Title: Nitric oxide-producing
United States Patent: 7,279,176
Issued: October 9, 2007
Inventors: West; Jennifer
L. (Houston, TX), Bohl; Kristyn Simcha (Houston, TX)
Assignee: Rice University
Appl. No.: 09/653,406
Filed: September 1, 2000
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Hydrogels releasing or producing NO, most
preferably photopolymerizable biodegradable hydrogels capable of releasing
physiological amounts of NO for prolonged periods of time, are applied to
sites on or in a patient in need of treatment thereof for disorders such
as restenosis, thrombosis, asthma, wound healing, arthritis, penile
erectile dysfunction or other conditions where NO plays a significant
role. The hydrogels are typically formed of macromers, which preferably
include biodegradable regions, and have bound thereto groups that are
released in situ to elevate or otherwise modulate NO levels at the site
where treatment is needed. The macromers can form a homo or
hetero-dispersion or solution, which is polymerized to form a hydrogel
material, that in the latter case can be a semi-interpenetrating network
or interpenetrating network. Compounds to be released can be physically
entrapped, covalently or ionically bound to macromer, or actually form a
part of the polymeric material. The hydrogel can be formed by ionic and/or
covalent crosslinking. Other active agents, including therapeutic,
prophylactic, or diagnostic agents, can also be included within the
SUMMARY OF THE
Biocompatible polymeric materials
releasing or producing physiological amounts of NO for prolonged periods
of time, are applied to sites on or in a patient in need of treatment
thereof for disorders such as restenosis, thrombosis, asthma, wound
healing, arthritis, penile erectile dysfunction or other conditions where
NO plays a significant role. The polymeric materials can also be formed
into films, coatings, or microparticles. The polymers are typically formed
of macromers, which may include biodegradable regions, and have bound
thereto groups that are released in situ to elevate or otherwise modulate
levels at the site where treatment is needed. The macromers can form a
homo or hetero-dispersion or solution, which is polymerized to form a
polymeric material, that in the latter case can be a semi-interpenetrating
network or interpenetrating network. Compounds to be released can be
physically entrapped, covalently or ionically bound to macromer, or
actually form a part of the polymeric material. Hydrogels can be formed by
ionic and/or covalent crosslinking. Other active agents, including
therapeutic, prophylactic, or diagnostic agents, can also be included
within the polymeric material.
OF THE INVENTION
I. Polymeric Materials for Release of NO
The polymeric materials are biocompatible and release or produce NO. In
various preferred embodiments, the polymers are also biodegradable, form
hydrogels, polymerize in situ and are tissue adherent. These properties
are conferred by the selection of the macromer components as well as
addition of various groups to the components.
The term "polymerizable" means that the regions have the capacity to form
additional covalent bonds resulting in macromer interlinking, for example,
carbon-carbon double bond of acrylate-type molecules. Such polymerization
is characteristically initiated by free-radical formation resulting from
photon absorption of certain dyes and chemical compounds to ultimately
produce free-radicals, although it can be obtained using other methods and
reagents known to those skilled in the art.
A. Polymeric Materials
The polymeric materials must be biocompatible, i.e., not eliciting a
significant or unacceptable toxic or immunogenic response following
administration to or implantation into an individual.
A number of polymeric materials are known which are biocompatible,
including both natural and synthetic polymers. Examples include proteins
(of the same origin as the recipient), polysaccharides such as chondroitin
sulfate and hyaluronic acid, polyurethanes, polyesters, polyamides, and
acrylates. Polymers can be degradable or non-degradable.
Most polymeric materials will be selected based on a combination of
properties conferred by the various components, which may include water
soluble regions such as PEG or PVA, biodegradable regions such as regions
that degrade hydrolytically, and groups that can be used to polymerize the
macromers in situ.
Water-Soluble and/or Tissue Adhesive Regions
There are a variety of water soluble materials that can be incorporated
into the polymers. The term "at least substantially water soluble" is
indicative that the solubility should be at least about 5 g/100 ml of
aqueous solution. In preferred embodiments, the core water soluble region
can consist of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl
acetate), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline),
poly(ethylene oxide)-co-poly(propyleneoxide) block copolymers,
polysaccharides or carbohydrates such as hyaluronic acid, dextran, heparin
sulfate, chondroitin sulfate, heparin, or alginate, or proteins such as
gelatin, collagen, albumin, or ovalbumin.
Hydrophilic (i.e., water soluble) regions will generally be tissue
adhesive. Both hydrophobic and hydrophilic polymers which include a large
number of exposed carboxylic groups will be tissue adhesive or bioadhesive.
Ligands such as RGD peptides and lectins which bind to carbohydrate
molecules on cells can also be bound to the polymer to increase tissue
Polyesters (Holland et al., 1986 Controlled Release, 4:155-180) of
.alpha.-hydroxy acids (viz., lactic acid, glycolic acid), are the most
widely used biodegradable materials for applications ranging from closure
devices (sutures and staples) to drug delivery systems (U.S. Pat. No.
4,741,337 to Smith et al.; Spilizewski et al., 1985 J. Control. Rel.
2:197-203). In addition to the poly(hydroxy acids), several other polymers
are known to biodegrade, including polyanhydrides and polyorthoesters,
which take advantage of labile backbone linkages, as reported by Domb et
al., 1989 Macromolecules, 22:3200; Heller et al., 1990 Biodegradable
Polymers as Drug Delivery Systems, Chasin, M. and Langer, R., Eds., Dekker,
New York, 121-161. Polyaminoacids have also been synthesized since it is
desirable to have polymers that degrade into naturally occurring
materials, as reported by Miyake et al., 1974, for in vivo use.
The time required for a polymer to degrade can be tailored by selecting
appropriate monomers. Differences in crystallinity also alter degradation
rates. Due to the relatively hydrophobic nature of these polymers, actual
mass loss only begins when the oligomeric fragments are small enough to be
water soluble. Hence, initial polymer molecular weight influences the
The biodegradable region is preferably hydrolyzable under in vivo
conditions. Hydrolyzable groups may be polymers and oligomers of glycolide,
lactide, .epsilon.-caprolactone, other .alpha.-hydroxy acids, and other
biologically degradable polymers that yield materials that are non-toxic
or present as normal metabolites in the body. Preferred poly(.alpha.-hydroxy
acid)s are poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic
acid). Other useful materials include poly(amino acids), poly(anhydrides),
poly(orthoesters), and poly(phosphoesters). Polylactones such as
poly(.epsilon.-caprolactone), poly(.epsilon.-caprolactone), poly(.delta.-valerolactone)
and poly(gamma-butyrolactone), for example, are also useful.
Biodegradable regions can also be constructed from polymers or monomers
using linkages susceptible to biodegradation by enzymes, such as ester,
peptide, anhydride, orthoester, and phosphoester bonds. Degradable
materials of biological origin are well known, for example, crosslinked
gelatin. Hyaluronic acid has been crosslinked and used as a degradable
swelling polymer for biomedical applications (U.S. Pat. No. 4,987,744 to
della Valle et al., U.S. Pat. No. 4,957,744 to Della Valle et al. (1991)
Polym. Mater. Sci. Eng., 62:731-735]).
A number of polymers have been described which include both water soluble
regions and biodegradable regions. Sawhney et al., (1990) J. Biomed.
Mater. Res. 24:1397-1411, copolymerized lactide, glycolide and .epsilon.-caprolactone
with PEG to increase its hydrophilicity and degradation rate. U.S. Pat.
No. 4,716,203 to Casey et al. (1987) synthesized a PGA-PEG-PGA block
copolymer, with PEG content ranging from 5-25% by mass. U.S. Pat. No.
4,716,203 to Casey et al. (1987) also reports synthesis of PGA-PEG diblock
copolymers, again with PEG ranging from 5-25%. U.S. Pat. No. 4,526,938 to
Churchill et al. (1985) described noncrosslinked materials with MW in
excess of 5,000, based on similar compositions with PEG; although these
materials are not water soluble. Cohn et al. (1988) J. Biomed. Mater. Res.
22:993-1009 described PLA-PEG copolymers that swell in water up to 60%;
these polymers also are not soluble in water, and are not crosslinked. The
features that are common to these materials are that they use both
water-soluble polymers and degradable polymers, and that they are
insoluble in water, collectively swelling up to about 60%.
U.S. Pat. No. 5,410,016 issued on Apr. 25, 1995 to Hubbell, et al.,
describes materials which are based on polyethylene glycol (PEG), because
of its high biocompatible and thromboresistant nature, with short
polylactide extensions to impart biodegradation and acrylate termini to
allow rapid photopolymerization without observable heat production. These
materials are readily modified to produce hydrogels which release or
The polymerizable regions are separated by at least one degradable region
to facilitate uniform degradation in vivo. There are several variations of
these polymers. For example, the polymerizable regions can be attached
directly to degradable extensions or indirectly via water soluble
nondegradable sections so long as the polymerizable regions are separated
by a degradable section. For example, if the macromer composition contains
a simple water soluble region coupled to a degradable region, one
polymerizable region may be attached to the water soluble region and the
other attached to the degradable extension or region. In another
embodiment, the water soluble region forms the central core of the
macromer composition and has at least two degradable regions attached to
the core. At least two polymerizable regions are attached to the
degradable regions so that, upon degradation, the polymerizable regions,
particularly in the polymerized gel form, are separated. Conversely, if
the central core of the macromer composition is formed by a degradable
region, at least two water soluble regions can be attached to the core and
polymerizable regions can be attached to each water soluble region. The
net result will be the same after gel formation and exposure to in vivo
In another embodiment, the macromer composition has a water soluble
backbone region and a degradable region affixed to the macromer backbone.
At least two polymerizable regions are attached to the degradable regions,
so that they are separated upon degradation, resulting in gel product
dissolution. In a further embodiment, the macromer backbone is formed of a
nondegradable backbone having water soluble regions as branches or grafts
attached to the degradable backbone. Two or more polymerizable regions are
attached to the water soluble branches or grafts. In another variation,
the backbone may be star shaped, which may include a water soluble region,
a biodegradable region or a water soluble region which is also
biodegradable. In this general embodiment, the star region contains either
water soluble or biodegradable branches or grafts with polymerizable
regions attached thereto. Again, the polymerizable regions must be
separated at some point by a degradable region.
The polymerizable regions may be polymerizable by photoinitiation by free
radical generation, most preferably in the visible or long wavelength
ultraviolet radiation. The preferred polymerizable regions are acrylates,
diacrylates, oligoacrylates, dimethacrylates, oligomethoacrylates, or
other biologically acceptable photopolymerizable groups. A preferred
tertiary amine is triethanol amine.
Useful photoinitiators are those which can be used to initiate by free
radical generation polymerization of the macromers without cytotoxicity
and within a short time frame, minutes at most and most preferably
seconds. Preferred dyes as initiators of choice for LWUV initiation are
ethyl eosin, 2,2-dimethoxy-2-phenyl acetophenone, other acetophenone
derivatives, and camphorquinone. In all cases, crosslinking and
polymerization are initiated among copolymers by a light-activated
free-radical polymerization initiator such as
2,2-dimethoxy-2-phenylacetophenone or a combination of ethyl eosin
(10.sup.-4-10.sup.-2 milliM) and triethanolamine (0.001 to 0.1 M), for
The choice of the photoinitiator is largely dependent on the
photopolymerizable regions. For example, when the macromer includes at
least one carbon-carbon double bond, light absorption by the dye causes
the dye to assume a triplet state, the triplet state subsequently reacting
with the amine to form a free radical which initiates polymerization.
Preferred dyes for use with these materials include eosin dye and
initiators such as 2,2-dimethyl-2-phenylacetophenone,
2-methoxy-2-phenylacetophenone, and camphorquinone. Using such initiators,
copolymers may be polymerized in situ by long wavelength ultraviolet light
or by laser light of about 514 nm, for example.
Initiation of polymerization is accomplished by irradiation with light at
a wavelength of between about 200-700 nm, most preferably in the long
wavelength ultraviolet range or visible range, 320 nm or higher, most
preferably about 514 nm or 365 nm.
There are several photooxidizable and photoreducible dyes that may be used
to initiate polymerization. These include acridine dyes, for example,
acriblarine; thiazine dyes, for example, thionine; xanthine dyes, for
example, rose bengal; and phenazine dyes, for example, methylene blue.
These are used with cocatalysts such as amines, for example,
triethanolamine; sulphur compounds, for example, RSO.sub.2R.sub.1;
heterocycles, for example, imidazole; enolates; organometallics; and other
compounds, such as N-phenyl glycine. Other initiators include
camphorquinones and acetophenone derivatives.
Thermal polymerization initiator systems may also be used. Such systems
that are unstable at 37.degree. C. and would initiate free radical
polymerization at physiological temperatures include, for example,
potassium persulfate, with or without tetramethyl ethylenediamine;
benzoylperoxide, with or without triethanolamine; and ammonium persulfate
with sodium bisulfite.
Other initiation chemistries may be used besides photoinitiation. These
include, for example, water and amine initiation schemes with isocyanate
or isothiocyanate containing macromers used as the polymerizable regions.
In a preferred embodiment, the polymeric materials are a biodegradable,
polymerizable and at least substantially water soluble macromer
composition. The first macromer includes at least one water soluble
region, at least one NO carrying region and at least one free radical-polymerizable
region. The second macromer includes at least one water soluble region and
at least two free radical polymerizable regions. The regions can, in some
embodiments, be both water soluble and biodegradable. The macromer
composition is polymerized by exposure of the polymerizable regions to
free radicals generated, for example, by photosensitive chemicals and
Examples of these macromers are PVA or PEG-oligoglycolyl-acrylates. The
choice of appropriate end caps permits rapid polymerization and gelation.
Acrylates are preferred because they can be polymerized using several
initiating systems, e.g., an eosin dye, by brief exposure to ultraviolet
or visible light. A poly(ethyleneglycol) or PEG central structural unit
(core) is preferred on the basis of its high hydrophilicity and water
solubility, accompanied by excellent biocompatibility. A short oligo or
poly(.alpha.-hydroxy acid), such as polyglycolic acid, is selected as a
preferred chain extension because it rapidly degrades by hydrolysis of the
ester linkage into glycolic acid, a harmless metabolite. Although highly
crystalline polyglycolic acid is insoluble in water and most common
organic solvents, the entire macromer composition is water-soluble and can
be rapidly gelled into a biodegradable network while in contact with
aqueous tissue fluids. Such networks can be used to entrap and
homogeneously disperse water-soluble drugs and enzymes and to deliver them
at a controlled rate. Further, they may be used to entrap particulate
suspensions of water-insoluble drugs. Other preferred chain extensions are
polylactic acid, polycaprolactone, polyorthoesters, and polyanhydrides.
Polypeptides may also be used. Such "polymeric" blocks should be
understood to include timeric, dimeric, and oligomeric blocks.
PVA contains many pendant hydroxyl groups. These hydroxyl groups are
easily reacted to form side chains such as various crosslinking agents and
nitric oxide donors. PVA is water soluble and has excellent
biocompatibility. Modification of PVA to attach methacrylate groups via a
diacetal bond with the pendant hydroxyl groups and addition of an
appropriate photoinitiator enables the PVA to be photopolymerized to form
hydrogels under long wavelength UV light. In another preferred embodiment,
the hydrogel is formed from modified polyvinyl alcohol (PVA) macromers,
such as those described in U.S. Pat. Nos. 5,508,317, 5,665,840, 5,849,841,
5,932,674, 6,011,077, 5,939,489, and 5,807,927. The macromers disclosed in
U.S. Pat. No. 5,508,317, for example, are PVA prepolymers modified with
pendant crosslinkable groups, such as acrylamide groups containing
crosslinkable olefinically unsaturated groups. These macromers can be
polymerized by photopolymerization or redox free radical polymerization,
for example. The starting polymers are, in particular, derivatives of
polyvinyl alcohol or copolymers of vinyl alcohol that contain, for
example, a 1,3-diol skeleton. The crosslinkable group or the further
modifier can be bonded to the starting polymer skeleton in various ways,
for example through a certain percentage of the 1,3-diol units being
modified to give a 1,3-dioxane, which contains a crosslinkable radical, or
a further modifier in the 2-position. Another possibility is for a certain
percentage of hydroxyl groups in the starting polymer to be esterified by
means of an unsaturated organic acid, these ester-bonded radicals
containing a crosslinkable group. The hydrophobicity of these macromers
can be increased by substituting some of the pendant hydroxyl groups with
more hydrophobic substituents. The properties of the macromers, such as
hydrophobicity, can also be modified by incorporating a comonomer in the
macromer backbone. The macromers can also be formed having pendant groups
crosslinkable by other means.
B. NO groups or Modulating Compounds
A number of molecules that produce NO under physiological conditions (NO
donors) have been identified and evaluated both in vitro and in vivo,
including S-nitrosothiols, organic nitrates, and complexes of NO with
nucleophiles. L-arginine is a NO donor, since L-arginine is a substrate
for NO synthase, and thus administration of L-arginine increases
endogenous NO production and elicits responses similar to those caused by
NO donors in most cases. Other NO donors include molsidomine, CAS754,
SPM-5185, and SIN-1. Other compounds capable of producing and/or donating
NO may also be used. These include organic nitrates, nitrosylating
compounds, nitrosoesters, and L-arginine.
The molecules which produce NO, or release or generate NO, are preferably
attached to regions containing nucleophiles and/or thiols such as S-nitrosothiols
capable of forming a complex with NO.
C. Prophylactic, Therapeutic and Diagnostic Agents
The polymeric materials can also be used for drug delivery, preferably
localized release of prophylactic, therapeutic or diagnostic agents at the
site where the materials are needed, although the polymeric materials can
be loaded with agent to be released systemically. These agents include
proteins or peptides, polysaccharides, nucleic acid molecules, and simple
organic molecules, both natural and synthetic. Representative materials
include antibiotics, antivirals, and antifungal drugs, anti-inflammatories
(steroidal or non-steroidal), hormones, growth factors, cytokines,
neuroactive agents, vasoconstrictors and other molecules involved in the
cardiovascular responses, enzymes, antineoplastic agents, local
anesthetics, antiangiogenic agents, antibodies, drugs affecting
reproductive organs, and oligonucleotides such as antisense
oligonucleotides. Diagnostic materials may be radioactive, bound to or
cleave a chromogenic substrate, or detectable by ultrasound, x-ray, MRI,
or other standard imaging means.
These agents can be mixed with macromer prior to polymerization, applied
into or onto the polymer, or bound to the macromer prior to or at the time
of polymerization, either covalently or ionically, so that the agent is
released by degradation (enzymatic or hydrolytic) or diffusion at the site
where the polymer is applied.
II. Method of Use
A. Coatings; Films; Microparticles
Although described primarily with respect to in vivo treatment, it is
apparent that the polymeric materials described herein can be used in cell
culture, on cell culture substrates, or as coatings on medical implants or
devices such as stents or catheters, or formed using standard techniques
into microparticles or other types of formulations which may be used in or
administered to a patient.
B. Therapeutic Applications
Polymeric materials capable of releasing physiological amounts of NO for
prolonged periods of time can be applied to sites on or in a patient in
need of treatment thereof. Representative disorders or conditions that can
be treated with NO include restenosis, thrombosis, asthma, would healing,
arthritis, and penile or female erectile dysfunction. The material is
typically applied as a macromer solution and polymerized in situ, although
polymerization can be initiated prior to application.
The formulations are particularly useful for treatment of all types of
wounds, including burns, surgical wounds, and open leg and foot wounds.
There are generally three types of open leg wounds, termed ulcers: venous
stasis ulcers, generally seen in sedentary elderly people when blood flow
to the leg becomes sluggish; decubitus ulcers, also termed pressure sores
or bed sores, which occurs most often in people who are bedridden and are
unable to frequently change position; and diabetic foot ulcers, caused by
poor blood circulation to the feet. Due to the aging of the population,
there will likely be a greater demand for effective and user friendly
wound treatments in the near future.
The term "wound" as used herein refers to all types of tissue injuries,
including those inflicted by surgery and trauma, including burns, as well
as injuries from chronic or acute medical conditions, such as
atherosclerosis or diabetes.
Treatment of Restenosis
A preferred application is a method of reducing the effects of restenosis
on post-surgical patients. The method includes coating the surface within
an artery with an aqueous solution of light-sensitive free radical
polymerizable initiator and a number of macromers. The coated artery is
subjected to a Xenon arc laser inducing polymerization of the macromers.
As the newly polymerized macromer composition is formed, the physiological
conditions within the artery will induce the release of NO. This release
will be strictly localized for prolonged periods of time.
Prevention of Surgical Adhesions
A preferred application is a method of reducing formation of adhesions
after a surgical procedure in a patient. In one embodiment the method
includes coating damaged tissue surfaces in a patient with an aqueous
solution of a light-sensitive free-radical polymerization initiator and a
macromer solution as described above. The coated tissue surfaces are
exposed to light sufficient to polymerize the macromer. The
light-sensitive free-radical polymerization initiator may be a single
compound (e.g., 2,2-dimethoxy-2-phenyl acetophenone) or a combination of a
dye and a cocatalyst (e.g., ethyl eosin and triethanol amine).
Another use of the polymers is in a method for adhering tissue surfaces in
a patient. In one embodiment the macromer is mixed with a photoinitiator
or photoinitiator/cocatalyst mixture to form an aqueous mixture and the
mixture is applied to a tissue surface to which tissue adhesion is
desired. The tissue surface is contacted with the tissue with which
adhesion is desired, forming a tissue junction. The tissue junction is
then irradiated until the macromers are polymerized.
In a particularly preferred application of these macromers, an ultrathin
coating is applied to the surface of a tissue, most preferably the lumen
of a tissue such as a blood vessel. One use of such a coating is in the
treatment or prevention of restenosis, abrupt reclosure, or vasospasm
after vascular intervention. An initiator is applied to the surface of the
tissue, allowed to react, adsorb or bond to tissue, the unbound initiator
is removed by dilution or rising, and the macromer solution is applied and
polymerized. This method is capable of creating uniform polymeric coating
of between one and 500 microns in thickness, most preferably about twenty
microns, which does not evoke thrombosis or localized inflammation.
The polymeric materials can also be used to create tissue supports by
forming shaped articles within the body to serve a mechanical function.
Such supports include, for example, sealants for bleeding organs, sealants
for bone defects and space-fillers for vascular aneurisms. Further, such
supports can include strictures to hold organs, vessels or tubes in a
particular position for a controlled period of time.
Controlled Drug Delivery
As noted above, the polymeric materials can be use as carriers for
biologically active materials such as therapeutic, prophylactic or
diagnostic agents, including hormones, enzymes, antibiotics,
antineoplastic agents, and cell suspensions. The polymeric material may be
used to temporarily preserve functional properties of an agent to be
released, as well as provide prolonged, controlled release of the agent
into local tissues or systemic circulation.
In a variation of the method for controlled drug deliver in which an agent
is mixed with the macromer solution then polymerized in situ, the
macromers are polymerized with the biologically active materials to form
microspheres or nanoparticles containing the biologically active material.
The macromer, photoinitiator, and agent to be encapsulated are mixed in an
aqueous mixture. Particles of the mixture are formed using standard
techniques, for example, by mixing in oil to form an emulsion, forming
droplets in oil using a nozzle, or forming droplets in air using a nozzle.
The suspension or droplets are irradiated with a light suitable for
photopolymerization of the macromer.
These materials are particularly useful for controlled drug delivery of
hydrophilic materials, since the water soluble regions of the polymer
enable access of water to the materials entrapped within the polymer.
Moreover, it is possible to polymerize the macromer composition containing
the material to be entrapped without exposing the material to organic
solvents. Release may occur by diffusion of the material from the polymer
prior to degradation and/or by diffusion of the material from the polymer
as it degrades, depending upon the characteristic pore sizes within the
polymer, which is controlled by the molecular weight between crosslinks
and the crosslink density. Deactivation of the entrapped material is
reduced due to the immobilizing and protective effect of the gel and
catastrophic burst effects associated with other controlled-release
systems are avoided. When the entrapped material is an enzyme, the enzyme
can be exposed to substrate while the enzyme is entrapped, provided the
gel proportions are chosen to allow the substrate to permeate the gel.
Degradation of the polymer facilitates eventual controlled release of free
macromolecules in vivo by gradual hydrolysis of the terminal ester
Claim 1 of 18 Claims
1. A method for controlled release of NO
or an NO donor comprising administering to tissue a biocompatible,
polymerizable, macromer composition comprising at least one NO carrying
region or the NO donor, wherein NO or the NO donor is complexed to the
macromer composition, and wherein the NO or the NO donor is released from
the macromer composition following polymerization in situ, under
physiological conditions, wherein the macromer composition comprises one
or more region selected from the group consisting of water soluble
regions, tissue adhesive regions, and polymerizable end group regions and
one or more therapeutic or diagnostic agents selected from the group
consisting of proteins, carbohydrates, nucleic acids, organic molecules,
inorganic molecules, biologically active molecules, cells, tissue, and
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