an
in-line device that contains an adsorption medium for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from the blood, making possible an
ambulatory treatment regime;
[0044] FIG. 8 is a side section view of a composite treatment
module which integrates a device for removing cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood with a blood processor, the removal device
being shown connected by intermediate tubing downstream from the
blood processor;
[0045] FIG. 9 is a side section view of a composite treatment
module which integrates a device for removing cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood with a blood processor, the removal device
being shown connected by intermediate tubing upstream from the
blood processor;
[0046] FIG. 10A is a side section view of a composite treatment
module which integrates a device for removing cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood with a blood processor, the removal device
and the blood processor comprising separate units adapted to be
joined together for use;
[0047] FIG. 10B is the composite treatment module shown in FIG. 10B
after being joined together for use;
[0048] FIG. 11 is a side section view of a composite treatment
module which integrates a device for removing cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood with a blood processor, the module
comprising a common housing compartmentalized into two chambers,
one chamber containing the blood processing component and the other
chamber containing an adsorption medium for removing cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators from the blood being processed;
[0049] FIG. 12 is a side section view of an adsorption particle
that can be used in association with the systems shown in FIGS. 1
and 2 for selectively adsorbing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the blood;
[0050] FIG. 13 is a side section view of a device that is usable in
association with the systems shown in FIGS. 1 and 2 for removing
both cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators and other targeted
proteins or toxins from the blood;
[0051] FIG. 14 is a schematic view of a system for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from a physiologic fluid, which takes the
form of regenerated peritioneal dialysis solution;
[0052] FIG. 15 is a schematic view of a system for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from a physiologic fluid, which takes the
form of preservation solution for an organ awaiting
transplantation;
[0053] FIG. 16 is a schematic diagram of a test system that is used
to characterize the biocompatibility index of a given adsorbant
medium;
[0054] FIG. 17 is a graph plotting the cytokine response in the
blood of a sepsis animal model as a result of treatment using a
biocompatible adsorbant medium;
[0055] FIGS. 18 A, 18B, and 18C are graphs showing the variations
in blood cell counts for red blood cells, white blood cells, and
platelets, respectively, during passage of 25 ml of the blood
through a treatment device containing an adsorbant medium useful
for removing cytokines from the blood;
[0056] FIG. 19 is a graph showing the variations in PMN elastase
concentrations (indicative of leukocyte activation) during passage
of 25 ml of the blood through a treatment device containing an
adsorbant medium useful for removing cytokines from the blood;
[0057] FIG. 20 is a graph showing the variations in LDH
concentrations (indicative of hemolysis) during passage of 25 ml of
the blood through a treatment device containing an adsorbant medium
useful for removing cytokines from the blood;
[0058] FIG. 21 is a graph showing the variations in C3a-desArg
concentrations(indicative of complement activation) during passage
of 25 ml of the blood through a treatment device containing an
adsorbant medium useful for removing cytokines from the blood;
[0059] FIG. 22 is a graph showing the variations in TAT
concentrations (indicative of coagulation) during passage of 25 ml
of the blood through a treatment device containing an adsorbant
medium useful for removing cytokines from the blood; and
[0060] FIG. 23 is a chart summarizes the results of
hemocompatibility testing conducted by Bosch et al of a
polyacrylate gel adsorbant material (for the selective adsorption
of low-density lipoproteins), based upon contact with blood that
was anticoagulated either only with heparin or with a mixture of
heparin and citrate.
[0061] The invention may be embodied in several forms without
departing from its spirit or essential characteristics. The scope
of the invention is defined in the appended claims, rather than in
the specific description preceding them. All embodiments that fall
within the meaning and range of equivalency of the claims are
therefore intended to be embraced by the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0062] I. Systems and Methods for Removing Cytokines from the
Blood
[0063] Cytokines and other species of pro-inflammatory or
anti-inflammatory stimulators or mediators are low molecular weight
proteins that are present in the blood. They are typically produced
by the body in response to viral or bacterial infection and in
response an immune response. Cytokines are also known to be capable
of stimulating their own synthesis, as well as the production of
other cytokines from a variety of cell types. Cytokines are
normally present in very low concentrations in a tissue, but, due
to an over-robust and unmodulated cytokine cascade or other causes,
cytokines can be present in abnormal concentrations. In abnormal
concentrations, cytokines can cause disease or septic shock.
[0064] As used in this Specification, the term "cytokine" as used
herein is meant any secreted polypeptide that affects the functions
of other cells, and is a molecule which modulates interactions
between cells in the immune or inflammatory response. Cytokines are
soluble protein and peptide humoral regulators. Type-1 cytokines
are produced by Type-1 helper cells, e.g. IL2 , IFN-gamma , IL12
and TNF-beta, and Type-2 cytokines are produced by Type-2 helper
cells, e.g. IL4 , IL5, IL6 , IL10, and IL13. These may be
pro-inflammatory or anti-inflammatory, chemotactic, paracrine,
endocrine, juxtacrine, autocrine, and retrocrine. They also
function as growth factors and apoptosis factors, involved in
inflammation, septic shock, the systemic inflammatory response
syndrome (SIRS), acute phase reactions, wound healing and
neuroimmune networks. Others include IFN-alpha, -beta, -gamma,
-omega, IL2-9, GCSF, MCSF, GMCSF, PGDF, IL-1-alpha, -beta,
TNF-alpha, FGF, IL8, IP10, PF4, GRO, 9E3 and recombinant cytokines,
muteins, and protein mimetics. Cytokines also comprise B-cell
differentiation factors (BCDF), B-cell growth factors (BCGF),
mitogenic cytokines, chemotactic cytokines (chemokines), colony
stimulating factor (CSF), angiogenesis factors, t-cell replacing
factor (TRF), heparin binding growth factor (HBGF), substance p
(tachykinin), and kinins.
[0065] A. Acute or "At Risk" Conditions
[0066] FIG. 1 generically shows a system 10 for removing cytokines
12 or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators (which are generally identified by circled
C's in FIG. 1) from the blood 14, and desirably from whole blood.
In the illustrated embodiment, the blood 14 emanates from a blood
source 16. In the embodiment shown in FIG. 1, it is contemplated
that the blood source 16 comprises the circulatory system of an
individual.
[0067] In FIG. 1, it is also contemplated that the cytokines 12 or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators exist in the blood in abnormal levels, or at least the
potential exists that the individual's levels of cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators may become abnormal, i.e., reach levels above normal
physiologic levels, or otherwise create an unregulated or excessive
inflammatory response interaction. Accordingly, as shown in FIG. 1,
the system 10 includes a device 18 through which the blood 14 is
circulated from the source 16 for the purpose of removing at least
a portion of the population of cytokines 12 or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators
carried in the blood 14. The removal of cytokines 12 or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the blood 14 serves to control, reduce, or alleviate
the severity of many physiologic conditions and disease states that
are associated with abnormal cytokine levels or an unregulated or
excessive inflammatory response. As shown in FIG. 1, the
cytokine-depleted blood 20 is returned to the individual blood
source 16.
[0068] The cytokines 12 or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators may be present or pose
the potential to exist in the blood 14 in abnormal levels for
various reasons. For example, the individual may be in an acute
condition, experiencing infection or an immune response. In this
situation, cytokines 12 or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators are being generated by
the individual to fight the infection or invasion. The concurrent
removal of cytokines 12 or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators by the device 18
modulates the inflammatory response, e.g., to prevent the onset of
a condition on a continuum from sepsis to septic shock or damage to
tissue elsewhere in the body. Alternatively, the individual may be
experiencing a condition on a continuum from sepsis to septic
shock. In this situation, the concurrent removal of cytokines 12 or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators by the device 18 modulates the inflammatory response
to terminate the deleterious hemodynamic changes and coagulopathy
occasioned by septic shock, to prevent organ failure and death. In
either situation, one prevention and the other treatment, the
removal of cytokines 12 or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators by the device 18 aims to
prevent an overly robust and possible lethal endogenous
response.
[0069] The device 18 can be used alone or in combination with other
forms of treatment targeted to the treatment of the bacterial
infection and/or immune response and/or septic shock. Examples of
other forms of treatment that can be used in combination with the
device 18 include antibiotics, antimicrobial agents, antifungal
agents, antiviral agents, and specific compounds such as activated
protein-C.
[0070] In another embodiment, the cytokines 12 or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators may
be present in abnormal levels because the individual possesses an
"at risk" acute or chronic disease state, which is caused by or
otherwise correlate with increased physiologic cytokine activity or
an unregulated inflammatory response. Such disease states include,
e.g., rheumatoid arthritis; or lung disease such as emphysema or
asthma; or pulmonary failure; or adult respiratory distress
syndrome (ARDS); viral hepatitis; or myocardial ischemia; or
autoimmune disease; AIDS; or as a result of exposure to biological
or chemical agents, such as anthrax. The removal of cytokines 12 or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators by the device 18 reduces the population of cytokines
or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators to treat the severity of the disease
condition. The treatment of the individual using the system 10 can
be under acute conditions (due to the presence of severe symptoms).
The treatment using the system 10 can also be under chronic
conditions, as a part of scheduled, periodic treatment of the
disease condition.
[0071] In either situation, the device 18 can be used alone or in
combination with other treatment modalities beneficial for the
disease condition. Examples of other forms of treatment that can be
used in combination with the device 18 include antibiotics,
antimicrobial agents, antifungal agents, antiviral agents, and
specific compounds such as activated protein-C.
[0072] In another embodiment, the cytokines 12 or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators may
be present in abnormal levels, or may potentially rise to abnormal
levels, because the individual is "at risk" due to present or
contemplated surgery, e.g., for treatment of burns or cardiac
conditions; or for organ transplantation or reconstructive surgery,
or other episodes involving ischemia-reperfusion injury.
Alternatively, the individual can be "at risk" because of trauma,
such as burns, or "the crush syndrome," which may or may not
require corrective surgery. In such situations, cytokines 12 or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators have likely already been generated by the individual
due to injury and trauma to the body, and resulting corrective
surgery is likely to maintain or even increase generation of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators. The removal of cytokines 12 or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators by the device 18, after the trauma and either before
surgery, or during surgery, or after surgery, or a combination
thereof, reduces the population of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators ,to
modulate the inflammatory response. The removal of cytokines 12 or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators by the device 18 aims to prevent an overly robust and
possible lethal endogenous response, to prevent, e.g., septic shock
or other unregulated or excessive inflammatory response conditions
that may occur. The treatment using the system 10 can occur under
acute conditions (i.e., as an adjunct to the surgical procedure or
other treatment of the trauma), and/or under chronic conditions, as
a part of a scheduled rehabilitation program following the trauma
or surgery.
[0073] In either situation, the device 18 can be used alone or in
combination with other treatment modalities beneficial for the
injury and surgical procedure. Examples of other forms of treatment
that can be used in combination with the device 18 include
antibiotics, antimicrobial agents, antifungal agents, antiviral
agents, and specific compounds such as activated protein-C.
[0074] B. Extracorporeal Blood Processing
[0075] FIG. 2 show a blood processing system 20 that removes
cytokines 12 or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the blood 14 as it
undergoes extracorporeal processing. In use, the system 20 is
intended to convey the blood from a blood source 22 (typically, the
circulatory system of a donor or patient) to an extracorpreal blood
processing assembly 24. After processing, all or a portion of the
blood is either returned to the circulatory system of the
individual donor or patient, or retained for storage and subsequent
transfusion to the same donor or patient, or to another recipient,
or a combination thereof.
[0076] Typically, the functional components of the blood processing
assembly 24 are a blood inlet line 26, a blood processor 28, and a
blood outlet line 27. The blood from the donor or patient is
conveyed by the blood inlet line 26 to the processor 28 for the
desired processing. After processing, the blood is convey from the
processor 28 by the blood outlet line 27. The system 20 may
continuously or intermittently convey the blood to and from the
blood processing assembly 24, typically using one or more
peristaltic pumps (designated P in FIG. 2).
[0077] Depending upon the objectives of the processing, the blood
outlet line 27 can be coupled directly to the donor or patient, so
that the processed blood is returned directly to that individual.
In other processing schemes, all or a portion of the processed
blood is retained for storage and not returned to the donor or
patient. In this arrangement, the blood outlet line 27 also
communicates with a blood storage container 32.
[0078] The blood processing assembly 24 can be constructed in
various ways and perform different processing functions.
[0079] 1. Blood Separation
[0080] The blood processing assembly 24 can serve to separate whole
blood into plasma and cellular blood components (i.e., blood
products), typically, red blood cells and platelets. In this
arrangement, the blood processing assembly 24 can comprise a
centrifuge or a membrane that separates whole blood into its
components. Depending upon the objectives of the device, all or
some of the components are collected for storage and later
transfusion. The components that are not collected are typically
returned to the blood donor.
[0081] For example, in a process called plasmapheresis, plasma can
be collected in an extracorpeal circuit for later fractionation to
harvest therapeutic plasma proteins, e.g., Factor VIII. The
remaining cellular components (red blood cells and platelets, along
with the leukocytes) are returned to the blood donor.
[0082] Or, in a process called plasma exchange, plasma can be
collected in an extracorpreal circuit. The plasma is discarded, and
the cellular components (red blood cells, leukocytes, and
platelets) are returned to the blood donor, along with a
plasma-replacement fluid. Alternatively, the plasma itself can be
treated by immunoadsorption, to remove undesired materials--e.g.,
antibodies--which is then returned with the cellular components to
the individual.
[0083] As another example, in a process called plateletpheresis,
the blood is circulated through an extracorpreal path through a
centrifuge, which centrifugally separates and collects concentrated
platelets for later transfusion. The remaining cellular components
and plasma are returned to the donor. Alternatively, a volume of
red blood cells or plasma, or both, can be retained for storage and
later transfusion to recipients undergoing blood component
therapy.
[0084] There are many other types of blood cell harvesting
procedures in addition to plateletpheresis, where a targeted blood
cell is collected, e.g., leukopheresis. There are also many other
types of blood processing procedures in general, such as
photopheresis (for inactivation of viral pathogens) or hypothermia,
which circulate blood in extracorporeal paths to achieve desired
therapeutic or diagnostic objectives.
[0085] The preceding examples process the blood on-line, that is,
while the donor remains coupled to the system. In another
arrangement, called manual collection, a unit of whole blood is
drawn into a plastic blood collection bag, to which one or more
plastic satellite bags are integrally connected. These arrangements
of integrally connected bags are called multiple blood bag systems.
After the unit of whole blood is drawn, the donor is disconnected.
The whole blood is then subjected to off-line centrifugation while
in the blood collection bag. The centrifugation separates the whole
blood into layers of red blood cells and plasma, with an
intermediate layer of leukocytes. The plasma can be either rich in
platelets or poor in platelets, depending upon the centrifugal
forces applied. The plasma component is transferred into a
satellite bags, leaving the red blood cells (and leukocytes) behind
in the blood collection bag. If rich in platelets, the plasma
component can be further centrifugally separated in the satellite
bag to obtain concentrated platelets. The components are stored in
the individual plastic bags for later transfusion to recipients
undergoing blood component therapy.
[0086] 2. Hemodialysis or Hemofiltration
[0087] The blood processing assembly 24 can also carry out
processes, called hemodialysis or hemofiltration, which emulate
normal kidney activities for an individual whose renal function is
impaired or lacking.
[0088] During hemodialysis, the blood from an individual is
conveyed in an extracorporeal path along one side of a membrane. A
dialysate is circulated on the other side of the membrane and forms
a concentration differential across the membrane. Liquid and uremic
toxins carried in the blood are drawn by the concentration
differential across the membrane and out of the blood.
[0089] During hemofiltration, the blood from an individual is
conveyed in an extracorporeal path along a semipermeable membrane,
across which a pressure difference (called transmembrane pressure)
exists. The pores of the membrane have a molecular weight cut-off
that can pass liquid and uremic toxins carried in the blood.
[0090] In both hemodialysis and hemofiltration, the membrane pores
do not pass formed cellular blood elements and plasma proteins.
These components are retained and returned to the individual with
the toxin-depleted blood, along with a replacement fluid. The
replacement fluid restores, at least partially, a normal
physiologic fluid and electrolytic balance to the blood.
Hemodialysis and hemofiltration can be carried out as individual
processes, or in combination.
[0091] A form of hemodialysis is also used to treat individuals
suffering from jaundice caused by inadequate liver function or
liver failure. In this indication, the blood carries abnormal
levels of bilirubin, a breakdown product of hemoglobin normally
removed by the liver. The blood is passed along one side of a
dialysis membrane. Healthy liver cells are located on the opposite
side of the membrane. The healthy liver cells remove bilirubin from
the processed blood. In this treatment, the blood is passed before
undergoing dialysis through an adsorption device (typically
contained activated charcoal) to remove certain blood materials
that are lethal to liver cells.
[0092] 3. Oxygenation (Cardiopulmonary Bypass)
[0093] The blood processing assembly 24 can alternatively carry out
a process called oxygenation. Oxygenation is carried out during
cardiopulmonary bypass, during which the blood is circulated
outside the heart and lungs while heart surgery occurs. During
oxygenation, the blood conveyed from an individual is transported
in an extracorporeal path along a membrane across which a oxygen
concentration differential exists. Oxygen from the opposite side of
the membrane is transported into the blood on the opposite side of
the membrane, to emulate lung function.
[0094] 4. Removal of Cytokines or Other Species of Pro-Inflammatory
or Anti-Inflammatory Stimulators or Mediators
[0095] Extracorporeal processing of the blood in the system 20 may
trigger an incidental or "obligatory" activation of the components
of the immune system carried by the blood. The sources of this
incidental activation can include exposure to biomaterials in the
inlet and return lines 26 and 28 or in the blood processing
assembly 24 itself. External pumping of the blood can also trigger
an incidental immune response. The centrifugal forces or shear
forces developed by passage along a membrane can also trigger an
incidental immune response.
[0096] The incidental activation of the immune system occasioned
during blood processing can lead to the incidental generation of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators. These cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators, to
the extent that they are incidentally produced as a result of blood
processing, will be transported by the blood that is returned to
the donor or patient during processing, or by stored blood
delivered to a recipient during transfusion. Entering the
circulatory system of the donor or other recipient, these
incidental cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators can serve to raise the
levels of cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators in the donor or other
recipient, and could lead to the generation of further cascades or
inflammatory responses, during which further cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators and additional by-products of immune system activation
are produced. Thus, processes that provide beneficial results in
one respect can lead to incidental, potentially adverse results in
another respect.
[0097] The blood processing system 20 therefore includes a device
30 that removes cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from the processed
blood.
[0098] In on-line blood processing systems--e.g., those systems in
which the circulatory system of the donor or patient remains
coupled to the processor 24 during processing--the device 30 can be
coupled in-line either upstream or downstream of the processor 24
(in FIG. 2, the device 30 is shown positioned in the return line 28
for purposes of illustration). In this arrangement, cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators are removed during circulation of the blood through
the extracorporeal circuit, thereby leading to reduced levels of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators in the blood returned to the donor or
patient.
[0099] In off-line blood processing systems--e.g., where the blood
is processed after disconnecting the donor from the collection
system--or in a system that collects a blood component for later
transfusion to a recipient (as FIG. 2 shows)--it is desirable to
place the device 30 either upstream of the blood component storage
bag (as shown in phantom lines in FIG. 2) (so cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators are removed after blood processing and before storage of
the blood component) or in a transfusion set coupled to the
satellite blood component storage bag (so that cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators are removed during the act of transfusion of the
processed blood component).
[0100] The device 30 serves to reduce the population of cytokines
or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators by removing cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the treated, handled, or stored blood. The device 30 thereby serves
to prevent incidental cytokine-induced or inflammatory response
conditions or disease states as a result of otherwise beneficial
blood treatment, handling or storage, by lessening the population
of cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators present in the returned
or re-infused blood. The removal by the device 30 of cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators generated as a result of extracorporeal blood
processing aims to maintain a status quo condition in the immune
system of the individual undergoing blood processing or the
recipient of stored blood.
[0101] II. Devices for Removing Cytokines or Other Species of
Pro-Inflammatory or Anti-Inflammatory Stimulators or Mediators from
the Blood
[0102] Cytokines and other species of pro-inflammatory or
anti-inflammatory stimulators or mediators are low molecular
weight, electrically neutral proteins, ranging in size from about
8000 to about 28,000 daltons. Cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators can
be removed from the blood by various mechanism, e.g. by selective
adsorption, or by ion exchange, or by non-specific adsorption to
dialysis membranes. The devices 18 or 30 for removing cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators from the blood can therefore be variously constructed,
depending upon the removal mechanism selected.
[0103] In the illustrated embodiment, selective removal by
adsorption is the selected mechanism.
[0104] A. Unitary Extracorporeal Devices
[0105] Either device 18 or 30 can comprise a stand-alone, or
unitary, extracorporeal component that can be coupled in-line to
blood tubing at time of use.
[0106] In this arrangement (see FIG. 3), either device 18 or 30
desirably includes in its most basic form a housing 32. The housing
32 contains a medium 34 that removes cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators by
adsorption.
[0107] The housing 32 includes an inlet 33 for conveying the blood
into the housing 32 for contact with the adsorption medium 34. The
housing 32 also includes an outlet 36 for conveying the blood from
the housing after contact with the adsorption medium 34, during
which all or a portion of the cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators
present are removed.
[0108] Desired characteristics of the adsorption medium 34 will be
described in greater detail later.
[0109] The transport of the blood through the adsorption medium 34
in the housing 32 can be accomplished in various ways, depending in
large part upon the environment in which the device 18 or 30 is
used. In the acute or chronic applications described, which involve
use of the device 18, an external pump can be used to convey the
blood through the housing 32 to remove cytokines or other species
of pro-inflammatory or anti-inflammatory stimulators or mediators.
Alternatively, blood tubing connected to the inlet 33 of the
housing 32 can be coupled via a suitable blood access to an artery,
while blood tubing connected to the outlet 36 of the housing 32 can
be coupled by a suitable blood access to a vein, thereby using
physiologic blood pressure to convey the blood through the housing
32 to remove cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators.
[0110] When used in association with a blood processing system,
which involves use of the device 30, an external pump (identified
as P in FIG. 2) is typically present to convey the blood through
the blood processing assembly 24. In this arrangement, the external
pump P that serves the blood processing assembly can concurrently
provide the pressure to convey the blood through the housing 32 to
remove cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators.
[0111] In an alternative embodiment shown in FIGS. 4A and 4B, the
housing 32 can be configured to comprise an exchangeable component
38 that can be releasably coupled to a conventional intravenous
blood access catheter 40, e.g., of the type widely used in
intensive care units. The exchangeable component 38 provides
particular ease of use in either acute or chronic indications, as
above described, as individuals in such circumstances are typically
already fitted with intravenous blood access catheters for other
purposes. However, the exchangeable components 38 would also
provide ease of use in the setting of extracorporeal blood
processing, as the intravenous blood tubing comprising the blood
inlet line 26 or blood outlet line 27 serving the processor 28
could be ready modified to include fittings to accommodate quick
exchange of the component 38.
[0112] In this arrangement, the inlet 33 and 36 of the exchangeable
component 38 and the catheter 40 (or inlet and outlet lines 26 and
27) would include, e.g., convention mating luer fittings 42, to
enable quick attachment and removal in-line in the intravenous
blood access catheter 40 or intravenous blood lines 26/27 serving
the processor 28, as FIGS. 4A and 4B demonstrate.
[0113] In another alternative embodiment shown in FIG. 5, all or a
portion of the wall of an intravenous catheter 44 can be
impregnated with the adsorption medium 34. In this arrangement,
transport of the blood through the catheter 44 exposes the blood to
the medium 34 for the removal of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators.
Alternatively (as shown in FIG. 6), an intravenous catheter 46 can
include an integrally formed chamber 48 in which the adsorption
medium 34 is housed. Thus, transport of the blood through the
catheter 44 exposes the blood to the medium 34 for the removal of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators. In the embodiments shown in FIGS. 5 and
6, the device 18 or 30 forms an integrated part of the blood
transport path, so that a separate housing 32 per se is not
required to contain the adsorption medium 34.
[0114] B. Ambulatory Applications
[0115] As FIG. 7 shows, either device 18 or 30 can comprise a
component 50 that is intended to be coupled to an indwelling
catheter 52, that is surgically fitted to the individual undergoing
treatment. The catheter 52 is surgically attached to the
circulatory system of the individual, e.g., between an artery and a
vein, to form a loop through which the blood continuously
circulates. In this arrangement, the component 50 carries the
adsorption medium 34 that serves to remove cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators from the individual's blood traversing the catheter 52.
As a part of an indwelling blood circulation loop, the component 50
removes cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators continuously on a daily
basis, as the individual ambulates and carries on life's activities
outside of a treatment facility.
[0116] The component 50 can be configured to be an external or
internal exchangeable device that can be releasable coupled to the
indwelling catheter 52, e.g., by use of luer fittings 42, in the
manner generally shown in FIGS. 4A and 4B. Alternatively, the wall
of the indwelling catheter 52 can itself be impregnated with the
adsorption medium 34, as generally shown in FIG. 5.
[0117] The component 50, in association with an indwelling catheter
52, makes possible a continuous, ambulatory treatment to remove
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators. This treatment modality would have
particular application for those "at risk" individuals whose
disease states are caused by or otherwise correlate with chronic,
increased physiologic cytokine activity or other unregulated
inflammatory response condition. The component 50 provides a new
form of ambulatory treatment for, e.g., rheumatoid arthritis; or
lung disease such as emphysema or asthma; or adult respiratory
distress syndrome (ARDS); or autoimmune disease; or AIDS. The
component 50 serves to maintain a reduced population of cytokines
or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators, by continuously removing cytokines or
other species of pro-inflammatory or anti-inflammatory stimulators
or mediators from the blood circulation. The component 50 can be
used alone or in combination with other treatment modalities for
the disease condition.
[0118] C. Integrated Composite Devices
[0119] FIGS. 8 and 9 show an absorption device 30 of a type shown
in FIG. 3, integrally coupled by intermediate tubing 43 to a blood
processor 28. Together, the device 30, processor 28, and linking
tubing 43 form a composite blood treatment module 54 that is
supplied to a user as an integrated unit.
[0120] The composite module 54 can be arranged so that the
absorption device 30 is integrally coupled in a downstream flow
direction to the blood processor 28 (as FIG. 8 shows), or,
alternatively arranged, in an upstream flow direction to the blood
processor 28 (as FIG. 9 shows). In yet another arrangement, the
adsorption device 30 can be placed both upstream and downstream of
the blood processor 28.
[0121] The module 54 can perform different blood processing
functions in association with a blood adsorption function, e.g., to
remove cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators, depending upon the
operational capabilities of the blood processor 28. The processor
28 can be configured to perform diverse functions, e.g.,
hemodialysis, or hemofiltration, or membrane separation of plasma
from whole blood, or blood filtering (e.g., to remove leukocytes),
or ionic exchange, etc., or combinations thereof.
[0122] As FIGS. 10A and 10B show, the adsorption device 30 can be
more intimately attached to the blood processor 28 to form the
module 54 without use of intermediate tubing 43. In this
arrangement (see FIG. 10A), both the adsorption device 30 and
processor 28 are manufactured as separate units. The adsorption
device 30 and processor 28 are configured with, e.g., a tubular
male fitting 56 on the device 30 that mates with a female fitting
58 in the processor 28. The fittings 56 and 58 couple the device 30
and the processor 28 together in fluid flow communication, as FIG.
10B shows.
[0123] Of course, the mating configuration of the fittings 56 and
58 can be reversed, so that the device 30 includes a female fitting
58 and the processor 28 includes the male fitting 56. Furthermore,
other attachment configurations, e.g., screw fit, keyed fittings,
etc., can be used. Mating stabilization struts 60 may also be
provided to further lock the device 30 and processor 28
together.
[0124] By manufacturing the adsorption device 30 and separator 28
separately, and then joining them together to form an integrated
module 54, different sterilization processes may be used. For
example, the device 30 and adsorption medium 34 may be sterilized
by a first sterilization process, e.g., hot water or steam or
external irradiation, whereas the processor 28 may be sterilized by
a second, different sterilization process, e.g., EtO sterilization.
This modular arrangement thereby accommodates the choice of
biomaterials for the adsorption medium 34 and the functional
component of the processor 28 having different physical properties
best suited for their particular functional objections, and not
constrained by similar sterilization requirements. The arrangement
shown in FIGS. 8 and 9 also accommodates different sterilization
techniques prior to joining the device 30 and processor 28 with the
tubing 43.
[0125] As with the embodiments shown in FIGS. 8 and 9, the fittings
56 and 58 can configured to join the device 30 in an upstream flow
direction to the blood processor 28, or (as FIG. 10B shows) in a
downstream flow direction to the blood processor 28, or at both
upstream and downstream ends of the blood processor 28.
[0126] The device 30 may be integrally coupled to the processor 28
during manufacturing, and be supplied to the customer as an
integrated module 54 (as FIG. 10B shows). Alternatively, the device
30 and processor 28 may be supplied separately to the customer (in
the manner shown in FIG. 10A), who is instructed to join the
adsorption device 30 to the processor 28 by plugging the fittings
56 and 58 together at time of use.
[0127] As FIG. 11 shows, the adsorption device 30 can be even more
intimately associated with the blood processor by placing the
processor 28 and device 30 within the confines of a single housing
62. The single housing 62 has an inlet port 68 and an outlet port
70. In this arrangement, an interior partition wall 72 in the
housing 62 compartmentalizes the housing 62 into a first
compartment 64 (which communicates with the inlet port 68) and a
second compartment 66 (which communicates with the outlet port 70).
One or more openings 74 in the interior wall 72 open flow
communication between the first and second compartments 64 and
66.
[0128] Each compartment 64 and 66 can contain either the functional
component of the processor 28 or the adsorption medium 34. In the
embodiment shown in FIG. 11, the functional component of the
processor 28 is contained in the first compartment 64, and the
adsorption medium 34 is contained in the second compartment 66. Of
course, the arrangement of the materials contained in the
compartments 64 and 66 can be reversed. The housing can also be
partitioned to place the adsorption medium 34 at both the inlet and
outlet sides of the blood processor 28, sandwiching the functional
component of the blood processor 28 between it.
[0129] This arrangement requires the selection of materials for the
processor 28 and adsorption medium 34 that accommodate the same
sterilization process, e.g., hot water sterilization.
[0130] It should be appreciated that the various composite
structures 54 just discussed, which join an adsorption device 30
with a blood processor 28, are not limited to a particular
adsorption function for the adsorption device 30. That is, while
the adsorption device 30 has be earlier described in this
application the context of the removal of cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators, the adsorption device 30 can, in association with the
processor 28, carry out other functions as well. For example, when
the processor 28 takes the form of a hemodialyzer, the adsorption
device 30 can serve the function of selectively adsorbing middle
molecular weight proteins (e.g., beta-2 macroglobulin) that
conventional hemodialysis membrane do not efficiently remove.
[0131] D. Adsorption Medium
[0132] The adsorption medium 34 can be variously constructed. In
the illustrated embodiment (see, e.g., FIG. 3), the adsorption
medium 34 desirable includes a group of porous polymeric particles
76, which are formed to selectively retain cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators. Taking into account the physical proportions of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators, the polymeric particles 76 of the medium
34 are predominantly mesoporous, with a pore size ranging from 2 to
70 nm, and preferably from 5 to 50 nm.
[0133] As FIG. 12 best shows, each polymer particle 76 desirably
possesses a porous hydrophobic core 78. The pores are sized to
provide close contact between the cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators and
the hydrophobic surface of the pores.
[0134] The surface of the hydrophobic particles 76 can be modified
to provide a hydrophilic coating 80, which imparts a high degree of
biocompatibility with the human organism, and, in particular, the
blood. This biocompatibility can be expressed in terms of a
biocompatible index, as will be described in greater detail later.
The hydrophilic coating 80 is desirably thin and permeable so as to
allow penetration of cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators to the hydrophobic
porous core 78 of the particles 76.
[0135] The hydrophobic cores 78 of the particles 76 can be
composed, for example, of crosslinked polymeric materials prepared
by polymerization or copolymerization of the following monomers:
styrene, ethylstyrene, .alpha.-methylstyrene, divinylbenzene, di
isopropenyl benzene, trivinylbenzene, alkyl methacrylate as methyl
methacrylate, butyl methacrylate. The hydrophilic biocompatible
coating 80 of the particles 76 can be composed for example of the
following materials: polyvinylpyrrolidone, polyhydroxyethyl
methacrylate, carboxymethylcellulose, polyurethane.
[0136] In a device of the type shown in FIG. 3, the particles 76
are sized, taking into account the size of the device, to obtain a
desired flow rate through the device. As an example, given a device
size of 400 ml, the particles 76 are sized greater than 300 .mu.m
in diameter to present an effective surface area to the blood of
about 500 m.sup.2/gram of adsorption medium 34 used.
[0137] Particles 76 having the characteristics described also
selectively adsorb superantigens. Superantigens are low molecular
weight proteins that are toxic. Superantigens are produced by
organisms and are strong activators of the immune system and
cytokine production. The presence of superantigens can therefore
also contribute to increased levels of cytokines or other species
of pro-inflammatory or anti-inflammatory stimulators or mediators.
The concurrent removal by the particles of both cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators and superantigens enhances the overall therapeutic
function of the adsorption medium 34.
REPRESENTATIVE ADSORPTION MEDIUM
Example 1
[0138] In one representative embodiment, the adsorption medium 34
can include particles or beads formed from hypercrosslinked
polystyrene-type resins. The surface of the beads is desirably
modified to prevent absorption of large proteins and platelet and
to minimize activation of blood complement system, without
affecting noticeably accessibility of an inner absorption space of
the beads for small and middle-sized molecules. The particles or
beads can comprise, e.g., styrene-divinylbenzene copolymers
subjected to an extensive crosslinking in a swollen state with
bifunctional crosslinking agents, such as monochlorodimethyl ether
or p-xylylene dichloride. Alternatively, the particles or beads can
comprise styrene-divinylbenzene copolymers subjected to
chloromethylation and post-crosslinking. Alternatively, the
material can comprise a porous hydrophobic acrylic polymer or a
mesoporous ethylstyrene-divinylbenzene copolymer.
[0139] The surface modification can be accomplished is various
ways, e.g., (i) by depositing on the surface of the particles or
beads high molecular weight poly(N-trifluoroalkoxy) phosphazene, by
treating the beads with a solution of phosphazene in an organic
solvent and evaporating the solvent; or (ii) electrostatically
binding of heparin from its aqueous solution onto the beads whose
chloromethyl groups have been substituted by amino functions
through a reaction with an amine, such as 2-ethanol amine; (iii)
substituting chloromethyl groups on the surface of the beads with
2-ethanol amine ligands and covalently binding heparin to the
ligands via a material such as a glutare dialdehyde and
hexamethylene diisocyanate moiety, and coupling groups consisting
of excessive pendant aldehyde groups and isocyanate groups with
L-aspartic acid; or (iv) substituting chloromethyl groups with a
material such as 2-ethanol amine and ethylene glycol ligands,
activating the ligands with a material such as glutare dialdehyde
and hexamethylene diisocynate, and covalently binding hydrophilic
polyethylene glycol chains; or (v) covalently binding hydrophilic
polyethylene glycol chains through reacting of sodium alcoholates
of the latter with polystyrene chloromethyl groups; or (vi)
covalently binding hydrophilic chains of chitosan through reacting
of amino groups of the latter with polystyrene chloromethyl groups;
or (vii) substituting chloromethyl groups with ligands such as
2-ethanol amine ligands or ethylene glycol ligands, activating the
ligands with phosphorus oxychloride, and covalently binding
hydrophilic moieties such as choline, serine and 2-ethanol
amine.
[0140] Further details regarding the composition of particles or
beads of this type can be found in U.S. Pat. No. 5,904,663, which
is incorporated herein by reference.
REPRESENTATIVE ADSORPTION MEDIUM
Example 2
[0141] In another representative embodiment, the adsorption medium
34 can include particles or beads formed from a porous hydrophobic
divinylbenzene copolymer with comonomers selected from the group of
styrene, ethylstyrene, acrylonitrile, and buthyl methacrylate. Such
particles or beads initially have surface exposed vinyl groups,
which are chemically modified to impart improved biocompatibility,
so as to form different surface exposed functional groups, such as
polymers of 2-hydroxyethyl methacrylate, N-vinylpyrrolidine,
N-vinylcaprolactame, or N-acrylamide. The surface exposed
functional groups can be products of oxidation of the vinyl groups
to expoxy groups and subsequent addition of polar compounds
selected from the group of water, ethylene glycol, primary or
secondary amines, and 2-hydroxethyl-amine. Alternatively, the
surface exposed functional groups can be the products of oxidation
of the vinyl groups to epoxy groups, the subsequent addition of
primary or secondary amines or 2-hydroxyethylamine, and the deposit
of high-molecular-weight poly(trifluoroethoxy) phosphazene.
[0142] Further details regarding the composition of particles or
beads of this type can be found in U.S. Pat. No. 6,114,466, which
is incorporated herein by reference.
REPRESENTATIVE ADSORPTION MEDIUM
Example 3
[0143] In another representative embodiment, the adsorption medium
34 can include particles or beads formed by polymerization of
aromatic divinyl compounds, such as p- or m-divinylbenzene or
mixtures thereof, or their copolymerization with aromatic monovinyl
compounds, such as styrene, methylstyrene, ethylvinylbenzene and
vinylbenzylchloride, in the presence of porogens or mixtures of
porogens with properties close to those of .theta.-solvents. The
porogens can comprise, e.g., cyclohexane, cyclohexanone and other
.theta.-solvents for polystyrene. Alternatively, the porogens can
comprise .theta.-solvents composed of mixtures of a good solvent
for polystyrene, such as toluene, benzene, ethylene dichloride,
propylene dichloride, tetrachloroethene, dioxane and methylene
dichloride, and a non-solvent for polystyrene, such as aliphatic
hydrocarbons, aliphatic alcohols and aliphatic acids.
[0144] Such hypercrosslinked polymeric adsorbents exhibit a
combination of micropores, mesopores and macropores. The adsorbents
may further be functionalized to enhance their
biocompatibility.
[0145] Further details regarding the composition of particles or
beads of this type can be found in U.S. patent application Ser. No.
09/143,407, filed Aug. 28, 1998, entitled "Hypercrosslinked
Polymeric Material for Purification of Physiological Liquids of
Organism, a Method for Producing the Material," which is
incorporated herein by reference.
[0146] 1. Biocompatibility Index
[0147] Desirably, the adsorption medium 34 is characterized by a
biocompatibility index that indicates a physiologically negligible
production of cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators in the blood as a result
to exposure to the medium. Thus, the adsorption medium 34, which
beneficial serves to remove cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the blood, does not itself produce an offsetting result of
generating additional cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators.
[0148] The biocompatibility index can be expressed as a
dimensionless, numeric quantity, which reflects the degree to which
a prescribed battery of blood characteristics change as a result of
contact between the blood and the adsorption medium.
[0149] The prescribed battery of blood characteristics that the
biocompatibility index encompasses rely upon several selected blood
indicators, which quantify, based upon contact between the blood
and a given adsorption medium, (i) the degree to which the numbers
of cellular blood components (red blood cells, white blood cells,
and platelets) are diminished; (ii) the degree to which leukocytes
are activated; (iii) the degree to which complement activation
occurs; (iv) the degree to which hemolysis occurs; and (v) the
degree to which clot formation is induced.
[0150] Indicator (i) is ascertained by Coulter Counter for red
blood cells, white blood cells, and platelets (this indicator this
comprises three individual indicators).
[0151] Indicator (ii) is ascertained by measuring polymorphonuclear
leukocyte elastase (PMN Elastase) concentrations using standard
laboratory techniques (e.g., PMN Elastase, Merck Immunoassay, Merk
KgaA, Darmstadt, Germany).
[0152] Indicator (iii) is ascertained by measuring anaphylatoxin
C3a-desArg concentrations using standard laboratory techniques
(e.g., Elisa, Progen Biotechnik GmbH, Heidelberg, Germany).
[0153] Indicator (iv) is ascertained by determining the
concentrations of Lactate dehydrogenase (LDH) by standard methods
of clinical chemistry.
[0154] Indicator (v) is ascertained by measuring the concentrations
of thrombin-antithrombin-complex (TAT) using standard laboratory
techniques (e.g., Enzygnost-TAT micro Elisa, Dade Behring Marburg
GmbH, Marburg, Germany).
[0155] There are therefore a total of seven indicators within the
battery of indicators for the Biocompatibility Index: (1) White
Blood Cell Count; (2) Red Blood Cell Count; (3) Platelet Count; (4)
PMN Elastase Concentration; (5) LDH Concentration; (6) C3a-desArg
Concentration; and (7) TAT Concentration. These indicators are
listed in Table 1, below.
[0156] In deriving the biocompatibility index, the technician
selects a housing for the media that is made of an acceptable
biocompatible material that possesses a biocompatibility comparable
to conventional medical grade plastics (e.g., polyvinylchloride,
polyurethane, polyester, etc) or glass. The technician
characterizes the blood according to the battery of indicators
after passing the blood through the housing in an empty condition,
i.e., a housing that contains no absorption medium.
[0157] The technician uses heparin to anticoagulate the blood in a
final concentration of 1.0 IU heparin/ml blood. Other types of
anticoagulant, such as nafamosat, may be used. However, citrate
anticoagulant is not be to used, alone or in combination with the
prescribed amount of heparin in deriving the biocompatibility
index, because the presence of citrate will mask changes in
thrombogenicity and complement activation that may arise due to
contact with the medium, thereby leading to false results.
[0158] FIG. 23 summarizes the results of hemocompatibility testing
conducted by Bosch et al of a polyacrylate gel adsorbant material
(for the selective adsorption of low-density lipoproteins), based
upon contact with blood that was anticoagulated either only with
heparin or with a mixture of heparin and citrate (Bosch et al,
Artif Organ 17(7) 640-52 1993). FIG. 23 demonstrates that, with
respect to the thrombogenicity and complement activation
indicators--PMN Elastase (indicating the degree to which leukocytes
are activated); thrombin-antithrombin-complex TAT (indicating the
degree to which clot formation is induced); and anaphylatoxin
C3a-desArg (indicating the degree to which complement activation
occurs)--each indicator level reads high (denoting thrombogenicity
and complement activation) when only heparin anticoagulant is used.
The mixture of citrate with heparin masks the actual indicator
levels in a significant way. FIG. 23 shows that, by binding calcium
(an important co-factor in many hemocompatibility reactions), the
presence of citrate lowers the indicator levels, so that they no
longer reflect the actual changes in thrombogenicity and complement
activation that arise due to contact with a given medium.
[0159] The forgoing protocol provides the background or baseline
sample, against which the magnitude of changes due to the presence
of a given adsorption medium within the housing can be ascertained
and scored.
[0160] In deriving the biocompatibility index, the technician also
characterizes the blood according to the battery of indicators
after passage through the selected housing that contains the
absorption medium. As before, the technician uses heparin to
anticoagulate the blood in a final concentration of 1.0 IU
heparin/ml blood. For the reasons stated above, citrate
anticoagulant is not be to used in deriving the biocompatibility
index, alone or in combination with the prescribed amount of
heparin.
[0161] In carrying out the steps just described, the technician
assembles a test system 300 as shown in FIG. 16. The test system
300 comprises two parallel channels 302 and 304 connected by a
y-connector 306 to a blood line 308. A housing 310 and 312 is
coupled in each channel, respectively 302 and 304. The housing 310
is empty (i.e., free of adsorption medium), and the housing 312
contains the adsorption medium 314. The blood line 308 can be
coupled, e.g., to the antecubital vein of a healthy volunteer. The
access system desirably allows for continuous heparinization at the
tip of the inserted cannula or needle to avoid systemic
heparinization. Peristaltic pumps P1 and P2 in the channels 302 and
304 (or a single, double tube peristaltic pump) convey the blood
through the housings 310 and 314. An infusion pump P3 meters
heperin, to achieve a final heparin concentration of 1.0 IU/ml.
[0162] The pumps P1, P2, and P3 are started simultaneously. On-line
blood perfusion of the two channels 302 and 304 is maintained
through each housing 310 and 312. The speeds of the pumps P1 and P2
are adjusted to 10 mL/min through each housing 310 and 312. Blood
samples are collected at the outlet of each channel 302 and 304
after 5, 10, 15, and 25 minutes of perfusion directly into
specially prepared polypropylene vials V stored on ice. The blood
samples are analyzed for the selected indicators immediately. Blood
counts are corrected for hemodilution due to the addition of
heparin.
[0163] The cell count indicators are corrected by the following
formula: X.sub.corr=X times (hct.sub.pre/hct.sub.t, where
X.sub.corr is the corrected parameter, X is the measured value of
the parameter at time point t, hct.sub.pre is the hematocit pre
value (t=0), and hct.sub.t is the hematocrit at time point t.
[0164] The plasma indicators for PMN Elastase Concentration, LDH
Concentration, C3a-desArg Concentration, and TAT Concentration are
corrected by the following formula: X.sub.corr=X times
(1-hct.sub.t/1-hct.sub.pre, where X.sub.corr is the corrected
plasma parameter, X is the measured value of the plasma parameter
at time point t, hct.sub.pre is the hematocit pre value (t=0), and
hct.sub.t is the hematocrit at time point t.
[0165] The technician reviews the assembled indicators to
ascertain, for each indicator, the maximum difference between the
indicator values over 25 ml of blood flow of the blood passed
through the housing 310 (without the medium--baseline) and the
blood passed through the housing 312 containing the medium 314. For
each indicator, the technician expresses the maximum change as a
percentage, relative to the baseline value.
[0166] The technician then scores the percentage change for each
indicator as a dimensionless numeric quantity 1, 2, or 3, depending
upon the magnitude of the percentage change, in accordance with
Table 1. In Table 1, a percentage change equal to or less than a
prescribed minimum for a given indicator is scored as a 1,
signifying a most desirable degree of biocompatibility. In Table 1,
a percentage change greater than a prescribed maximum for a given
indicator is scored as a 3, signifying a least desirable degree of
biocompatibility. In Table 1, a percentage change between the
prescribed minimum and the prescribed maximum for a given indicator
is scored as a 2, signifying an acceptable degree of
biocompatibility, albeit not the most desired.
1TABLE 1 The Biocompatibility Index Score Table Numeric Scores 1 2
3 (Signifying (Signifying (Signifying Most an a Least Desired
Acceptable Desired Blood Degree of Degree of Degree of Indicator
Biocompatibility) Biocompatibility) Biocompatibility) Loss of White
Maximum Maximum Maximum Blood Cells Difference Difference
Difference Between Between Between Baseline Baseline and Baseline
and and Medium Medium (25 ml) Medium (25 ml) (25 ml) >15%
>20% .ltoreq.15% .ltoreq.20% Loss of Red Maximum Maximum Maximum
Blood Cells Difference Difference Difference Between Between
Between Baseline Baseline and Baseline and and Medium Medium (25
ml) Medium (25 ml) (25 ml) >15% >20% .ltoreq.15% .ltoreq.20%
Loss of Maximum Maximum Maximum Platelets Difference Difference
Difference Between Between Between Baseline Baseline and Baseline
and and Medium Medium (25 ml) Medium (25 ml) (25 ml) >15%
>20% .ltoreq.15% .ltoreq.20% PMN Elastase Maximum Maximum
Maximum Concentration Difference Difference Difference Between
Between Between Baseline Baseline and Baseline and and Medium
Medium (25 ml) Medium (25 ml) (25 ml) >15% >20% .ltoreq.15%
.ltoreq.20% LDH Maximum Maximum Maximum Concentration Difference
Difference Difference Between Between Between Baseline Baseline and
Baseline and and Medium Medium (25 ml) Medium (25 ml) (25 ml)
>15% >20% .ltoreq.15% .ltoreq.20% C3a-desArg Maximum Maximum
Maximum Concentration Difference Difference Difference Between
Between Between Baseline Baseline and Baseline and and Medium
Medium (25 ml) Medium (25 ml) (25 ml) >20% >25% .ltoreq.20%
.ltoreq.25% TAT Maximum Maximum Maximum Concentration Difference
Difference Difference Between Between Between Baseline Baseline and
Baseline and and Medium Medium (25 ml) Medium (25 ml) (25 ml)
>15% >20% .ltoreq.15% .ltoreq.20%
[0167] After scoring each indicator with a numeric quantity of 1,
2, or 3, the technician adds the numeric quantities scored for all
the indicators to obtain a total. The total constitutes the
biocompatibility index for the given adsorption medium.
[0168] The Biocompatibility Index for a given material is a
reliable indicator of blood compatibility. There is a strong
correlation between the value of the Biocompatibility Index,
derived in the manner just described, and the ability of given
material to selectively remove targeted proteins from the blood
without significant destruction of cellular components and
hemolysis and without significant clot formation (i.e., low
thrombogenicity). Materials characterized by a Biocompatibility
Index equal to or less than 14, and, most desirably, by a
Biocompatible Index not greater than 7, contact the blood with no
significant loss of blood cells, no significant hemolysis, no
significant activation of luekocytes or monocytes, and, at most,
only very mild complement activation, even with the use of heparin
as the sole anticoagulant. Because such materials are not likely to
induce the generation of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators,
they are well suited for use to remove cytokines or other species
of pro-inflammatory or anti-inflammatory stimulators or mediators
from the blood, blood products, or physiologic fluids.
[0169] On the other hand, materials characterized by a
Biocompatibility Index greater than 14, contact the blood with
adverse effects in terms of significant blood cell loss, or
significant hemolysis, or significant leukocyte activation, or
significant compliment activation, or significant combinations
thereof. Such materials are therefore likely to induce the
generation of cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators and are not acceptable
for use to remove cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators
[0170] E. Multiple Functionality
[0171] As previously discussed, the devices, systems, and methods
are directed to the removal of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators to
reduce levels of such agents in the blood in situations where
abnormal levels of such agents occur, or during events that do
induce or have the potential for inducing abnormal production of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators. In this way, the devices, systems, and
methods serve to control, reduce, or alleviate the severity of many
physiologic conditions and disease states that are associated with
abnormal levels of cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators.
[0172] It should be appreciated that the devices, systems, and
methods can be adapted to perform other functions in tandem with
removal of cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators as well.
[0173] FIG. 13 shows a device 82 that is usable in association with
the systems and methods previously discussed to provide adsorption
of both cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators and other material or
materials from the blood. The device 82 includes a first
compartment 84, which contains the adsorption medium 34, previously
described, to remove cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators. The device 82
includes a second compartment 86, which contains a different medium
88, which can comprise an adsorption medium or an ion exchange
medium, to remove another type of material from the blood. A
partition 90 in the device 82 (e.g., made of a mesh material to
accommodate fluid flow) separates the first compartment 84 from the
second compartment 86. In use, the blood is conveyed into the
device 82 through an inlet 92. The blood passes in succession
through the adsorption medium 34 and the different, second medium
88. The blood exits the device 82 through an outlet 94. During
passage, cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators are removed from the
blood by the adsorption medium 34 and the other material is removed
from the blood by the different, second medium 88. The order of
passage through the mediums 34 and 88 can be reversed.
[0174] The adsorption medium 88 can be variously constructed
depending upon the material intended to be removed.
[0175] 1. Removal of LPS EndoToxin
[0176] For example, the adsorption medium 88 can be constructed to
remove LPS endotoxin, which is released into the blood of an
individual suffering from a gram-negative bacterial infection. In
the blood, LPS endotoxin coalesce into vesicles ranging in size
from 300,000 to 1,000,000 daltons. Phosphoryl groups contained
within the LPS endotoxin give it an overall negative charge at
physiologic pH. The release of LPS endotoxin into the blood can
cause fever, low blood pressure, and organ failure.
[0177] As previously discussed, the presence of LPS endotoxin also
stimulates the secretion of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators. The
presence of LPS endotoxin can therefore also contribute to
increased levels of cytokines or other species of pro-inflammatory
or anti-inflammatory stimulators or mediators, and even to the
onset of a septic shock episode.
[0178] In the illustrated embodiment (see FIG. 13), the adsorption
medium 88 includes a group of polymer particles 96 comprising
hydrophobic porous core to which LPS endotoxin binds. To provide a
reliable interaction between the endotoxin and the polymer core,
the polymer particles have pores of a corresponding large size. For
example, the size of the pores can be within the range of 20 to 150
nm, and preferably between 30 and 100 nm. The polymeric particles
96 are thus predominantly macroporous.
[0179] The polymer for the core of the particles 96 can be selected
from the same group of materials as the polymer for the core 78 of
the particles 76 of the adsorption medium 34, as before
described.
[0180] Like the particles 76 of the first adsorption medium 34, the
particles 96 of the adsorption medium 88 desirable include a
hydrophilic coating or shell to provide biocompatibility, which is
also desirably characterized by a high biocompatibility index. The
coating material for the particles 96 can be selected from the same
group of materials as the coating 80 for the particles 76 of the
first adsorption medium 34.
[0181] In addition, the polymer particles 96 can also possess
positively charged functional groups on the surface of the
hydrophobic pores to further attract endotoxin through an ionic
interaction. The amount of these positively charged groups
desirably remains low, preferably below 1 meq/ml. Thus, the overall
hydrophobic nature of the core of the polymeric particle is not
compromised, so that hydrophobic interactions still remain the
major mechanism of adsorption of LPS endotoxin. The positively
charged functional groups covalently bonded to the surface of the
pores of the polymeric particles 96 can be selected from the group
composed of amino-, methylamino-, ethylamino-, dimethylamino-,
diethylamino-, ethanolamino-, diethanolamino-,
polyethylenimino-groups, imidazole, histamine, or basic amino acids
as lysine, arginine, histidine.
[0182] 2. Removal of Other Materials
[0183] The adsorption medium 88 can also be composed to selectively
adsorb other targeted proteins or toxins that can be released into
the blood as a result of injury or trauma, e.g., myoglobin, which
can be released during a crush injury. The adsorption medium 88 can
also be composed to selectively adsorb targeted chemical moieties
that can be released into the blood as a result of injury or
trauma, e.g., potassium, which can be released with myoglobin
during a crush injury.
[0184] The device 18 or 30 can also be used in combination with
other devices that remove materials from the blood other than by
selective adsorption, e.g., by ion exchange effects.
[0185] III. Systems and Methods for Removing Cytokines or Other
Species of Pro-Inflammatory or Anti-Inflammatory Stimulators or
Mediators from Physiologic Fluids
[0186] FIG. 14 shows an embodiment of a system 100 for removing
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from a physiologic fluid. In this
embodiment, the physiologic fluid comprises fresh peritioneal
dialysis solution that has been regenerated from spent peritoneal
dialysis solution.
[0187] As shown in FIG. 14, the system 100 is configured for
conducting a form of automated peritoneal dialysis. The system 100
includes a cycler 114, to automatically infuse, dwell, and drain
peritoneal dialysis solution to and from the patient's peritoneal
cavity 120, typically at night while the patient is asleep.
[0188] The system 100 includes a peritoneal dialysis solution flow
set 112 that establishes communication between the system 100 and
the peritoneal cavity 120 of the patient. The cycler 114 interacts
with the flow set 112, to pump peritoneal dialysis solution into
and out of the patient's peritoneal cavity 120 in prescribed
infuse, dwell, and drain cycles.
[0189] The flow set 112 includes an in-line regeneration module
122. The cycler 114 circulates peritoneal dialysis solution,
removed from the patient's peritoneal cavity 120, into the module
122 The cycler 114 also circulates a regeneration solution
containing, e.g., electrolytes and/or buffering materials, from a
source 115 into the module 122.
[0190] The module 122 includes a component, e.g., a membrane, that
transports waste and uremic toxins from the spent peritoneal
dialysis solution into the regeneration solution, while also
transporting electrolytes and buffering materials from the
regeneration solution 115 into the peritoneal dialysis solution.
Typically, the regeneration fluid, laden with toxins and depleted
of electrolytes and buffers, is sent to waste.
[0191] The module 122 thereby performs on-line regeneration of
peritoneal dialysis solution. Upon regeneration, the cycler 114
re-circulates the peritoneal dialysis solution back to the
peritoneal cavity 120 of the patient.
[0192] The spent peritoneal dialysis solution may carry cytokines
or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators generated while the solution dwelled
within the peritoneal cavity of the patient. Extracorporeal
processing of the spent solution by the cycler 114 can also trigger
additional production of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators.
[0193] The system 100 therefore includes a device 130 that removes
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from the physiologic peritoneal dialysis
solution prior to its return to the patient's peritoneal cavity
120. The device 130 can be coupled to the system 100 either
upstream or downstream of the regeneration module 122. In this
arrangement, cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators are removed from the
peritoneal dialysis solution either before or after regeneration,
and prior to return to the regenerated solution to the peritoneal
cavity 120 of the patient. This leads to overall reduced levels of
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators in the peritoneal dialysis patient.
[0194] It should be appreciated that the device 122 can be used in
other peritoneal dialysis modalities where regeneration of
peritoneal dialysis solution is performed.
[0195] Body fluids that are removed from and then recycled back to
the body during a given treatment modality can also carry cytokines
or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators, or cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators can
be generated as a result of such treatment modalities. Treatment
systems and methods exist for removing and recycling such fluids,
e.g., lymphatic fluid, synovial fluid, spinal fluid, or
cerebrospinal fluid. The devices, systems, and methods that embody
this aspect of the invention, as just discussed in the context of
peritoneal dialysis, can likewise be used in association with such
treatment modalities, to remove cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators from
the body fluids before, during, or after other forms of primary
treatment.
[0196] FIG. 15 shows another embodiment of a system 200 for
removing cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators from a physiologic
fluid. In this embodiment, the physiologic fluid comprises
preservation solution 206 for a harvested organ 202 awaiting
transplantation.
[0197] As shown in FIG. 15, the system 200 includes a bath 204
holding the organ 202. The preservation solution 206 is circulated
from a source 208 through the bath 204 and through the organ 202.
FIG. 15 depicts a harvested kidney 202, but the organ can be any
solid organ harvested for transplant.
[0198] The organ 202 may generate cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators
while immersed in the bath 204. The cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators
will, in turn enter the preservation solution 206 contacting and
perfusing the organ 202. Circulation of the preservation solution
may also trigger additional production of cytokines or other
species of pro-inflammatory or anti-inflammatory stimulators or
mediators.
[0199] The system 200 therefore includes a device 230 that removes
cytokines or other species of pro-inflammatory or anti-inflammatory
stimulators or mediators from the preservation solution. The device
230 can be coupled to the system 200 either upstream or downstream
of the bath 204. In this arrangement, cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators are
removed from the preservation solution, so that the overall
population of cytokines or other species of pro-inflammatory or
anti-inflammatory stimulators or mediators to which the organ 202
is exposed prior to transplantation is minimized. This leads to
overall reduced levels of cytokines or other species of
pro-inflammatory or anti-inflammatory stimulators or mediators in
the patient who receives the organ transplant.
[0200] Either device 120 or 230 can be constructed in generally the
same fashion already described with respect to devices 18 or
30.
EXAMPLE 1
(Blood Purification Using an Adsorption Medium to Restore
Immunologic Stability)
[0201] A study was conducted to demonstrate the ability of a
biocompatible adsorption medium to selectively adsorb cytokines
(TNF, IL-6, and IL-10) from the blood. The medium comprised
particles (as generally shown in FIG. 12) formed of a core of
hydrophobic, crosslinked porous divinylbenzene material coated with
a thin, permeable biocompatible hydrophilic polyvinylpyrrolidone
material. The core material of the particles possessed a mean pore
size of about 16 nm. The particles were contained within a housing
(as generally shown in FIG. 3)and presented a surface area to blood
flow of about 650 sq.mg. The medium was obtained from RenalTech
International, New York, N.Y. (BetaSorb.TM. Adsorption Medium).
[0202] The medium was tested in an experiment using in three
animals subjected to cecal ligation and puncture (CLP) 18 hrs
earlier. The animals tolerated treatment with the medium without
difficulty. The cytokine response was characterized over the four
hours of treatment (see FIG. 17).
[0203] The results demonstrate that the medium removed all three
cytokines from the blood. As FIG. 17 shows, there was a flattening
out or even downward trend in the concentrations of TNF, IL-6 and
IL-10 (in order to keep the scales similar, the units for TNF in
FIG. 17 are pg/ml, IL-6 are ng/dl, and IL-10 are pg/cl). Previous
experience with this model has shown a progressive increases in
IL-6 and IL-10 over a similar time period and a more persistent TNF
signal.
EXAMPLE 2
Biocompatibility Index of the Adsorption Medium
[0204] The adsorption medium employed in Example 1 was subjected to
the prescribed battery of tests under the biocompatibility index
test protocol described above. The blood drawn from six individual
healthy donors was subjected to the test protocol and the test
results were averaged.
[0205] FIGS. 18A, 18B, and 18C show the average variations in blood
cell counts for red blood cells, white blood cells, and platelets,
respectively, incrementally during passage of 25 ml of the blood
through the treatment device containing the medium. With respect to
red blood cells, white blood cells, and platelets, the maximum
difference between the base line (line S.K./A) and the medium (line
S.K./B) was less than 15%.
[0206] FIG. 19 shows the average variations in PMN elastase
concentrations (indicative of leukocyte activation) incrementally
during passage of 25 ml of the blood through the treatment device
containing the medium. The maximum difference between the based
line (line S.K./A) and the medium (line S.K./B) was less than
15%.
[0207] FIG. 20 shows the average variations in LDH
concentrations(indicati- ve of hemolysis) incrementally during
passage of 25 ml of the blood through the treatment device
containing the medium. The maximum difference between the based
line (line S.K./A) and the medium (line S.K./B) was less than
15%.
[0208] FIG. 21 shows the average variations in C3a-desArg
concentrations(indicative of complement activation) incrementally
during passage of 25 ml of the blood through the treatment device
containing the medium. One donor experienced a rapid increase in
the C3a-desArg level from 86 up to 822 .mu.g/L due to clotting in
the test system. The other five donors (who experienced no clotting
in the test system) underwent more moderate increases, with a mean
increase of from 113 to 392 .mu.g/L. The maximum difference between
the based line (line S.K./A) and the medium (line S.K./B) was
greater than 25%.
[0209] FIG. 22 shows the average variations in TAT
concentrations(indicati- ve of coagulation) incrementally during
passage of 25 ml of the blood through the treatment device
containing the medium. The maximum difference between the based
line (line S.K./A) and the medium (line S.K./B) was less than
15%.
[0210] The following table lists the scoring the results for the
indications as the dimensionless quantities 1, 2, and 3.
2 Numeric Scores 1 2 3 (Signifying (Signifying (Signifying Most an
a Least Desired Acceptable Desired Blood Degree of Degree of Degree
of Indicator Biocompatibility) Biocompatibility) Biocompatibility)
Loss/of 1 White Blood Cells Loss of Red 1 Blood Cells Loss of 1
Platelets PMN Elastase 1 Concentration LDH 1 Concentration
C3a-desArg 3 Concentration TAT 1 Concentration
[0211] The Biocompatibility Index for the Medium is 9, which
indicates the medium can contact the blood with no significant loss
of blood cells, no significant hemolysis, no significant activation
of luekocytes or monocytes, and, at most, only moderate complement
activation, even with the use of heparin as the sole anticoagulant.
Because such materials are not likely to induce the generation of
cytokines, they are well suited for use to remove cytokines from
the blood, blood products, or physiologic fluids.
[0212] Various features of the invention are set forth in the
following claims.
* * * * *