U.S. patent application number 17/538241 was filed with the patent office on 2022-03-24 for augmented biocontainment materials and augmented biocontainment enclosures.
The applicant listed for this patent is THE SECANT GROUP, LLC. Invention is credited to Peter D. GABRIELE, Jeremy J. HARRIS, Steven LU, Charles Brendan NICHOLSON, Gael PERON, Jeffrey H. ROBERTSON.
Application Number | 20220090006 17/538241 |
Document ID | / |
Family ID | 1000005999809 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220090006 |
Kind Code |
A1 |
GABRIELE; Peter D. ; et
al. |
March 24, 2022 |
AUGMENTED BIOCONTAINMENT MATERIALS AND AUGMENTED BIOCONTAINMENT
ENCLOSURES
Abstract
A biocontainment vessel includes a vessel structure including a
structural composition and an enhancement composition associated
with the structural composition. The enhancement composition
includes a co-polymer. The co-polymer is a poly(glycerol sebacate)
or a poly(glycerol sebacate urethane). The enhancement composition
may also include an augmentation agent associated with the
co-polymer. The enhancement composition is located with respect to
the structural composition such that the enhancement composition
benefits biological cells contained in the biocontainment vessel. A
composition includes a co-polymer and an augmentation agent
contained by the co-polymer. A method of containing biological
cells includes placing the biological cells in an augmented
biocontainment vessel and storing them in the augmented
biocontainment vessel under predetermined conditions. An augmented
substrate includes a substrate and an enhancement composition
coating a surface of the substrate.
Inventors: |
GABRIELE; Peter D.; (Frisco,
TX) ; HARRIS; Jeremy J.; (Doylestown, PA) ;
NICHOLSON; Charles Brendan; (Coopersburg, PA) ; LU;
Steven; (Somerville, MA) ; ROBERTSON; Jeffrey H.;
(Sellersville, PA) ; PERON; Gael; (Winston-Salem,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE SECANT GROUP, LLC |
Telford |
PA |
US |
|
|
Family ID: |
1000005999809 |
Appl. No.: |
17/538241 |
Filed: |
November 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16250457 |
Jan 17, 2019 |
11208627 |
|
|
17538241 |
|
|
|
|
62618419 |
Jan 17, 2018 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12M 41/46 20130101;
C12M 25/14 20130101; C12N 5/0068 20130101; C12M 23/20 20130101;
C12M 23/28 20130101; C12M 23/52 20130101; C12M 23/26 20130101; C12N
2533/30 20130101; C12M 23/14 20130101 |
International
Class: |
C12N 5/00 20060101
C12N005/00; C12M 1/00 20060101 C12M001/00; C12M 1/12 20060101
C12M001/12; C12M 1/34 20060101 C12M001/34 |
Claims
1. A filtration system comprising a plurality of fibers coated with
a coating comprising a co-polymer selected from the group
consisting of a poly(glycerol sebacate) and a poly(glycerol
sebacate urethane) and an augmentation agent associated with the
co-polymer.
2. The filtration system of claim 1, wherein the co-polymer is
poly(glycerol sebacate).
3. The filtration system of claim 1, wherein the co-polymer is
poly(glycerol sebacate urethane).
4. The filtration system of claim 1, wherein the augmentation agent
is physically mixed with the co-polymer.
5. The filtration system of claim 1, wherein the augmentation agent
is chemically attached to the co-polymer.
6. The filtration system of claim 1, wherein the coating is an
affinity coating for toxins.
7. The filtration system of claim 1, wherein the coating is an
affinity coating for biologics separation, biologics harvest, or
biologics neutralization.
8. The filtration system of claim 1, wherein the coating is a
buffer coating.
9. The filtration system of claim 1, wherein the coating protects
against hemoglobin scavenging of nitrous oxide.
10. The filtration system of claim 1, wherein the augmentation
agent comprises a nutrient.
11. A method comprising coating a plurality of fibers of a
filtration system with a coating comprising a co-polymer selected
from the group consisting of a poly(glycerol sebacate) and a
poly(glycerol sebacate urethane) and an augmentation agent
associated with the co-polymer.
12. The method of claim 11, wherein the co-polymer is poly(glycerol
sebacate).
13. The method of claim 11, wherein the co-polymer is poly(glycerol
sebacate urethane).
14. The method of claim 11 further comprising physically mixing the
augmentation agent with the co-polymer to form the coating.
15. The method of claim 11 further comprising chemically attaching
the augmentation agent to the co-polymer.
16. A composition comprising a plurality of fibers coated with a
coating comprising a co-polymer selected from the group consisting
of a poly(glycerol sebacate) and a poly(glycerol sebacate urethane)
and an augmentation agent associated with the co-polymer.
17. The coating of claim 16, wherein the co-polymer is
poly(glycerol sebacate).
18. The coating of claim 16, wherein the co-polymer is
poly(glycerol sebacate urethane).
19. The coating of claim 16, wherein the augmentation agent is
physically mixed with the co-polymer.
20. The coating of claim 16, wherein the augmentation agent is
chemically attached to the co-polymer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 16/250,457 filed Jan. 17, 2019, which
claims priority to and the benefit of U.S. Provisional Application
No. 62/618,419 filed Jan. 17, 2018, both of which are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] This application is directed to biocontainment and cell
culture. More specifically, this application is directed to
augmented biocontainment materials, augmented biocontainment
enclosures, and methods for making and using the same.
BACKGROUND OF THE INVENTION
[0003] Disposable bioreactors and storage containment devices for
living cells of various types are conventionally based on man-made
polymers, and in most cases polymer films, assembled into bags or
assemblies that have characteristics of volume, but these polymers
and associated materials of construction expose the cell culture or
cell load to non-biocompatible, fugitive, and potentially toxic
materials.
[0004] Current technology limitations raise two important questions
about cell culture, cell expansion, and blood storage and biologic
cell containment in cell culture research. First, to what temporal
extent do blood cells and tissue cells maintain their intended or
innate function in man-made storage containment, where they are
cultivated in an artificial ex vivo environment, and remain viable
to deliver an efficacious therapy? Second, what are the unseen
secondary effects of ex vivo cultivation in man-made polymeric
containment, and can these secondary effects be eliminated in
man-made materials in contact with cells that dictate the medical
sequelae of toxic metabolic substances, contamination of cultures
from materials of construction, or the milieu of personalized
biochemistry of the donor to the patient treatment?
[0005] The polymeric surface and the indigenous polymer chemistries
of many materials conventionally used in the construction of
bioreactors are not optimum. Examples include polyvinyl chloride
(PVC) and polyethylene terephthalate (PET) plasticized with
phthalate esters, which are known to be cancer-causing.
[0006] Attempts have been made to improve standard materials of
construction. Conventional material attempting to modify surfaces
use, for instance, polymeric lactides and glycolides as
biodegradable vehicles and resins for such modifications. Lactide
and glycolide biodegradable polymers biodegrade into "anaerobic"
waste by-products that cell systems must mitigate in their
environments. Therefore, the conventional use or "gravitation" to
polyglycolic acid (PGA), polylactic acid (PLA), or
poly(lactic-co-glycolic) acid (PLGA) as a biodegradable resin is
also not ideal. One problem is that degradation of the lactide and
glycolide, like certain other "biodegradable polymers", results in
breakdown products that are considered antagonistic cellular waste
and require an immunologic response to "neutralize" the by-product
effects, a biological response that is unavailable in vitro.
BRIEF DESCRIPTION OF THE INVENTION
[0007] It would be desirable to create biocompatible surfaces and
release mechanisms, to mitigate noxious environmental components
having adverse interactions with living systems, and to advance
improvements in cell culture viability, bioreactor constructs for
cell culture, support, and development, and storage related to cell
therapeutics, blood storage, microbial culture, and/or tissue
engineering.
[0008] Similarly, it would be desirable to improve cell culture
viability, bioreactor constructs for cell culture, and/or cell
support, cell development, and/or cell storage related to somatic,
stem, and/or microbiological cell therapeutics, blood storage,
microbial culture, and/or tissue engineering.
[0009] In an embodiment, a biocontainment vessel includes a vessel
structure including a structural composition and an enhancement
composition associated with the structural composition. The
enhancement composition includes a co-polymer. The co-polymer is a
poly(glycerol sebacate) or a poly(glycerol sebacate urethane).
[0010] In another embodiment, a composition includes a co-polymer
and an augmentation agent contained by the co-polymer. The
co-polymer is a poly(glycerol sebacate) or a poly(glycerol sebacate
urethane).
[0011] In yet another embodiment, a method of containing biological
cells includes placing the biological cells in an augmented
biocontainment vessel. The method also includes storing the
biological cells in the augmented biocontainment vessel under
predetermined conditions.
[0012] In another embodiment, an augmented substrate includes a
substrate and an enhancement composition coating a surface of the
substrate.
[0013] Various features and advantages of the present invention
will be apparent from the following more detailed description,
taken in conjunction with the accompanying drawings which
illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows a schematic cross section of a biocontainment
vessel augmented with a PGS or poly(glycerol sebacate urethane)
(PGSU) plasticizer in an embodiment of the present disclosure.
[0015] FIG. 2 shows a schematic cross section of a biocontainment
vessel augmented with a coating in an embodiment of the present
disclosure.
[0016] FIG. 3 shows a schematic cross section of a double-layered
containment film with a reservoir layer between the two film layers
in an embodiment of the present disclosure.
[0017] FIG. 4 is a perspective view of the augmented biocontainment
vessel of FIG. 2.
[0018] Wherever possible, the same reference numbers will be used
throughout the drawings to represent the same parts.
DETAILED DESCRIPTION OF THE INVENTION
[0019] Augmented biocontainment vessels for controlled storage, for
cell expansion for therapy, and for general protection include
constructions for the improvement and enhancement of cellular
maintenance in storage, culture incubation, or expansion, where
cellular environments require management of cell viability and
reduction of adverse transfer of toxic components or
by-products.
[0020] The embodiments described herein may include an article of
manufacture, a composition of matter, methods of using, and/or
methods for forming or using the same. Preferred embodiments may
include biocompatible surfaces, release mechanisms, and mitigation
of noxious environmental components having adverse interactions
with living systems.
[0021] Benefits may include improved artificial polymer-based
bioreactors and storage containment. Many man-made polymeric
materials have non-cyto-compatible surfaces that inadvertently
expose or produce fugitive (indigenous) debris at these surfaces,
counteracting environments that attempt to biomimic a natural
environment. Present embodiments may create pristine,
cell-compatible environments similar to natural incubation as well
as improving permanent glass reactors, thereby enhancing the cell
environment.
[0022] A composition includes a biofriendly polymer and an
augmentation agent contained by, or otherwise associated with, the
biofriendly polymer. In some embodiments, the augmentation agent is
physically mixed with the biofriendly polymer. In some embodiments,
the augmentation agent is chemically attached to the biofriendly
polymer. The composition is preferably in a solid or substantially
solid state and is free or substantially free of solvent. In some
embodiments, the composition is used in an augmented biocontainment
vessel.
[0023] Biofriendly polymers may support the engineering changes
required for the construction of bioreactors. In some embodiments,
the biofriendly polymers are co-polymers. In some embodiments, the
co-polymers are poly(glycerol sebacate) (PGS) and/or poly(glycerol
sebacate urethane) (PGSU) and associated co-polymers of glycerol
esters of fatty and diacids, which are desirable candidates to
support surface modifications. These, as well as new resins for
extrusion and consequently films for containment construction, may
be derived from these chemistries for use as engineering films or
surface treatments either as coatings or for polymer annealing.
[0024] In some embodiments, the biofriendly polymer contains one or
more augmentation agents, which may be covalently attached to the
biofriendly polymer or physically mixed in with the biofriendly
polymer. The augmentation agent positively contributes to cell life
or provides at least one biological benefit to cells, either by
being located on the surface of the biofriendly polymer or upon
release of the augmentation agent from the biofriendly polymer.
Functions of the augmentation agent may include, but are not
limited to, providing nutrition, preventing coagulation, and/or
scavenging lactic acid. In some embodiments, the augmentation agent
functionally modifies the biofriendly polymer.
[0025] The augmentation agent may include, but is not limited to, a
cell nutrient; a 2-3-diphosphoglycerate scavenger; a composition
protecting against hemoglobin scavenging of nitrous oxide such as,
for example, a stabilized hemoglobin protease, heme lipase, heme
metalloprotease, or amino peptidases specific for hemoglobin; an
affinity composition for toxins such as, for example, chelating
agents or charged chemistries such as, for example, zwitterion
entities; a fiber extrudate having specific enzymatic activity for
hemoglobin; a paramagnetic material such as, for example, super
paramagnetic iron oxide and other paramagnetic metals; a lactic
acid scavenger through lactate dehydrogenase denaturation and other
mechanisms to preserve aerobic respiration in storage including
confined O.sub.2 within polymer matrices including microparticles
containing calcium peroxide and sodium percarbonate and other
O.sub.2-releasing oxides that may be bound to the film surface,
incorporated by way of microparticle dispersion within the matrix,
or dispersed within the polymer, the idea being that available
O.sub.2 within the storage containment avoids anerobic pathways
leading to lactic acid production; a cell preservation composition
such as, for example, citric acid and citric acid compositions with
amino acids such as, for example, arginine, adenosine, and adenine;
an anti-coagulation composition such as, for example, citric acid,
phosphate, dextrose, and adenine (CPDA); a sanitation composition
such as, for example, a biocide, an antibiotic, or a biostatic
compound; a surface passivation composition that mitigates pH
shifting or reduces surface energy to minimize cell attachment to
sidewalls; or combinations thereof.
[0026] Certain biocontainment embodiments are contemplated,
including, but not limited to, manipulations of surfaces, materials
of construction, or designed mechanisms, to improve biocontainment
vessels.
[0027] FIG. 1 through FIG. 4 show approaches for producing a
formulated coating or layer on a low-cost film, glass, or plastic,
a reservoir within a low-cost film, or the reformulation and
compounding of polymer raw resin components used in the extrusion
and development of enhanced polymer films or plastic
structures.
[0028] FIG. 1 shows one embodiment of an augmented biocontainment
vessel 10 including a structural composition 12 and an enhancement
composition 14. The outer surface 16 of the augmented
biocontainment vessel 10 is shown as relatively smooth and the
inner surface 18, which is on the containment side of the augmented
biocontainment vessel 10, is shown as relatively rough compared to
the outer surface 16, but either may be rough or smooth. In an
exemplary embodiment, the enhancement composition 14 is PGS or PGSU
used as a plasticizer in the augmented biocontainment vessel 10. In
an exemplary embodiment, the augmented biocontainment vessel 10 is
a blood bag with polyvinyl chloride (PVC) as the bulk plastic for
the structural composition 12.
[0029] FIG. 2 shows another embodiment of an augmented
biocontainment vessel 10. In this embodiment, the enhancement
composition 14 is a layer on the structural composition 12 on the
containment side of the augmented biocontainment vessel 10.
Although the outer surface 16 of the augmented biocontainment
vessel 10 and the inner surface 18, which is on the containment
side of the augmented biocontainment vessel 10, are shown as
relatively smooth and the containment side surface of the
structural composition 12 is shown as relatively rough compared to
the outer surface 16 and inner surface 18, each may independently
be rough or smooth. The inner surface 18 of the augmented
biocontainment vessel 10 may be provided by the enhancement
composition 14 to have a roughness similar to or different from the
roughness of the containment side of the structural composition
12.
[0030] In an exemplary embodiment, the structural composition 12
includes PGSU as a bulk material in the augmented biocontainment
vessel 10. The enhancement composition 14 is a coating on the
structural composition 12 and forms the inner surface 18 of the
augmented biocontainment vessel 10, whereas the outer surface 16 is
uncoated. The enhancement composition 14 includes a
nutrient-containing or functionally-modified PGS (NPGS). The
containment-side surface of the structural composition 12 is shown
as rough in FIG. 2 but is preferably smooth in this embodiment.
[0031] In another exemplary embodiment, the structural composition
12 includes a low-cost stock film or PVC with the outer surface 16
being uncoated. The enhancement composition 14 includes PGS or PGSU
and may be provided as a coating, a film, a co-extruded layer, a
polymer surface modification, or by coupling agent chemistry to the
bulk material. The enhancement composition 14 may provide the
augmented biocontainment vessel 10 with passivation, nutrients, a
barrier, preservation, and/or anticoagulation.
[0032] In yet another exemplary embodiment, the structural
composition 12 includes a low-cost stock film or PVC as a bulk
material of the augmented biocontainment vessel 10. The enhancement
composition 14 is a coating on the structural composition 12 that
forms the inner surface 18 of the augmented biocontainment vessel
10, whereas the outer surface 16 is uncoated. The enhancement
composition 14 includes an NPGS or a nutrient-containing or
functionally-modified PGSU (NPGSU). The functional modification may
be a preservation component, an anticoagulation component, citric
acid, phosphate, dextrose, and/or adenine.
[0033] FIG. 3 shows another embodiment of an augmented
biocontainment vessel 10. The augmented biocontainment vessel 10
includes an enhancement composition 14 as a reservoir layer on the
containment side of a structural composition 12. The augmented
biocontainment vessel 10 further includes an inner film layer 32 on
the containment side of the enhancement composition 14 and
providing the inner surface 18. The enhancement composition 14
includes NPGS or NPGSU. The structural composition 12, the
enhancement composition 14, and the inner film layer 32 may be
coextruded or otherwise formed next to each other. The nutrients or
functional modifications 34 in the enhancement composition 14 may
travel 36 from the enhancement composition 14 through the inner
film layer 32 by active diffusion to be released into the interior
of the augmented biocontainment vessel 10 at the inner surface
18.
[0034] The structural composition 12 in FIG. 3 may include, but is
not limited to, polymers or biopolymers composed of metabolic
building blocks including, but not limited to, carbohydrate, small
chain fatty acid, sugar, amino acid, oligomeric protein, functional
group chemistries that are nonimmunogenic or may provide
nutritional support, and combinations thereof as monomeric units.
Appropriate polymer may also include manmade polymers void of toxic
catalysts and characterized by thermoplastic features including
elastomeric properties such as, for example, vinyls, urethanes, and
polyesters. Catalysis may be driven by physical means such as, for
example, high energy radiation, thermal conversion, ultraviolet
(UV), infrared (IR), X-ray, gamma to drive initiator-free free
radical polymerization, polycondensation, acid-base, and/or redox
reactions.
[0035] FIG. 4 shows a partial perspective view of the augmented
biocontainment vessel 10 of FIG. 2 in the form of a blood bag. The
augmented biocontainment vessel 10 includes a vessel structure
defining an enclosed or contained space. An enhancement composition
14 on one side of the augmented biocontainment vessel 10 provides
the inner surface 18 of the augmented biocontainment vessel 10,
whereas the outer surface 16 provided by the structural composition
12 is uncoated. The enhancement composition 14 may include PGS or
PGSU and may be provided as a coating, a film, a co-extruded layer,
a polymer surface modification, or by coupling agent chemistry to
the structural composition 12. Any of the vessel embodiments of
FIGS. 1, 2, and 3 may have such a shape or any other appropriate
biocontainment vessel shape.
[0036] In some embodiments, a surface modification of a film of a
biocontainment vessel improves the topography, improves the
physiology, provides nutrition, or provides protection.
[0037] Cells in culture often adhere to reactor side-walls. Polymer
films may be physically modified or chemically treated to provide a
mechanism that may prevent adhesion or may release essential
components into the culture media from the interior walls of the
containment device.
[0038] Comparative scanning electron microscopy (SEM) surface
analysis has shown that the interior topography of a surface may
adversely influence thrombogenic action by having an impact on cell
membrane shearing. Exemplary embodiments may create
non-thrombogenic surfaces.
[0039] Not all cells respire or metabolize in the same manner, and
therefore not all cells expand in the same manner. Consequently,
cell-specific bioreactors and cell storage containment devices of
custom additive design or specialized surface modification for the
physiology of the cell are desirable.
[0040] Living cells in containment metabolize. Under certain
conditions, aerobic respiration may shift to anaerobic respiration.
Shifts may be the result of low O.sub.2 tension and/or depletion of
necessary metabolites. Containment walls may be thought of as
"pantry shelves", where both metabolites and gases may be
exchanged. Here the interior containment walls may be treated as
reservoirs of nutrition and cell support. In some embodiments, a
film containing nutrient support is co-extruded with one or more
base films to provide the custom surface. Containment walls may be
configured with a free-energy of diffusion mechanism of release of
growth components, much like transdermal reservoirs. Likewise,
controlled release and augmented stimulated release mechanisms may
be integrated using heat, light, and/or electromagnetic
radiation.
[0041] In addition to nutrition, containment surfaces may protect
the contents from deterioration or cell death by autoimmune
response. For instance, anticoagulants and preservatives may be
embedded into contact films such that the essential components
either fugitively migrate into the culture or are released by
stimulated release or controlled degradation.
[0042] In some embodiments, a surface coating transforms the
functionality of a film.
[0043] Coatings and surface treatments are a simple way of
transforming a non-biocompatible surface into a biocompatible
surface. Coatings may be considered as vehicles that in the culture
environment may deliver a plurality of essential components or
transform a non-biocompatible surface into a biocompatible surface
through barrier passivation.
[0044] In some embodiments, polymer compounding provides a new
material of construction for film resins. Polymer resins may be
compounded with essential components that may be released from the
interior walls of the containment device during storage or
incubation. Surface coating of interior film walls is an
alternative to compounding essential physiological and nutritional
agents into the film polymer structure.
[0045] Polymer films may be considered 3-D structures at the
molecular level that may modify the film's incubation function with
engineering properties or hold onto additives and essential
components for delivery into the culture medium for cell survival.
These additives and essential components may include, but are not
limited to, plasticizers, nutritional compounds, active
pharmaceutical ingredients (APIs), biologics, active small
molecules not considered drugs, preservatives, gases, or
antioxidants.
[0046] In some embodiments, polymer synthesis provides new
materials of construction for films and coating vehicles.
[0047] General-use film stock in the disposable biocontainment
industry has not had a custom designed material for the
biocontainment use. Like most things in the medical device field,
these materials of construction are borrowed and with the borrowing
comes the contending with cytocompatibility issues.
[0048] Polymeric film stock may, however, be developed having not
only the engineering properties required for fabrication but also
the matrix purity for biocompatibility. For instance, a pristine
polymer may be developed that is process-compounded with
metabolites to eliminate any toxic or detrimental effect to the
contained cells, should material migrate or bloom from the surface
of the films.
[0049] In some embodiments, a biocontainment enhancement provides
smart containment. Electronic and photonic integration into film
composite structures may create "intelligent" systems that may
monitor and analyze in real time. Lab-on-a-chip technology may be
integrated into film stock to provide process control, as well as
essential physiological and biological information.
[0050] In one embodiment, a classic passive or neutral interior
containment volume constructed from man-made materials is
transformed to include active surfaces that may be customized to
provide the cultured cells or stored cells with essential
biochemistry or mechano-biologic conditions.
[0051] In some embodiments, a multitude of reactor and storage
container configurations include modified surfaces to address
specific biological needs or consequences. These surfaces modified
by coatings and films may be specifically designed for the intended
and specific use in culture and storage. In contrast, most of the
containment industry relies on materials that are normally used for
other biomedical or industrial uses.
[0052] In some embodiments, existing film surfaces from standard
stocks are modified or activated to accept such coatings. Coating
vehicles may be derived from specialized biocompatible resin
vehicles, such as PGS, PGSU, or co-polymers of such, that provide
bio-inertness or bio-stimulation depending upon the mechanism in
use. For instance, PGS monomers are metabolites and as such the
breakdown by-products of PGS may provide components to the Krebs
cycle. On the other hand, the benign nature of the glycerol esters
may also permit their use as controlled release matrices. Coatings
may act as passivation or scavenger surfaces when formulated with
counterion or polymer affinity functionality.
[0053] Films may be compounded and formulated for extrusion to
create wall structures, either as stand-alone or composite
surfaces, to the interior that deliver a specific requirement or
service preservation. Compounded films may also act as constructed
composites that hold materials as a reservoir.
[0054] In some embodiments, chemical and/or physical film
modifications, including reformation compounding based on film
chemistry and surface science, provide biocontainment for
integration into cell contact and interfacial stability.
[0055] In one embodiment, PGS is incorporated as a "non-phthalate"
plasticizer for PVC and polyurethane (PU) film stock. In another
embodiment, a compounded resin system as a film stock includes PGSU
derived from PGS for biocompatibility in cell contact interfacing.
In yet another embodiment, smart materials for containment
monitoring and management may include diagnostic systems such as
active (integrated circuit-based technology) and passive
(chemistry-based technology) diagnostic systems.
[0056] In some embodiments, biocontainment enhancements include
polymer resin and coating vehicles, such as PGS resin and
modifications for web stock coating.
[0057] In one embodiment, PGS is formulated as an anti-coagulant,
an anti-adhesion composition, a self-"cleaning" film coating, or a
combination thereof The PGS may act as a backbone vehicle support
for anchored nutrient and additive film coatings, such as, for
example, with components like citrate phosphate dextrose adenine
(CPDA) solution or citrate phosphate dextrose (CPD) solution for
anticoagulation blood storage. In another embodiment, PGS serves as
a nutrient support, a passivation layer, and/or a barrier film
coating modification to support cell survival and culture and use
of stock film.
[0058] In one embodiment, the use of PGS or PGS and co-polymers and
crosslink options may be preferred in the case of coatings
technology. Without wishing to be bound by theory, the coating may
passivate harmful chemistry from the interior wall and provide a
biocompatible and bioactive surface to the benefit of the culture
or storage needs.
[0059] In another embodiment, the use of PGS or PGS and co-polymers
and crosslink options may be preferred in the case of film
technology. Films and film-like technologies such as, for example,
sputter coats, lacquers, passivation treatments, and coupling aged
fixation may serve as barrier coating layers to prevent fugitive
loss of toxic materials into containment vessels. Without wishing
to be bound by theory, the developed film is a polymer option as a
new material of construction that passivates harmful chemistry from
the interior wall and provides a biocompatible and bioactive
surface to the benefit of the culture or storage needs.
[0060] In one embodiment, PGS resin vehicles are based on specific
molecular weight (MW) and stoichiometric variations of metabolite
monomers for coatings formulated with specialized culture media
requirements for treatment of containment interiors for nutrition,
for buffering, for preservation or homeostatic development, for red
blood cell (RBC) transfusion and storage, for progenitor cell
expansion and monitoring of culture processes for cell therapy, for
somatic cell tissue engineering and organ regeneration, or
combinations thereof. In some such embodiments, the device may be
an "instant" media single-use device characterized by just adding
water to provide nutrient support that originates from the
containment walls. The wall nutrition may be in the form of
"dehydrated" compositions, where a wall coating converts to media
support or media compositions.
[0061] In another embodiment, high-MW PGS extrusion resins and
co-polymers are synthesized, compounded, and formulated with
specialized culture media formulations for extruded film stock of
containment interiors for nutrition, buffering, preservation, or
homeostatic development in RBC transfusion and storage, progenitor
expansion and incubation, somatic cell tissue engineering, or
combinations thereof. In some embodiments, the high-MW PGS
extrusion resin has a weight average molecular weight of at least
25 kilodaltons (kDa), alternatively 25 kDa to 40 kDa, alternatively
at least 60 kDa, alternatively 60 kDa to 100 kDa, or any value,
range, or sub-range therebetween, to provide solid thermoplastic
surfaces.
[0062] In another embodiment, non-lactide and/or non-glycolide
biodegradable or biocompatible film coating systems are prepared
for cell contact mediation and film-wall passivation from standard
film stocks to level and remove antagonistic topographies, for
barrier film composite construction to block out fugitive toxic
polymer additives, or combinations thereof.
[0063] In another embodiment, CPDA solution "additives" (citric
acid, phosphate, dextrose, and/or adenine/adenosine) are introduced
to interior wall coatings or film stock polymers formulated from
PGS, PGSU, a co-polymer thereof, or another non-lactide or
non-glycolide for preservation, anticoagulation, nutrition, or
combinations thereof.
[0064] CPDA solution components all contain functional groups that
may be incorporated or reacted into the backbone of PGS, PGSU, or a
co-polymer thereof. In another embodiment, one or more CPDA
solution components are incorporated into the PGS or PGSU polymer,
creating coatings with anchored (polymerized-in) additives to PGS
or PGSU. The CPDA-modified resins may be further converted into
extrusion resins or coating vehicles for preservation,
anticoagulation, nutrition, self-buffering, or combinations
thereof.
[0065] Nitrous oxide (NO) is a vasodilator, and hemoglobin (Hgb)
scavenges any free NO in collected and stored blood. This
aggravates the depletion of NO as blood ages from cell membrane
lysing, consequently releasing Hgb. Also, vasoconstriction is
antagonistic in blood transfusions, especially for hypovolemic
patients. In some embodiments, passivation or a coating for
film-wall saturation protects against Hgb scavenging of NO.
Likewise in other embodiments, wall reservoirs release or diffuse
NO throughout blood storage to counter Hgb action by Hgb saturation
with NO.
[0066] Blood is collected from a diverse population with varying
degrees of blood factors related to hygiene, health, and
contamination. In another embodiment, a passive indicator or active
integrated electronic or photonic chemical indicator system or
lab-on-a-chip is integrated into film stock for blood factor
profiling and contaminant identification. Further embodiments
include integrated chemical indicator strips or chemo-responsive
films, totally smart blood profiling device units, diabetes blood
glucose monitors, immunomodulatory markers for disease-specific
blood recipients, or combinations thereof.
[0067] As blood ages in storage, its metabolic behavior influences
its efficacy as an oxygen (O.sub.2) delivery "device". Blood
metabolic by-product chemicals such as 2,3-diphosphoglycerate
(2,3-DPG) may antagonize the O.sub.2 uptake once transfused to the
patient. In some embodiments, indigenous 2,3-DPG film response for
metabolic activity includes an "indicator strip" film on a bag for
2,3-DPG, incorporation of a 2,3-DPG scavenger in vessel wall
constructs, or combinations thereof.
[0068] In another embodiment, a coating is applied to a
quick-treatment nutrient bag. Coating vehicles may be considered
stock treatments to a formed film material of construction before
container assembly. The film surface pretreatment has either a
selective affinity or a broad affinity to a solution that may be
added to a constructed container immediately prior to use. Such
containment vessels may include a pre-activated surface that
captures and couples respective treatments as needed on the
fly.
[0069] A buffy coat is the fraction of an anticoagulated blood
sample that contains most of the white blood cells and platelets
following density gradient centrifugation of the blood. In another
embodiment, a gradient coating on side walls of a container is
designed with surface energy properties that have a super-affinity
for plasma, the leukocytes and platelets of a buffy coat, and the
erythrocytes via surface energy distinction, thereby stabilizing
separation. A buffy coat bag may include greater separation
efficiencies than achieved by centrifugation.
[0070] In another embodiment, a container includes interior gas
(O.sub.2 and/or NO) diffusion walls. As noted above, creating
side-wall NO gas release may mitigate Hgb NO scavenging. Likewise,
time-dependent storage of blood depletes O.sub.2. Further
embodiment may include an NO film diffuser, an O.sub.2 film
diffuser, or combinations thereof. These diffusers may be separate
layers or may be incorporated into a single enhancement
composition. For example, the diffusers may be incorporated in
microparticles. Alternatively, the diffusers may be part of a
matrix chemistry designed to degrade and release NO and/or O.sub.2
as a function of activated moisture permeation into a layer or by
thermal or radiant activation to initiate release.
[0071] In another embodiment, an antimicrobial, non-antibiotic
film-wall coating reduces sepsis and transmission of communicable
diseases. Likewise, polymers compounded and formulated for
extrusion may also serve as an assembly for materials of
construction. Further embodiments may include PGS coatings, small
chain fatty acid glycerol ester polymer coatings, nanostructure
film modification, or combinations thereof.
[0072] In another embodiment, a PGS, a PGSU, or a co-polymer
thereof fiber coating (cladding) coats a portion of an advanced
filtration system. The coating may, for example, be an affinity
coating for toxins and/or for biologics separation, harvest, or
neutralization. The coating may, for example, be a buffer coating,
an Hgb scavenging coating, or a nutrient coating. The coating may
be for a "chromatographic" system, an ionic exchange system, a
gradient release system, or a material transfer system and release
fibers and fiber claddings. In another embodiment, the coating
creates a filtration exchange to simulate a kidney-in-a-bag for
toxin filtration.
[0073] In another embodiment, fiber materials are used in
filtration of an apparatus. The fibers may act as support structure
for functional coatings that have a selective affinity for
biomolecules and a chemistry that allows for scavenging unwanted
materials or selective isolation of incorporated materials. The
fibers may be important components to composite constructs
including coatings.
[0074] In another embodiment, PGS, PGSU, or a co-polymer thereof
coats extruded fibers of alginates for advanced filtration systems.
A fiber extrudate may be prepared based on 100% resin
composition.
[0075] In another embodiment, the coated component is a hyperbaric
bag to "pressurize" cell containment, a pressurized bag, a
double-walled, gas-filled bag, a balloon bag with a metabolic gas
mixture, or combinations thereof.
[0076] RBCs are under constant pressure (120 mm Hg +/-) as blood
leaves the heart and travels to the capillaries in a normal in vivo
arterial blood environment. Once the RBCs "feel" the 0.0 mm Hg
pressure on the venous side of the vascular stream, the RBCs swell,
which alters their natural oxygen-bearing homeostasis. Venous blood
is not under pressure and does not carry O.sub.2. In one
embodiment, a device recreates the natural hyperbaric blood
environment to mitigate RBC deterioration.
[0077] In some embodiments, an electromagnetic (EM) and/or
pulsatile beat bag reduces O.sub.2 release by RBCs. In one
embodiment, the bag pulses either as an individual bag or an
external storage device, whereby the blood container is pulsed or
designed to simulate cardiovascular pulsatile behavior by contact
with or placement in the storage device. In one embodiment, the
device electrolytically generates O.sub.2 from water. In one
embodiment, a specialized EM cryo-device provides EM pulsing in
cryostorage to align cells.
[0078] Normal cellular in vivo environments expose tissues to sinus
electro-cardio potentials and pressure pulsation. When RBCs are
stagnant at zero pressure, O.sub.2 release accelerates. Without
wishing to be bound by theory, extraction of RBCs from their normal
hyperbaric, EM exposure is believed to significantly negatively
affect their behavior.
[0079] In one embodiment, an EM blood preservation bag includes a
bag film infused with paramagnetic materials and/or strong dipole
materials to enhance the EM field. Appropriate paramagnetic
materials may include, but are not limited to, magnesium, sodium,
iron, aluminum, or any other metal or element so coordinated to
feature a paramagnetic property having available coordination
complexes with d and f electrons to respond to field effects.
Blood, like all human tissue, is bathed in EM fields in vivo. An EM
field has been shown to benefit RBC storage ex vivo. Exemplary
containment embodiments simulate the in vivo exposure to EM
fields.
[0080] Cells produce lactic acid when respiration is shifted from
aerobic to anaerobic. In storage, cells continue to metabolize and
produce lactic acid, which is considered to be a toxic metabolic
by-product. In one embodiment, chemotactic walls of a containment
vessel include a lactic acid scavenger. Appropriate lactic acid
scavengers may include, but are not limited to, lactase enzymes,
lactate dehydrogenase, or any other biomolecules exhibiting Lewis
base characteristics. In some embodiments, a containment vessel has
an affinity for adsorption or conversion of lactic acid from the
culture or fluid environment.
[0081] The concepts described herein may be extended to other
bio-ecological applications, including, but not limited to,
microbiological retrieval and storage and sample storage. The
coatings and films disclosed herein may be applied to glass or
rigid plastic surfaces such that the standard glass or rigid
plastic enclosure is converted to a bioreactor environment
providing a plurality of shapes, sizes, and configurations.
Coatings that resist cell attachment may serve as environmental
anti-fouling coatings. Film resins for molding of coatings with
specific affinities or actions, where cell adhesion is to be
promoted or cell adhesion is to be avoided, may be useful in
prosthetic implants to prevent adverse tissue and cellular
obstruction of use. Newly-formulated resins may be designed for
micro-extrusion in applications, including, but not limited to,
three-dimensional (3-D) printing. Formulated resins may also be
used as tissue scaffolds. Coatings that encourage cell
proliferation may be considered for use in wound care dressing
treatments. Hyperbaric blood storage bags may help in transfusion
to patients with low blood volume as well as low blood
pressure.
[0082] In exemplary embodiments, the PGS resin is formed in a
water-mediated reaction following a method described in U.S. Pat.
No. 9,359,472, which is hereby incorporated by reference in its
entirety.
[0083] While the foregoing specification illustrates and describes
exemplary embodiments, it will be understood by those skilled in
the art that various changes may be made, and equivalents may be
substituted for elements thereof without departing from the scope
of the invention. In addition, many modifications may be made to
adapt a particular situation or material to the teachings of the
invention without departing from the essential scope thereof.
Therefore, it is intended that the invention not be limited to the
particular embodiment disclosed as the best mode contemplated for
carrying out this invention, but that the invention will include
all embodiments falling within the scope of the appended
claims.
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