Biomedical Applications of Biodegradable Polymers: Bret D. Ulery, Lakshmi S. Nair, Cato T. Laurencin

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Biomedical Applications of Biodegradable Polymers
Bret D. Ulery,1,2 Lakshmi S. Nair,1,2,3 Cato T. Laurencin1,2,3

1
Department of Orthopaedic Surgery, New England Musculoskeletal Institute, University of Connecticut Health Center,
Farmington, Connecticut 06030
2
Institute of Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030
3
Department of Chemical, Materials & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut 06268
Correspondence to: C. T. Laurencin (E-mail: Laurencin@uchc.edu)
Received 28 February 2011; revised 10 April 2011; accepted 11 April 2011; published online
DOI: 10.1002/polb.22259
ABSTRACT: Utilization of polymers as biomaterials has greatly for biomedical applications with novel materials constantly being
impacted the advancement of modern medicine. Specifically, developed to meet new challenges. This review summarizes the
polymeric biomaterials that are biodegradable provide the signifi- most recent advances in the field over the past 4 years, specifi-
cant advantage of being able to be broken down and removed af- cally highlighting new and interesting discoveries in tissue engi-
ter they have served their function. Applications are wide ranging neering and drug delivery applications. VC 2011 Wiley Periodicals,
with degradable polymers being used clinically as surgical Inc. J Polym Sci Part B: Polym Phys 49: 832–864, 2011
sutures and implants. To fit functional demand, materials with
desired physical, chemical, biological, biomechanical, and degra- KEYWORDS: biodegradable; biomaterials; polyamides; polycar-
dation properties must be selected. Fortunately, a wide range of bonates; polyesters; polyethers; polylactide; polyphosphazenes;
natural and synthetic degradable polymers has been investigated polysaccharides; polyurethanes
INTRODUCTION A biomaterial is defined as any natural or physical, and biological properties of the biomaterials. When
synthetic substance engineered to interact with biological these materials are also biodegradable, there exists the addi-
systems to direct medical treatment.1 Biomaterials must be tional issue of continuing changes in the material properties
biocompatible meaning that they perform their function with induced by degradation over time. These changes can cause
an appropriate host response.2 To meet the needs of the bio- long-term host responses to these biomaterials to be greatly
medical community, materials composed of everything from different than the initial response. These issues are nontrivial
metals and ceramics to glasses and polymers have been and have contributed to the slow evolution of biodegradable
researched. Polymers possess significant potential because polymeric biomaterials as a field of research.
flexibility in chemistry gives rise to materials with great di-
versity of physical and mechanical properties. Degradable To better address many issues in biomaterial design and
polymers are of utmost interest because these biomaterials expedite progress, biomaterials scientists have fundamentally
are able to be broken down and excreted or resorbed with- changed their approach to the research. Especially in the last
out removal or surgical revision. 10 years, there has been a shift in paradigm from investiga-
tors working independently on narrow research goals to col-
Although natural polymers such as collagen have been used
laborative teams that facilitate solving greater objectives.
biomedically for thousands of years, research into biomedical
Researchers with expertise in chemistry, biology, materials,
applications of synthetic degradable polymers is relatively
engineering, and clinical practices now work together to
new, starting in the 1960s.3,4 In the 50 years since, successes
advance biomaterials research more rapidly.5–13
have been numerous, but grand challenges still exist in both
the basic and translational elements of biomaterial design. In the design of biodegradable biomaterials, many important
From a basic science perspective, the capacity to modulate properties must be considered. These materials must (1) not
biomaterial chemistry to convey unique material properties evoke a sustained inflammatory response; (2) possess a deg-
is endless yet requires significant time and resources to com- radation time coinciding with their function; (3) have appro-
plete the research. As biomaterials are applied in the clinical priate mechanical properties for their intended use; (4) pro-
setting, numerous issues arise that cannot be adequately duce nontoxic degradation products that can be readily
identified and addressed in previous in vitro and model in resorbed or excreted; and (5) include appropriate permeabil-
vivo experiments. The host response to both tissue engineer- ity and processability for designed application.14 These prop-
ing and drug delivery devices depends on the chemical, erties are greatly affected by a number of features of
V
C 2011 Wiley Periodicals, Inc.
832 JOURNAL OF POLYMER SCIENCE PART B: POLYMER PHYSICS 2011, 49, 832–864
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Dr. Bret D. Ulery received his B.S. and B.S.E. in Biochemistry and Chemical Engineering,
respectively, from the University of Iowa in 2006. He was a graduate student in the Chemical
and Biological Engineering department at Iowa State University from 2006 until he earned
his Ph.D. in 2010. Since September 2010, he has served as a Post-Doctoral Fellow in the
Orthopaedic Surgery department and Institute for Regenerative Engineering at the
University of Connecticut Health Center. His research interests include novel degradable
polymer synthesis, composite tissue engineering scaffolds, and immunomodulatory
biomaterials.
Dr. Lakshmi S. Nair received her Ph.D. from SCTIMST, India in Polymer Chemistry and
Biomaterials in 2000. After finishing her graduate work, she completed postdoctoral training
at Drexel University and the University of Virginia. In 2006, she became a research assistant
professor in the department of Orthopaedic Surgery at the University of Virginia. She has
served as an assistant professor in the departments of Orthopaedic Surgery and Chemical,
Materials and Biomolecular Engineering at the University of Connecticut and as a core
member of the Institute for Regenerative Engineering since 2008. Her research interests
include cell-biomaterial interactions, tissue regeneration devices, immunomodulatory
biomaterials and cell delivery devices.
Dr. Cato T. Laurencin is the Van Dusen Endowed Chair in Academic Medicine, Distinguished
Professor of Orthopaedic Surgery, and Professor of Chemical, Materials and Biomolecular
Engineering at the University of Connecticut. Dr. Laurencin is Vice President for Health
Affairs at the University of Connecticut, and Dean of the UConn School of Medicine. Dr.
Laurencin is an elected member of the Institute of Medicine of the National Academy of
Sciences. He is also an elected member of the National Academy of Engineering. Dr.
Laurencin earned his B.S.E. in chemical engineering from Princeton, his M.D., Magna Cum
Laude from Harvard Medical School, and his Ph.D. in biochemical engineering/biotechnol-
ogy from the Massachusetts Institute of Technology.
degradable polymeric biomaterials including but not limited bonds that are susceptible to hydrolysis including esters,
to: material chemistry, molecular weight, hydrophobicity, sur- anhydrides, acetals, carbonates, amides, urethanes, and phos-
face charge, water adsorption, degradation, and erosion mech- phates. One of the major features that conveys significant
anism. Because of the wide-ranging use of polymeric biomate- impact on the capacity of these polymeric families to func-
rials, a single, ideal polymer or polymeric family does not tion as biomaterials is their relative degradation rates and
exist. Instead a library of materials is available to researchers erosion mechanisms. An extensive investigation into a num-
that can be synthesized and engineered to best match the ber of different degradable polymeric families showed that
specifications of the material’s desired biomedical function. the degradation rates (Table 1) can vary 12-fold from very
hydrolytically unstable (polyphosphazenes) to extremely
Biomaterial applications of biodegradable polymers have al-
hydrolytically stable (polyamides).17 It should be noted with
ready been extensively reviewed in the past, so no attempt
certain families’ (polyphosphazenes and polyanhydrides)
will be made to provide a further exhaustive review. Instead,
degradation rate can be greatly modulated based on polymer
the reader is referred to comprehensive articles in Advances
chemistry conveying significant flexibility in material proper-
in Biochemical Engineering/Biotechnology15 and Progress in
ties for these families. Degradation rates are incorporated
Polymer Science,16 which include research prior to and includ-
with other factors such as water diffusion, monomer solubil-
ing 2006. This review will focus on the numerous advance-
ity and diffusion, and device geometry and size, to determine
ments made in the development of hydrolytically and enzy-
how a degradable polymeric biomaterial will erode. Erosion
matically degradable polymers over the past 4 years.
HYDROLYTICALLY DEGRADABLE POLYMERS
Hydrolytically degradable polymers are materials that pos-

sess hydrolytically labile chemical bonds in their backbone
and can be broken down without secondary influence as
shown in Figure 1. The broken bond yields two species with
one product gaining a hydrogen atom and the other gaining FIGURE 1 The hydrolytically sensitive bond XAY is cleaved by
a hydroxyl group. A number of degradable polymers possess a water molecule yielding the products of XAH and HOAY.
WWW.MATERIALSVIEWS.COM JOURNAL OF POLYMER SCIENCE PART B: POLYMER PHYSICS 2011, 49, 832–864 833
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TABLE 1 Summary of Different Polymeric Families’ Applications, Advantages, Disadvantages, Degradation Rate, and Structure
k, Degradation
Rate Constant
Polymer Applications Advantages Disadvantages (s1) Structure
Polyphosphazenes Tissue Engine- Synthetic Flexibility; Complex 4.5 102 – 1.4

ering; Vaccine Controllable Mechani- Synthesis 107 (refs. 13
Adjuvant cal Properties and 776)
Polyanhydrides Drug Delivery; Significant Monomer Low-molecular 1.9 103 – 9.4

Tissue Flexibility; Controlla- Weights; Weak 109 (refs. 17
Engineering ble Degradation Mechanical and 777)
Rates Properties
Polyacetals Drug Delivery Mild pH Degradation Low Molecular 6.4 105
Products; pH Sensi- Weights; Complex (ref. 17)
tive Degradation Synthesis
Poly(ortho esters) Drug Delivery Controllable Degrada- Weak Mechanical 4.8 105
tion Rates; pH Sensi- Properties; Com- (ref. 17)
tive Degradation plex Synthesis
Polyphosphoesters Drug Delivery; Biomolecule Compat- Complex 1.4 106

Tissue ibility; Highly Bio- Synthesis (refs. 778 and
Engineering compatible Degrada- 779)
tion Products
Polycaprolactone Tissue Highly Processable; Limited 3.5 108
Engineering Many Commercial Degradation (ref. 27)
Vendors Available
Polyurethanes Prostheses; Mechanically Strong; Limited Degrada- 8.3 109
Tissue Handle Physical tion; Require (ref. 780)
Engineering Stresses Well Copolymerization
with Other
Polymers
Polylactide Tissue Engine- Highly Processable; Limited Degrada- 6.6 109
ering; Drug Many Commercial tion; Highly Acidic (ref. 17)
Delivery Vendors Available Degradation
Products
Polycarbonates Drug Delivery; Chemistry-Dependent Limited Degrada- 4.1 1010
Tissue Engine- Mechanical Proper- tion; Require (ref. 285)
ering; Fixators ties; Surface Eroding Copolymerization
with Other
Polymers
Polyamides Drug Delivery Conjugatable Side Very Limited 2.6 1013
Group; Highly Degradation; (ref. 17)
Biocompatible Charge Induced
Degradation Products Toxicity
is typically categorized as surface erosion, bulk erosion, or a can undergo surface erosion may be desired because stable,
combination of the two.18 Surface erosion is characterized by near zeroth-order release can be maintained and payload
the rate of polymer degradation and mass relief at the release kinetics can be more easily tailored,19 whereas for
water-device interface being much greater than the rate at applications requiring a permeable membrane like in tissue
which water diffuses into the bulk of the material leading to engineering, bulk eroding materials would allow for
a device that degrades almost entirely at its surface. Bulk necessary hydrolytic diffusion.20 The following sections dis-
erosion is characterized by the reverse in which water diffu- cuss a number of hydrolytically sensitive polymers and their
sion is much faster than degradation leading to degradation biomedical applications.
and subsequent mass loss occurring throughout the bulk of
the material. These categorizations are extremely important Poly(a-esters)
in determining which material is best for a desired applica- Poly(a-esters) are a class of polymers that contain an ali-
tion. For example, in sustained drug delivery a material that phatic ester bond in their backbone. Although a number of
polyesters are commercially available and all are theoreti- either developed modification techniques or have blended or
cally degradable, the hydrolytically stable nature of the ester copolymerized PLLA with other degradable polymers. One
bond (Table 1) means only polyesters with reasonably short interesting modification technique has been through the use
aliphatic chains can be utilized as degradable polymers for of radiation.52,53 This process works by creating radicals in
biomedical applications. Although these polymers are often the ester alpha carbon, which upon rearrangement shortens
mildly hydrophobic, ester bond stability causes them to the polymer backbone through the removal of an ester bond
undergo bulk erosion.21 Because of the relative ease of their and the release of carbon dioxide. Recombination of carbon
synthesis (via ring-opening or condensation polymerization) radicals induces branching and crosslinking causing a
and commercial availability, poly(a-esters) have been the decrease in crystallinity due to the modified polymers pos-
most heavily researched degradable biomaterials to date.22 sessing unique molecular architectures. Shortening of the
polymer and decrease in crystallinity work in concert to
Polyglycolide
facilitate more rapid device degradation. Although this pro-
Polyglycolide or poly(glycolic acid) (PGA) was one of the
cess is very predictable, allowing for fine tuning of PLLA
very first degradable polymers ever investigated for biomedi-
degradation behavior, even heavily irradiated PLLA is not
cal use. With a melting point (Tm) greater than 200 C, a
completely absorbed until months after being delivered in
glass transition temperature (Tg) of 35–40 C, and very high
vivo. This holds promise for drug eluting depots (i.e., birth
tensile strength (12.5 GPa),23 PGA found favor as the degrad-
control delivery devices), but further research must be com-
able suture DEXONV, which has been actively used since
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pleted in order for PLLA to be more widely used for short-

1970.24 From 1984 to 1996, PGA was marketed as an inter-
term controlled delivery applications. Under the product
nal bone pin under the name BiofixV, but since 1996 Biofix
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name FixsorbV, PLLA has been used as a bone fixator.54

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has been converted to a poly(L-lactide) base for better long-

PLLA has also been extensively utilized in tissue engineering
term stability.25,26
applications ranging from scaffolds for bone,55–58 carti-
Because of PGA’s rapid degradation and insolubility in many lage,59,60 tendon,61 neural,62,63 and vascular64 regeneration.
common solvents, limited research has been conducted with Specifically, Dr. Peter Ma’s group has produced some very
PGA-based drug delivery devices. Instead, most recent exciting research on the design of PLLA-based patient spe-
research has focused on short-term tissue engineering scaf- cific scaffolds (Fig. 2).65 A CT image of a digit was converted
folds and the utilization of PGA as a filler material coupled to a three-dimensional (3D) structured wax mold through
with other degradable polymer networks. PGA is often fabri- layer-by-layer (LBL) printing. By utilizing a solvent-extraction
cated into a mesh network and has been used as a scaffold process and paraffin spheres, a 3D PLLA scaffold that
for bone,27–30 cartilage,31–33 tendon,34,35 tooth,36 vaginal,37 matched the structure of the digit was manufactured. The
intestinal,38 lymphatic,39 and spinal regeneration.40 Although authors were able to uniquely control the nanostructure,
there has been research conducted into a wide range of microstructure, and macrostructure of the scaffold. This
applications, there exists significant issues with PGA. Rapid promising technique has the potential to be used for a num-
degradation leads to the loss of mechanical strength and sig- ber of different degradable polymers and parameters could
nificant local production of glycolic acid. Although glycolic be optimized for a wide-range of applications. Composite
acid is bioresorbable by cells via the citric acid cycle,41 high materials include PLLA combined with PDLLA,66 poly(lac-
level of glycolic acid have been linked to a strong, undesired tide-co-glycolide) (PLGA),67 poly(caprolactone),68,69 poly(eth-
inflammatory response.42–44 In addition, PGA has mechani- ylene glycol) (PEG),70 collagen,71 and chitosan.72
cally failed as a biomaterial when used to facilitate colonic
PDLLA is an amorphous polymer due to the random posi-
anastomosis formation38 and prevent intrapericardial
tions of its two isomeric monomers within the polymer chain
adhesions.45
yielding a slightly lower Tg of 55–60 C and lower mechani-
Polylactide cal strength of 1.9 GPa.23 Although possessing more desira-
As polylactide (PLA) possesses chiral molecules, PLAs come ble degradation properties than PLLA, PDLLA still takes over
in four forms: poly(L-lactic acid) (PLLA), poly(D-lactic acid) a year to properly erode which has kept it from being
(PDLA), poly(D,L-lactic acid) (PDLLA)—a racemic mixture of researched as a particle-based delivery vehicle. Instead
PLLA and PDLA, and meso-poly(lactic acid). As far as use in PDLLA has been commonly used as a drug delivery film for
biomedical research, only PLLA and PDLLA have shown inorganic implants,73–76 or as a tissue engineering scaf-
promise and have been extensively studied. fold.77–79 Like PLLA, PDLLA has been often combined with
other degradable polymers such as PLGA,80 PEG,81,82 and
PLLA has a Tg of 60–65 C, a melting temperature of around
chitosan83 to create composites with desirable material
175 C and a mechanical strength of 4.8 GPa.46 The addi-
properties.
tional methyl group in PLA causes the polymer to be much
more hydrophobic and stable against hydrolysis than PGA. Poly(lactide-co-glycolide)
High molecular weight PLLA has been shown to take greater Random copolymerization of PLA (both L- and D,L-lactide
than 5 years to be completely resorbed in vivo.47 Because of forms) and PGA, known as PLGA, is the most investigated
the slow degradation time, limited research has been degradable polymer for biomedical applications and has
recently conducted into drug delivery by PLLA systems been used in sutures, drug delivery devices, and tissue engi-
alone.48–51 To reduce degradation time, investigators have neering scaffolds. With a number of commercial
FIGURE 2 Conversion of CT images into microstructure- and nanostructure-controlled PLA scaffolds. A CT image of a hand (left)
with a nontraditional defect (shown in purple) is converted into a wax mold which can be filled with PLA to create a scaffold with
controllable pore size on the micro scale (center) and fiber size on the nano scale (right). (Reproduced from ref. 65, with permis-
sion from Elsevier.)
manufacturers and easy polymer processability, researchers protein release profiles can vary.54 Unfortunately, bulk ero-
do not have to be polymer synthesis experts to utilize PLGA sion of the polymer prevents significant modulation of the
in their work. One particular advantage is that because PLA release rate. Water diffusion in, payload dissolution and sub-
and PGA have significantly different properties, careful sequent diffusion out is not controlled by polymer degrada-
choice of copolymer composition allows for the optimization tion rate and often PLGA delivery devices have a significant
of PLGA for intended applications. Property modulation is bolus release of their payload. Additionally, hydration of the
even more significant for PLGA copolymers because with entire matrix can often damage or deactivate hydrolytically
25–75% lactide composition, PLGA forms amorphous poly- sensitive encapsulated materials through constant water ex-
mers, which are very hydrolytically unstable compared with posure and the high acidity of PLGA degradation prod-
the more stable homopolymers.41,84 This is evident in the ucts.111,112 The use of surface eroding polymers is better for
degradation times of 50:50 PLGA, 75:25 PLGA, and 85:15 zeroth-order and controlled release kinetics as well as pay-
PLGA being 1–2 months, 4–5 months, and 5–6 months, load protection.
respectively.85
PLGA demonstrates great cell adhesion and proliferation
PLGA has been used as a suture material since 197486 under properties making it an excellent candidate for application in
the product name VicrylV (Ethicon), a 10:90 PLGA braided
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tissue engineering. PLGA has been fabricated into scaffolds by
construct. More recently a modified version, Vicryl RapideV, a number of different techniques including gas foaming,113,114
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has come to market. Vicryl RapideV degrades much more microsphere sintering,115–117 porogen leaching,118–120 electro-
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quickly than traditional VicrylV, because it is irradiated dur- spinning,121–124 polymer printing,125,126 or a combination of
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ing production. PanacrylV (Ethicon) is another product which these techniques80,127,128 to create unique nanostructured
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has a higher LA/GA ratio (90:10) than VicrylV causing it to

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and microstructured materials that can facilitate tissue devel-
undergo more rapid degradation. Unfortunately, PanacrylV
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opment. Polymer printing in particular is a novel technique
has seen a significant drop in recent use due to public con- that holds great promise in the design of tissue engineering
cern that it induces significant inflammation after implanta- scaffolds. Dr. James Dunn’s group has demonstrated the
tion even though a recent report refutes this argument.87 capacity of 3D printing with PLGA.126,129 As shown in Figure
Although Ethicon produces the most widely used PLGA 3, very complex designs with controllable features can be gen-
sutures, PolysorbV (Syneture) and PurasorbV (Purac Bioma-
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erated to mimic structured tissue like villi for smooth muscle
terials) are also commonly used suture materials composed tissue engineering.126 The ability to utilize this technology
of PLGA. with other degradable polymers holds promise in allowing for
the design of organ-like structures that until now have been
With rapid degradation compared to other polyesters, PLGA
impossible to replicate. PLGA scaffolds have been used in
has been utilized extensively in drug delivery applications.
the engineering of bone,10,79,115,116 cartilage,60,92,117 ten-
PLGA has been used to deliver chemotherapeutics,88,89 pro-
don,117,123,130,131 skin,108,122,132 liver,133–135 and nerve
teins,90–92 vaccines,93–95 antibiotics,96–98 analgesics,99,100
tissue.136–138
anti-inflammatory drugs,101,102 and siRNA.103–105 Most often
PLGA is fabricated into microspheres,90–95,97,98,101 microcap- Polyhydroxyalkanoates
sules,106–108 nanospheres,88,89,95,96,100 or nanofibers109,110 to Polyhydroxyalkanoates are biodegradable polyesters that can
facilitate controlled delivery of encapsulated or adsorbed be produced by both bacterial and synthetic routes. The
payloads. Depending on the composition of the PLGA used most common polymer in this family is poly(3-hydroxybuty-
and the interactions between payload and polymer, drug or rate) (PHB), a semicrystalline isotactic polymer that
FIGURE 3 PLGA scaffolds with villi architecture generated by indirect three-dimensional printing with villus diameter, height and
intervillus spacing of (a) 0.5, 1, and 0.5, mm; (b) 0.5, 1, and 1 mm; (c) 1, 1, and 1 mm, respectively. (Reproduced from ref. 126,
with permission from Wiley.)
undergoes surface erosion due to the hydrophobicity of its Although somewhat limited in drug delivery applications, tissue
backbone and its crystallinity.139 PHB has a Tg around 5 C engineering implications of PCL are numerous. PCL has low ten-
and a melting temperature from 160 to 180 C.140 Hydrolytic sile strength (23 MPa), but very high elongation at breakage
degradation of PHB results in the formation of D-()-3- (4700%) making it a very good elastic biomaterial.41 PCL’s proc-
hydroxybutyric acid, a normal blood constituent.141 The bio- essability allows for the formation of scaffolds composed of
compatibility, processibility, and degradability of PHB make it adhered microspheres177,178 electrospun fibers,179–181 or
an excellent candidate for use in long-term tissue engineering through porous networks created by porogen leaching.182–184
applications.142–147 Unfortunately, the stability of PHB makes PCL and PCL composites have been used as tissue engineering
it a poor candidate for controlled delivery applications. scaffolds for the regeneration of bone,182,185,186 ligament,187,188
cartilage,133,189 skin,177,181,190 nerve,184,191,192 and vascular tis-
To widen the applicability of PHB as a biomaterial, most com-
sues.183,193,194 A recent advancement using PCL hybrid scaffolds
monly PHB is copolymerized with 3-hydroxyvalerate to create
has been used in interfacial tissue engineering. Lee and co-
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). PHBV
workers have shown that if distinct scaffold regions are seeded
is less crystalline than PHB with a lower melting temperature
with appropriate cells harvested from cartilage or ligament
of 80–160 C and a Tg in the range of 5 to 20 C depending
sources (Fig. 4), complex tissue interfaces like the bone-ligament
on HV content.148 PHBV has been used in tissue engineering
interface can be regenerated.195
of bone,147,149,150 cartilage,151 tendon,152 skin,143,153 and
nerves.143,147 Although the addition of HV content improves
the biomaterial potential of PHB, degradation is still too slow Poly(propylene fumarate)
for other biomedical applications. Significant research is Poly(propylene fumarate) (PPF) is a high-strength polymeric
underway to speed degradation rates through copolymerizing biomaterial that while technically a polyester, possesses the
or blending PHB or PHBV with PLLA,153 PDLLA,154,155 unique ability to be crosslinked through the unsaturated
PLGA,114,156–158 poly(dioxanone),159 poly(caprolactone),160–162 bonds in its backbone. As PPF can be crosslinked, polymer
and polyethers.163–165 degradation is dependent on molecular weight, crosslinker,
and crosslinking density.196 PPF is a liquid injectable, which
Polycaprolactone
Polycaprolactone (PCL) is a semicrystalline polyester with
great organic solvent solubility, a melting temperature of 55–
60 C and Tg ¼ 54 C.166 Because of PCL’s very low in vivo
degradation rate and high drug permeability, it has found
favor as a long-term implant delivery device. CapronorV is a
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commercial contraceptive PCL product that is able to deliver

levonorgestrel in vivo for over a year and has been on the
market for over 25 years.167 Current research is being con-
ducted into the development of microsized and nanosized
drug delivery vehicles, but the degradation rate (2–3 years)
is a significant issue for pure PCL products to be FDA FIGURE 4 Cylindrical porous poly(L-lactide-co-caprolactone)
approved for this use. Instead PCL is often blended or scaffold loaded with fibrochondryocytes (fibrocartilage sec-
copolymerized with other polymers such as PLLA,68,168,169 tions) on either end with fibroblasts (ligament section) in the
PDLLA,170,171 PLGA,104,172,173 and polyethers174–176 to expe- center in order to mimic the ligament-bone interfacial tissues.
dite overall polymer erosion. (Reproduced from ref. 195, with permission from Elsevier.)
becomes solid during crosslinking; therefore, it has found

favor in biomedical applications such as filling bone
defects197–199 and the depot, long-term delivery of ocular
drugs.200–202 For osteogenic tissue engineering, PPF is often
mixed with ceramics such as hydroxyapatite203–205 or alu-
moxane206–208 to create stronger, more-bioactive scaffolds.
Recent research has focused on the use of PPF to fill irregu-
lar shaped bone defects such as ear ossicle209 or mandibular
defects.210 In both circumstances, PPF-based scaffolds allow
the design of structures that may not be attainable from
noncrosslinkable degradable polymers.
Polyanhydrides
Polyanhydrides are a class of surface eroding polymers that
contain two carbonyl groups bound together by an ether
bond and have been almost exclusively studied for biomedi-
cal applications. While originally developed as textile fibers
in the 1930s, their hydrolytic instability precluded their
wide-spread usage.211 Beginning in the 1980s, polyanhy-
drides were investigated for the biomaterial potential,212
eventually leading to their FDA approval as drug delivery
vehicles in 1996.213 One particularly unique property of FIGURE 5 In vitro release of bovine serum albumin from poly
polyanhydrides is that the degradation of the anhydride (CPH:SA) microparticles in phosphate-buffered saline (pH 7.4).
bond is highly dependent on polymer backbone chemistry. In (Reproduced from ref. 19, with permission from Elsevier.)
fact degradation rate can vary by over six orders of magni-
tude based on monomer chemistry (Table 1). Surface erosion
and control over degradation rate allow for precision tuning polyanhydrides have been studied as injectable, crosslinkable
of payload release rate which is why polyanhydrides have biomaterials. Methacrylic groups are typically incorporated
found significant favor in drug delivery applications. Polyan- by reacting diacids with methacryloyl chloride to create
hydrides have been used for the delivery of chemotherapeu- dimethacrylate monomers.232 Dimethacrylate monomers
tics,214,215 antibiotics,216,217 vaccines,218–221 and pro- exist as liquids (i.e., dimethacrylic SA) or soft solids (i.e.,
teins.106,222,223 Polyanhydrides are often fabricated into dimethacrylic CPH, which can be injected and crosslinked
microparticles106,218,220,222 or nanoparticles214,215,219,221,223 into solid scaffolds for tissue engineering applications.233
to allow for injectable, oral, or aerosol delivery. Aliphatic Crosslinked polyanydrides have been mostly studied for utili-
homo-polyanhydrides, such as poly(sebacic anhydride) zation in drug delivery and structural support for bone tis-
(poly(SA)) have been found to have limited applications due sue engineering,234,235 but due to monomer flexibility have
to their rapid degradation. To retard polymer degradation the potential to be used in other tissue engineering applica-
and extend payload delivery, aliphatic diacid monomers have tions as well.
been copolymerized with hydrophobic aromatic diacid mono-
mers218,222,224–226 or aliphatic fatty acid dimers.227,228 By
Polyacetals
varying aromatic monomer, (1,3-bis-p-(carboxyphenoxy)hex-
Polyacetals are degradable polymers in which two ether
ane) (CPH), content, Determan and coworkers have fabricated
bonds are connected to the same carbon molecule (geminal).
polyanhydride particles that release their payload over a few
The molecular closeness of the normally stable ether bonds
days to a couple of years, as shown in Figure 5.19 Additional
conveys hydrolytic instability close to that seen for polyanhy-
research in polyanhydrides has focused on novel monomer
drides (Table 1) and gives polyacetals surface eroding
development to allow for the replacement of SA due to its
properties. Polyacetals are normally subdivided into two sub-
high acidity in solution (pH ¼ 4.2).229 A monomer of interest
groups: polyacetals and polyketals. Although all geminal-
is 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane, which is an ar-
diether polymers are technically polyacetals, the namesake is
omatic diacid monomer that contains a triethylene glycol
normally reserved for polymers with only one of the two
backbone that together convey amphiphiliticity.230,231 Copoly-
other geminal bonds possessing an R group. Polyketals
merizing this polymer with traditional aromatic diacid mono-
instead have both other geminal bonds with R groups. Both
mers yields degradable polymers that can be used as long-
polyacetals and polyketals have gained traction in biomedical
term delivery vehicles that have shown to stabilize acid-sensi-
research recently because their degradation products possess
tive payloads like recombinant proteins.220,223
no carboxylic acids yielding significantly milder pH microen-
Although polyanhydrides have been extensively investigated vironments,236 and their degradation is acid-catalyzed.236–238
for drug delivery applications, their low molecular weights Milder pH microenvironments allow for the delivery of acid-
yield poor mechanical properties precluding their use in tis- and hydrolytically sensitive payloads. Dr. Niren Murthy’s
sue engineering. To increase their strength, methacrylated group has shown acid-catalyzed degradation allows for
in the academic community. Although four classes of poly(or-

tho esters) have been developed (POE I-IV), inherent issues
with POE I–III have led to nearly all research focusing on
POE IV. POE IV incorporates short segments of lactic or gly-
colic acid into the polymer backbone to expedite degradation
because POE I–III possess too slow erosion rates to be clini-
cally relevant as drug delivery vehicles.250 POE IV polymers
have been used for the delivery of analgesics,251 DNA vac-
cines,252,253 and antiproliferative drugs.254 Their capacity to
be used as tissue engineering scaffolds is limited due to their
weak mechanical properties and their capacity to induce a
mild to moderate inflammatory response.255
Polycarbonates
FIGURE 6 In vitro hydrolysis of poly(cyclohexane-1,4-diyl ace- Polycarbonates are linear polymers that have two geminal
tone dimethyl ketal) is greatly influenced by surrounding pH ether bonds and a carbonyl bond. Although this bond is
evidenced by its half-life of 24.1 days in pH 4.5 and 4 years in extremely hydrolytically stable (Table 1), research has shown
pH 7.4. (Reproduced from ref. 237, with permission from the in vivo degradation to be much more rapid presumably due
American Chemical Society.) to enzymatic degradation, which causes these polymers to
be surface eroding.256 The most extensively studied polycar-
intracellular payload delivery, because particle-based delivery bonate is poly(trimethylene carbonate) (PTMC), which has a
vehicles are stable under normal physiological pH (7.4), but Tg of 17 C.257 PTMC is an elastomeric aliphatic polymer
rapidly degrade when they reach lysosomal pH (4–5), as with great flexibility and a slow degradation profile, but
shown in Figure 6.237 So far polyketal microparticles and poor mechanical strength. Its degradation into biocompatible,
nanoparticles have been used to directionally deliver non-acidic 1,3-propanediol, and carbonic acid make it an
siRNA,238 DNA,239 and proteins237,240–244 in the treatment of ideal candidate for drug delivery applications. PTMC has
acute inflammatory disease,237,242 ischemic heart disease,244 been fabricated into microparticles,258,259 discs,260,261 and
and cancer,241 as well as in the delivery of vaccines.240,243 gels262–264 for the delivery of angiogenic agents264 and antibi-
otics.260,261 To enhance the delivery potential of PTMC, it is
For most implant applications, polyacetals have found lim-
often copolymerized with PLA,265,266 PCL,265 polyether,266–268
ited use because they are often unable to be synthesized at
or poly(L-glutamic acid)269,270 to allow for the fabrication of
high enough molecular weights to meet mechanical strength
sutures,265 micelles,266–268 and polymersomes267,269,270 with
needs. A notable exception is DelrinV (polyoxymethylene),
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superior mechanical and degradation properties for delivery of

which is the homopolymer of formaldehyde that can be poly-
chemotherapeutics266–268,270 and antibiotics.265
merized by acid or anionic catalysis to high molecular
weights. DelrinV-based implants found favor as tilting disc
R
In addition to PTMC, new polycarbonates have been recently
valves in the repair of faulty heart valves in the late researched for tissue engineering applications. One approach
1960s.245 Unfortunately, it was found that these implants to create stiffer polycarbonates than PTMC is the use of
swelled when they were used in vivo and other materials cyclohexane or propylene instead of trimethylene in the
have since replaced DelrinV in artificial valves.246 Also, the monomer backbone.271 Another approach has been attaching
R
degradation product of DelrinV is formaldehyde, which is bulky side groups through an ester bond to the b-carbon of
R
toxic. To create tissue engineering scaffolds from polyacetals, the backbone.272 A particularly interesting novel polycarbon-
cyclic polyacetal monomers with two ester acrylate end ate has been created using the glucose metabolism interme-
groups have been synthesized that can then be cross- diate dihydroxacetone (DHA).273 When DHA is copolymer-
linked.247 Cyclic polyacetal homopolymers and those copoly- ized with methyl PEG, the resulting rapidly gelating, rapidly
merized with PEG diacrylate (PEGDA) have shown prelimi- degrading (100% mass loss within days) copolymer has
nary promise as osteogenic biomaterials for bone tissue been shown to assist the body in clotting through the devel-
engineering.248,249 opment of new vascular tissue274 and the prevention of sero-
mas, fluid filled gaps commonly created following ablative or
reconstructive surgeries.275 The continued exploration of
Poly(ortho esters)
new polycarbonates holds potential for the expansion of this
Poly(ortho esters) are hydrophobic, surface eroding poly-
class of degradable polymers in biomedical applications.
mers that have three geminal ether bonds. Like polyacetals,
control of poly(ortho ester) backbone chemistry allows for Other polycarbonates that are used as fixators and in tissue
the synthesis of polymers with varied acid-catalyzed degra- engineering scaffolds are tyrosine-derived polycarbonates.
dation rates and material properties. These polymers were These polymers are variations of poly(amino acids) in which
specifically developed for drug delivery applications by the amino acid like backbones are connected by carbonate bonds
ALZA Corporation in the early 1970’s.250 While ALZA no giving them strong mechanical properties while maintaining
longer exists, research in poly(ortho esters) is still ongoing the biocompatibility of their degradation products. The most
extensively studied of these pseudo poly(amino acids) are clinically relevant biomaterials. In addition to control over
poly(desaminotyrosyl-tyrosine alkyl ester carbonates) degradation rates, physical properties of the polymer are
(PDTEs). Because of aromatic groups in the polymer back- also greatly affected by side group substitution. By changing
bone, PDTEs possess significant mechanical strength allowing disubsituted polyphosphazene side groups for one particular
for their use in load-bearing applications. PDTEs have a vari- system, thermal and mechanical properties were greatly var-
able pendant alkyl chain allowing for modulation of their ied with Tg ¼ 10 to 35 C, contact angle 63 –107 , tensile
thermal and mechanical properties with Tgs of 50–81 C, Tms strength 2.4–7.6 MPa, and modulus of elasticity 31.4–455.9
of 75–118 C, tensile strengths of 50–70 MPa and stiffnesses MPa.296 Another unique feature is that polyphosphazenes de-
of 1–2 GPa.276 Their processibility has allowed for the fabrica- grade into neutral products that have been found to have a
tion of scaffolds composed of films,276–281 fibers,282 and pH buffering effect when combined with polymers, such as
gels.283,284 PDTEs have been investigated for their potential in polyesters, that have highly acidic degradation products.297 A
tissue engineering of bone,277,278,280 vasculature,283 and mus- commercially available product Polyzene-FV (poly[bis(tri-
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cle.281 Slow degradation (Mw half life of over 200 days285) fluoroethoxy)phosphazene], CeloNova BioSciences) has
and minimal mass loss of PDTEs allows for them to maintain shown tremendous potential as stent coatings298 and embol-
their physical properties for very long times making them izing microspheres,299 and was FDA approved in 2008.
good candidates for slow regenerative processes. Although original research found the material to cause lim-
ited inflammation,300 a more recent study showed a signifi-
Polyurethanes
cant, sustained foreign body response that is of concern.301
Polyurethanes are biocompatible, biostable, moldable, strong
More research into this phenomenon is warranted before
polymers that possess ester bonds with geminal amide bonds
Polyzene-FV can be used clinically.
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that have a degradation rate similar to polyesters and polycar-

bonates (Table 1). They are typically synthesized by polycon- Polyphosphazenes have shown significant promise in drug
densation of diisocyanates with alcohols and amines.286 delivery and tissue engineering applications. The large
Polyurethanes are composed of hard and soft segments that library of side groups and the processibility of polyphospha-
can undergo microphase separation allowing for these poly- zenes has allowed for them to be fabricated into par-
mers to handle physical stresses very well.287 Polyurethanes ticles,302–304 micelles,305–309 microneedle coatings,310,311 and
have been used extensively in prostheses such as cardiac gels.312–315 They have been used in the delivery of anti-
assist devices,288 small vascular shunts,289 and tracheal inflammatory drugs,306 chemotherapeutics,307,309,315 growth
tubes.290,291 A commercial polyurethane product, NovoSorbTM factors,313,316 DNA,302–304 proteins,312,314 and vac-
(PolyNovoV), is a two component system that cures in situ.
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305,308,310,311
cines. One particular promising application has
The self setting system is an injectable liquid that not only pol- been in the design of biodegradable microneedle coatings to
ymerizes at physiological temperatures creating a biomaterial
deliver vaccines.310 Andrianov and coworkers have shown
that has been shown to be mechanically similar to bone
polyphosphazene-vaccine covered metallic cones can be used
cements but also promotes favorable cell adhesion and prolif-
to pierce the skin to deposit rapidly degrading polymer films
eration.292 Under most conditions, pure polyurethanes are
(90% in 15 min) into the dermis layer (Fig. 7). An added
degradation resistant making them poor candidates for drug
benefit of utilizing polyphosphazene as the delivery vehicle
delivery and many tissue engineering applications. To expand
the biomedical potential of polyurethanes they have been uti- is that prior research has found that certain polyphospha-
lized in multidegradable group polymers, combination poly- zenes are strongly immunoactivating and hold great potential
mers, which will be discussed later in this review. as adjuvants, nonspecific immune boosting substances.305,308
This research has shown the induction of stronger immune
Polyphosphazenes responses than comparable intramuscular injections without
Polyphosphazenes are a unique class of degradable polymers the pain and strong inflammation seen with traditional nee-
in that their backbone is completely inorganic consisting of dle use providing promise for this new technology.
phosphorous and nitrogen bonded linearly through alternat-
ing single and double bonds. Although these polymers have Although many rapidly degrading polyphosphazenes have
been synthesized with high molecular weights since the mid shown promise in drug delivery applications, more hydro-
1960s,293 only in the past two decades have they been inves- phobic side group substitutions have allowed for the use of
tigated in biomedical research.294 What distinguishes these polyphosphazenes in tissue engineering applications. Poly-
materials is that they are highly flexible both physically and phosphazene scaffolds have been composed of films,317,318
chemically. With two phosphorous side groups open to con- fibers,319–322 and sintered microspheres.323 These matrices
jugation via esterification, etherification or amidification, have been used to assist in nerve regeneration,317,319,322 but
over 500 different polyphosphazenes have been synthesized recent research has almost exclusively focused on orthopedic
to date.295 Although the phosphonitrilic backbone is not applications of polyphosphazenes.318,320,321,323 Often poly-
intrinsically hydrolytically sensitive, careful choice of side phosphazenes have been blended with polyesters to increase
groups greatly impacts the degradation rate (Table 1). Cer- mechanical strength and provide a moderate pH microenvir-
tain side groups, such as amino acid esters, glucosyl, glyceryl, onment for developing tissues. Interestingly, miscible blends
glycolate, lactate, and imidazole, have been found to sensitize of poly[(glycine ethyl glycinato)1 (phenylphenoxy)1 phospha-
hydrolysis of the backbone to allow for the design of zene] and PLGA that are originally cast as films undergo
FIGURE 7 Optical microscopy image of a polyphosphazene coated metallic microneedle (left) and histological section of porcine
skin after coated microneedle insertion (right). (Reproduced from ref. 310.)
varied rates of degradation of the principal components ized with polyethers and polyesters. Polyphosphoesters and
under aqueous conditions.13 As the PLGA degrades and polyphosphoester composites have shown significant prom-
erodes from the matrix the more hydrophobic polyphospha- ise as chemotherapy326–328 and DNA329–331 delivery devices.
zene reforms into a scaffold with a microstructure very simi- Polyphosphoesters have also been utilized as scaffolds in the
lar to adhered microspheres. Porous scaffolds of adhered engineering of bone tissue.328,329,332–335 These polymers
microspheres have been used heavily in tissue engineering have been formed into particles,328,330 micelles,326,327
applications because they allow for the infiltration of host films,329,331 and gels332–335 for these applications. Recent
cells into the scaffold that will eventually become new tissue. research utilizing polyphosphoesters has been limited, but
Having biomaterials with the strength and flexibility of films their chemical flexibility and similarity to biomacromolecules
that can form into porous scaffolds over time greatly enhan- gives them great promise for future applications.
ces the biomedical potential of these materials.
Combination Polymers
A growing trend in degradable polymer research is the devel-
Polyphosphoesters
opment of combination polymers. These are polymers in which
Polyphosphoesters form another interesting class of biomate-
monomers contain multiple degradable groups. Unlike copoly-
rials that is composed of phosphorous-incorporated mono-
merization of different monomers, the molecular proximity of
mers. These polymers consist of phosphates with two R
these groups yields functionally novel biomaterials. These
groups (one in the backbone and one side group) and can
materials often have properties that cannot be obtained by sin-
be synthesized by a number of routes including ring opening
gle degradable group polymer families or through simple
polymerization, polycondensation, and polyaddition. Origi-
copolymerization. With the goal of developing new polymers,
nally developed in the 1970s,324,325 polyphosphoesters have
this research area has yielded a large number of new families,
great biocompatibility and similarity to biomacromolecules
which will not be completely reviewed in this section. Below
such as RNA and DNA. Relatively rapid hydrolytic cleavage
are a couple examples of interesting degradable combination
(Table 1) of the phosphate bonds in the backbone leads to
polymer families that have been recently developed.
the production of bioresorbable or excretable phosphates,
alcohols, and diols. Although a commercial polyphos- Poly(ester ether)s are an interesting class of degradable
phoester-based microsphere delivery device (PACLIMERV)
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polymers in which typically an ether bond in incorporated
has shown promise in Phase I/II trials for the treatment of into the backbone of a polyester to expedite hydrolytic cleav-
ovarian and lung disease, MGI Pharma discontinued further age of the ester bond. One very common poly(ester ether) is
research with the product after purchasing the original de- polydioxanone (PDO). PDO is a colorless, semicrystalline
velopment company, Guilford Pharmaceuticals. Polyphos- polymer synthesized by ring-opening polymerization of p-
phoesters are divided into two different classes: polyphosph- dioxanone that has a Tg about 10 to 0 C and a Tm of 115
336
onates (alkyl/aryl R groups) and polyphosphates (alkoxy/ C. Although quicker degrading than longer aliphatic poly-
aryloxy R groups). Because of the flexibility in choosing R esters of similar backbone length, PDO can still be consid-
groups, polymers of significantly varying physical properties ered a slow degrading polymer (6–12 months for complete
and degradation rates can be synthesized. To enhance physi- mass loss).23 With a low modulus (1.5 GPa),23 but good flexi-
cal properties, polyphosphoesters are commonly copolymer- bility and strength maintenance (1–2 months), PDO has been
commercialized as the monofilament suture PDSV for nearly of biofilm formation,360,361 the prevention of bone resorp-
R
30 years.337 In an effort to create faster degrading polyest- tion,356,359 and the creation of a local anti-inflammatory
ers, research has been conducted into the synthesis of poly effect.356,360
(ether ester)s via polycondensation. This is carried out by
Polyurethanes have shown some applicability in biomedical
the use of a catalyst to create alternating blocks from dicar-
research, but their hydrolytic stability limits their potential.
boxylic acids and diols. Oligomeric ethylene glycol (n ¼ 2–4)
To expedite degradation, ester bonds have been introduced
and trans-b-hydromuconic acid are condensed to create low-
into the polymer backbone. Poly(ester urethane)s are typi-
molecular-weight poly(ether ester)s (4,000–6,000 g/mol)
cally synthesized by reacting diisocyanates with polyester
that are amorphous and have low Tgs (36 to 32
diols or triols composed of glycolide, lactide, or caprolactone
C).338,339 These polymers are liquid at room temperature
to create the soft segments of the polymer.362 Often the hard
and possess crosslinkable double bonds in their backbone
segments are composed of polypeptides or diols or triols of
making them promising biomaterials for filling nonuniform
3-hydroxybutyrate to give biomaterials that are degradable,
defects. By creating random copolymers between crosslink-
but still relatively hydrolytically stable.362,363 To better com-
able and noncrosslinkable (adipic acid) monomers, control
mercialize the aforementioned PolySorb, more recent
over crosslinking density can be obtained. These materials
research has focused on including degradable ester groups
are able to be synthesized with Young’s moduli varying three
into the injectable prepolymers. This has allowed for devel-
orders of magnitude (0.02–20 MPa).339 Also, the liquid poly
opment of biomaterials that has shown promise in bone364
(ester ether)s are able to be fabricated into complex archi-
and articular cartilage regeneration.365 Another poly(ester
tectures not easily obtainable by solid polyesters.339
urethane) is the highly porous DegrapolV (Ab Medica), which
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Poly(amide ester)s are cationic, degradable polymers origi- has shown promise in engineering tracheal soft tissue366,367
nally investigated for their biomedical potential in the 1990s and bone tissue.368
by Robert Langer.340 The most widely studied subgroup of
these polymers are poly(b-amino esters) (PBAEs), which are ENZYMATICALLY DEGRADABLE POLYMERS
synthesized by a Michael addition reaction of diester diacry-
Enzymatically degradable polymers are materials that pos-
lates and primary or secondary amines.341,342 Having control
sess bonds that while technically hydrolytically sensitive, in
over both components’ backbone chemistry, a wide range of
reality require catalysis to undergo meaningful degradation
PBAEs can be synthesized. The fidelity of the reaction and
under physiological conditions. Most of these polymers con-
the subsequent library of polymers that can be synthesized
tain ether or amide bonds which have hydrolytic degradation
have led to the use of combinatorial research methods to
rates much lower than the polymers discussed in the previ-
identify polymers that show particular promise as biomateri-
ous section (Table 1). This section details a number of these
als.343–346 In one particular study, over 2,000 polymers were
polymeric families and their application as biomaterials.
synthesized and screened combinatorially.345 PBAEs show
tremendous promise in DNA delivery due to their positively
Synthetic Polyethers
charged amide bonds347–350 and in tissue engineering
Synthetically derived polyethers are highly biocompatible
because they can be synthesized with high molecular
polymers that have been used in polymeric drug delivery
weights and hydrolytically stable bonds allowing for long-
and tissue engineering for over 30 years.369 Nearly all bio-
term maintenance of their mechanical strength.351–353
medical research with synthetic polyethers has focused on
Although copolymers and blends of polyesters and polyanhy- the use of PEG and poly(propylene glycol) (PPG), while a
drides have been studied for a few decades, the synthesis of limited amount of work has been conducted using poly(te-
poly(anhydride ester)s for biomedical applications have only trahydrofuran).370–373 Polyethers do not readily undergo
been investigated for the last decade.354 The original impetus hydrolytic degradation and while bacterial etherases have
for their development was the creation of prodrug polymers. been discovered,374,375 human equivalents of these enzymes
If commonly used aromatic diacid monomers have two inter- have yet to be identified. Instead polyether chains are nor-
nal ester bonds instead of ether bonds, their degradation mally dissociated from the biomaterial and removed via the
products are resorbable carboxylic diacids and salicylic acid, excretory system. Because of a near absence of in vivo degra-
a nonsteroidal anti-inflammatory drug and the active com- dation and the fear of accumulation, it is recommended that
pound of aspirin. Polycondensation of salicylate-containing only polyethers with lower molecular weights be utilized for
diester diacids yields poly(anhydride ester)s very similar to biomedical applications. In addition to issues associated with
classical polyanhydrides with moderate hydrophobicity, sur- high-molecular-weight PEG, very low-molecular-weight PEG
face erosion, and good processability.354,355 These polymers has been found to induce bodily harm. Specifically, tetraethy-
have been found to have Tgs lower than physiological tem- lene glycol and PEG 200 have been shown to induce clasto-
peratures (12–34 C),354,356,357 and are often copolymerized genic effects (chromosomal disruption) in Chinese Hamster
with traditional aromatic diacid monomers to improve epithelial liver cells.376 Most research with synthetic poly-
mechanical properties.356,358 Salicylic acid-derived poly ethers has focused on triblock Pluronic ([PEG]n-[PPG]m-
(anhydride ester)s and their composites have been fabricated [PEG]n), crosslinkable oligomers or these polymers in union
into particles,357,359 fibers,358 and films355,356,360,361 for bio- with many of the previously mentioned hydrolytically
medical application. They have been used in the prevention degradable polymers.
Pluronic is of particular interest, because PEG is hydrophilic polyanhydrides,232,234,235,435,436 and chitosan,437,438 a poly-
whereas PPG is hydrophobic allowing for the formation of saccharide that will be discussed later in this review. The
very small micelles (10–100 nm in diameter)377 by self- polyether diacrylate monomers give the crosslinked network
assembly in water. These micelles allow for high payload hydrophilicity whereas the other degradable components
loading (30 wt %)378 of hydrophobic drugs into the core convey significantly greater mechanical strength (compres-
while the hydrophilic shell makes the particles easy to sive moduli as great as 100 MPa)232 than crosslinked poly-
administer. Drug delivery devices composed of Pluronic ether diacrylate homopolymers. Greater strength and compo-
micelles have been used to deliver chemotherapeutics,379–381 nent flexibility have lead to the use of these composites in a
antibacterials,382,383 antidiuretics,384 anti-inflammatory wide range of tissue engineering applications including in
drugs,385 and DNA.386 Pluronic has also been formulated the regeneration of ligament,433 cartilage,434 bone,232,432 and
into hydrogels. These hydrogels possess relatively weak me- epithelial tissue.437
chanical properties (maximum shear storage modulus of
Proteins and Poly(amino acids)
13.7 kPa at 20 wt % Pluronic)387 making them candidates
Proteins are essentially high-molecular-weight polymers
for drug delivery388–391 and soft tissue engineering.392,393
composed of amino acid monomers joined by amide bonds.
To enhance the mechanical strength of polyether-based They often occur in 3D folded structures and are one of the
hydrogels, crosslinkable oligomers are synthesized by react- most common materials found in the human body. Proteins
ing PEG with excess acryloyl chloride or methacryloyl chlo- and amino acid-derived polymers have been utilized as bio-
ride yielding the products PEGDA or PEG dimethacrylate materials in sutures, scaffolds, and drug delivery devices.
(PEGDMA), respectively. PEGDA and PEGDMA can then be Although amide bonds are hydrolytically stable, the body
polymerized by their double bond yielding crosslinked net- possesses a wide-array of proteases that can rapidly degrade
works, which upon degradation yield poly(acrylic acid) or proteins.
poly(methacrylic acid) and PEG. PEGDA hydrogels (shear
storage modulus of 68 kPa at 20 wt %)394 and PEGDMA Collagen
hydrogels (shear storage modulus of 125 kPa at 20 wt %)395 Collagen is the most abundant protein in the human body
are stronger than their Pluronic counterparts. PEGDA, and is a major component of ligament, cartilage, tendon,
PEGDMA, and PEGDA/PEGDMA hydrogels have been used in skin, and bone. It also forms the structural network of other
the delivery of chemotherapeutics,396 hormones,397 antibac- tissues such as blood vessels. Collagen is composed of poly-
terials,398 and anti-inflammatory drugs399 as well as scaf- peptide strands bearing triamino acid blocks of Glycine-X-Y
folds in the engineering of cartilage,400,401 bone,402–404 endo- where X and Y can be any of a number of different amino
thelial,405 and vascular tissues.406 acids and are most commonly proline and hydroxyproline.439
These polypeptides are formed into left-handed triple helix
Although synthetic polyethers have shown some promise microfibrils that organize together in a number of different
when utilized by themselves, they have much greater biomed- architectures to create collagen fibers with appropriate me-
ical potential when utilized in combination with other degrad- chanical properties for their function. To date, at least 28 dif-
able polymers. PEG is commonly used to cap (PEGylation) or ferent types of collagen have been identified, however types
coat other degradable polymers to convey steric stabilization I, II, III, and IV are the most heavily investigated with over
limiting the interactions between the device and the host. 90% of all collagen being type I.440
This is especially important in preventing phagocytosis, cellu-
Collagen has been extensively researched for various medical
lar uptake, of particle-based delivery vehicles.407–409 Unlike
applications due to its biocompatibility, mechanical strength,
polyanhydrides and polyesters, PEG does not initiate the com-
and enzymatic degradability by collagenases and metallopro-
plement cascade, which is known to facilitate particle phago-
teinases.441 In addition, it is very processable with high solu-
cytosis.410 PEG incorporation has been used to enhance the bility in acidic aqueous solutions allowing for the fabrication
biocompatibility and delivery properties of polyanhy- of collagen sponges,442–444 tubes,445,446 sheets,447 pow-
drides,411–414 poly(ortho esters),415 PLA,416–419 PLGA,420–423 ders,448 and injectables.449–452 Collagen has been used for
and PCL.424–427 Of particular interest is the work being con- centuries as a suture material of which one form, catgut, is
ducted with poly(ether anhydride)s. The addition of a low- still sometimes utilized in surgery,453,454 but due to collagen
molecular-weight PEG shell to polyanhydride microparticles suture’s increased infection rates and inflammation, synthetic
and nanoparticles conveys ‘‘virus-like’’ behavior and allows sutures are much more commonly used today. Collagen has
for them to pass through mucosal membranes much more also been used as a depot payload delivery device in the
rapidly than uncoated particles.428,429 Being able to transport local extended release of antibiotics,455,456 DNA,457,458
drug delivery devices across mucosal barriers is important in siRNA,459,460 and proteins.461–463 In each case collagen had a
improving therapeutic efficacy against diseases such as cystic burst release due to bulk erosion making it less ideal than
fibrosis430 and lung cancer414 (lung mucosa) and HIV431 the aforementioned surface eroding hydrolytically sensitive
(vaginal mucosa). polymers for drug delivery applications.
PEGDA and PEGDMA have also been heavily researched in More recently collagen has found use as a haemostatic seal-
composite systems with other acrylated and methacrylated ant.464 Collagen is highly thrombogenic and plays a role in
degradable polymers, most commonly polyesters,432–434 the body’s natural clotting process by activating fibrogen
FIGURE 8 Photomicrographs of keratinocyte-fibroblast coculture engineered skin tissue with the addition of collagen microsphere
supported sweat gland cell constructs. (A) Hemotoxylin and Eosin (H&E) staining after 2 weeks of in vitro cocultivation showed dif-
ferentiated tissue layers (E: epithelium and D: dermis) with a bud-like structure (black arrow) where sweat gland constructs were
loaded. (B) H&E staining of 6-week postimplantation in vivo skin tissue showed the continued presence of bud-like structures in
the dermis layer (black arrow). (C) Fluorescence microscope observation showed DiO-positive cells (green) confirming the pres-
ence of still viable sweat glands. (Reproduced from ref. 485, with permission from Elsevier.)
conversion into fibrin, heavily crosslinked mesh networks of cation. Although these products provide excellent support to
fibrogen. Fibrin captures activated platelets to make a clot. regenerating tissue, they lack many of the constituent struc-
By creating a collagen based sealent, wounds can be coated tures found within skin like hair, nerves and glands as well
and blood flow halted much more quickly. The FDA has as tissue layer separation necessary to truly replicate skin’s
approved a couple of collagen-containing solutions, including 3D structure. Several approaches to these problems have
HelistatV (Integra Life Sciences) and FloSealV (Baxter), for
R R
been proposed, but two concepts of particular interest are
the treatment of bleeding during surgery. outlined. To develop sweat glands within regenerated skin,
Because of collagen’s structural integrity conveyed by its fi- Huang and coworkers have developed growth-factor releas-
brous nature, a majority of biomedical research using colla- ing collagen microspheres that can support differentiating
gen as a biomaterial has focused on its potential as a tissue sweat gland cells.485 These constructs are then embedded
engineering scaffold, specifically in load bearing applications. into a keratinocyte/fibroblast coculture with structural main-
Collagen sponges have been used as tissue supports and tenance provided by a collagen matrix to create substruc-
scaffolds for nearly 50 years.465 Because of collagen’s ability tures within the developing skin that are maintained even af-
to withstand high tensile loads (92.5 MPa ultimate tensile ter implantation in vivo (Fig. 8). To create keratinocyte-
strength),466 it has often been used in bone tissue engineer- fibroblast separated layers, keratinocytes are normally cul-
ing.467–469 Composites of hydroxyapatite and collagen are tured on top of a preformed fibroblast layer, which is time-
utilized, because these materials closely mimic the composi- consuming and inefficient. A new method has been devel-
tion of natural bone.470–472 CollagraftV (Angiotech Pharma- oped for creating controlled large pore scaffolds that allow
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ceuticals) is a synthetic bone-graft substitute composed of for keratinocyte and fibroblast structures to separate natu-
bovine type I collagen and hydroxyapatite/tricalcium phos- rally creating better skin mimicking constructs, which are
phate granules, which has been approved by the FDA and also well integrated into the collage scaffold.486 These advan-
used clinically.473 Collagen has also been widely researched ces hold promise not only for collagen-based biomaterials
as a tissue engineering scaffold for cartilage,474–476 ten- and skin engineering but also for tissue engineering as a
don,477–479 and ligament.480,481 whole because as the field moves toward creating and regen-
erating more complex structures such as organs 3D pattern-
Although often used for load bearing applications, collagen’s
ing of multiple tissue types will be paramount to continued
biocompatibility and ease of use has lead to its investigation
success.
as a scaffold in skin engineering as well.482–484 Because of
collagen’s ability to improve cellular adhesion and prolifera- To improve collagen’s potential as a biomaterial, it has often
tion, burn treatment and reconstructive surgery is often con- been modified or combined with other degradable polymers.
ducted with an acellular collagen matrix taken from human Modifications such as crosslinking,487–489 association of bioac-
cadavers, which is marketed as AllodermV (LifeCell). tive molecules,490,491 and enzymatic pretreatment492–494 have
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Although Alloderm is the most commonly used commercial all led to novel collagen-based materials with expanded func-
product for skin engineering and wound healing, several tionality. In composite materials, collagen has been combined
other FDA collagen-based products exist in the market place with PLA,60,495,496 PLGA,60,497,498 PCL,60,497,499 and chito-
including PromogranV (Johnson & Johnson), BiobraneV (UDL san.500–502 These multipolymer constructs are typically either
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Laboratories), and OrCelV (Ortec International) for this appli-

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polymeric blends or intermixed devices (e.g., microparticles of
one polymer dispersed in a fibrous scaffold of another chondrocytes they have been shown to possess dynamic
polymer). sheer moduli (1.7 kPa)521 similar to normal cartilage. The
elastic behavior of ELPs makes them uniquely suited for the
Although heavily researched, collagen possesses many nega-
engineering of soft tissues.522–524
tive attributes limiting its biomedical potential and clinical
utility. Collagen-based biomaterials have been known to Albumin
induce a moderate immunological response in vivo due to Albumin is an abundant water-soluble blood protein com-
collagen’s terminal region composition and a series of anti- prising almost 50% of total plasma mass in the body. Albu-
genic sites in the central helix.503 The degree and nature of min carries hydrophobic fatty acids in the blood stream as
this response greatly depends on the source and postpro- well as carefully maintains blood pH. As Albumin is essen-
cessing of the collagen used. Other issues include the high tially ubiquitous in the body, nearly all tissues have enzymes
cost of pure collagen, significantly varying physicochemical that can degrade it making it a promising polymer for bio-
properties, and risk of transmitted infection from the graft- medical applications.525 Albumin’s solubility allows for the
ing source. Although current research is underway to pro- protein to be easily processed into a number of different
duce recombinant human collagen,504 animals and cadavers shapes including fibers,526,527 microparticles,528,529 and
still remain the most common sources. Until alternative bio- nanoparticles.530–532 Because of its serological compatibility
logical sources are identified or purely synthetic collagen can and weak mechanical strength, albumin has been primarily
be synthesized/collagen-based biomaterials will continue to investigated for payload delivery,529–531 coating,533,534 and
possess significant limitations. suturing applications.535,536 Currently, a bovine albumin-
based adhesive marketed as BioGlueV (CryoLife) is FDA
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Elastin and Elastin-Like Polypeptides approved for vascular surgery.535

Elastin is an insoluble, highly elastic polymer composed of
heavily crosslinked tropoelastin molecules that is a major Fibrin
component of vascular and lung tissue and is responsible for Fibrin, a large crosslinked biopolymer composed of fibronec-
the contraction of these tissues following stress. Soluble tro- tin, is involved in the natural clotting process. In the pres-
poelastin molecules are produced intracellularly by smooth ence of the enzyme thrombin, cleavage of an internal fibrin
muscle cells and fibroblasts and are crosslinked extracellu- linker yields linear fibrils that laterally associate into nano-
larly to form their elastic polymeric network.505 As it is fibers (10–200 nm) that form a clot. This clot is able to be
prevalent in vascular tissue, elastin has been found to not degraded by a complex cascade of enzymes.537 The use of
activate platelets making it a promising material for syn- fibrin as a biomaterial goes back centuries, and it has been
thetic vascular grafts.506,507 Although some biomaterials shown to be biocompatible, biodegradable, injectable, and
research has been conducted with elastin, its ability to elicit able to enhance cell proliferation.538 Fibrin glues has been
an immune response and its insolubility have limited its studied as a surgical supplement under the market name
EvicilV (Ethicon), which has been FDA approved as a tissue
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use.508
sealant and hemostatic agent. Fibrin glues are prepared as
To overcome the limitations inherent to elastin, synthetic
solutions containing thrombin and fibronectin separately
elastins have been developed. Soluble recombinant human
that are mixed right before application. Thrombin rapidly
tropoelastin can be molded, coaservated, and crosslinked at
crosslinks the fibronectin into a fibrin clot closing the
37 C to create soluble elastin with controlled architec-
wound. Fibrin has also been investigated for use as a drug
ture.509,510 Also, tropoelastin undergoes an irreversible tem-
delivery device539–542 and cell carrier.543–545 Due to its
perature transition (ITT) above 25 C where its molecular
potential for crosslinking, fibrin can be uniquely modified, so
organization goes from a disordered to ordered state. This
that its material properties can be tailored for desired
transition gives synthetic elastin promise as a smart, inject-
applications.546
able drug delivery system.511,512
Natural Poly(amino acids)
Another attempt to utilize elastin-based materials as bioma-
Natural poly(amino acids) are biodegradable, ionic polymers
terials has been in the investigation of elastin-like polypep-
similar to proteins in that they possess amide linkages, but
tides (ELPs). ELPs are artificial polypeptides that are com-
poly(amino acids) are only composed of one type of amino
posed of pentapeptide repeats (VPGXG) similar to those
acid. The two most commonly studied natural poly(amino
found in elastin where X can be any of a number of different
acids) as biomaterials are poly(c-glutamic acid) (cPGA) and
amino acids except proline.513 Although very flexible like
poly(L-lysine).
elastin, ELPs are biocompatible and non-immunogenic. They
also can be synthesized to undergo ITT, as well as respond cPGA is a water soluble, biodegradable polyamide composed
to pH, ionic strength and light based on which amino acid is of both enantiomeric D- and L-glutamic acid units commonly
synthesized in the X position.514 While once synthesized produced by a number of different bacteria.547–549 The bio-
chemically, ELPs have been more recently produced in material promise of cPGA centers on its reactive side carbox-
E. Coli.515 Because of the variety of phase transitions that ylate, which allows for the covalent attachment of other
ELPs can undergo, they have been investigated as delivery functional groups and drugs. Benzyl ester,550 sulfonate,551
vehicles for chemotherapeutics,516,517 antibiotics,518 and pro- sulfide,552 and chemotherapeutic attachment553,554 have all
teins.519,520 Also, when crosslinked ELPs are seeded with allowed for its further development as a biomaterial. It has
also been used in particle-based555–558 delivery of antibiot- agents.590–592 Tian and coworkers have demonstrated the
ics,556 vaccines,557,558 DNA,555 and proteins.556 As a homo- capacity of a L-PGA-gadolinium complex whose molecular
polymer, it is too physically weak to be used in supportive weight keeps the contrast agent from diffusing out of the
tissue engineering scaffolds, but as a crosslinked hydrogel it vasculature. When tested in rhesus monkeys, the vasculature
has found some promise in soft tissue engineering.559,560 Of- contrast of subjects given the complex was much greater
ten it is blended with other polymers such as PLA,561,562 than those given a small molecular weight contrast agent
PLGA,563 PCL,564 collagen,565 and chitosan566–568 to give (Magnevist) at 2-h post-injection (Fig. 9).593 This complex
composites that are mechanically strong but possess some allows for the use of less contrast agent while getting clearer
hydrophilicity. Research using cPGA as a biomaterial has MRI of small vasculature, which can lead to earlier detection
been limited due to its scarcity. of tumors, atherosclerosis, and gross hemorrhage. L-PGA has
also been combined with other degradable polymers such as
Like cPGA, poly(L-lysine) is synthesized using by bacteria
PCL594,595 and PTMC269,270 for drug delivery applications
and is currently being investigated as a tissue engineering
and collagen596 and chitosan597 to create novel tissue engi-
scaffold and drug delivery device. It has been shown to pos-
neering scaffolds.
sess intrinsic antibacterial,569 antiviral,570 and antitumor
activities571 that make it a very promising polymer. Unfortu- PAA is a highly water-soluble ionic polymer with a greater
nately, its very high positive charge causes it to be rather carboxylate content than PGA or L-PGA because it has one
toxic, which has limited its applicability. It has found some less carbon atom in its backbone. Like poly(glutamic acid),
use in blends with other degradable polymers such as PAA has been found to be degradable by lysosomal
PLA,572 PLGA,573,574 PCL,575 cPGA,576,577 and chitosan.578 enzymes.598 It has been copolymerized with a number of
degradable polymers (PLA,599,600 PCL,601 PEG,600–602 etc.) to
Synthetic Poly(amino acids) create materials that form micellar structures, which have
Synthetic poly(amino acids) have been investigated for a shown promise as smart delivery vehicles. PAA can also be
number of biomedical applications due to their similarity to easily converted to a hydrogel by high energy radiation
naturally occurring proteins. Although several homo- and co- which has shown promise in biomedical applications.603
poly(amino acids) have been synthesized and evaluated; high
Polysaccharides
crystallinity, low degradation rate, unfavorable mechanical
Polysaccharides are polymers composed of monosaccharide
properties, and immunogenicity have kept a majority of
units joined together by glycosidic linkages, a type of ether
these polymers from being utilized clinically.579 However,
bond. Their use as biomaterials has become much more
two poly(amino acids) have been found to function as prom-
common as new biological functions are identified for these
ising biomaterials: poly(L-glutamic acid) L-PGA and poly(as-
materials. Also, the array of materials that can be investi-
partic acid) (PAA).
gated has increased due to new synthetic routes that have
L-PGA is different than cPGA because its amide linkage is been developed for modifying polysaccharides. Their biode-
made with the a-carbon amine group instead of the c-carbon gradability, processability, and bioactivity make polysaccha-
amine group. The shorter distance between amide bonds in rides very promising natural biomaterials.
L-PGA makes it more flexible than its cPGA counterpart. Also,
Human Origin
synthetic techniques allow for L-PGA to be more easily pro-
Hyaluronic acid (HA) was originally isolated by Meyer and
duced. Although L-PGA is typically synthesized as a linear
Palmer in 1934604 and has shown significant promise as a
polymer, the development of new synthesis techniques
biomaterial. HA is a linear anionic polysaccharide consisting
allows for the creation of unique structures like den-
of alternating units of N-acetyl-D-glucosamine and glucuronic
drimers.580 L-PGA is very biocompatible and non-immuno-
acid making it a member of the glycosaminoglycan family.
genic and has been shown to be highly susceptible to degra-
HA is the largest polymer in the family and has been found
dation by lysosomal enzymes.581,582 Due to its negative
in molecular weights up to a few million.605 It has been tra-
charge at physiological pH L-PGA has found significant prom-
ditionally isolated from rooster combs and bovine vitreous
ise as a DNA delivery device.555,583 Also L-PGA’s negative
humor. However, recent advances in microbiological techni-
charge allows for the construction of LBL film assembly with
ques have led to the production of the first animal-free so-
negatively charged polymers such as poly(L-lysine)584,585 and
dium hyaluronate which is synthesized by Bacillius subtilis
chitosan.586 LBLs are relatively new drug delivery devices,
and has been patented by Novozymes Biopharma. HA is
which alternate layers of charged polymer allowing for the
water soluble and forms highly viscous solutions. Synovial
repeated delivery of either positively or negatively charged
fluid and vitreous humor have a large quantity of HA con-
payloads holding significant promise for future biomedical
tributing to these tissues’ viscoelastic properties. HA also
applications. Like cPGA, the reactive side carboxylate of
plays an important structural role in articular cartilage and
L-PGA allows for conjugation. So far this has been used for
skin.
the creation of soluble, long-lasting polymer-chemotherapy
conjugates,587,588 one of which is a Paclitaxel-conjugate HA possesses several properties that make it unique. It has
marketed as OPAXIOV (Cell Therapeutics) that has shown been shown to scavenge free radicals,606 cause bacteriosta-
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promise in phase III clinical trials.589 Conjugates with sis,607 and assist in tissue repair.608 These factors have made
small molecules have yielded degradable MRI contrast it a promising material for tissue engineering applications,
FIGURE 9 Magnetic resonance imaging of rhesus monkeys before contrast injection and at 2 h and 2 days after injection of Mag-
nevist at 0.1 mmol Gd/kg (left) and PG-Gd 0.01 mmol Gd/kg (right). Contrast enhancements of blood vessel, heart, kidney and liver
are clearly visualized at 2 h after PG-Gd injection at a tenth of the dose of Magnevist. By 2 days, the contrast agent has been
mostly cleared with both contrast agents. (Reproduced from ref. 593, with permission from Wiley.)
but HA homopolymer is too weak and structurally fluid to untreated controls. Injectable, crosslinkable polymers such
create a supportive scaffold. To overcome this limitation, HA as MeHA hold tremendous promise for a number of regener-
has been crosslinked with ethyl esters or benzyl esters yield- ative therapies especially in soft tissue engineering because
ing hydrogels, which have been commercialized as HYAFFV
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they can fit defects or structural abnormalities in vivo.
(Fidia Farmaceutici). HYAFFV undergoes hydrolytic degrada-
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HA has also shown promise as a payload delivery vehicle

tion that causes scission of the ester bond converting it back
and has been formed into nanoparticles621–624 and hydro-
to HA. Depending on the extent of esterification, degradation
gels625–628 for this application. These constructs have been
rate can be varied from 1–2 weeks609,610 to 4–5
used to deliver chemotherapeutics,622,624 antibiotics,625 anal-
months.611,612 HYAFFV hydrogels are extremely versatile as
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gesics,626 siRNA,621 and proteins.623,627,628 Composites of HA

shown by their capacity to be fabricated into sheets,613
with PLA,629,630 PLGA,630–632 PCL,633,634 PLL,635–637 and
membranes,614 sponges,615 tubes,612,616,617 or fibers618,619
chitosan.638–641 have all been developed to create delivery
and their usefulness as scaffolds for wound healing618 and
vehicles with enhanced mechanical properties while retain-
the regeneration of the trachea,613 articular cartilage,619
ing excellent biocompatibility.
nasal cartilage,615 respiratory epithelium,614 vascula-
ture,612,616 and nerve tissue.617 Other HA tissue engineering Another human carbohydrate that has shown promise as a
devices include injectables such as SYNVISC ONEV
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biomaterial is chondroitin sulfate (CS). CS is a glycosamino-
(Genzyme) and ORTHOVISCV (Johnson & Johnson), which
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glycan with very similar structure to HA (CS has a sulfate
have been developed to be injected into the knee to relieve group in at least one of its side groups). It has been found to
pain from osteoarthritis and improve joint mobility. A partic- be a major component of the body’s natural, hydrophilic
ularly novel injectable regenerative tissue scaffold has been would healing matrix produced by fibroblasts.642 CS has also
developed by reacting HA with methacrylic anhydride creat- been shown to stimulate the metabolic response of carti-
ing injectable, crosslinkable methacrylated HA (MeHA). Dr. lage,643 possess anti-inflammatory properties,644 and connect
Jason Burdick’s group has shown MeHA possesses tremen- cells to extracellular matrix components.645 Because of CS’s
dous promise as a supportive network for heart tissue that role in natural wound healing and chondrogenesis, it has
is recovering from infarction.620 Figure 10 shows the ease of been studied extensively as a hydrogel for wound dress-
injecting the polymer into the heart wall as well as the ings135,646 and cartilage tissue engineering. In cartilage tissue
thicker resulting walls from sheep given these scaffolds over engineering, the successful regeneration of cartilage requires
FIGURE 10 MeHA injection into a sheep heart after infarction helps prevent subsequent myocardial damage. Multiple injections
(dots) of MeHA were given into the infarcted area (right of dashed line) (left). Representative images of myocardial wall thickness
8 weeks post treatment with no scaffold (top right), MeHA High scaffold (middle right), and MeHA Low scaffold (bottom right).
(Reproduced from ref. 620).
a scaffold that causes the correct phenotypic development of ing, which can be disrupted by the inclusion of bulky side
seeded cells. Because CS plays a crucial role in the natural groups like isobutyl leading to faster polymer degradation.665
development of cartilage, CS,647,648 and CS composites with Due to chitosan’s processability and versatility, it has been
PCL,649 PEG,650,651 collagen,649,652 HA,653 and chitosan654 used in a wide range of biomedical applications.
have been used to direct proper cellular chondrogenesis and
As chitosan is water absorptive, oxygen permeable, and hae-
successful regeneration of cartilage tissue.655
mostatic, it has been extensively studied as a wound dress-
Other carbohydrates of human origin that have shown prom- ing material over the past 20 years.666–668 In addition, chito-
ise as potential biomaterials include heparin, keratin, and san is much more bioactive than many of its degradable
dermatan. polymer counterparts leading to acceleration of wound heal-
ing. Induction of interleukin-8 production from fibro-
Non-Human Origin
blasts,669 stimulatation of macrophages,670,671 and chemoat-
In addition to polysaccharides of human origin, there exist a
traction of neutrophils672 by chitosan are all important steps
number of molecules from other sources that have shown
necessary to initiate the body’s wound healing cascade. Chi-
promise as degradable polymeric biomaterials. Although a
tosan’s intrinsic antibacterial property,673 minimal foreign
number of candidates have been identified, two of particular
body reaction,664 and polymer degradation into N-acetylglu-
interest are chitosan found in crustacean skeletons and
cosamine (a major component of dermal tissue) also assist
alginate found in brown algae.
in rapid wound healing. As chitosan by itself is mechanically
Chitin is a linear polysaccharide consisting of b-1,4-linked N- weak, it is often crosslinked669,674 or combined with other
acetylglucosamine units that forms the exoskeletons of many degradable polymers such as PLA,675 PLGA,676,677 PEG,437,678
arthropods. Chitin is structurally similar to HA and has collagen,679,680 and alginate681,682 which are formed into
shown a similar capacity to accelerate wound healing.656 Chi- films,437 membranes,667,682 sponges,673,678,679 particles,676
tin fibers,657,658 sponges,659,660 and membranes661 have all fibers,675,677,680 and gels668,669,681 to create stronger ban-
been investigated as wound dressing materials. Unfortu- dages. Often times, antibiotics are trapped within chitosan
nately, chitin is insoluble in many common solvents limiting and chitosan-based composite wound healing materials to
prevent bacterial infection.683,684 HemConV dressings
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its processability and potential in biomedical applications.
(HemCon Medical Technologies) are a FDA-approved chito-
To overcome insolubility issues, chitosan, a chitin derivative,
san-based wound dressing that is often used in combat,685
is created by deacetylation of chitin giving a polysaccharide
emergency medicine,686 and dentistry.687
composed of randomly located units of D-glucosamine and N-
acetylglucosamine. A number of enzymes have been found in Chitosan has also been investigated as a delivery device. Chi-
vitro to degrade chitosan including chitosanase, lysozyme, tosan is so hydrophilic that it almost always is either cross-
and papain.662 Physiologically, lysozyme is the primary linked688,689 or blended with other degradable polymers to
degrading enzyme and chitosan degradation rate is depend- yield materials with physiologically relevant release rates.
ent on the degree of acetylation and crystallinity.663 Chitosan Some blended systems include chitosan with PLA,690–692
with lower acetylation percentages have been shown to last PLGA,690,692–695 PEG,692,696–699 collagen,700–702 cPGA,703,704
in vivo up to several months.664 Side group modification has and alginate.705–707 Formation of the polymer composites
been found to be a secondary technique for modulating deg- into particles,690–696,701,703,704,706,707 micelles,698,699 fibers,697
radation rate. Chitosan undergoes significant hydrogen bond- hydrogels,705 and porous scaffolds700–702 has allowed for the
delivery of chemotherapeutics,693,694,698 antibiotics,704 anti- nificant promise when blended or copolymerized with other
inflammatory drugs,697 antipsychotics,690 immunosuppres- degradable polymers. Composites of PLGA,751–753 colla-
sants,691 vaccines,695,706 DNA,696,699,702,703 siRNA,692 and gen,754–757 PLL,758–762 and chitosan746,753,763–765 with algi-
proteins.700,701,705,707 Due to chitosan’s positive charge and nate have been formed into scaffolds composed of films,760
significantly high charge density, its ability to condense DNA sponges,759 fibers,763 adhered micro-
751,755,757,758,761,762
has made it most promising as a DNA/gene delivery mate- spheres, gels,746,753,754,756,764 and freeze
rial. Also, chitosan has been found to be very mucoadhesive, casted porous networks.752,765 These constructs have been
so it has great potential for pulmonary drug delivery.708–710 used in the regenerative engineering of bone,752,757,759 carti-
lage,746,751,753,756,765 corneal,764 liver,758,760 nerve,761 vascu-
The ease with which chitosan can be processed into porous
lar,755 pancreas,762 and connective tissue.754
matrices gives it promise as a tissue engineering scaffold. So
far chitosan and chitosan-composites have been formed into Modification of alginate through reactions with its carboxy-
membranes,500,711–713 sponges,443,714–716 fibers,717–721 fused late side groups have yielded novel, bioactive materials. Spe-
microspheres,722–724 and hydrogels725–729 for regenerative cifically, adding acetal aldehyde crosslinker yields a pH-sensi-
applications. Cellular and acellular scaffolds have been used tive contracting gel,766 and adding laminin peptides causes
for the engineering of bone,443,719,722–724 tendon,717 liga- better adhesion, cell spreading, and neurite outgrowth.767
ment,717,721 cartilage,428,726,728 nerve,714,718,725,729 Further investigation into adding functional groups is under-
500,713,716,720 711,712,715
skin, and vascular tissue. By side group way and will hopefully yield promising hybrid materials that
modification, deacetylation and polymer blending, chitosan can overcome some of the current limitations found with
can be incorporated into scaffolds with a wide range of using alginate.
physical properties but still retain the novel bioactive func-
Although possessing many great properties, alginate has two
tion of chitosan itself.
significant drawbacks as a biomaterial: limited in vivo degra-
Alginate is a linear copolymer composed of b-D-mannuronic dation and poor cellular adhesion. Mammals do not produce
acid and a-L-guluronic acid joined by a 1-4 glycosidic bond. alginate lyase, the enzyme that cleaves alginate polymers,768
The composition and patterning of the monomers is depend- so the in vivo degradation of alginate is very slow. To over-
ent on the source of the polysaccharide. The most common come this issue, alginate is often either irradiated or oxidized
source of alginate is the cell wall of brown algae, and it is through the use of gamma radiation or periodate, respec-
normally extracted via a basic solution followed by acidic tively. Low level radiation causes cleavage at the mannu-
precipitation to achieve alginic acid. These polymers have ronic-gluronic glycoside bond allowing for more rapid poly-
been found to have molecular weights up to 500 kDa. Algi- mer degradation and material solvation.769 Oxidation by
nate has shown great promise in biomedical applications periodate, an ion composed of iodine and oxygen, causes the
due to the reactivity of its carboxylate side groups and its formation of a hemiacetal ring with an open urinate residue
capacity to form spontaneous gelation when exposed to diva- with a hydrolytic bond that can cleave much more quickly
lent cations such as calcium. than the glycoside bond normally does.770 In most tissue en-
gineering applications, the scaffold is designed to provide
The simple and mild reaction conditions necessary for algi-
structure support as well as mimic natural extracellular ma-
nate hydrogel formation has led to its extensive use as a
trix, so poor cell attachment is highly undesirable.771 Most
drug and cell delivery device, wound healing dressing and
cells that do not interact with their surroundings tend to not
tissue engineering scaffold. Although some pure alginate
differentiate and eventually die off. Side group modification
hydrogel-based drug delivery devices have been used to
of alginate with the peptides RGD772,773 and GRGDSP774,775
deliver payloads,730–733 most research has focused on com-
have lead to the development of scaffolds that interact more
posite systems of blends or intermixed constructs (e.g., par-
favorably with transplanted cells and host cells.
ticles within a hydrogel). Alginate-based drug delivery com-
posites include the incorporation of PLGA,734–737 PCL,738,739 In addition to the polymers above, a variety of other polysac-
polyethers,740–742 and chitosan705,743–745 to effectively charides, such as dextran, agarose, mannan, and inulin have
deliver chemotherapeutics,735,739 antibiotics,741 anti-inflam- been investigated for potential as biomaterials.
matory drugs,734,738,740 calcium channel blockers,744 and
proteins.705,736,737,742,745 Supportive alginate-based hydrogels CONCLUSIONS
have also been researched for the delivery of chondro-
There currently exists a wide range of degradable polymers
cytes,746 osteoblasts,747 myoblasts,748 fibroblasts,749 kerati-
that hold potential as biomaterials. With advancements in
nocytes,749 and adipose-derived stem cells.750 Alginate
polymer synthesis techniques, the paradigm of utilizing a
wound healing dressings have been FDA approved and mar-
few well-characterized polymers (e.g., PLGA and collagen)
keted as AlgiDERMV (Bard Medical Division), AlgiSite M
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for all biomedical applications has shifted to using polymers,

(Smith & Nephew), Hyperion Advanced Alginate Dressing
both heavily researched and newly developed, that can fit
KALTOSTATV
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(Hyperion Medical), (ConvaTec), and
VR certain niches (e.g., DNA and RNA association with phos-
Tegaderm (3M).
phoesters and inherent bioactivity of chitosan). In addition,
Although alginate alone is too mechanically weak to be used the emergence of combination polymers holds promise for
as a structural tissue engineering scaffold, it has shown sig- the creation of novel materials that possess desired
properties for highly specific applications. The further devel- 21 Gopferich, A. Macromolecules 1997, 30, 2598–2604.
opment of processing techniques, especially with the assis- 22 Coulembier, O.; Degee, P.; Hedrick, J. L.; Dubois, P. Prog.
tance of computer-aided technology, is allowing for the forma- Polym. Sci. 2006, 31, 723–747.
tion of particles and scaffolds with extremely complex 23 Maurus, P. B.; Kaeding, C. C. Oper. Techn. Sports Med.
architectures that can mimic their biological counterparts. 2004, 12, 158–160.
Although these developments in polymer research have been 24 Katz, A. R.; Turner, R. J. Surg. Gynecol. Obstet. 1970, 131,
critical, it should be noted that the advancements in biological 701–716.
research have led to a better understanding of how biomateri- 25 Burns, A. E. J. Foot Ankle Surg. 1995, 34, 276–282.
als interact with the host on cellular, tissue, organ and sys- 26 Reed, T. M. J. Foot Ankle Surg. 1999, 38, 14–23.
temic levels. The field of degradable polymeric biomaterials 27 Knight, S.; Erggelet, C.; Endres, M.; Sittinger, M.; Kaps, C.;
will only continue to progress if the recent creation of strong Stussi, E. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2007,
83, 50–57.
collaboration teams composed of chemists, biologists, material
28 Wang, L.; Dormer, N. H.; Bonewald, L. F.; Detamore, M. S.
scientists, engineers and clinicians is encouraged.
Tissue Eng. Part A 2010, 16, 1937–1948.
29 Dunne, N.; Jack, V.; O’Hara, R.; Farrar, D.; Buchanan, F. J.
Mater. Sci. Mater. Med. 2010, 21, 2263–2270.
REFERENCES AND NOTES 30 Pihlajamaki, H. K.; Salminen, S. T.; Tynninen, O.; Bostman,
O. M.; Laitinen, O. Calcif. Tissue Int. 2010, 87, 90–98.
1 Williams, D. F. Biomaterials 2009, 30, 5897–5909.
31 Erggelet, C.; Neumann, K.; Endres, M.; Haberstroh, K.; Sit-
2 The Williams Dictionary of Biomaterials; Williams, D. F., Ed.;
tinger, M.; Kaps, C. Biomaterials 2007, 28, 5570–5580.
Liverpool University Press: Liverpool, 1999.
32 Frisbie, D. D.; Lu, Y.; Kawcak, C. E.; DiCarlo, E. F.; Binette,
3 Schmitt, E. E.; Polistina, R. A.; USPTO, Ed.: United States,
F.; McIlwraith, C. W. Am. J. Sports Med. 2009, 37, 71S–80S.
Patent 3,297,033, 1967.
33 Mahmoudifar, N.; Doran, P. M. Biomaterials 2010, 31,
4 Schmitt, E. E.; Polistina, R. A.; USPTO, Ed.: United States,
3858–3867.
Patent 3,463,158, 1963.
34 Pihlajamaki, H.; Tynninen, O.; Karjalainen, P.; Rokkanen, P.
5 Ibim, S. E. M.; Ambrosio, A. M. A.; Kwon, M. S.; El-Amin, S.
J. Biomed. Mater. Res. A 2007, 81, 987–993.
F.; Allcock, H. R.; Laurencin, C. T. Biomaterials 1997, 18,
1565–1569. 35 Xu, L.; Cao, D.; Liu, W.; Zhou, G.; Zhang, W. J.; Cao, Y. Bio-
materials 2010, 31, 3894–3902.
6 Vehof, J. W. M.; Fisher, J. P.; Dean, D.; Waerden, J.-P. C. M.
v. d.; Spauwen, P. H. M.; Mikos, A. G.; Jansen, J. A. J. Biomed. 36 Ohara, T.; Itaya, T.; Usami, K.; Ando, Y.; Sakurai, H.; Honda,
Mater. Res. 2002, 60, 241–251. M. J.; Ueda, M.; Kagami, H. J. Biomed. Mater. Res. A 2010, 94,
800–805.
7 Pangas, S. A.; Saudye, H.; Shea, L. D.; Woodruff, T. K. Tissue
Eng. 2003, 9, 1013–1021. 37 Sayasneh, A.; Johnson, H. J. Obstet. Gynaecol. 2010, 30,
721–724.
8 Holland, T. A.; Bodde, E. W. H.; Baggett, L. S.; Tabata, Y.;
Mikos, A. G.; Jansen, J. A. J. Biomed. Mater. Res. A 2005, 75, 38 Aysan, E.; Bektas, H.; Ersoz, F.; Sari, S.; Kaygusuz, A. Int. J.
156–167. Clin. Exp. Med. 2010, 3, 341–346.
9 Greish, Y. E.; Bender, J. D.; Nair, L. S.; Brown, P. W.; Allcock, 39 Dai, T. T.; Jiang, Z. H.; Li, S. L.; Zhou, G. D.; Kretlow, J. D.;
H. R.; Laurencin, C. T. J. Biomed. Mater. Res. A 2006, 77, Cao, W. G.; Liu, W.; Cao, Y. L. J. Biotechnol. 2010, 150,
416–425. 182–189.
10 West, E. R.; Xu, M.; Woodruff, T. K.; Shea, L. D. Biomaterials 40 Abbushi, A.; Endres, M.; Cabraja, M.; Kroppenstedt, S. N.;
2007, 28, 4439–4448. Thomale, U. W.; Sittinger, M.; Hegewald, A. A.; Morawietz, L.;
Lemke, A.-J.; Bansemer, V.-G.; Kaps, C.; Woiciechowsky, C.
11 Xu, M.; Banc, A.; Woodruff, T. K.; Shea, L. D. Biotechnol. Spine 2008, 33, 1527–1532.
Bioeng. 2009, 103, 378–386.
41 Gunatillake, P.; Mayadunne, R.; Adhikari, R. Biotechnol.
12 Kretlow, J. D.; Spicer, P. P.; Jansen, J. A.; Vacanti, C. A.; Annu. Rev. 2006, 12, 301–347.
Kasper, F. K.; Mikos, A. G. Tissue Eng. Part A 2010, 16,
42 Ceonzo, K.; Gaynor, A.; Shaffer, L.; Kojima, K.; Vacanti, C.
3555–3568.
A.; Stahl, G. L. Tissue Eng. 2006, 12, 301–308.
13 Deng, M.; Nair, L. S.; Nukavarapu, S. P.; Kumbar, S. G.;
43 Pihlajamaki, H.; Salminen, S.; Laitinen, O.; Tynninen, O.;
Jiang, T.; Weikel, A. L.; Krogman, N. R.; Allcock, H. R.; Lauren-
Bostman, O. J. Orthop. Res. 2006, 24, 1597–1606.
cin, C. T. Adv. Funct. Mater. 2010, 20, 2794–2806.
44 Otto, J.; Binnebosel, M.; Pietsch, S.; Anurov, M.; Titkova, S.;
14 Lloyd, A. W. Med. Device Technol. 2002, 13, 18–21.
Ottinger, A. P.; Jansen, M.; Rosch, R.; Kammer, D.; Klinge, U.
15 Nair, L. S.; Laurencin, C. T. Adv. Biochem. Eng. Biotechnol. J. Invest. Surg. 2010, 23, 190–196.
2006, 102, 47–90.
45 Patila, T.; Jokinen, J. J.; Salminen, J.; Kankuri, E.; Harjula,
16 Nair, L. S.; Laurencin, C. T. Prog. Polym. Sci. 2007, 32, A. J. Surg. Res. 2008, 148, 181–184.
762–798.
46 Middleton, J. C.; Tipton, A. J. Biomaterials 2000, 21,
17 Burkersroda, F. v.; Schedl, L.; Gopferich, A. Biomaterials 2335–2346.
2002, 23, 4221–4231.
47 Suuronen, R.; Pohjonen, T.; Hietanen, J.; Lindqvist, C. J.
18 Tamada, J. A.; Langer, R. Proc. Natl. Acad. Sci. USA 1993, Oral Maxillofac. Surg. 1998, 56, 604–614.
90, 552–556.
48 Zielhuis, S. W.; Nijsen, J. F. W.; Seppenwoolde, J.-H.; Bak-
19 Determan, A. S.; Trewyn, B. G.; Lin, V. S.-Y.; Nilsen-Hamil- ker, C. J. G.; Krijger, G. C.; Dullens, H. F. J.; Zonnenbery, B. A.;
ton, M.; Narasimhan, B. J. Control. Release 2004, 100, 97–109. Rijk, P. P. V.; Hennink, W. E.; Schip, A. D. V. G. Biomaterials
20 Wen, X.; Tresco, P. A. Biomaterials 2006, 27, 3800–3809. 2007, 28, 4591–4599.
49 Lu, J.; Jackson, J. K.; Gleave, M. E.; Burt, H. M. Cancer Che- 75 Blaker, J. J.; Bismarck, A.; Boccaccinni, A. R.; YOung, A. M.;
mother. Pharmacol. 2008, 61, 997–1005. Nazhat, S. N. Acta Biomater. 2010, 6, 756–762.
50 Chen, A.-Z.; Li, Y.; Chau, F.-T.; Lau, T.-Y.; Hu, J.-Y.; Zhao, Z.; 76 Tang, L.; Zhao, C.; Xiong, Y.; Wang, A. International Ortho-
Mok, D. K.-w. Acta Biomater. 2009, 5, 2913–2919. paedics 2010, 34, 755–759.
51 Lensen, D.; Breukelen, K. v.; Vriezema, D. M.; Hest, J. C. M. 77 Hasegawa, S.; Neo, M.; Tamura, J.; Fujibayashi, S.; Take-
v. Macromol. Biosci. 2010, 10, 475–480. moto, M.; Shikinami, Y.; Okazaki, K.; Nakamura, T. J. Biomed.
52 Loo, J. S. C.; Oooi, C. P.; Boey, F. Y. C. Biomaterials 2005, Mater. Res. A 2007, 81, 930–938.
26, 1359–1367. 78 Carletti, E.; Endogan, T.; Hasirci, N.; Hasirci, V.; Maniglio, D.;
53 Loo, S. C. J.; Tan, H. T.; Ooi, C. P.; Boey, Y. C. F. Acta Bio- Motta, A.; Migliaresi, C. J. Tissue Eng. Regen. Med., in press.
mater. 2006, 2, 287–296. 79 Yu, N. Y.; Schindeler, A.; Peacock, L.; Mikulec, K.; Baldock,
54 Ueda, H.; Tabata, Y. Adv. Drug Deliv. Rev. 2003, 55, P. A.; Ruys, A. J.; Little, D. G. Eur. Cell Mater. 2010, 22,
501–518. 431–442.
55 Chan, P.-C.; Liu, B.-Y.; Liu, C.-M.; Chou, H.-H.; Ho, M.-H.; Liu, 80 Leung, L.; Chan, C.; Baek, S.; Naguib, H. Biomed. Mater.
H.-C.; Wang, D.-M.; Hou, L.-T. J. Biomed. Mater. Res. A 2007, 2008, 3, 025006.
81, 771–780. 81 Tsallas, A.; Jackson, J.; Burt, H. Cancer Chemother. Pharma-
56 Schofer, M. D.; Fuchs-Winkelmann, S.; Grabedunkel, C.; col., in press.
Wack, C.; Dersch, R.; Rudisile, M.; Wendorff, J. H.; Greiner, A.; 82 Seck, T. M.; Melchels, F. P. W.; Feijen, J.; Grijpma, D. W. J.
Paletta, J. R. J.; Boudriot, U. ScientificWorldJournal 2008, 25, Control. Release 2010, 148, 34–41.
1269–1279. 83 Cai, K.; Yao, K.; Yang, Z.; Qu, Y.; Li, X. J. Mater. Sci. Mater.
57 Shim, I. K.; Jung, M. R.; Kim, K. H.; Seol, Y. J.; Park, Y. J.; Med. 2007, 18, 2017–2024.
Park, W. H.; Lee, S. J. J. Biomed. Mater. Res. Part B: Appl. Bio- 84 Miller, R. A.; Brady, J. M.; Cutright, D. E. J. Biomed. Mater.
mater. 2010, 95, 150–160. Res. 1977, 11, 711–719.
58 Cai, Y. Z.; Wang, L. L.; Cai, H. X.; Qi, Y. Y.; Zou, X. H. J. 85 Middleton, J. C.; Tipton, A. J. Med. Plast. Biomater. 1998,
Biomed. Mater. Res. A 2010, 95, 49–57. 31–38.
59 Ju, Y. M.; Park, K.; Son, J. S.; Kim, J.-J.; Rhie, J.-W.; Han, D. 86 Conn, J.; Oyasu, R.; Welsh, M.; Beal, J. M. Am. J. Surg.
K. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2007, 85, 1974, 128, 19–23.
252–260. 87 Clavert, P.; Warner, J. J. P. Arthrosc. J. Arthrosc. Relat.
60 Tanaka, Y.; Yamaoka, H.; Nishizawa, S.; Nagata, S.; Ogasa- Surg. 2005, 21, 200–203.
wara, T.; Asawa, Y.; Fujihara, Y.; Takato, T.; Hoshi, K. Biomate- 88 Betancourt, T.; Brown, B.; Brannon-Peppas, L. Nanomedi-
rials 2010, 31, 4506–4516. cine 2007, 2, 219–232.
61 Inui, A.; Kokubu, T.; Makino, T.; Nagura, I.; Toyokawa, N.; 89 Liu, J.; Qiu, Z.; Wang, S.; Zhou, L.; Zhang, S. Biomed.
Sakata, R.; Kotera, M.; Nishino, T.; Fujioka, H.; Kurosaka, M. Mater. 2010, 5, 065002.
Int. Orthopaed. 2010, 34, 1327–1332. 90 Gavenis, K.; Schneider, U.; Groll, J.; Schmidt-Rohlfing, B.
62 Hu, J.; Sun, X.; Ma, H.; Xie, C.; Chen, Y. E.; Ma, P. X. Bioma- Int. J. Artif. Organs 2010, 33, 45–53.
terials 2010, 31, 7971–7977. 91 Ye, M.; Kim, S.; Park, K. J. Control. Release 2010, 146,
63 Wang, H. B.; Mullins, M. E.; Cregg, J. M.; McCarthy, C. W.; 241–260.
Gilbert, R. J. Acta Biomater. 2010, 6, 2970–2978. 92 Andreas, K.; Zehbe, R.; Kazubek, M.; Grzeschik, K.; Stern-
64 Francois, S.; Chakfe, N.; Durand, B.; Laroche, G. Acta Bio- berg, N.; Baumler, H.; Schubert, H.; Sittinger, M.; Ringe, J. Acta
mater. 2009, 5, 2418–2428. Biomater. 2011, 7, 1485–1495.
65 Wang, P.; Hu, J.; Ma, P. X. Biomaterials 2009, 30, 2735–2740. 93 Jiang, W.; Schwendeman, S. P. Mol. Pharm. 2008, 5,
66 Wright, L. D.; Young, R. T.; Andric, T.; Freeman, J. W. 808–817.
Biomed. Mater. 2010, 5, 055006. 94 Quintilio, W.; Takata, C. S.; Sant’Anna, O. A.; Costa, M. H. B.
67 Wei, G.; Jin, Q.; Giannobile, W. V.; Ma, P. X. Biomaterials D.; Raw, I. Curr. Drug Deliv. 2009, 6, 297–304.
2007, 28, 2087–2096. 95 Thomas, C.; Gupta, V.; Ahsan, F. Pharm. Res. 2010, 27,
68 Lu, X. L.; Sun, Z. J.; Cai, W.; Gao, Z. Y. J. Mater. Sci. Mater. 905–919.
Med. 2008, 19, 395–399. 96 Jeong, Y.-I.; Na, H.-S.; Seo, D.-H.; Kim, D.-G.; Lee, H.-C.;
69 Idris, S. B.; Arvidson, K.; Plikk, P.; Ibrahim, S.; Finne-Wis- Jang, M.-K.; Na, S.-K.; Roh, S.-H.; Kim, S.-I.; Nah, J.-W. Int. J.
trand, A.; Albertsson, A.-C.; Bolstad, A. I.; Mustafa, K. J. Pharm. 2008, 352, 317–323.
Biomed. Mater. Res. Part A 2010, 94, 631–639. 97 Jhunjhunwala, S.; Raimondi, G.; Thomson, A. W.; Little, S.
70 Luo, X.; Qiu, D.; He, B.; Wang, L.; Luo, J. Macromol. Biosci. R. J. Control. Release 2009, 133, 191–197.
2006, 6, 373–381. 98 Farazuddin, M.; Alam, M.; Khan, A. A.; Khan, N.; Parvez, S.;
71 Pu, F.; Rhodes, N. P.; Bayon, Y.; Chen, R.; Brans, G.; Benne, Dutt, G. U.; Mohammad, O. J. Drug Target. 2010, 18, 45–52.
R.; Hunt, J. A. Biomaterials 2010, 31, 4330–4340. 99 Tang, Y.; Singh, J. Int. J. Pharm. 2008, 357, 119–125.
72 Tan, H.; Wu, J.; Huang, D.; Gao, C. Macromol. Biosci. 2010, 100 Vega, E.; Gamisans, F.; Garcia, M. L.; Chauvet, A.; Lacou-
10, 156–163. lonche, F.; Egea, M. A. J. Pharm. Sci. 2008, 97, 5306–5317.
73 Grundmann, S.; Royen, N. v.; Pasterkamp, G.; Gonzalez, N.; 101 Zolnik, B. S.; Burgess, D. J. J. Control. Release 2008, 127,
Tijsma, E. J.; Piek, J. J.; Hoefer, I. E. J. Am. College Cardiol. 137–145.
2007, 50, 351–358. 102 Eperon, S.; Bossy-Nobs, L.; Petropoulos, I. K.; Gurny, R.;
74 Luderer, F.; Lobler, M.; Rohm, H. W.; Gocke, C.; Kunna, K.; Guex-Crosier, Y. Int. J. Pharm. 2008, 352, 240–247.
Kock, K.; Kroemer, H. K.; Weitschies, W.; Schmitz, K.-P.; Stern- 103 Murata, N.; Takashima, Y.; Toyoshima, K.; Yamamoto, M.;
berg, K. J. Biomater. Appl., in press. Okada, H. J. Control. Release 2008, 126, 246–254.
104 Singh, A.; Nie, H.; Ghosn, B.; Qin, H.; Kwak, L. W.; Roy, K. 132 Blackwood, K. A.; McKean, R.; Canton, I.; Freeman, C. O.;
Mol. Ther. 2008, 16, 2011–2021. Franklin, K. L.; Cole, D.; Brook, I.; Farthing, P.; Rimmer, S.; Hay-
105 Patil, Y.; Panyam, J. Int. J. Pharm. 2009, 367, 195–203. cock, J. W.; Ryan, A. J.; MacNeil, S. Biomaterials 2008, 29,
3091–3104.
106 Berkland, C.; Pollauf, E.; Varde, N.; Pack, D. W.; Kim, K.
Pharm. Res. 2007, 24, 1007–1013. 133 Li, J.; Li, L.; Yu, H.; Cao, H.; Gao, C.; Gong, Y. ASAIO J.
2006, 52, 321–327.
107 Kim, B. S.; Oh, J. M.; Hyun, H.; Kim, K. S.; Lee, S. H.; Kim,
Y. H.; Park, K.; Lee, H. B.; Kim, M. S. Mol. Pharm. 2009, 6, 134 Wen, F.; Chang, S.; Toh, Y. C.; Arooz, T.; Zhuo, L.; Teoh, S.
353–365. H.; Yu, H. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2008,
108 Haddadi, A.; Aboofazeli, R.; Erfan, M.; Farboud, E. S. J. 87, 154–162.
Microencapsul. 2008, 25, 379–386. 135 Wang, W.; Zhang, M.; Lu, W.; Zhang, X.; Ma, D.; Rong, X.;
109 Xie, J.; Wang, C.-H. Pharm. Res. 2006, 23, 1817–1826. Yu, C.; Jin, Y. Tissue Eng. Part C Methods 2010, 16, 269–279.
110 Ionescu, L. C.; Lee, G. C.; Sennett, B. J.; Burdick, J. A.; 136 Bhang, S. H.; Lim, J. S.; Choi, C. Y.; Kwon, Y. K.; Kim, B.-S.
Mauck, R. L. Biomaterials 2010, 31, 4113–4120. J. Biomater. Sci. Polym. Ed. 2007, 18, 223–239.
111 Fu, K.; Pack, D. W.; Klibanov, A. M.; Langer, R. Pharm. Res. 137 He, L.; Zhang, Y.; Zeng, C.; Ngiam, M.; Liao, S.; Quan, D.;
2000, 17, 100–106. Zeng, Y.; Lu, J.; Ramakrishna, S. Tissue Eng. Part C Methods
2009, 15, 243–255.
112 Ding, A. G.; Schwendeman, S. P. Pharm. Res. 2008, 25,
2041–2052. 138 Olson, H. E.; Rooney, G. E.; Gross, L.; Nesbitt, J. J.; Galvin,
K. E.; Knight, A.; Chen, B.; Yaszemski, M. J.; Windebank, A. J.
113 Chung, H. J.; Kim, I. K.; Kim, T. G.; Park, T. G. Tissue Eng.
Tissue Eng. Part A 2009, 15, 1797–1805.
Part A 2008, 14, 607–615.
139 Abe, H.; Doi, Y. Int. J. Biol. Macromol. 1999, 25, 185–192.
114 Zhu, X. H.; Lee, L. Y.; Jackson, J. S. H.; Tong, Y. W.; Wang,
C.-H. Biotechnol. Bioeng. 2008, 100, 998–1009. 140 Zhijiang, C.; Zhihong, W. J. Mater. Sci. 2007, 42,
5886–5890.
115 Simpson, R. L.; Wiria, F. E.; Amis, A. A.; Chua, C. K.;
Leong, K. F.; Hansen, U. N.; Chandrasekaran, M.; Lee, M. W. 141 Laeger, T.; Metges, C. C.; Kuhla, B. Appetite 2010, 54,
J. Biomed. Mater. Res. Part B: Appl. Biomater. 2008, 84, 450–455.
17–25. 142 Zhijiang, C. J. Mater. Sci. Mater. Med. 2006, 17, 1297–1303.
116 Jabbarzadeh, E.; Starnes, T.; Khan, Y. M.; Jiang, T.; Wirtel, 143 Suwantong, O.; Waleetorncheepsawat, S.; Sanchavanakit,
A. J.; Deng, M.; Lv, Q.; Nair, L. S.; Doty, S. B.; Laurencin, C. T. N.; Pavasant, P.; Cheepsunthorn, P.; Bunaprasert, T.; Supaphol,
Proc. Natl. Acad. Sci. USA 2008, 105, 11099–11104. P. Int. J. Biol. Macromol. 2007, 40, 217–223.
117 Spalazzi, J. P.; Vyner, M. C.; Jacobs, M. T.; Moffat, K. L.; 144 Kalbermatten, D. F.; Erba, P.; Mahay, D.; Wiberg, M.;
Lu, H. H. Clin. Orthop. Relat. Res. 2008, 466, 1938–1948. Pierer, G.; Terenghi, G. J. Hand Surg. Eur. vol. 2008, 33,
118 Arnold, M. M.; Gorman, E. M.; Schieber, L. J.; Munson, E. 587–594.
J.; Berkland, C. J. Control. Release 2007, 121, 100–109. 145 Bernd, H. E.; Kunze, C.; Freier, T.; Sternberg, K.; Kramer,
119 Narayan, D.; Venkatraman, S. S. J. Biomed. Mater. Res. A S.; Behrend, D.; Prall, F.; Donat, M.; Kramp, B. Acta Otolaryn-
2008, 87, 710–718. gol. 2009, 129, 1010–1017.
120 Ren, J.; Ren, T.; Zhao, P.; Huang, Y.; Pan, K. J. Biomater. 146 Gredes, T.; Spassov, A.; Mai, R.; Mack, H.; Loster, B. W.;
Sci. Polym. Ed. 2007, 18, 505–517. Mazurkiewicz-Janik, M.; Kubein-Meesenburg, D.; Fanghanel, J.;
121 Bashur, C. A.; Dahlgren, L. A.; Goldstein, A. S. Biomaterials Gedrange, T. J. Physiol. Pharmacol. 2009, 60, 77–81.
2006, 27, 5681–5688. 147 Ahmed, T.; Marcal, H.; Lawless, M.; Wanandy, N. S.;
122 Kumbar, S. G.; Nukavarapu, S. P.; James, R.; Nair, L. S.; Chiu, A.; Foster, L. J. R. Biomacromolecules 2010, 11,
Laurencin, C. T. Biomaterials 2008, 29, 4100–4107. 2707–2715.
123 Moffat, K. L.; Kwei, A. S.-P.; Spalazzi, J. P.; Doty, S. B.; Lev- 148 Pouton, C. W.; Akhtar, S. Adv. Drug Deliv. Rev. 1996, 18,
ine, W. N.; Lu, H. H. Tissue Eng. Part A 2009, 15, 115–126. 133–162.
124 Aviss, K. J.; Gough, J. E.; Downes, S. Euro. Cells Mater. 149 Cool, S. M.; Kenny, B.; Wu, A.; Nurcombe, V.; Trau, M.;
2010, 19, 193–204. Cassady, A. I.; Grondahl, L. J. Biomed. Mater. Res. A 2007, 82,
599–610.
125 Ge, Z.; Wang, L.; Heng, B. C.; Tian, X.-F.; Lu, K.; Fan, V. T.
W.; Yeo, J. F.; Cao, T.; Tan, E. J. Biomater. Appl. 2008, 23, 150 Ke, Y.; Wang, Y. J.; Ren, L.; Zhao, Q. C.; Huang, W. Acta
533–547. Biomater. 2010, 6, 1329–1336.
126 Lee, M.; Wu, B. M.; Dunn, J. C. Y. J. Biomed. Mater. Res. A 151 Liu, J.; Zhao, B.; Zhang, Y.; Lin, Y.; Hu, P.; Ye, C. J.
2008, 87, 1010–1016. Biomed. Mater. Res. A 2010, 94, 603–610.
127 Yoon, J. J.; Chung, H. J.; Lee, H. J.; Park, T. G. J. Biomed. 152 Rathbone, S.; Furrer, P.; Lubben, J.; Zinn, M.; Cartmell, S.
Mater. Res. A 2006, 79, 934–942. J. Biomed. Mater. Res. A 2010, 93, 1391–1403.
128 Perron, J. K.; Naguib, H. E.; Daka, J.; Chawla, A.; Wilkins, 153 Ji, Y.; Li, X.-T.; Chen, G.-Q. Biomaterials 2008, 29,
R. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2009, 91, 3807–3814.
876–886. 154 Zorlutana, P.; Tezcaner, A.; Hasirci, V. J. Biomater. Sci.
129 Lee, M.; Dunn, J. C. Y.; Wu, B. M. Biomaterials 2005, 26, Polym. Ed. 2008, 19, 399–410.
4281–4289. 155 Yucel, D.; Kose, G. T.; Hasirci, V. Biomaterials 2010, 31,
130 Xie, J.; Li, X.; Lipner, J.; Manning, C. N.; Schwartz, A. G.; 1596–1603.
Thomopoulos, S.; Xia, Y. Nanoscale 2010, 2, 923–926. 156 Yang, C.; Plackett, D.; Needham, D.; Burt, H. M. Pharm.
131 Stoll, C.; John, T.; Endres, M.; Rosen, C.; Kaps, C.; Kohl, B.; Res. 2009, 26, 1644–1656.
Sittinger, M.; Ertel, W.; Schulze-Tanzil, G. J. Orthop. Res. 2010, 157 Errico, C.; Bartoli, C.; Chiellini, F.; Chiellini, E. J. Biomed.
28, 1170–1177. Biotechnol. 2009, 2009, 571702.
158 Huang, W.; Shi, X.; Ren, L.; Du, C.; Wang, Y. Biomaterials 186 Zuo, Y.; Yang, F.; Wolke, J. G. C.; Li, Y.; Jansen, J. A. Acta
2010, 31, 4278–4285. Biomater. 2010, 6, 1238–1247.
159 Dias, M.; Antunes, M. C. M.; Santos, A. R.; Felisberti, M. I. 187 Mountziaris, P. M.; Tzouanas, S. N.; Mikos, A. G. Biomate-
J. Mater. Sci. Mater. Med. 2008, 19, 3535–3544. rials 2010, 31, 1666–1675.
160 Dai, S.; Li, Z. Biomacromolecules 2008, 9, 1883–1893. 188 Hayami, J. W. S.; Surrao, D. C.; Waldman, S. D.; Amsden,
161 Wu, L.; Wang, L.; Wang, X.; Xu, K. Acta Biomater. 2010, 6, B. G. J. Biomed. Mater. Res. A 2010, 92, 1407–1420.
1079–1089. 189 Vaquette, C.; Kahn, C.; Frochot, C.; Nouvel, C.; Six, J.-L.;
162 Xue, L.; Dai, S.; Li, Z. Biomaterials 2010, 31, 8132–8140. Isla, N. D.; Luo, L.-H.; Cooper-White, J.; Rahouadj, R.; Wang, X.
163 Chen, C.; Yu, C. H.; Cheng, Y. C.; Yu, P. H. F.; Cheung, M. J. Biomed. Mater. Res. A 2010, 94, 1270–1282.
K. Biomaterials 2006, 27, 4804–4814. 190 Li, W.-J.; Chiang, H.; Kuo, T.-F.; Lee, H.-S.; Jiang, C.-C.;
164 Chen, C.; Cheng, Y. C.; Yu, C. H.; Chan, S. W.; Cheung, M. Tuan, R. S. J. Tissue Eng. Regen. Med. 2009, 3, 1–10.
K.; Yu, P. H. F. J. Biomed. Mater. Res. A 2008, 87, 290–298. 191 Jeong, S. I.; Lee, A.-Y.; Lee, Y. M.; Shin, H. J. Biomater.
165 Li, X.; Liu, K. L.; Wang, M.; Wong, S. Y.; Tjiu, W. C.; He, C. Sci. Polym. Ed. 2008, 19, 339–357.
B.; Goh, S. H.; Li, J. Acta Biomater. 2009, 5, 2002–2012. 192 Nisbet, D. R.; Rodda, A. E.; Horne, M. K.; Forsythe, J. S.;
166 Patlolla, A.; Collins, G.; Arinzeh, T. L. Acta Biomater. 2010, Finkelstein, D. I. Biomaterials 2009, 30, 4573–4580.
6, 90–101. 193 Liu, J.-J.; Wang, C.-Y.; Wang, J.-G.; Ruan, H.-J.; Fan, C.-Y.
167 Darney, P. D.; Monroe, S. E.; Klaisle, C. M.; Alvarado, A. J. Biomed. Mater. Res. A 2011, 96, 13–20.
Am. J. Obstet. Gynecol. 1989, 160, 1292–1295. 194 Heydarkhan-Hagvall, S.; Schenke-Layland, K.; Dhanasopon,
168 Ito, Y.; Ochii, Y.; Fukushima, K.; Sugioka, N.; Takada, K. Int. A. P.; Rofail, F.; Smith, H.; Wu, B. M.; Shemin, R.; Beygui, R. E.;
J. Pharm. 2010, 384, 53–59. MacLellan, W. R. Biomaterials 2008, 29, 2907–2914.
169 Lee, W. L.; Foo, W. L.; Widjaja, E.; Loo, S. C. J. Acta Bio- 195 Lee, J.; Choi, W. I.; Tae, G.; Kim, Y. H.; Kang, S. S.; Kim, S.
mater. 2010, 6, 1342–1352. E.; Kim, S.-H.; Jung, Y.; Kim, S. H. Acta Biomater. 2011, 7,
244–257.
170 Rieger, J.; Freichels, H.; Imberty, A.; Putaux, J.-L.; Delair,
T.; Jerome, C.; Auzely-Velty, R. Biomacromolecules 2009, 10, 196 He, S.; Timmer, M. D.; Yaszemski, M. J.; Yasko, A. W.;
651–657. Engel, P. S.; Mikos, A. G. Polymer 2001, 42, 1251–1260.
171 Richter, A.; Olbrich, C.; Krause, M.; Kissel, T. Int. J. Pharm. 197 Christenson, E. M.; Soofi, W.; Holm, J. L.; Cameron, N. R.;
2010, 389, 244–253. Mikos, A. G. Biomacromolecules 2007, 8, 3806–3814.
172 Singh, J.; Pandit, S.; Bramwell, V. W.; Alpar, H. O. Methods 198 Kim, C. W.; Talac, R.; Lu, L.; Moore, M. J.; Currier, B. L.;
2006, 38, 96–105. Yaszemski, M. J. J. Biomed. Mater. Res. A 2008, 85, 1114–1119.
173 Mundargi, R. C.; Srirangarajan, S.; Agnihotri, S. A.; Patil, S. 199 Young, S.; Patel, Z. S.; Kretlow, J. D.; Murphy, M. B.;
A.; Ravindra, S.; Setty, S. B.; Aminabhavi, T. M. J. Control. Mountziaris, P. M.; Baggett, L. S.; Ueda, H.; Tabata, Y.; Jansen,
Release 2007, 119, 59–68. J. A.; Wong, M.; Mikos, A. G. Tissue Eng. Part A 2009, 15,
2347–2362.
174 Huang, M. J.; Gou, M. L.; Qian, Z. Y.; Dai, M.; Li, X. Y.;
Cao, M.; Wang, K.; Zhao, J.; Yang, J. L.; Lu, Y.; Tu, M. J.; Wei, 200 Haesslein, A.; Ueda, H.; Hacker, M. C.; Jo, S.; Ammon, D.
Y. Q. J. Biomed. Mater. Res. A 2008, 86, 979–986. M.; Borazjani, R. N.; Kunzler, J. F.; Salamone, J. C.; Mikos, A.
175 Hassan, A. S.; Sapin, A.; Lamprecht, A.; Emond, E.; Gha- G. J. Control. Release 2006, 114, 251–260.
zouani, F. E.; Maincent, P. Eur. J. Pharm. Biopharm. 2009, 73, 201 Ueda, H.; Hacker, M. C.; Haesslein, A.; Jo, S.; Ammon, D.
337–344. M.; Borazjani, R. N.; Kunzler, J. F.; Salamone, J. C.; Mikos, A.
176 Huang, M.-H.; Chou, A.-H.; Lien, S.-P.; Chen, H.-W.; Huang, G. J. Biomed. Mater. Res. A 2007, 83, 656–666.
C.-Y.; Chen, W.-W.; Chong, P.; Liu, S.-J.; Leng, C.-H. J. Biomed. 202 Hacker, M. C.; Haesslein, A.; Ueda, H.; Foster, W. J.; Garcia,
Mater. Res. Part B: Appl. Biomater. 2009, 90, 832–841. C. A.; Ammon, D. M.; Borazjani, R. N.; Kunzler, J. F.; Salamone,
177 Garkhal, K.; Verma, S.; Tikoo, K.; Kumar, N. J. Biomed. J. C.; Mikos, A. G. J. Biomed. Mater. Res. A 2009, 88, 976–989.
Mater. Res. A 2007, 82, 747–756. 203 Lee, K.-W.; Wang, S.; Yaszemski, M. J.; Lu, L. Biomaterials
178 Danhier, F.; Vroman, B.; Lecouturier, N.; Crokart, N.; Pour- 2008, 29, 2839–2848.
celle, V.; Freichels, H.; Jerome, C.; Marchand-Brynaert, J.; 204 Jayabalan, M.; Shalumon, K. T.; Mitha, M. K.; Ganesan, K.;
Feron, O.; Preat, V. J. Control. Release 2009, 140, 166–173. Epple, M. Acta Biomater. 2010, 6, 763–775.
179 Li, W.-J.; Cooper, J. A.; Mauck, R. L.; Tuan, R. S. Acta Bio- 205 Lee, K.-W.; Wang, S.; Dadsetan, M.; Yaszemski, M. J.; Lu,
mater. 2006, 2, 377–385. L. Biomacromolecules 2010, 11, 682–689.
180 Luciani, A.; Coccoli, V.; Orsi, S.; Ambrosio, L.; Netti, P. A. 206 Mistry, A. S.; Mikos, A. G.; Jansen, J. A. J. Biomed. Mater.
Biomaterials 2008, 29, 4800–4807. Res. A 2007, 83, 940–953.
181 Chung, S.; Ingle, N. P.; Montero, G. A.; Kim, S. H.; King, M. 207 Mistry, A. S.; Cheng, S. H.; Yeh, T.; Christenson, E.; Jan-
W. Acta Biomater. 2010, 6, 1958–1967. sen, J. A.; Mikos, A. G. J. Biomed. Mater. Res. A 2009, 89,
182 Pankajakshan, D.; Philipose, L. P.; Palakkal, M.; Krishnan, 68–79.
K.; Krishnan, L. K. J. Biomed. Mater. Res. Part B: Appl. Bio- 208 Mistry, A. S.; Pham, Q. P.; Schouten, C.; Yeh, T.; Christen-
mater. 2008, 87, 570–579. son, E. M.; Mikos, A. G.; Jansen, J. A. J. Biomed. Mater. Res. A
183 Chen, H.; Huang, J.; Yu, J.; Liu, S.; Ge, P. Int. J. Biol. Mac- 2010, 92, 451–462.
romol. 2011, 48, 13–19. 209 Danti, S.; D’Alessandro, D.; Pietrabissa, A.; Petrini, M.; Ber-
184 Guarino, V.; Ambrosio, L. Acta Biomater. 2008, 4, rettini, S. J. Biomed. Mater. Res. A 2010, 92, 1343–1356.
1778–1787. 210 Nguyen, C.; Young, S.; Kretlow, J. D.; Mikos, A. G.; Wong,
185 Plikk, P.; Malberg, S.; Albertsson, A.-C. Biomacromolecules M. J. Oral Maxillofac. Surg. 2011, 69, 11–18.
2009, 10, 1259–1264. 211 Hill, J. W. J. Am. Chem. Soc. 1932, 54, 4105–4106.
212 Rosen, H. B.; Chang, J.; Wnek, G. E.; Linhardt, R. J.; 240 Murthy, N.; Xu, M.; Schuck, S.; Kunisawa, J.; Shastri, N.;
Langer, R. Biomaterials 1983, 4, 131–133. Frechet, J. M. J. Proc. Natl. Acad. Sci. USA 2003, 100,
213 Katti, D. S.; Lakshmi, S.; Langer, R.; Laurencin, C. T. Adv. 4995–5000.
Drug Deliv. Rev. 2002, 54, 933–961. 241 Standley, S. M.; Kwon, Y. J.; Murthy, N.; Kunisawa, J.;
214 Agueros, M.; Ruiz-Gaton, L.; Vauthier, C.; Bouchemal, K.; Shastri, N.; Guillaudeu, S. J.; Lau, L.; Frechet, J. M. J. Biocon-
Espuelas, S.; Ponchel, G.; Irache, J. M. Eur. J. Pharm. Sci. 2009, jug. Chem. 2004, 15, 1281–1288.
38, 405–413. 242 Yang, S. C.; Bhide, M.; Crispe, I. N.; Pierce, R. H.; Murthy,
215 Agueros, M.; Zabaleta, V.; Espuelas, S.; Campanero, M. A.; N. Bioconjug. Chem. 2008, 19, 1164–1169.
Irache, J. M. J. Control. Release 2010, 145, 2–8. 243 Heffernan, M. J.; Kasturi, S. P.; Yang, S. C.; Pulendran, B.;
216 Krasko, M. Y.; Golenser, J.; Nyska, A.; Nyska, M.; Brin, Y. Murthy, N. Biomaterials 2009, 30, 910–918.
S.; Domb, A. J. J. Control. Release 2007, 117, 90–96. 244 Seshadri, G.; Sy, J. C.; Brown, M.; Dikalov, S.; Yang, S. C.;
217 Brin, Y. S.; Golenser, J.; Mizrahi, B.; Maoz, G.; Domb, A. J.; Murthy, N.; Davis, M. E. Biomaterials 2010, 31, 1372–1379.
Peddada, S.; Tuvia, S.; Nyska, A.; Nyska, M. J. Control. Release 245 Bjork, V. O. Scand. J. Thorac. Cardiovasc. Surg. 1969, 3, 1–10.
2008, 131, 121–127. 246 Larmi, T. K.; Karkola, P. J. Thorac. Cardiovasc. Surg. 1974,
218 Kipper, M. J.; Wilson, J. H.; Wannemuehler, M. J.; Nara- 68, 66–69.
simhan, B. J. Biomed. Mater. Res. A 2006, 76, 798–810. 247 Moreau, J. L.; Kesselman, D.; Fisher, J. P. J. Biomed.
219 Salman, H. H.; Irache, J. M.; Gamazo, C. Vaccine 2009, 27, Mater. Res. A 2007, 81, 594–602.
4784–4790. 248 Betz, M. W.; Modi, P. C.; Caccamese, J. F.; Coletti, D. P.;
220 Carrillo-Conde, B.; Schiltz, E.; Yu, J.; Minion, F. C.; Phillips, Sauk, J. J.; Fisher, J. P. J. Biomed. Mater. Res. A 2008, 86,
G. J.; Wannemuehler, M. J.; Narasimhan, B. Acta Biomater. 662–670.
2010, 6, 3110–3119. 249 Falco, E. E.; Roth, J. S.; Fisher, J. P. J. Surg. Res. 2008,
221 Tamayo, I.; Irache, J. M.; Mansilla, C.; Ochoa-Reparaz, J.; 149, 76–83.
Lasarte, J. J.; Gamazo, C. Clin. Vaccine Immunol. 2010, 17, 250 Choi, N. S.; Heller, J.; USPTO, Ed.: United States, Patent
1356–1362. 4,093,709, 1978.
222 Sun, L.; Zhou, S.; Wang, W.; Su, Q.; Li, X.; Weng, J. J. 251 Qi, M.; Li, X.; Yang, Y.; Zhou, S. Eur. J. Pharm. Biopharm.
Mater. Sci. Mater. Med. 2009, 20, 2035–2042. 2008, 70, 445–452.
223 Petersen, L. K.; Sackett, C. K.; Narasimhan, B. Acta Bio-
252 Wang, C.; Ge, Q.; Ting, D.; Nguyen, D.; Shen, H.-R.; Chen,
mater. 2010, 6, 3873–3881.
J.; Eisen, H. N.; Heller, J.; Langer, R.; Putnam, D. Nat. Mater.
224 Ulery, B. D.; Phanse, Y.; Sinha, A.; Wannemuehler, M. J.; 2004, 3, 190–196.
Narasimhan, B.; Bellaire, B. H. Pharm. Res. 2009, 26, 683–690.
253 Nguyen, D. N.; Raghavan, S. S.; Tashima, L. M.; Lin, E. C.;
225 Petersen, L. K.; Xue, L.; Wannemuehler, M. J.; Rajan, K.; Fredette, S. J.; Langer, R. S.; Wang, C. Biomaterials 2008, 29,
Narasimhan, B. Biomaterials 2009, 30, 5131–5142. 2783–2793.
226 Manoharan, C.; Singh, J. J. Pharm. Sci. 2009, 98, 254 Polak, M. B.; Valamanesh, F.; Felt, O.; Torriglia, A.; Jeanny,
4237–4250. J.-C.; Bourges, J.-L.; Rat, P.; Thomas-Doyle, A.; BenEzra, D.;
227 Tian, Y.; Li, L.; Gao, X.; Deng, J.; Stephens, D.; Robinson, Gurny, R.; Behar-Cohen, F. Invest. Opththalmol. Visual Sci.
D.; Chang, H. Drug Dev. Ind. Pharm. 2002, 28, 897–903. 2008, 49, 2993–3003.
228 Jain, J. P.; Modi, S.; Kumar, N. J. Biomed. Mater. Res. A 255 Ekholm, M.; Helander, P.; Hietanen, J.; Lindqvist, C.; Salo,
2008, 84, 740–752. A.; Kellomaki, M.; Suuronen, R. Int. J. Oral Maxillofac. Surg.
229 Determan, A. S.; Wilson, J. H.; Kipper, M. J.; Wannemueh- 2006, 35, 631–635.
ler, M. J.; Narasimhan, B. Biomaterials 2006, 27, 3312–3320. 256 Zhang, Z.; Kuijer, R.; Bulstra, S. K.; Grijpma, D. W.; Feijen,
230 Torres, M. P.; Vogel, B. M.; Narasimhan, B.; Mallapragada, J. Biomaterials 2006, 27, 1741–1748.
S. K. J. Biomed. Mater. Res. A 2006, 76, 102–110. 257 Pego, A. P.; Luyn, M. J. A. V.; Brouwer, L. A.; Wachem, P.
231 Torres, M. P.; Determan, A. S.; Anderson, G. L.; Mallapra- B. V.; Poot, A. A.; Grijpma, D. W.; Feijen, J. J. Biomed. Mater.
gada, S. K.; Narasimhan, B. Biomaterials 2007, 28, 108–116. Res. A 2003, 67, 1044–1054.
232 Weiner, A. A.; Shuck, D. M.; Bush, J. R.; Shastri, V. P. Bio- 258 Zhang, Z.; Foks, M. A.; Grijpma, D. W.; Feijen, J. J. Control.
materials 2007, 28, 5259–5270. Release 2005, 101, 392–394.
233 Tarcha, P. J.; Su, L.; Baker, T.; Langridge, D.; Shastri, V.; 259 Habraken, W. J. E. M.; Zhang, Z.; Wolke, J. G. C.; Grijpma,
Langer, R. J. Polym. Sci. Part A: Polym. Chem. 2001, 39, D. W.; Mikos, A. G.; Feijen, J.; Jansen, J. A. Biomaterials 2008,
4189–4195. 29, 2464–2476.
234 Weiner, A. A.; Bock, E. A.; Gipson, M. E.; Shastri, V. P. Bio- 260 Kluin, O. S.; Mei, H. C. v. d.; Busscher, H. J.; Neut, D. Bio-
materials 2008, 29, 2400–2407. materials 2009, 30, 4738–4742.
235 Weiner, A. A.; Moore, M. C.; Walker, A. H.; Shastri, V. P. 261 Neut, D.; Kluin, O. S.; Crielaard, B. J.; Mei, H. C. V. d.;
Int. J. Pharm. 2008, 360, 107–114. Busscher, H. J.; Grijpma, D. W. Acta Orthop. 2009, 80, 514–519.
236 Heffernan, M. J.; Murthy, N. Bioconjug. Chem. 2005, 16, 262 Timbart, L.; Tse, M. Y.; Pang, S. C.; Babasola, O.; Amsden,
1340–1342. B. G. Macromol. Biosci. 2009, 9, 786–794.
237 Lee, S.; Yang, S. C.; Heffernan, M. J.; Taylor, W. R.; Mur- 263 Bat, E.; Feijen, J.; Grijpma, D. W. Biomacromolecules 2010,
thy, N. Bioconjug. Chem. 2007, 18, 4–7. 11, 2692–2699.
238 Lee, S.; Yang, S. C.; Kao, C.-Y.; Pierce, R. H.; Murthy, N. 264 Amsden, B. G.; Timbart, L.; Marecak, D.; Chapanian, R.;
Nucl. Acids Res. 2009, 37. Tse, M. Y.; Pang, S. C. J. Control. Release 2010, 145, 109–115.
239 Goh, S. L.; Murthy, N.; Xu, M.; Frechet, J. M. J. Bioconjug. 265 Zurita, R.; Puiggali, J.; Rodriguez-Galan, A. Macromol. Bio-
Chem. 2004, 15, 2004. sci. 2006, 6, 767–775.
266 Chen, W.; Meng, F.; Li, F.; Ji, S.-J.; Zhong, Z. Biomacromo- 291 Backman, S.; Bjorling, G.; Johansson, U.-B.; Lysdahl, M.;
lecules 2009, 10, 1727–1735. Markstrom, A.; Schedin, U.; Aune, R. E.; Frostell, C.; Karlsson,
267 Chen, W.; Meng, F.; Cheng, R.; Zhong, Z. J. Control. S. Laryngoscope 2009, 119, 657–664.
Release 2010, 142, 40–46. 292 Bonzani, I. C.; Adhikari, R.; Houshyar, S.; Mayadunne, R.;
268 Kim, S. H.; Tan, J. P. K.; Nederberg, F.; Fukushima, K.; Col- Gunatillake, P.; Stevens, M. M. Biomaterials 2007, 28,
son, J.; Yang, C.; Nelson, A.; Yang, Y.-Y.; Hedrick, J. L. Bioma- 423–433.
terials 2010, 31, 8063–8071. 293 Allcock, H. R.; Kugel, R. L. J. Am. Chem. Soc. 1965, 87,
269 Sanson, C.; Schatz, C.; Meins, J.-F. L.; Brulet, A.; Soum, A.; 4216–4217.
Lecommandoux, S. Langmuir 2010, 26, 2751–2760. 294 Laurencin, C. T.; Koh, H. J.; Neenan, T. X.; Allcock, H. R.;
270 Sanson, C.; Schatz, C.; Meins, J.-F. L.; Soum, A.; Thevenot, Langer, R. J. Biomed. Mater. Res. 1987, 21, 1231–1246.
J.; Garanger, E.; Lecommandoux, S. J. Control. Release 2010, 295 Lakshmi, S.; Katti, D. S.; Laurencin, C. T. Adv. Drug Deliv.
147, 428–435. Rev. 2003, 55, 467–482.
271 Welle, A.; Kroger, M.; Doring, M.; Niederer, K.; Pindel, E.; 296 Singh, A.; Krogmas, N. R.; Sethuraman, S.; Nair, L. S.;
Chronakis, I. S. Biomaterials 2007, 28, 2211–2219. Sturgeon, J. L.; Brown, P. W.; Laurencin, C. T.; Allcock, H. R.
272 Suriano, F.; Pratt, R.; Tan, J. P. K.; Wiradharma, N.; Nelson, Biomacromolecules 2006, 7, 914–918.
A.; Yang, Y.-Y.; Dubois, P.; Hedrick, J. L. Biomaterials 2010, 31, 297 Weikel, A. L.; Owens, S. G.; Morozowich, N. L.; Deng, M.;
2637–2645. Nair, L. S.; Laurencin, C. T.; Allcock, H. R. Biomaterials 2010,
273 Zelikin, A. N.; Zawaneh, P. N.; Putnam, D. Biomacromole- 31, 8507–8515.
cules 2006, 7, 3239–3244. 298 Radeleff, B.; Thierjung, H.; Stampfl, U.; Stampfl, S.; Lopez-
274 Henderson, P. W.; Kadouch, D. J. M.; Singh, S. P.; Zawa- Benitez, R.; Sommer, C.; Berger, I.; Richter, G. M. Cardiovasc.
neh, P. N.; Wieser, J.; Yazdi, S.; Weinstein, A.; Krotscheck, U.; Interv. Radiol. 2008, 31, 971–980.
Wechsler, B.; Putnam, D.; Spector, J. A. J. Biomed. Mater. Res. 299 Smeets, A. J.; Nijenhuis, R. J.; Rooij, W. J. v.; Lampmann,
A 2010, 93, 776–782. L. E. H.; Boekkooi, P. F.; Vervest, H. A. M.; Vries, J. D.; Lohle, P.
275 Zawaneh, P. N.; Singh, S. P.; Padera, R. F.; Henderson, P. N. M. J. Vasc. Interv. Radiol. 2010, 21, 1830–1834.
W.; Spector, J. A.; Putnam, D. Proc. Natl. Acad. Sci. USA 2010, 300 Stampfl, U.; Sommer, C.-M.; Thierjung, H.; Stampfl, S.;
107, 11014–11019. Lopez-Benitez, R.; Radeleff, B.; Berger, I.; Richter, G. M. Cardio-
276 Ertel, S. I.; Kohn, J. J. Biomed. Mater. Res. 1994, 28, vasc. Interv. Radiol. 2008, 31, 1184–1192.
919–930. 301 Verret, V.; Wasser, M.; Pelage, J.-P.; Ghegediban, S. H.;
277 Asikainen, A. J.; Noponen, J.; Mesimaki, K.; Laitinen, O.; Jouneau, L.; Moine, L.; Labarre, D.; Golzarian, J.; Schwartz-Cor-
Peltola, J.; Pelto, M.; Kellomaki, M.; Ashammakhi, N.; Lindqvist, nil, I.; Laurent, A. Biomaterials 2011, 32, 339–351.
C.; Suuronen, R. J. Mater. Sci. Mater. Med. 2005, 16, 753–758. 302 Jun, Y. J.; Kim, J. H.; Choi, S. J.; Lee, H. J.; Jun, M. J.;
278 Asikainen, A. J.; Noponen, J.; Lindqvist, C.; Pelto, M.; Kel- Sohn, Y. S. Bioorg. Med. Chem. Lett. 2007, 17, 2975–2978.
lomaki, M.; Juuti, H.; Pihlajamaki, H.; Suuoronen, R. J. R. Soc. 303 Yang, Y.; Xu, Z.; Chen, S.; Gao, Y.; Gu, Y.; Chen, L.; Pei, Y.;
Interface 2006, 3, 629–635. Li, Y. Int. J. Pharm. 2008, 353, 277–282.
279 Bailey, L. O.; Becker, M. L.; Stephens, J. S.; Gallant, N. D.; 304 Yang, Y.; Zhang, Z.; Chen, L.; Gu, W.; Li, Y. Bioconjug.
Mahoney, C. M.; Washburn, N. R.; Rege, A.; Kohn, J.; Amis, E. Chem. 2010, 21, 419–426.
J. J. Biomed. Mater. Res. 2006, 76, 491–502. 305 Andrianov, A. K.; Marin, A.; Chen, J. Biomacromolecules
280 Briggs, T.; Treiser, M. D.; Holmes, P. F.; Kohn, J.; Moghe, 2006, 7, 394–399.
P. V.; Arinzeh, T. L. J. Biomed. Mater. Res. A 2009, 91, 975–984. 306 Zhang, J. X.; Li, X. J.; Qiu, L. Y.; Li, X. H.; Yan, M. Q.; Jin,
281 Johnson, P. A.; Luk, A.; Demtchouk, A.; Patel, H.; Sung, H.- Y.; Zhu, K. J. J. Control. Release 2006, 116, 322–329.
J.; Treiser, M. D.; Gordonov, S.; Sheihet, L.; Bolikal, D.; Kohn, 307 Qiu, L. Y.; Wu, X. L.; Jin, Y. Pharm. Res. 2009, 26, 946–957.
J.; Moghe, P. V. J. Biomed. Mater. Res. A 2010, 93, 505–514. 308 Kovacs-Nolan, J.; Mapletoft, J. W.; Lawman, Z.; Babiuk, L.
282 Meechaisue, C.; Dubin, R.; Supaphol, P.; Hoven, V. P.; A.; Hurk, S. V. D. L.-V. d. J. Gen. Virol. 2009, 90, 1892–1905.
Kohn, J. J. Biomater. Sci. Polym. Ed. 2006, 17, 1039–1056. 309 Zheng, C.; Qiu, L.; Yao, X.; Zhu, K. Int. J. Pharm. 2009, 373,
283 Sung, H. J.; Labazzo, K. M. S.; Bolikal, D.; Weiner, M. J.; 133–140.
Zimnisky, R.; Kohn, J. Eur. Cells Mater. 2008, 25, 77–87. 310 Andrianov, A. K.; DeCollibus, D. P.; Gillis, H. A.; Kha, H. H.;
284 Costache, M. C.; Qu, H.; Ducheyne, P.; Devore, D. I. Bioma- Marin, A.; Prausnitz, M. R.; Babiuk, L. A.; Townsend, H.; Mut-
terials 2010, 31, 6336–6343. wiri, G. Proc. Natl. Acad. Sci. USA 2009, 106, 18936–18941.
285 Tangpasuthadol, V.; Pendharkar, S. M.; Peterson, R. C.; 311 Andrianov, A. K.; Marin, A.; DeCollibus, D. P. Pharm. Res.
Kohn, J. Biomaterials 2000, 21, 2379–2387. 2011, 28, 58–65.
286 Guelcher, S. A. Tissue Eng. Part B Rev. 2008, 14, 3–17. 312 Seong, J.-Y.; Jun, Y. J.; Kim, B. M.; Park, Y. M.; Sohn, Y. S.
287 Wen, J.; Somorjai, G. Macromolecules 1997, 30, Int. J. Pharm. 2006, 314, 90–96.
7206–7213. 313 Park, M.-R.; Chun, C.; Ahn, S.-W.; Ki, M.-H.; Cho, C.-S.;
288 Asai, T.; Lee, M.-H.; Arrecubieta, C.; Bayern, M. P. V.; Ces- Song, S.-C. J. Control. Release 2010, 147, 359–367.
pedes, C. A.; Baron, H. M.; Cadeiras, M.; Sakguchi, T. J. Thorac. 314 Potta, T.; Chun, C.; Song, S.-C. Biomaterials 2009, 30,
Cardiovasc. Surg. 2007, 133, 1147–1153. 6178–6192.
289 Uttayarat, P.; Perets, A.; Li, M.; Pimpton, P.; Stachelek, S. 315 Chun, C.; Lee, S. M.; Kim, C. W.; Hong, K.-Y.; Kim, S. Y.;
J.; Alferiev, I.; Composto, R. J.; Levy, R. J.; Lelkes, P. I. Acta Yang, H. K.; Song, S.-C. Biomaterials 2009, 30, 4752–4762.
Biomater. 2010, 6, 4229–4237. 316 Oredein-McCoy, O.; Krogman, N. R.; Weikel, A. L.; Hinden-
290 Poelaert, J.; Depuydt, P.; Wolf, A. D.; Velde, S. V. d.; Herck, lang, M. D.; Allcock, H. R.; Laurencin, C. T. J. Microencapsul.
I.; Blot, S. J. Thorac. Cardiovasc. Surg. 2008, 135, 771–776. 2009, 26, 544–555.
317 Aldini, N. N.; Fini, M.; Rocca, M.; Giavaresi, G. Int. Orthop- 346 Jere, D.; Yoo, M.-K.; Arote, R.; Kim, T.-H.; Cho, M.-H.;
aed. 2000, 24, 121–125. Nah, J.-W.; Choi, Y.-J.; Cho, C.-S. Pharm. Res. 2008, 25,
318 Deng, M.; Nair, L. S.; Nukavarapu, S. P.; Kumbar, S. G.; 875–885.
Jiang, T.; Krogman, N. R.; Singh, A.; Allcock, H. R.; Laurencin, 347 Little, S. R.; Lynn, D. M.; Puram, S. V.; Langer, R. J. Con-
C. T. Biomaterials 2008, 29, 337–349. trol. Release 2005, 107, 449–462.
319 Conconi, M. T.; Lora, S.; Baiguera, S.; Boscolo, E.; Folin, 348 Greenland, J. R.; Liu, H.; Berry, D.; Anderson, D. G.; Kim,
M.; Scienza, R.; Rebuffat, P.; Parnigotto, P. P.; Nussdorfer, G. W.-K.; Irvine, D. J.; Langer, R.; Letvin, N. L. Mol. Ther. 2005, 12,
G. J. Biomed. Mater. Res. A 2004, 71, 669–674. 164–170.
320 Nair, L. S.; Bhattacharyya, S.; Bender, J. D.; Greish, Y. E.; 349 Zugates, G. T.; Peng, W.; Zumbuehl, A.; Jhunjhunwala, S.;
Brown, P. W.; Allcock, H. R.; Laurencin, C. T. Biomacromole- Huang, Y. H.; Langer, R.; Sawicki, J. A.; Anderson, D. G. Mol.
cules 2004, 5, 2212–2220. Ther. 2007, 15, 1306–1312.
321 Conconi, M. T.; Lora, S.; Menti, A. M.; Carampin, P.; Parni- 350 Brito, L.; Little, S.; Langer, R.; Amiji, M. Biomacromolecules
gotto, P. P. Tissue Eng. 2006, 12, 811–819. 2008, 9, 1179–1187.
322 Zhang, Q. S.; Yan, Y. H.; Li, S. P.; Feng, T. Biomed. Mater. 351 Bettinger, C. J.; Bruggeman, J. P.; Borenstein, J. T.;
2009, 4, 035008. Langer, R. S. Biomaterials 2008, 29, 2315–2325.
323 Nukavarapu, S. P.; Kumbar, S. G.; Brown, J. L.; Krog- 352 Brey, D. M.; Chung, C.; Hankenson, K. D.; Garino, J. P.;
man, N. R.; Weikel, A. L.; Hindenlang, M. D.; Nair, L. S.; All- Burdick, J. A. J. Biomed. Mater. Res. A 2010, 93, 807–816.
cock, H. R.; Laurencin, C. T. Biomacromolecules 2008, 9,
353 Horwitz, J. A.; Shum, K. M.; Bodle, J. C.; Deng, M.; Chu,
1818–1825.
C.-C.; Reinhart-King, C. A. J. Biomed. Mater. Res. A 2010, 95,
324 Lapienis, G.; Penczek, S. Macromolecules 1974, 7, 166–174. 371–380.
325 Kaluzynski, K.; Libisowski, J.; Penczek, S. Macromolecules 354 Erdmann, L.; Uhrich, K. E. Biomaterials 2000, 21,
1976, 9, 365–367. 1941–1946.
326 Wang, Y.-C.; Liu, X.-Q.; Sun, T.-M.; Xiong, M.-H.; Wang, J. 355 Whitaker-Brothers, K.; Uhrich, K. J. Biomed. Mater. Res. A
J. Control. Release 2008, 128, 32–40. 2006, 76, 470–479.
327 Wang, Y.-C.; Tang, L.-Y.; Sun, T.-M.; Li, C.-H.; Xiong, M.-H.; 356 Erdmann, L.; Macedo, B.; Uhrich, K. E. Biomaterials 2000,
Wang, J. Biomacromolecules 2008, 9, 388–395. 21, 2507–2512.
328 Liu, J.; Huang, W.; Pang, Y.; Zhu, X.; Zhou, Y.; Yan, D. Bio- 357 Yeagy, B. A.; Prudencio, A.; Schmeltzer, R. C.; Uhrich, K.
macromolecules 2010, 11, 1564–1570. E.; Cook, T. J. J. Microencapsul. 2006, 23, 643–653.
329 Lu, Z.-Z.; Wu, J.; Sun, T.-M.; Ji, J.; Yan, L.-F.; Wang, J. Bio-
358 Whitaker-Brothers, K.; Uhrich, K. J. Biomed. Mater. Res. A
materials 2008, 29, 733–741.
2004, 70, 309–318.
330 Ditto, A. J.; Shah, P. N.; Gump, L. R.; Yun, Y. H. Mol.
359 Harten, R. D.; Svach, D. J.; Schmeltzer, R.; Uhrich, K. E. J.
Pharm. 2009, 6, 986–995.
Biomed. Mater. Res. A 2005, 72, 354–362.
331 Yang, X.-Z.; Sun, T.-M.; Dou, S.; Wu, J.; Wang, Y.-C.;
360 Bryers, J. D.; Jarvis, R. A.; Lebo, J.; Prudencio, A.; Kyria-
Wang, J. Biomacromolecules 2009, 10, 2213–2220.
kides, T. R.; Uhrich, K. Biomaterials 2006, 27, 5039–5048.
332 Li, Q.; Wang, J.; Shahani, S.; Sun, D. D. N.; Sharma, B.; Eli-
361 Rosenberg, L. E.; Carbone, A. L.; Romling, U.; Uhrich, K.
sseeff, J. H.; Leong, K. W. Biomaterials 2005, 27, 1027–1034.
E.; Chikindas, M. L. Lett. Appl. Microbiol. 2008, 46, 593–599.
333 Du, J.-Z.; Sun, T.-M.; Weng, S.-Q.; Chen, X.-S.; Wang, J.
362 Henry, J. A.; Simonet, M.; Pandit, A.; Neuenschwander, P.
Biomacromolecules 2007, 8, 3375–3381.
J. Biomed. Mater. Res. A 2007, 82, 669–679.
334 Zhang, Z.; Mao, J.; Feng, X.; Xiao, J.; Qiu, J. J. Huazhong
363 Zhang, J. Y.; Beckman, E. J.; Piesco, N. P.; Agarwal, S. Bio-
Univ. Sci. Technol. Med. Sci. 2008, 28, 604–607.
materials 2000, 21, 1247–1258.
335 Qiu, J.-J.; He, Z.-X.; Liu, C.-M.; Guo, X.-D.; Zheng, Q.-X.
Biomed. Mater. 2008, 3, 044107. 364 Adhikari, R.; Gunatillake, P. A.; Griffiths, I.; Tatai, L.;
Wichramaratna, M.; Houshyar, S.; Moore, T.; Mayadunne, R. T.
336 Qiu, Z.-C.; Zhang, J.-J.; Zhou, Y.; Song, B.-Y.; Chang, J.-J.; M.; Field, J.; McGee, M.; Carbone, T. Biomaterials 2008, 29,
Yang, K.-K.; Wang, Y.-Z. Polym. Adv. Technol. 2009.
3762–3770.
337 Malnati, G. A.; Stone, E. A. Vet. Surg. 1983, 12, 24–25.
365 Werkmeister, J. A.; Adhikari, R.; White, J. F.; Tebb, T. A.;
338 Olson, D. O.; Sheares, V. V. Macromolecules 2006, 39, Le, T. P. T.; Taing, H. C.; Mayadunne, R.; Gunatillake, P. A.;
2808–2814. Danon, S. J.; Ramshaw, J. A. M. Acta Biomater. 2010, 6,
339 Olson, D. A.; Gratton, S. E. A.; DeSimone, J. M.; Sheares, 3471–3481.
V. V. J. Am. Chem. Soc. 2006, 128, 13625–13633. 366 Yang, L.; Korom, S.; Welti, M.; Hoerstrup, S. P.; Zund, G.;
340 Barrera, D. A.; Zylstra, E.; Lansbury, P. T.; Langer, R. J. Jung, F. J.; Neuenschwander, P.; Weder, W. Eur. J. Cardio--
Am. Chem. Soc. 1993, 115, 11010–11011. Thorac. Surg. 2003, 24, 201–207.
341 Putnam, D.; Langer, R. Macromolecules 1999, 32, 367 Brizzola, S.; Eguileor, M. D.; Brevini, T.; Grimaldi, A.; Con-
3658–3662. giu, T.; Neuenschwander, P.; Acocella, F. Interact. Cardiovasc.
342 Green, J. J.; Zugates, G. T.; Langer, R.; Anderson, D. G. Thorac. Surg. 2009, 8, 610–614.
Macromol. Drug Deliv. 2009, 480, 53–63. 368 Riboldi, S. A.; Sadr, N.; Pigini, L.; Neuenschwander, P.;
343 Lynn, D. M.; Anderson, D. G.; Putnam, D.; Langer, R. J. Simonet, M.; Mognol, P.; Sampaolesi, M.; Cossu, G.; Mantero,
Am. Chem. Soc. 2001, 123, 8155–8156. S. J. Biomed. Mater. Res. A 2008, 84, 1094–1101.
344 Akinc, A.; Lynn, D. M.; Anderson, D. G.; Langer, R. J. Am. 369 Kaetsu, I.; Yoshida, M.; Yamada, A. J. Biomed. Mater. Res.
Chem. Soc. 2003, 125, 5316–5323. 1980, 14, 185–197.
345 Anderson, D. G.; Lynn, D. M.; Langer, R. Angew. Chem. 370 Park, J. H.; Bae, Y. H. J. Biomater. Sci. Polym. Ed. 2002, 13,
Int. Ed. Engl. 2003, 42, 3153–3158. 527–542.
371 Park, J. H.; Bae, Y. H. J. Biomed. Mater. Res. A 2003, 64, 397 DiRamio, J. A.; Kisaalita, W. S.; Majetich, G. F.; Shimkus, J.
309–319. M. Biotechnol. Prog. 2005, 21, 1281–1288.
372 Hsu, S.-H.; Tseng, H.-J. J. Biomater. Appl. 2004, 19, 398 Fu, Y.; Kao, W. J. Pharm. Res. 2009, 26, 2115–2124.
135–146. 399 Woldum, H. S.; Larsen, K. L.; Madsen, F. Drug Deliv. 2008,
373 Pomel, C.; Leborgne, C.; Cheradame, H.; Scherman, D.; 15, 69–80.
Kichler, A.; Guegan, P. Pharm. Res. 2008, 25, 2963–2971. 400 Hwang, N. S.; Varghese, S.; Elisseeff, J. Methods Mol. Biol.
374 Frings, J.; Schramm, E.; Schink, B. Am. Soc. Microbiol. 2007, 407, 351–373.
1992, 58, 2164–2167. 401 Buxton, A. N.; Zhu, J.; Marchant, R.; West, J. L.; Yoo, J. U.;
375 Ohta, T.; Tani, A.; Kimbara, K.; Kawai, F. Appl. Microbiol. Johnstone, B. Tissue Eng. 2007, 13, 2549–2560.
Biotechnol. 2005, 68, 639–646. 402 Nuttelman, C. R.; Benoit, D. S. W.; Tripod, M. C.; Anseth,
376 Biondi, O.; Motta, S.; Mosesso, P. Mutagenesis 2002, 17, K. S. Biomaterials 2006, 27, 1377–1386.
261–264. 403 Zhou, Z.; Ren, Y.; Yang, D.; Nie, J. Biomed. Mater. 2009, 4,
377 Kabanov, A. V.; Nazarova, I. R.; Astafieva, I.; Batrakova, E. 035007.
V.; Alakhov, V. Y.; Yaroslavov, A. A.; Kabanov, V. A. Macromo- 404 Betz, M. W.; Yeatts, A. B.; Richbourg, W. J.; Caccamese, J.
lecules 1995, 28, 2303–2314. F.; Coletti, D. P.; Falco, E. E.; Fisher, J. P. Biomacromolecules
378 Kozlov, M. Y.; Melik-Nubarov, N. S.; Batrakova, E. V.; Kaba- 2010, 11, 1160–1168.
nov, A. V. Macromolecules 2000, 33, 3305–3313. 405 Moon, J. J.; Hahn, M. S.; Kim, I.; Nsiah, B. A.; West, J. L.
379 Sezgin, Z.; Yuksel, N.; Baykara, T. Eur. J. Pharm. Biopharm. Tissue Eng. Part A 2009, 15, 579–585.
2006, 64, 261–268. 406 Jimenez-Vergara, A. C.; Guiza-Arguello, V.; Becerra-Bay-
380 Kwon, S. H.; Kim, S. Y.; Ha, H. W.; Kang, M. J.; Huh, J. S.; ona, S.; Munoz-Pinto, D. J.; McMahon, R. E.; Morales, A.;
Jong, I. T.; Kim, Y. M.; Park, Y. M.; Kang, H. H.; Lee, S.; Chang, Cubero-Ponce, L.; Hahn, M. S. Ann. Biomed. Eng. 2010, 38,
J. Y.; Lee, J.; Choi, Y. W. Arch. Pharm. Res. 2007, 30, 2885–2895.
1138–1143. 407 Lacasse, F. X.; Filion, M. C.; Phillips, N. C.; Escher, E.;
381 Zhang, W.; Shi, Y.; Chen, Y.; Yu, S.; Hao, J.; Luo, J.; Sha, McMullen, J. N.; Hildgen, P. Pharm. Res. 1998, 15, 312–317.
X.; Fang, X. Eur. J. Pharm. Biopharm. 2010, 75, 341–353. 408 Romberg, B.; Hennink, W. E.; Storm, G. Pharm. Res. 2008,
382 Chen, F.; Liu, X.-M.; Rice, K. C.; Li, X.; Yu, F.; Reinhardt, R. 25, 55–71.
A.; Bayles, K. W.; Wang, D. Antimicrob. Agents Chemother. 409 Zhang, X.; He, H.; Yen, C.; Ho, W.; Lee, L. J. Biomaterials
2009, 53, 4898–4902. 2008, 29, 4253–4259.
383 Chen, F.; Rice, K. C.; Liu, X.-M.; Reinhardt, R. A.; Bayles, K. 410 Shan, X.; Yuan, Y.; Liu, C.; Tao, X.; Sheng, Y.; Xu, F.
W.; Wang, D. Pharm. Res. 2010, 27, 2356–2364. Biomed. Microdevices 2009, 11, 1187–1194.
384 Kadam, Y.; Yerramilli, U.; Bahadur, A.; Bahadur, P. Colloids 411 Yoncheva, K.; Guembe, L.; Campanero, M. A.; Irache, J. M.
Surf. B Biointerfaces 2011, 83, 49–57. Int. J. Pharm. 2007, 334, 156–165.
385 Foster, B.; Cosgrove, T.; Hammouda, B. Langmuir 2009, 25, 412 Hou, S.; McCauley, L. K.; Ma, P. X. Macromol. Biosci. 2007,
6760–6766. 7, 620–628.
386 Roques, C.; Bouchemal, K.; Ponchel, G.; Fromes, Y.; Fattal, 413 Yoncheva, K.; Centelles, M. N.; Irache, J. M. J. Microencap-
E. J. Control. Release 2009, 138, 71–77. sul. 2008, 25, 82–89.
387 Jones, D. S.; Bruschi, M. L.; Freitas, O. d.; Fremiao, M. P. 414 Tang, B. C.; Fu, J.; Watkins, D. N.; Hanes, J. Biomaterials
D.; Lara, E. H. G.; Andrews, G. P. Int. J. Pharm. 2009, 372, 2010, 31, 339–344.
49–58. 415 Schacht, E.; Toncheva, V.; Vandertaelen, K.; Heller, J. J.
388 Liu, Y.; Lu, W.-L.; Wang, J.-C.; Zhang, X.; Zhang, H.; Wang, Control. Release 2006, 116, 219–225.
X.-Q.; Zhou, T.-Y.; Zhang, Q. J. Control. Release 2007, 117, 416 Gao, X.; Tao, W.; Lu, W.; Zhang, Q.; Zhang, Y.; Jiang, X.;
387–395. Fu, S. Biomaterials 2006, 27, 3482–3490.
389 Derakhshandeh, K.; Fashi, M.; Seifoleslami, S. Drug Design 417 Lee, W.-C.; Li, Y.-C.; Chu, I.-M. Macromol. Biosci. 2006, 6,
Dev. Ther. 2010, 24, 255–262. 846–854.
390 Lee, J. W.; Lim, T.-H.; Park, J. B. J. Biomed. Mater. Res. A 418 Xu, X.; Chen, X.; Wang, Z.; Jing, X. Eur. J. Pharm. Bio-
2010, 92, 378–385. pharm. 2009, 72, 18–25.
391 Aka-Any-Grah, A.; Bouchemal, K.; Koffi, A.; Agnely, F.; 419 Zhang, Y.; Wu, X.; Han, Y.; Mo, F.; Duran, Y.; Li, S. Int. J.
Zhang, M.; Djabourov, M.; Ponchel, G. Eur. J. Pharm. Bio- Pharm. 2010, 386, 15–22.
pharm. 2010, 76, 296–303. 420 Cheng, J.; Teply, B. A.; Sherifi, I.; Sung, J.; Luther, G.; Gu,
392 Cortiella, J.; Nichols, J. E.; Kojima, K.; Bonassar, L. J.; Dar- F. X.; Levy-Nissenbaum, E.; Radovic-Moreno, A. F.; Langer, R.;
gon, P.; Roy, A. K.; Vacant, M. P.; Niles, J. A.; Vacanti, C. A. Tis- Farokhzad, O. C. Biomaterials 2007, 28, 869–876.
sue Eng. 2006, 12, 1213–1225. 421 Cu, Y.; Saltzman, W. M. Mol. Pharm. 2009, 6, 173–181.
393 Vashi, A. V.; Keramidaris, E.; Abberton, K. M.; Morrison, 422 Gao, Y.; Sun, Y.; Ren, F.; Gao, S. Drug Dev. Ind. Pharm.
W. A.; Wilson, J. L.; O’Connor, A. J.; Cooper-White, J. J.; 2010, 36, 1131–1138.
Thompson, E. W. Biomaterials 2008, 29, 573–579. 423 Song, Z.; Feng, R.; Sun, M.; Guo, C.; Gao, Y.; Li, L.; Zhai,
394 Beamish, J. A.; Zhu, J.; Kottke-Marchant, K.; Marchant, R. G. J. Colloid Interface Sci. 2011, 354, 116–123.
E. J. Biomed. Mater. Res. A 2010, 92, 441–450. 424 Liu, J.; Zeng, F.; Allen, C. Eur. J. Pharm. Biopharm. 2007,
395 Pfister, P. M.; Wendlandt, M.; Neuenschwander, P.; Suter, 65, 309–319.
U. W. Biomaterials 2007, 28, 567–575. 425 Yanez, J. A.; Forrest, M. L.; Ohgami, Y.; Kwon, G. S.;
396 Ainslie, K. M.; Kraning, C. M.; Desai, T. A. Lab Chip 2008, Davies, N. M. Cancer Chemother. Pharmacol. 2008, 61,
8, 1042–1047. 133–144.
426 Forrest, M. L.; Yanez, J. A.; Remsberg, C. M.; Ohgami, Y.; 452 Liu, X.; Wang, X.-M.; Chen, Z.; Cui, F.-Z.; Liu, H.-Y.; Mao,
Kwon, G. S.; Davies, N. M. Pharm. Res. 2008, 25, 194–206. K.; Wang, Y. J. Biomed. Mater. Res. Part B: Appl. Biomater.
427 Feng, M.; Cai, Q.; Shi, X.; Huang, H.; Zhou, P.; Guo, X. J. 2010, 94, 72–79.
Drug Target. 2008, 16, 502–508. 453 Lamphongsai, S.; Eshraghi, Y.; Totonchi, A.; Midler, J.;
428 Wang, Y.-Y.; Lai, S. K.; Suk, J. S.; Pace, A.; Cone, R.; Abdul-Karim, F. W.; Guyuron, B. Aesthetic Surg. J. 2010, 29,
Hanes, J. Angew. Chem. Int. Ed. Engl. 2008, 47, 9726–9729. 93–97.
429 Tang, B. C.; Dawson, M.; Lai, S. K.; Wang, Y.-Y.; Suk, J. S.; 454 Yilmaz, N.; Inal, S.; Muglali, M.; Guvenc, T.; Bas, B. Med.
Yang, M.; Zetilin, P.; Boyle, M. P.; Fu, J.; Hanes, J. Proc. Natl. Oral Patol. Oral Cir. Bucal 2010, 15, e526–e530.
Acad. Sci. USA 2009, 106, 19268–19273. 455 Kleinmann, G.; Larson, S.; Hunter, B.; Stevens, S.; Mama-
430 Suk, J. S.; Lai, S. K.; Wang, Y.-Y.; Ensign, L. M.; Zeitlin, lis, N.; Olson, R. J. Ophthalmologica 2007, 221, 51–56.
P. L.; Boyle, M. P.; Hanes, J. Biomaterials 2009, 30, 456 Friberg, O.; Dahlin, L.-G.; Kallman, J.; Kihlstrom, E.; Soder-
2591–2597. quist, B.; Svedjeholm, R. Interact. Cardiovasc. Thorac. Surg.
431 Whaley, K. J.; Hanes, J.; Shattock, R.; Cone, R. A.; Friend, 2009, 9, 454–458.
D. R. Antiviral Res. 2010, 88, S55–S66. 457 Holladay, C.; Keeney, M.; Greiser, U.; Murphy, M.; O’Brein,
432 Benoit, D. S. W.; Durney, A. R.; Anseth, K. S. Tissue Eng. T.; Pandit, A. J. Control. Release 2009, 136, 220–225.
2006, 12, 1663–1673. 458 Peng, L.; Cheng, X.; Zhuo, R.; Lan, J.; Wang, Y.; Shi, B.; Li,
433 Freeman, J. W.; Woods, M. D.; Cromer, D. A.; Ekwueme, E. S. J. Biomed. Mater. Res. A 2009, 90, 564–576.
C.; Atiemo, T. A. E. A.; Bijoux, C. H.; Laurencin, C. T. J. Bio- 459 Krebs, M. D.; Jeon, O.; Alsberg, E. J. Am. Chem. Soc.
mech. 2010. 2009, 131, 9204–9206.
434 Papadopoulos, A.; Bichara, D. A.; Zhao, X.; Ibusuki, S.; 460 Castells, R. V.; Holladay, C.; Luca, A. d.; Diaz, V. M.; Pandit,
Randolph, M. A.; Anseth, K. S.; Yaremchuk, M. J. Tissue Eng. A. Bioconjug. Chem. 2009, 20, 2262–2269.
Part A 2011, 17, 161–169. 461 Wang, L.; Cao, J.; Lei, D.-l.; Cheng, X.-b.; Yang, Y.-w.; Hou,
435 Kim, J.; Lee, K.-W.; Hefferan, T. E.; Currier, B. L.; Yaszem- R.; Zhao, Y.-h.; Cui, F.-z. J. Craniofac. Surg. 2009, 20,
ski, M. J.; Lu, L. Biomacromolecules 2008, 9, 149–157. 2188–2192.
436 Poon, Y. F.; Cao, Y.; Zhu, Y.; Judeh, Z. M. A.; Chan-Park, 462 Maehara, H.; Sotome, S.; Yoshii, T.; Torigoe, I.; Kawasaki,
M. B. Biomacromolecules 2009, 10, 2043–2052. Y.; Sugata, Y.; Yuasa, M.; Hirano, M.; Mochizuki, N.; Kikuchi,
437 Zhang, X.; Yang, D.; Nie, J. Int. J. Biol. Macromol. 2008, M.; Shinomiya, K.; Okawa, A. J. Orthop. Res. 2010, 28,
43, 456–462. 677–686.
438 Ma, G.; Zhang, X.; Han, J.; Song, G.; Nie, J. Int. J. Biol. 463 Solorio, L.; Zwolinski, C.; Lund, A. W.; Farrell, M. J.; Stege-
Macromol. 2009, 45, 499–503. mann, J. P. J. Tissue Eng. Regen. Med. 2010, 4, 514–523.
439 Ramshaw, J. A. M.; Shah, N. K.; Brodsky, B. J. Struct. Biol. 464 Baik, S. H.; Kim, J. H.; Cho, H. H.; Park, S.-N.; Kim, Y. S.;
1998, 122, 86–91. Suh, H. J. Surg. Res. 2010, 164, e221–e228.
440 Przybyla, D. E.; Chmielewski, J. Biochemistry 2010, 49, 465 Bellucci, R. J.; Wolff, D. Laryngoscope 1964, 74, 668–688.
4411–4419. 466 Sionkowska, A.; Skopinska-Wisniewska, J.; Gawron, M.;
441 Krane, S. M. Amino Acids 2008, 35, 703–710. Kozlowska, J.; Planecka, A. Int. J. Biol. Macromol. 2010, 47,
442 Matsuno, T.; Nakamura, T.; Kuremoto, K.-i.; Notazawa, S.; 570–577.
Nakahara, T.; Hashimoto, Y.; Satoh, T.; Shimizu, Y. Dent. 467 Kakudo, N.; Shimotsuma, A.; Miyake, S.; Kushida, S.;
Mater. J. 2006, 25, 138–144. Kusumoto, K. J. Biomed. Mater. Res. Part A 2008, 84,
443 Oliveira, S. M.; Amaral, I. F.; Barbosa, M. A.; Teixeira, C. C. 191–197.
Tissue Eng. Part A 2008, 15, 625–634. 468 Dong, S.-W.; Ying, D.-J.; Duan, X.-J.; Xie, Z.; Yu, Z.-J.; Zhu,
444 Fukushima, K.; Enomoto, M.; Tomizawa, S.; Takahashi, M.; C.-H.; Yang, B.; Sun, J.-S. Biosci. Biotechnol. Biochem. 2009,
Wakabayashi, Y.; Itoh, S.; Kuboki, Y.; Shinomiya, K. J. Med. 73, 2226–2233.
Dent. Sci. 2008, 55, 71–79. 469 Hesse, E.; Hefferan, T. E.; Tarara, J. E.; Haasper, C.; Meller,
445 Bushnell, B. D.; McWilliams, A. D.; Whitener, G. B.; Messer, R.; Krettek, C.; Lu, L.; Yaszemski, M. J. J. Biomed. Mater. Res.
T. J. Hand Surg. 2008, 33, 1081–1087. A 2010, 94, 442–449.
446 Soltysiak, P.; Hollwarth, M. E.; Saxena, A. K. Bio-Med. 470 Sachlos, E.; Gotora, D.; Czernuszka, J. T. Tissue Eng. 2006,
Mater. Eng. 2010, 20, 1–11. 12, 2479–2487.
447 Komura, M.; Komura, H.; Kanamori, Y.; Tanaka, Y.; Suzuki, 471 Venugopal, J.; Low, S.; Choon, A. T.; Kumar, T. S. S.; Ram-
K.; Sugiyama, M.; Nakahara, S.; Kawashima, H.; Hatanaka, A.; akrishna, S. J. Mater. Sci. Mater. Med. 2008, 19, 2039–2046.
Hoshi, K.; Ikada, Y.; Tabata, Y.; Iwanaka, T. J. Pediatr. Surg. 472 Gleeson, J. P.; Plunkett, N. A.; O’Brien, F. J. Euro. Cells
2008, 43, 2141–2146. Mater. 2010, 20, 218–230.
448 Choi, J. S.; Yang, H.-J.; Kim, B. S.; Kim, J. D.; Kim, J. Y.; 473 Grimes, J. S.; Bocklage, T. J.; Pitcher, J. D. Orthopedics
Yoo, B.; Park, K.; Lee, H. Y.; Cho, Y. W. J. Control. Release 2006, 29, 145–148.
2009, 139, 2–7. 474 Minura, T.; Imai, S.; Kubo, M.; Isoya, E.; Ando, K.; Oku-
449 Huang, Z.; Tian, J.; Yu, B.; Xu, Y.; Feng, Q. Biomed. Mater. mura, N.; Matsusue, Y. Osteoarthr. Cartil. 2008, 16, 1083–1091.
2009, 4, 055005. 475 Pulkkinen, H. J.; Tiitu, V.; Valonen, P.; Jurvelin, J. S.;
450 Sulica, L.; Rosen, C. A.; Postma, G. N.; Simpson, B.; Amin, Lammi, M. J.; Kiviranta, I. Osteoarthr. Cartil. 2010, 18,
M.; Courey, M.; Merati, A. Laryngoscope 2010, 120, 319–325. 1077–1087.
451 Wang, F.; Li, Z.; Khan, M.; Tamara, K.; Kuppusamy, P.; 476 Mueller-Rath, R.; Gavenis, K.; Andereya, S.; Mumme, T.;
Wagner, W. R.; Sen, C. K.; Guan, J. Acta Biomater. 2010, 6, Albrand, M.; Stoffel, M.; Weichert, D.; Schneider, U. Bio-Med.
1978–1991. Mater. Eng. 2010, 20, 317–328.
477 Kuo, C. K.; Tuan, R. S. Tissue Eng. Part A 2008, 14, 503 Ye, Q.; Harmsen, M. C.; Luyn, M. J. A. V.; Bank, R. A. Bio-
1615–1627. materials 2010, 31, 9192–9201.
478 Butler, D. L.; Gooch, C.; Kinneberg, K. R.; Boivin, G. P.; Gal- 504 Xu, C.; Yu, Z.; Inouye, M.; Brodsky, B.; Mirochnitchenko, O.
loway, M. T.; Nirmalanandhan, V. S.; Shearn, J. T.; Dyment, N. Biomacromolecules 2010, 11, 348–356.
A.; Juncosa-Melvin, N. Nat. Protoc. 2010, 5, 849–863. 505 Kothapalli, C. R.; Ramamurthi, A. Acta Biomater. 2010, 6,
479 Gurkan, U. A.; Cheng, X.; Kishore, V.; Uquillas, J. A.; 170–178.
Akkus, O. J. Biomed. Mater. Res. A 2010, 94, 1070–1079. 506 Kurane, A.; Simionescu, D. T.; Vyavahare, N. R. Biomateri-
480 Zeugolis, D. I.; Paul, G. R.; Attenburrow, G. J. Biomed. als 2007, 28, 2830–2838.
Mater. Res. A 2009, 89, 895–908. 507 Kurane, A.; Vyavahare, N. J. Tissue Eng. Regen. Med.
481 Robayo, L. M.; Moulin, V. J.; Tremblay, P.; Cloutier, R.; 2009, 3, 280–289.
Lamontagne, J.; Larkin, A.-M.; Chabaud, S.; Simon, F.; Islam, 508 Mithieux, S. M.; Rasko, J. E. J.; Weiss, A. S. Biomaterials
N.; Goulet, F. Wound Repair Regen. 2011, 19, 38–48. 2004, 25, 4921–4927.
482 George, J.; Onodera, J.; Miyata, T. J. Biomed. Mater. Res. 509 Nivison-Smith, L.; Rnjak, J.; Weiss, A. S. Acta Biomater.
A 2008, 87, 1103–1111. 2010, 6, 354–359.
483 Helary, C.; Bataille, I.; Abed, A.; Illoul, C.; Anglo, A.; Loue- 510 Tu, Y.; Wise, S. G.; Weiss, A. S. Micron 2010, 41, 268–272.
dec, L.; Letourneur, D.; Meddahi-Pelle, A.; Giraud-Guille, M. M. 511 Kaufmann, D.; Weberskirch, R. Macromol. Biosci. 2006, 6,
Biomaterials 2010, 31, 481–490. 952–958.
484 Reckenrich, A. K.; Hopfner, U.; Krotz, F.; Zhang, Z.; Koch, 512 Liu, Y.; Jia, Z.; Li, L.; Chen, F. Med. Hypotheses 2011, 76,
C.; Kremer, M.; Machens, H.-G.; Plank, C.; Egana, J. T. Biomate- 239–240.
rials 2011, 32, 1996–2003.
513 Floss, D. M.; Schallau, K.; Rose-John, S.; Conrad, U.; Schel-
485 Huang, S.; Xu, Y.; Wu, C.; Sha, D.; Fu, X. Biomaterials ler, J. Trends Biotechnol. 2010, 28, 37–45.
2010, 31, 5520–5525.
514 MacEwan, S. R.; Chilkoti, A. Peptide Sci. 2010, 94, 60–77.
486 Ahn, S.; Yoon, H.; Kim, G.; Kim, Y.; Lee, S.; Chun, W. Tis- 515 Chu, H.-S.; Park, J.-E.; Kim, D.-M.; Kim, B.-G.; Won, J.-I.
sue Eng. Part C Methods 2010, 16, 813–820. Protein Exp. Purif. 2010, 74, 298–303.
487 Bastiaansen-Jenniskens, Y. M.; Koevoet, W.; Bart, A. C. W. 516 Massodi, I.; Thomas, E.; Raucher, D. Molecules 2009, 14,
d.; Linden, J. C. V. D.; Zuurmond, A. M.; Weinans, H.; Verhaar, 1999–2015.
J. A. N.; Osch, G. J. V. M. V.; DeGroot, J. Osteoarthr. Cartil.
517 Bidwell, G. L.; Fokt, I.; Priebe, W.; Raucher, D. Biochem.
2008, 16, 359–366.
Pharmacol. 2007, 73, 620–631.
488 Lu, X.; Zhai, W.; Zhou, Y.; Zhang, Y. Z. H.; Chang, J. J.
518 Adams, S. B.; Shamji, M. F.; Nettles, D. L.; Hwang, P.; Set-
Mater. Sci. Mater. Med. 2010, 21, 473–480.
ton, L. A. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2009,
489 Yan, L.-P.; Wang, Y.-J.; Ren, L.; Wu, G.; Caridade, S. G.; Fan, 90, 67–74.
J.-B.; Wang, L.-Y.; Ji, P.-H.; Oliveira, J. M.; Oliveria, J. T.; Mano,
519 Betre, H.; Liu, W.; Zalutsky, M. R.; Chilkoti, A.; Kraus, V. B.;
J. F.; Reis, R. L. J. Biomed. Mater. Res. A 2010, 95, 465–475.
Setton, L. A. J. Control. Release 2006, 115, 175–182.
490 Casper, C. L.; Yang, W.; Farach-Carson, M. C.; Rabolt, J. F.
520 Bessa, P. C.; Machado, R.; Nurnberger, S.; Dopler, D.;
Biomacromolecules 2007, 8, 1116–1123.
Banerjee, A.; Cunha, A. M.; Rodriquez-Cabello, J. C.; Redl, H.;
491 Sahoo, S.; Ang, L.-T.; Goh, J. C.-H.; Toh, S.-L. Differentia- Griensven, M. v.; Reis, R. L.; Casal, M. J. Control. Release 2010,
tion 2010, 79, 102–110. 142, 312–318.
492 Spurlin, T. A.; Bhadriraju, K.; Chung, K.-H.; Tona, A.; Plant, 521 Betre, H.; Ong, S. R.; Guilak, F.; Chilkoti, A.; Fermor, B.;
A. L. Biomaterials 2009, 30, 5486–5496. Setton, L. A. Biomaterials 2006, 27, 91–99.
493 Torres-Giner, S.; Gimeno-Alcaniz, J. V.; Ocio, M. J.; 522 Lim, D. W.; Nettles, D. L.; Setton, L. A.; Chilkoti, A. Bioma-
Lagaron, J. M. ACS Appl. Mater. Interfaces 2009, 1, 218–223. cromolecules 2008, 9, 222–230.
494 Ciardelli, G.; Gentile, P.; Chiono, V.; Mattioli-Belmonte, M.; 523 Srokowski, E. M.; Woodhouse, K. A. J. Biomater. Sci.
Vozzi, G.; Barbani, N.; Giusti, P. J. Biomed. Mater. Res. A 2010, Polym. Ed. 2008, 19, 785–799.
92, 137–151. 524 Nettles, D. L.; Chilkoti, A.; Setton, L. A. Adv. Drug Deliv.
495 Zhang, C.; Hu, Y.-Y.; Cui, F.-Z.; Zhang, S.-M.; Ruan, D.-K. Rev. 2010, 62, 1479–1485.
Biomed. Mater. 2006, 1, 56–62. 525 Prinsen, B. H. C. M. T.; Velden, M. G. M. D. S.-V. D. Clin.
496 Liu, X.; Huang, C.; Feng, Y.; Liang, J.; Fan, Y.; Gu, Z.; Chim. Acta 2004, 347, 1–14.
Zhang, X. J. Biomater. Sci. Polym. Ed. 2010, 21, 963–977. 526 Dror, Y.; Ziv, T.; Makarov, V.; Wolf, H.; Admon, A.; Zuss-
497 Sahoo, S.; Cho-Hong, J. G.; Siew-Lok, T. Biomed. Mater. man, E. Biomacromolecules 2008, 9, 2749–2754.
2007, 2, 169–173. 527 Regev, O.; Khalgin, R.; Zussman, E.; Cohen, Y. Int. J. Biol.
498 Tatekawa, Y.; Kawazoe, N.; Chen, G.; Shirasaki, Y.; Macromol. 2010, 47, 261–265.
Komuro, H.; Kaneko, M. Pediatr. Surg. Int. 2010, 26, 575–580. 528 Gayakwad, S. G.; Bejugam, N. K.; Akhavein, N.; Uddin, N.
499 Ladd, M. R.; Lee, S. J.; Stitzel, J. D.; Atala, A.; Yoo, J. J. A.; Oettinger, C. E.; D’Souza, M. J. J. Microencapsul. 2009, 26,
Biomaterials 2011, 32, 1549–1559. 692–700.
500 Chen, K.-Y.; Liao, W.-J.; Kuo, S.-M.; Tsai, F.-J.; Chen, Y.-S.; 529 Okoroukwu, O. N.; Green, G. R.; D’Souza, M. J. J. Microen-
Huang, C.-Y.; Yao, C.-H. Biomacromolecules 2009, 10, capsul. 2010, 27, 142–149.
1642–1649. 530 Kapoor, D. N.; Manvi, F. V.; Doijad, R. C.; Dhawan, S. PDA
501 Sun, L. P.; Wang, S.; Zhang, Z. W.; Wang, X. Y.; Zhang, Q. J. Pharm. Sci. Technol. 2008, 62, 111–124.
Q. Biomed. Mater. 2009, 4, 055008. 531 Li, J.-M.; Chen, W.; Wang, H.; Jin, C.; Yu, X.-J.; Lu, W.-Y.;
502 Wang, L.; Stegemann, J. P. Biomaterials 2010, 31, Cui, L.; Fu, D.-L.; Ni, Q.-X.; Hou, H.-M. Acta Pharmacol. Sin.
3976–3985. 2009, 30, 1337–1343.
532 Shen, Z.; Li, Y.; Kohama, K.; Oneill, B.; Bi, J. Pharmacol. 559 Izumi, Y.; Yamamoto, M.; Kawamura, M.; Adachi, T.;
Res. 2011, 63, 51–58. Kobayashi, K. Surgery 2007, 141, 678–681.
533 Khan, W.; Kapoor, M.; Kumar, N. Acta Biomater. 2007, 3, 560 Matsusaki, M.; Yoshida, H.; Akashi, M. Biomaterials 2007,
541–549. 28, 2729–2737.
534 Wei, Q.; Li, B.; Yi, N.; Su, B.; Yin, Z.; Zhang, F.; Li, J.; Zhao, 561 Deng, C.; Tian, H.; Zhang, P.; Sun, J.; Chen, X.; Jing, X.
C. J. Biomed. Mater. Res. A 2011, 96, 38–45. Biomacromolecules 2006, 7, 590–596.
535 Zehr, K. J. Ann. Thorac. Surg. 2007, 84, 1048–1052. 562 Sun, J.; Deng, C.; Chen, X.; Yu, H.; Tian, H.; Sun, J.; Jing,
536 Somer, F. D.; Delanghe, J.; Somers, P.; Debrouwere, M.; X. Biomacromolecules 2007, 8, 1013–1017.
Nooten, G. V. J. Biomed. Mater. Res. A 2008, 86, 1106–1112. 563 Gryparis, E. C.; Mattheolabakis, G.; Bikiaris, D.; Avgousta-
537 Rijken, D. C.; Lijnen, H. R. J. Thrombosis Haemostasis kis, K. Drug Deliv. 2007, 14, 371–380.
2008, 7, 4–13. 564 Cao, N.; Cheng, D.; Zou, S.; Ai, H.; Gao, J.; Shuai, X. Bio-
538 Shaikh, F. M.; Callanan, A.; Kavanagh, E. G.; Burke, P. E.; materials 2011, 32, 2222–2232.
Grace, P. A.; McGloughlin, T. M. Cells Tissues Organs 2008, 565 Hsu, F.-Y.; Cheng, Y.-Y.; Tsai, S.-W.; Tsai, W.-B. J. Biomed.
188, 333–346. Mater. Res. Part B: Appl. Biomater. 2010, 95, 29–35.
539 Schillinger, U.; Wexel, G.; Hacker, C.; Kullmer, M.; Koch, 566 Colonna, C.; Conti, B.; Perugini, P.; Pavanetto, F.; Modena,
C.; Gerg, M.; Vogt, S.; Ueblacker, P.; Tischer, T.; Hensler, D.; T.; Dorati, R.; Genta, I. J. Microencapsul. 2007, 24, 553–564.
Wilisch, J.; Aigner, J.; Walch, A.; Stemberger, A.; Plank, C. 567 Wei, L.; Cai, C.; Lin, J.; Chen, T. Biomaterials 2009, 30,
Pharm. Res. 2008, 25, 2946–2962. 2606–2613.
540 Zhibo, X.; Miaobo, Z. Aesthetic Surg. J. 2009, 29, 32–34. 568 Peng, S.-F.; Tseng, M. T.; Ho, Y.-C.; Wei, M.-C.; Liao, Z.-X.;
541 Yang, H. S.; Bhang, S. H.; Hwang, J. W.; Kim, D.-I.; Kim, B.- Sung, H.-W. Biomaterials 2011, 32, 239–248.
S. Tissue Eng. Part A 2010, 16, 2113–2119. 569 Takehara, M.; Hibino, A.; Saimura, M.; Hirohara, H. Bio-
542 Kuehn, C.; Graf, K.; Mashaqi, B.; Pichlmaier, M.; Heuer, W.; technol. Lett. 2010, 32, 1299–1303.
Hilfiker, A.; Stiesch, M. J. Surg. Res. 2010, 164, e185–e191. 570 Couffin-Hoarau, A.-C.; Aubertin, A.-M.; Boustta, M.;
543 Hou, T.; Xu, J.; Li, Q.; Feng, J.; Zen, L. Tissue Eng. Part A Schmidt, S.; Fehrentz, J.-A.; Martinez, J.; Vert, M. Biomacromo-
2008, 14, 1173–1182. lecules 2009, 10, 865–876.
544 Dickhut, A.; Dexheimer, V.; Martin, K.; Lauinger, R.; Heisel, 571 Tang, C. K.; Sheng, K.-C.; Pouniotis, D.; Esparon, S.; Son,
C.; Richter, W. Tissue Eng. Part A 2010, 16, 453–464. H.-Y.; Kim, C.-W.; Pietersz, G. A.; Apostolopoulos, V. Vaccine
2008, 26, 3827–3834.
545 Peura, M.; Siltanen, A.; Saarinen, I.; Soots, A.; Bizik, J.;
Vuola, J.; Harjula, A.; Kankuri, E. J. Biomed. Mater. Res. A 572 Yu, H.; Guo, X.; Qi, X.; Liu, P.; Shen, X.; Duan, Y. J. Mater.
2010, 95, 658–664. Sci. Mater. Med. 2008, 19, 1275–1281.
546 Mana, M.; Cole, M.; Cox, S. Wound Repair Regen. 2006, 573 Bertram, J. P.; Jay, S. M.; Hynes, S. R.; Robinson, R.;
14, 72–80. Criscione, J. M.; Lavik, E. B. Acta Biomater. 2009, 5,
2860–2871.
547 Candela, T.; Moya, M.; Haustant, M.; Fouet, A. Can. J.
Microbiol. 2009, 55, 627–632. 574 Tahara, K.; Furukawa, S.; Yamamoto, H.; Kawashima, Y.
Int. J. Pharm. 2010, 392, 311–313.
548 Yeh, C.-M.; Wang, J.-P.; Lo, S.-C.; Chan, W.-C.; Lin, M.-Y.
Biotechnol. Prog. 2010, 26, 1001–1007. 575 Nottelet, B.; Ghzaoui, A. E.; Coudane, J.; Vert, M. Bio-
macromolecules 2007, 8, 2594–2601.
549 Liu, J.; He, D.; Li, X.-z.; Gao, S.; Wu, H.; Liu, W.; Gao, X.;
Zhou, T. Int. J. Food Microbiol. 2010, 142, 190–197. 576 Itoh, K.; Tokumi, S.; Kimura, T.; Nagase, A. Langmuir 2008,
24, 13426–13433.
550 Jeong, Y.-I.; Na, H.-S.; Cho, K.-O.; Lee, H.-C.; Nah, J.-W.;
Cho, C.-S. Int. J. Pharm. 2009, 365, 150–156. 577 Isaksson, K.; Akerberg, D.; Andersson, R.; Tingstedt, B. Eur.
Surg. Res. 2010, 44, 17–22.
551 Matsusaki, M.; Akashi, M. Biomacromolecules 2005, 6,
3351–3356. 578 Zheng, Z.; Zhang, L.; Kong, L.; Wang, A.; Gong, Y.; Zhang,
X. J. Biomed. Mater. Res. A 2009, 89, 453–465.
552 Yoshida, H.; Klinkhammer, K.; Matsusaki, M.; Moller, M.;
Klee, D.; Akashi, M. Macromol. Biosci. 2009, 9, 568–574. 579 Bourke, S. L.; Kohn, J. Adv. Drug Deliv. Rev. 2003, 55,
447–466.
553 Homsi, J.; Simon, G. R.; Garrett, C. R.; Springett, G.; Conti,
R. D.; Chiappori, A. A.; Munster, P. N.; Burton, M. K.; Stromatt, 580 Yuan, H.; Luo, K.; Lai, Y.; Pu, Y.; He, B.; Wang, G.; Wu, Y.;
S.; Allievi, C.; Angiuli, P.; Eisenfeld, A.; Sullivan, D. M.; Daud, Gu, Z. Mol. Pharm. 2010, 7, 953–962.
A. I. Clin. Cancer Res. 2007, 13, 5855–5861. 581 Chiu, H.-C.; Kopeckova, P.; Deshmane, S. S.; Kopecek, J. J.
554 Van, S.; Das, S. K.; Wang, X.; Feng, Z.; Jin, Y.; Hou, Z.; Biomed. Mater. Res. 1997, 34, 381–392.
Chen, F.; Pham, A.; Jiang, N.; Howell, S. B.; Yu, L. Int. J. 582 Wadhwa, S.; Mumper, R. J. Mol. Pharm. 2010, 7, 854–862.
Nanomed. 2010, 5, 825–837. 583 Chen, L.; Tian, H.; Chen, J.; Chen, X.; Huang, Y.; Jing, X. J.
555 Sun, Y.; Tang, Y.; Chu, M.; Song, S.; Xin, Y. Int. J. Gene Med. 2010, 12, 64–76.
Nanomed. 2008, 3, 249–256. 584 Jessel, N.; Oulad-Abdelghani, M.; Meyer, F.; Lavalle, P.;
556 Portilla-Arias, J. A.; Camargo, B.; Garcia-Alzarez, M.; IIar- Haikel, Y.; Schaaf, P. Proc. Natl. Acad. Sci. USA 2006, 103,
duya, A. M. d.; Munoz-Guerra, S. J. Biomater. Sci. Polym. Ed. 8618–8621.
2009, 20, 1065–1079. 585 Pilbat, A.-M.; Ball, V.; Schaaf, P.; Voegel, J.-C.; Szalontai, B.
557 Okamoto, S.; Matsuura, M.; Akagi, T.; Akashi, M.; Tani- Langmuir 2006, 22, 5753–5759.
moto, T.; Ishikawa, T. Vaccine 2009, 27, 5896–5905. 586 Song, Z.; Yin, J.; Luo, K.; Zheng, Y.; Yang, Y.; Li, Q.; Yan,
558 Matsuo, K.; Ishii, Y.; Matsuo, K.; Yoshinaga, T.; Akashi, M.; S.; Chen, X. Macromol. Biosci. 2009, 9, 268–278.
Mukai, Y.; Yoshioka, Y.; Okada, N.; Nakagawa, S. Biol. Pharm. 587 Feng, X.; Lv, F.; Liu, L.; Tang, H.; Xing, C.; Yang, Q.; Wang,
Bull. 2010, 33, 2003–2007. S. ACS Appl. Mater. Interfaces 2010, 2, 2429–2435.
588 Huang, W.; Wang, W.; Wang, P.; Tian, Q.; Zhang, C.; 615 Wolf, F.; Haug, M.; Farhadi, J.; Candrian, C.; Martin, I.; Bar-
Wang, C.; Yuan, Z.; Liu, M.; Wan, H.; Tang, H. Acta Biomater. bero, A. Cells Mater. J. 2008, 15, 1–10.
2010, 6, 3927–3935. 616 Pandis, L.; Zavan, B.; Abatangelo, G.; Lepidi, S.; Cortivo,
589 O’Brien, M. E. R.; Socinski, M. A.; Popovich, A. Y.; Bondar- R.; Vindigni, V. J. Biomed. Mater. Res. A 2010, 93, 1289–1296.
enko, I. N.; Tomova, A.; Bilynskyi, B. T.; Hotko, Y. S.; Ganul, V. 617 Zavan, B.; Abatangelo, G.; Mazzoleni, F.; Bassetto, F.; Cor-
L.; Kostinsky, I. Y.; Eisenfeld, A. J.; Sandalic, L.; Oldham, F. B.; tivo, R.; Vindigni, V. Neurol. Res. 2008, 30, 190–196.
Bandstra, B.; Sandler, A. B.; Singer, J. W. J. Thorac. Oncol. 618 Pasquinelli, G.; Orrico, C.; Foroni, L.; Bonafe, F.; Carboni,
2008, 3, 728–734. M.; Guarnieri, C.; Raimondo, S.; Penna, C.; Geuna, S.; Pagliaro,
590 Ke, T.; Feng, Y.; Guo, J.; Parker, D. L.; Lu, Z.-R. Magn. P.; Freyrie, A.; Stella, A.; Caldarera, C. M.; Muscari, C. J. Anat.
Reson. Imaging 2006, 24, 931–940. 2008, 213, 520–530.
591 Zhang, G.; Zhang, R.; Wen, X.; Li, L.; Li, C. Biomacromole- 619 Grigolo, B.; Lisignoli, G.; Desando, G.; Cavallo, C.; Marconi,
cules 2008, 9, 36–42. E.; Tschon, M.; Giavaresi, G.; Fini, M.; Giardino, R.; Facchini, A.
592 Melancon, M. P.; Lu, W.; Huang, Q.; Thapa, P.; Zhou, D.; Tissue Eng. Part C Methods 2009, 15, 647–658.
Ng, C.; Li, C. Biomaterials 2010, 31, 6567–6573. 620 Ifkovits, J. L.; Tous, E.; Minakawa, M.; Morita, M.; Robb, J.
593 Tian, M.; Wen, X.; Jackson, E. F.; Ng, C.; Uthamanthil, R.; D.; Koomalsingh, K. J.; Gorman, J. H.; Gorman, R. C.; Burdick,
Liang, D.; Gelovani, J. G.; Li, C. Contrast Media Mol. Imaging, J. A. Proc. Natl. Acad. Sci. USA 2010, 107, 11507–11512.
in press. 621 Lee, H.; Mok, H.; Lee, S.; Oh, Y.-K.; Park, T. G. J. Control.
594 Deng, M.; Wang, R.; Rong, G.; Sun, J.; Zhang, X.; Chen, X.; Release 2007, 119, 245–252.
Jing, X. BIomaterials 2004, 25, 3553–3558. 622 Al-Ghananeem, A. M.; Malkawi, A. H.; Mauammer, Y. M.;
595 Pang, Z.; Lu, W.; Gao, H.; Hu, K.; Chen, J.; Zhang, C.; Gao, Balko, J. M.; Black, E. P.; Mourad, W.; Romoud, E. AAPS
X.; Jiang, X.; Zhu, C. J. Control. Release 2008, 128, 120–127. PharmSciTech 2009, 10, 410–417.
596 Layman, H.; Spiga, M.-G.; Brooks, T.; Pham, S.; Webster, 623 Zavan, B.; Vindigni, V.; Vezzu, K.; Zorzato, G.; Luni, C.; Aba-
K. A.; Anderopoulos, F. M. Biomaterials 2007, 28, 2646–2654. tangelo, G.; Elvassore, N.; Cortivo, R. J. Mater. Sci. Mater.
597 Cao, B.; Yin, J.; Yan, S.; Cui, L.; Chen, X.; Xie, Y. Macro- Med. 2009, 20, 235–247.
mol. Biosci. 2011, 11, 427–434. 624 Choi, K. Y.; Chung, H.; Min, K. H.; Yoon, H. Y.; Kim, K.;
598 Kakizawa, Y.; Furukawa, S.; Kataoka, K. J. Control. Release Park, J. H.; Kwon, I. C.; Jeong, S. Y. Biomaterials 2010, 31,
2004, 97, 345–356. 106–114.
599 Arimura, H.; Ohya, Y.; Ouchi, T. Biomacromolecules 2005, 625 Heijink, A.; Yaszemski, M. J.; Patel, R.; Rouse, M. S.; Lew-
6, 720–725. allen, D. G.; Hanssen, A. D. Clin. Orthop. Relat. Res. 2006, 451,
29–33.
600 Karal-Yilmaz, O.; Kayaman-Apohan, N.; Misirli, Z.; Baysal,
K.; Baysal, B. M. J. Mater. Sci. Mater. Med. 2006, 17, 213–227. 626 Gianolio, D. A.; Philbrook, M.; Avila, L. Z.; Young, L. E.;
Plate, L.; Santos, M. R.; Bernasconi, R.; Liu, H.; Ahn, S.; Sun,
601 Cha, E.-J.; Kim, J. E.; Ahn, C.-H. Eur. J. Pharm. Sci. 2009, W.; Jarrett, P. K.; Miller, R. J. Bioconjug. Chem. 2008, 19,
38, 341–346.
1767–1774.
602 Ponta, A.; Bae, Y. Pharm. Res. 2010, 27, 2330–2342. 627 Lee, F.; Chung, J. E.; Kurisawa, M. J. Control. Release
603 Pitarresi, G.; Saiano, F.; Cavallaro, G.; Mandracchia, D.; Pal- 2009, 134, 186–193.
umbo, F. S. Int. J. Pharm. 2007, 335, 130–137. 628 Hirakura, T.; Yasugi, K.; Nemoto, T.; Sato, M.; Shimoboji,
604 Meyer, K.; Palmer, J. W. J. Biol. Chem. 1934, 107, 629–634. T.; Aso, Y.; Morimoto, N.; Akiyoshi, K. J. Control. Release 2010,
605 Fraser, J. R. E.; Laurent, T. C.; Laurent, U. B. G. J. Intern. 142, 483–489.
Med. 1997, 242, 27–33. 629 Pitarresi, G.; Palumbo, F. S.; Albanese, A.; Fiorica, C.;
606 Rapta, P.; Valachova, K.; Gemeiner, P.; Soltes, L. Chem. Picone, P.; Giammona, G. J. Drug Target. 2010, 18, 264–276.
Biodivers 2009, 6, 162–169. 630 Zille, H.; Paquet, J.; Henrionnet, C.; Scala-Bertola, J.; Leon-
607 Carlson, G. A.; Dragoo, J. L.; Samimi, B.; Bruckner, D. A.; ard, M.; Six, J. L.; Deschamp, F.; Netter, P.; Verges, J.; Gillet,
Bernard, G. W.; Hedrick, M.; Benhaim, P. Biochem. Biophys. P.; Grossin, L. Bio-Med. Mater. Eng. 2010, 20, 235–242.
Res. Commun. 2004, 321, 472–478. 631 Lee, H.; Ahn, C.-H.; Park, T. G. Macromol. Biosci. 2009, 9,
608 Lloyd, L. L.; Kennedy, J. F.; Methacanon, P.; Paterson, M.; 336–342.
Knill, C. J. Carbohydr. Polym. 1998, 37, 315–322. 632 Mondalek, F. G.; Ashley, R. A.; Roth, C. C.; Kibar, Y.; Sha-
609 Benedetti, L.; Cortivo, R.; Berti, T.; Berti, A.; Pea, F.; Mazzo, kir, N.; Ihnat, M. A.; Fung, K.-M.; Grady, B. P.; Kropp, B. P.; Lin,
M.; Moras, M.; Abatangelo, G. Biomaterials 1993, 14, H.-K. J. Biomed. Mater. Res. A 2010, 94, 712–719.
1154–1160. 633 Yadav, A. K.; Mishra, P.; Jain, S.; Mishra, P.; Mishra, A. K.;
610 Avitabile, T.; Marano, F.; Castiglione, F.; Bucolo, C.; Cro, Agrawal, G. P. J. Drug Target. 2008, 16, 464–478.
M.; Ambrosio, L.; Ferrauto, C.; Reibaldi, A. Biomaterials 2001, 634 Yenice, I.; Mocan, M. C.; Palaska, E.; Bochot, A.; Bilensoy,
22, 195–200. E.; Vural, I.; Irkec, M.; Hincal, A. A. Exp. Eye Res. 2008, 87,
611 Lepidi, S.; Abatangelo, G.; Vindigni, V.; Deriu, G. P.; Zavan, 162–167.
B.; Tonello, C.; Cortivo, R. FASEB J. 2006, 20, 103–105. 635 Lee, H.; Jeong, Y.; Park, T. G. Biomacromolecules 2007, 8,
612 Zavan, B.; Vindigni, V.; Lepidi, S.; Iacopetti, I.; Avruscio, G.; 3705–3711.
Abatangelo, G.; Cortivo, R. FASEB J. 2008, 22, 2853–2861. 636 Zhang, X.; Sharma, K. K.; Boeglin, M.; Ogier, J.; Mainard,
613 Temiz, A.; Kazikdas, K. C.; Ergur, B.; Tugyan, K.; Bozok, S.; D.; Voegel, J.-C.; Mely, Y.; Benkirane-Jessel, N. Nano Lett.
Kaya, D.; Guneli, E. Otolarygol Head Neck Surg. 2010, 143, 2008, 8, 2432–2436.
772–778. 637 Wang, X.; Ji, J. Langmuir 2009, 25, 11664–11671.
614 Huang, T.-W.; Cheng, P.-W.; Chan, Y.-H.; Yeh, T.-H.; Young, 638 Fuente, M. d. l.; Seijo, B.; Alonso, M. J. Invest. Opththal-
Y.-H.; Young, T.-H. Biomaterials 2010, 31, 6701–6709. mol. Visual Sci. 2008, 49, 2016–2024.
639 Luppi, B.; Bigucci, F.; Mercolini, L.; Musenga, A.; Sorrenti, 663 Ren, D.; Yi, H.; Wang, W.; Ma, X. Carbohydr. Polym. 2005,
M.; Catenacci, L.; Zecchi, V. J. Pharm. Pharmacol. 2009, 61, 340, 2403–2410.
151–157. 664 Patois, E.; Cruz, S. O.-d.; Tille, J.-C.; Walpoth, B.; Gurny, R.;
640 Oyarzun-Ampuero, F. A.; Brea, J.; Loza, M. I.; Torres, D.; Jordan, O. J. Biomed. Mater. Res. A 2009, 91, 324–330.
Alonso, M. J. Int. J. Pharm. 2009, 381, 122–129. 665 Li, D.-H.; Liu, L.-M.; Tian, K.-L.; Liu, J.-C.; Fan, X.-Q. Carbo-
641 Ravina, M.; Cubillo, E.; Olmeda, D.; Novoa-Carballal, R.; hydr. Polym. 2007, 67, 40–45.
Fernandez-Megia, E.; Riguera, R.; Sanchez, A.; Cano, A.; 666 Biagini, G.; Bertani, A.; Muzzarelli, R.; Damadei, A.; Bene-
Alonso, M. J. Pharm. Res. 2010, 27, 2544–2555. detto, G. D.; Belligolli, A.; Riccotti, G.; Zucchini, C.; Rizzoli, C.
642 Kosir, M. A.; Quinn, C. C. V.; Wang, W.; Tromp, G. J. Surg. Biomaterials 1991, 12, 281–286.
Res. 2000, 92, 45–52. 667 Clasen, C.; Wilhelms, T.; Kulicke, W.-M. Biomacromole-
643 Chan, P. S.; Caron, J. P.; Rosa, G. J. M.; Orth, M. W. Osteo- cules 2006, 7, 3210–3222.
arthr. Cartil. 2005, 13, 387–394. 668 Ribiero, M. P.; Espiga, A.; Silva, D.; Baptista, P.; Henriques,
644 Souich, P. D.; Garcia, A. G.; Verges, J.; Montell, E. J. Cell. J.; Ferreira, C.; Silva, J. C.; Borges, J. P.; Pires, E.; Chaves, P.;
Mol. Med. 2009, 13, 1451–1463. Correia, I. J. Wound Repair Regen. 2009, 17, 817–824.
645 Malavaki, C.; Mizumoto, S.; Karamanos, N.; Sagahara, K. 669 Ishihara, M.; Nakanishi, K.; Ono, K.; Sato, M.; Kikuchi, M.;
Connect. Tissue Res. 2008, 49, 133–139. Saito, Y.; Yura, H.; Matsui, T.; Hattori, M.; Uenoyama, M.; Kur-
646 Liu, Y.; Cai, S.; Shu, X. Z.; Shelby, J.; Prestwich, G. D. ita, A. Biomaterials 2002, 23, 833–840.
Wound Repair Regen. 2007, 15, 245–251. 670 Peluso, G.; Petillo, O.; Ranieri, M.; Santin, M.; Ambrosic, L.;
647 Wang, D.-A.; Varghese, S.; Sharma, B.; Strehin, I.; Ferma- Calabro, D.; Avallone, B.; Balasamo, G. Biomaterials 1994, 15,
nian, S.; Gorham, J.; Fairbrother, D. H.; Cascio, B.; Elisseeff, J. 1215–1220.
H. Nat. Mater. 2007, 6, 385–392. 671 Bianco, I. D.; Balsinde, J.; Beltramo, D. M.; Castagna, L. F.;
648 Park, J. S.; Yang, H. J.; Woo, D. G.; Yang, H. N.; Na, K.; Landa, C. A.; Dennis, E. A. FEBS Lett. 2000, 466, 292–294.
Park, K.-H. J. Biomed. Mater. Res. A 2010, 92, 806–816. 672 Park, C. J.; Gabrielson, N. P.; Pack, D. W.; JAmison, R. D.;
649 Chang, K.-Y.; Hung, L.-H.; Chu, I.-M.; Ko, C.-S.; Lee, Y.-D. J. Johnson, A. J. W. Biomaterials 2009, 30, 436–444.
Biomed. Mater. Res. A 2010, 92, 712–723. 673 Burkatovskaya, M.; Tegos, G. P.; Swietlik, E.; Demidova, T.
650 Villanueva, I.; Gladem, S. K.; Kessler, J.; Bryant, S. J. Ma- N.; Castano, A. P.; Hamblin, M. R. Biomaterials 2006, 27,
trix Biol. 2010, 29, 51–62. 4157–4164.
651 Nguyen, L. H.; Kudva, A. K.; Guckert, N. L.; Linse, K. D.; 674 Azab, A. K.; Orkin, B.; Doviner, V.; Nissan, A.; Klein, M.;
Roy, K. Biomaterials 2011, 32, 1327–1338. Srebnik, M.; Rubinstein, A. J. Control. Release 2006, 111,
652 Liang, W.-H.; Kienitz, B. L.; Penick, K. J.; Welter, J. F.; 281–289.
Zawodzinski, T. A.; Baskaran, H. J. Biomed. Mater. Res. A 2010, 675 Ignatova, M.; Manolova, N.; Markova, N.; Rashkov, I. Mac-
94, 1050–1060. romol. Biosci. 2009, 9, 102–111.
653 Shu, X. Z.; Ahmad, S.; Liu, Y.; Prestwich, G. D. J. Biomed. 676 Rahmani-Neishaboor, E.; Jackson, J.; Burt, H.; Ghahary, A.
Mater. Res. A 2006, 79, 902–912. Pharm. Res. 2009, 26, 2002–2014.
654 Chen, Y.-L.; Lee, H.-P.; Chan, H.-Y.; Sung, L.-Y.; Chen, H.-C.; 677 Wu, L.; Li, H.; Li, S.; Li, X.; Yuan, X.; Li, X.; Zhang, Y. J.
Hu, Y.-C. Biomaterials 2007, 28, 2294–2305. Biomed. Mater. Res. A 2010, 92, 563–574.
655 Susante, J. L. C. V.; Pieper, J.; Buma, P.; Kuppevelt, T. H. 678 Kim, I. Y.; Yoo, M. K.; Seo, J. H.; Park, S. S.; Na, H. S.;
V.; Beuningen, H. V.; Kraan, P. M. V. D.; Veerkamp, J. H.; Lee, H. C.; Kim, S. K.; Cho, C. S. Int. J. Pharm. 2007, 341,
Berg, W. B. V. D.; Veth, R. P. H. Biomaterials 2001, 22, 35–43.
2359–2369. 679 Chen, R.-N.; Wang, G.-M.; Chen, C.-H.; Ho, H.-O.; Sheu, M.-
656 Kojima, K.; Okamoto, Y.; Kojima, K.; Miyatake, K.; Fujise, T. Biomacromolecules 2006, 7, 1058–1064.
H.; Shigemasa, Y.; Minami, S. J. Vet. Med. Sci. 2004, 66,
680 Liu, B.-S.; Yao, C.-H.; Fang, S.-S. Macromol. Biosci. 2008, 8,
1595–1598.
432–440.
657 Min, B.-M.; Lee, S. W.; Lee, J. W.; Lim, J. N.; You, Y.; Lee,
681 Murakami, K.; Aoki, H.; Nakamura, S.; Nakamura, S.-i.;
T. S.; Kang, P. H. Polymer 2004, 45, 7137–7142.
Takikawa, M.; Hanzawa, M.; Kishimoto, S.; Hattori, H.; Tanaka,
658 Noh, H. K.; Lee, S. W.; Kim, J.-M.; Oh, J.-E.; Kim, K.-H.; Y.; Kiyosawa, T.; Sato, Y.; Ishihara, M. Biomaterials 2010, 31,
Chung, C.-P.; Choi, S.-C.; Park, W. H.; Min, B.-M. Biomaterials 83–90.
2006, 27, 3934–3944.
682 Meng, X.; Tian, F.; Yang, J.; He, C.-N.; Xing, N.; Li, F. J.
659 Suzuki, D.; Takahashi, M.; Abe, M.; Sarukawa, J.; Tamura, Mater. Sci. Mater. Med. 2010, 21, 1751–1759.
H.; Tokura, S.; Kurahashi, Y.; Nagano, A. J. Mater. Sci. Mater.
683 Aoyagi, S.; Onishi, H.; Machida, Y. Int. J. Pharm. 2007, 330,
Med. 2008, 19, 1307–1315.
138–145.
660 Ehrlich, H.; Steck, E.; Ilan, M.; Maldonado, M.; Muricy, G.;
684 Campos, M. G. N.; Rawls, H. R.; Innocentini-Mei, L. H.; Sat-
Bavestrello, G.; Kljajic, Z.; Carballo, J. L.; Schiaparelli, S.; Ere-
sangi, N. J. Mater. Sci. Mater. Med. 2009, 20, 537–542.
skovsky, A.; Schupp, P.; Born, R.; Worch, H.; Bazhenov, V. V.;
Kurek, D.; Varlamov, V.; Vyalikh, D.; Kummer, K.; Sivkov, V. V.; 685 Wedmore, I.; McManus, J. G.; Pusateri, A. E.; Holcomb, J.
Molodtsov, S. L.; Meissner, H.; Richter, G.; Hunoldt, S.; B. J. Trauma-Injury Inf. Critic. Care 2006, 60, 655–658.
Kammer, M.; Paasch, S.; Krasokhin, V.; Patzke, G.; Brunner, E.; 686 Brown, M. A.; Daya, M. R.; Worley, J. A. J. Emerg. Med.
Richter, W. Int. J. Biol. Macromol. 2010, 47, 141–145. 2009, 37, 1–7.
661 Nagahama, H.; Nwe, N.; Jayakumar, R.; Koiwa, S.; Furuike, 687 Malmquist, J. P.; Clemens, S. C.; Oien, H. J.; Wilson, S. L.
T.; Tamura, H. Carbohydr. Polym. 2008, 73, 295–302. J. Oral Maxillofac. Surg. 2008, 66, 1177–1183.
662 Xia, W.; Liu, P.; Liu, J. Bioresour. Technol. 2008, 99, 688 Gan, Q.; Wang, T. Colloids Surf. B Biointerfaces 2007, 59,
6751–6762. 24–34.
689 Amsden, B. G.; Sukarto, A.; Knight, D. K.; Shapka, S. N. 714 Ishikawa, N.; Suzuki, Y.; Dezawa, M.; Kataoka, K.; Ohta, M.;
Biomacromolecules 2007, 8, 3758–3766. Cho, H.; Ide, C. J. Biomed. Mater. Res. A 2009, 89, 1118–1124.
690 Budhian, A.; Siegel, S. J.; Winey, K. I. Int. J. Pharm. 2008, 715 Fan, J.; Shang, Y.; Yuan, Y.; Yang, J. J. Mater. Sci. Mater.
346, 151–159. Med. 2010, 21, 319–327.
691 Yuan, X.-B.; Yuan, Y.-B.; Jiang, W.; Liu, J.; Tian, E.-J.; 716 Deshpande, M. S.; Kuchroo, P. V. Biotechnol. Prog. 2010,
Shun, H.-M.; Huang, D.-H.; Yuan, X.-Y.; Li, H.; Sheng, J. Int. J. 26, 1424–1430.
Pharm. 2008, 349, 241–248. 717 Majima, T.; Irie, T.; Sawaguchi, N.; Funakoshi, T.; Iwasaki,
692 Wang, J.; Feng, S.-S.; Wang, S.; Chen, Z.-y. Int. J. Pharm. N.; Harada, K.; Minami, A.; Nishimura, S. Proc. IME H J. Eng.
2010, 400, 194–200. Med. 2007, 221, 537–546.
693 Yang, R.; Shim, W.-S.; Cui, F.-D.; Cheng, G.; XuHan; Jin, 718 Wang, W.; Itoh, S.; Konno, K.; Kikkawa, T.; Ichinose, S.;
Q.-R.; Kim, D.-D.; Chung, S.-J.; Shim, C.-K. Int. J. Pharm. 2009, Sakai, K.; Ohkuma, T.; Watabe, K. J. Biomed. Mater. Res. A
371, 142–147. 2008, 91, 994–1005.
694 Chen, H.; Yang, W.; Chen, H.; Liu, L.; Gao, F.; Yang, X.; 719 Weir, M. D.; Xu, H. H. K. Acta Biomater. 2010, 6,
Jiang, Q.; Zhang, Q.; Wang, Y. Colloids Surf. B Biointerfaces 4118–4126.
2009, 73, 212–218. 720 Dhandayuthapani, B.; Krishnan, U. M.; Sethuraman, S. J.
695 Slutter, B.; Bal, S.; Keijzer, C.; Mallants, R.; Hagenaars, N.; Biomed. Mater. Res. Part B: Appl. Biomater. 2010, 94, 264–277.
Que, I.; Kaijzel, E.; Eden, W. V.; Augustihns, P.; Lowik, C.; 721 Sarukawa, J.; Takahashi, M.; Abe, M.; Suzuki, D.; Tokura,
Bouwstra, J.; Broere, F.; Jiskoot, W. Vaccine 2010, 28, S.; Furuike, T.; Tamura, H. J. Biomater. Sci. Polym. Ed. 2011,
6282–6291. 22, 717–732.
696 Zhang, Y.; Chen, J.; Zhang, Y.; Pan, Y.; Zhao, J.; Ren, L.; 722 Chesnutt, B. M.; Yuan, Y.; Buddington, K.; Haggard, W. O.;
Liao, M.; Hu, Z.; Kong, L.; Wang, J. Biotechnol. Appl. Biochem. Bumgardner, J. D. Tissue Eng. Part A 2009, 15, 2571–2579.
2007, 46, 197–204. 723 Li, L. H.; Kommareddy, K. P.; Pilz, C.; Zhou, C. R.; Fratzl, P.;
697 Wang, Q.; Zhang, N.; Hu, X.; Yang, J.; Du, Y. J. Biomed. Manjubala, I. Acta Biomater. 2010, 6, 2525–2531.
Mater. Res. A 2008, 85, 881–887. 724 Jiang, T.; Nukavarapu, S. P.; Deng, M.; Jabbarzadeh, E.;
698 Hu, F.-Q.; Meng, P.; Dai, Y.-Q.; Du, Y.-Z.; You, J.; Wei, X.- Kofron, M. D.; Doty, S. B.; Abdel-Fattah, W. I.; Laurencin, C. T.
H.; Yuan, H. Eur. J. Pharm. Biopharm. 2008, 70, 749–757. Acta Biomater. 2010, 6, 3457–3470.
699 Germershaus, O.; Mao, S.; Sitterberg, J.; Bakowsky, U.; 725 Pfister, L. A.; Papaloizos, M.; Merkle, H. P.; Gander, B. J.
Kissel, T. J. Control. Release 2008, 125, 145–154. Biomed. Mater. Res. A 2007, 80, 932–937.
700 Shi, H.; Han, C.; Mao, Z.; Ma, L.; Gao, C. Tissue Eng. Part A 726 Tan, H.; Chu, C. R.; Payne, K. A.; Marra, K. G. Biomaterials
2008, 14, 1775–1785. 2009, 30, 2499–2506.
701 Niu, X.; Feng, Q.; Wang, M.; Guo, X.; Zheng, Q. J. Control. 727 Wang, P.-Y.; Chow, H.-H.; Lai, J.-Y.; Liu, H.-L.; Tsai, W.-B. J.
Release 2009, 134, 111–117. Biomed. Mater. Res. Part B: Appl. Biomater. 2009, 91, 143–152.
702 Mao, Z.; Shi, H.; Guo, R.; Ma, M.; Gao, C.; Han, C.; Shen, J. 728 Hao, T.; Wen, N.; Cao, J.-K.; Wang, H.-B.; Lu, S.-H.; Liu, T.;
Acta Biomater. 2009, 5, 2983–2994. Lin, Q.-X.; Duan, C.-M.; Wang, C.-Y. Osteoarthr. Cartil. 2010, 18,
703 Peng, S.-F.; Yang, M.-J.; Chun-Jen; Chen, H.-L.; Lee, P.-W.; 257–265.
Wei, M.-C.; Sung, H.-W. Biomaterials 2009, 30, 1797–1808. 729 Zuidema, J. M.; Pap, M. M.; Jaroch, D. B.; Morrison, F. A.;
704 Chang, C.-H.; Lin, Y.-H.; Yeh, C.-L.; Chen, Y.-C.; Chiou, S.- Gilbert, R. J. Acta Biomater. 2011, 7, 1634–1643.
F.; Hsu, Y.-M.; Chen, Y.-S.; Wang, C.-C. Biomacromolecules 730 Tan, C. S.; Jejurikar, A.; Rai, B.; Bostrom, T.; Lawrie, G.;
2009, 11, 133–142. Grondahl, L. J. Biomed. Mater. Res. A 2009, 91, 866–877.
705 Matsusaki, M.; Sakaguchi, H.; Serizawa, T.; Akashi, M. J. 731 Ruvinov, E.; Leor, J.; Cohen, S. Biomaterials 2010, 31,
Biomater. Sci. Polym. Ed. 2007, 18, 775–783. 4573–4582.
706 Borges, O.; Silva, M.; Sousa, A. d.; Borchard, G.; Jung- 732 Rabbany, S. Y.; Pastore, J.; Yamamoto, M.; Miller, T.; Rafii,
inger, H. E.; Cordeiro-da-Silva, A. Int. Immunopharmacol. 2008, S.; Aras, R.; Penn, M. Cell Transplant. 2010, 19, 399–408.
8, 1773–1780. 733 Chan, A. W.; Neufeld, R. J. Biomaterials 2010, 31,
707 Woitiski, C. B.; Neufeld, R. J.; Ribeiro, A. J.; Veiga, F. Acta 9040–9047.
Biomater. 2009, 5, 2475–2484. 734 Kim, D.-H.; Martin, D. C. Biomaterials 2006, 27, 3031–3037.
708 Perioli, L.; Ambrogi, V.; Pagano, C.; Scuota, S.; Rossi, C. 735 Ranganath, S. H.; Kee, I.; Krantz, W. B.; Chow, P. K.-H.;
Int. J. Pharm. 2009, 377, 120–127. Wang, C.-H. Pharm. Res. 2009, 26, 2101–2114.
709 Patil, S.; Babbar, A.; Mathur, R.; Mishra, A.; Sawant, K. J. 736 Lee, J.; Bhang, S. H.; Park, H.; Kim, B.-S.; Lee, K. Y. Pharm.
Drug Target. 2010, 18, 321–331. Res. 2010, 27, 767–774.
710 Pawar, D.; Goyal, A. K.; Mangal, S.; Mishra, N.; Vaidya, 737 Choi, D. H.; Park, C. H.; Kim, I. H.; Chun, H. J.; Park, K.;
B.; Tiwari, S.; Jain, A. K.; Vyas, S. P. AAPS J. 2010, 12, Han, D. K. J. Control. Release 2010, 147, 193–201.
130–137. 738 Colinet, I.; Dulong, V.; Mocanu, G.; Picton, L.; Cerf, D. L.
711 Zhang, L.; Ao, Q.; Wang, A.; Lu, G.; Kong, L.; Gong, Y.; Eur. J. Pharm. Biopharm. 2009, 73, 345–350.
Zhao, N.; Zhang, X. J. Biomed. Mater. Res. A 2006, 77, 739 Gou, M.; Men, K.; Shi, H.; Xiang, M.; Zhang, J.; Song, J.;
277–284. Long, J.; Wan, Y.; Luo, F.; Zhao, X.; Quan, Z. Nanoscale 2011,
712 Ni, R.-F.; Kranokpiraksa, P.; Pavcnik, D.; Kakizawa, H.; 3, 1558–1567.
Uchida, B. T.; Keller, F. S.; Rosch, J. Cardiovasc. Interv. Radiol. 740 Giovagnoli, S.; Tsai, T.; DeLuca, P. P. AAPS PharmSciTech
2009, 32, 313–316. 2010, 11, 212–220.
713 Lu, G.; Ling, K.; Zhao, P.; Xu, Z.; Deng, C.; Zheng, H.; 741 Shastri, D. H.; Prajapati, S. T.; Patel, L. D. Curr. Drug Deliv.
Huang, J.; Chen, J. Wound Repair Regen. 2010, 18, 70–79. 2010, 7, 238–243.
742 Lim, S. M.; Oh, S. H.; Lee, H. H.; Yuk, S. H.; Im, G. I.; Lee, 761 Purcell, E. K.; Singh, A.; Kipke, D. R. Tissue Eng. Part C:
J. H. J. Mater. Sci. Mater. Med. 2010, 21, 2593–2600. Methods 2009, 15, 541–550.
743 Dai, Y.-N.; Li, P.; Zhang, J.-P.; Wang, A.-Q.; Wei, Q. Bio- 762 Liu, X. Y.; Nothias, J.-M.; Scavone, A.; Garfinkel, M.; Millis,
pharm. Drug Dispos. 2008, 29, 173–184. J. M. ASAIO J. 2010, 56, 241–245.
744 Meng, X.; Li, P.; Wei, Q.; Zhang, H.-X. Pharm. Dev. Tech- 763 Wang, J.-Z.; Huang, X.-B.; Xiao, J.; Yu, W.-T.; Wang, W.;
nol. 2011, 16, 22–28. Xie, W.-Y.; Zhang, Y.; Ma, X.-J. J. Biomed. Mater. Res. A 2010,
745 Zhao, L.; Tang, M.; Weir, M. D.; Detamore, M. S.; Xu, H. H. 93, 910–919.
K. Tissue Eng. Part A 2011, 17, 969–979. 764 Liang, Y.; Liu, W.; Han, B.; Yang, C.; Ma, Q.; Song, F.; Bi,
746 Marsich, E.; Borgogna, M.; Donati, I.; Mozetic, P.; Strand, Q. Colloids Surf. B Biointerfaces 2011, 82, 1–7.
B. L.; Salvador, S. G.; Vittur, F.; Paoletti, S. J. Biomed. Mater. 765 Qi, J.; Chen, A.; You, H.; Li, K.; Zhang, D.; Guo, F. Biomed.
Res. A 2008, 84, 364–376. Mater. 2011, 6, 015006.
747 Xu, H. H. K.; Weir, M. D.; Simon, C. G. Dent. Mater. 2008, 766 Chan, A. W.; Whitney, R. A.; Neufeld, R. J. Biomacromole-
24, 1212–1222. cules 2009, 10, 609–616.
748 Orive, G.; Castro, M. D.; Kong, H.-J.; Hernandez, R. M.; 767 Yamada, Y.; Hozumi, K.; Katagiri, F.; Kikkawa, Y.; Nomizu,
Ponce, S.; Mooney, D. J.; Pedraz, J. L. J. Control. Release 2009, M. Peptide Sci. 2010, 94, 711–720.
135, 203–210.
768 Wong, T. Y.; Preston, L. A.; Schiller, N. L. Ann. Rev. Micro-
749 Hunt, N. C.; Shelton, R. M.; Grover, L. Biotechnol. J. 2009, biol. 2000, 54, 289–340.
4, 730–737.
769 Simmons, C. A.; Alsberg, E.; Hsiong, S.; Kim, W. J.;
750 Moyer, H.; Kinney, R.; Singh, K. A.; Williams, J. K.; Mooney, D. J. Bone 2004, 35, 562–569.
Schwartz, Z.; Boyan, B. D. Ann. Plast. Surg. 2010, 65, 497–503.
770 Boontheekul, T.; Kong, H.-J.; Mooney, D. J. Biomaterials
751 Jin, X. B.; Sun, Y. S.; Zhang, K.; Wang, J.; Shi, T. P.; Ju, X. 2005, 26, 2455–2465.
D.; Lou, S. Q. J. Biomed. Mater. Res. A 2008, 86, 1077–1087.
771 Pokrywczynska, M.; Drewa, T.; Jundzill, A.; Lysik, J. Trans-
752 Qi, X.; Ye, J.; Wang, Y. J. Biomed. Mater. Res. A 2009, 89,
plant. Proc. 2009, 40, 1664–1667.
980–987.
772 Evangelista, M. B.; Hsiong, S. X.; Fernandes, R.; Sampaio,
753 Wang, Q.; Jamal, S.; Detamore, M. S.; Berkland, C. J.
P.; Kong, H.-J.; Barrias, C. C.; Salema, R.; Barbosa, M. A.;
Biomed. Mater. Res. A 2011, 96, 520–527.
Mooney, D. J.; Granja, P. L. Biomaterials 2007, 28, 3644–3655.
754 Hahn, M. S.; Teply, B. A.; Stevens, M. M.; Zeitels, S. M.;
773 Lee, J. W.; Park, Y. J.; Lee, S. J.; Lee, S. K.; Lee, K. Y. Bio-
Langer, R. Biomaterials 2006, 27, 1104–1109.
materials 2010, 31, 5545–5551.
755 Jay, S. M.; Shepherd, B. R.; Andrejecsk, J. W.; Kyriakides,
774 Hill, E.; Boontheekul, T.; Mooney, D. J. Tissue Eng. 2006,
T. R.; Pober, J. S.; Saltzman, W. M. Biomaterials 2010, 31,
12, 1295–1304.
3054–3062.
775 Jeong, S. I.; Krebs, M. D.; Bonino, C. A.; Khan, S. A.; Als-
756 Zheng, L.; Fan, H. S.; Sun, J.; Chen, X. N.; Wang, G.;
berg, E. Macromol. Biosci. 2010, 10, 934–943.
Zhang, L.; Fan, Y. J.; Zhang, X. D. J. Biomed. Mater. Res. A
2009, 93, 783–792. 776 Crommen, J.; Vandorpe, J.; Schacht, E. J. Control. Release
757 Tan, R.; Feng, Q.; Jin, H.; Li, J.; Yu, X.; She, Z.; Wang, M.; 1993, 24, 167–180.
Liu, H. J. Biomater. Sci. Polym. Ed., in press. 777 Leong, K. W.; Brott, B. C.; Langer, R. J. Biomed. Mater.
758 Maguire, T.; Novik, E.; Schloss, R.; Yarmush, M. Biotech- Res. 1985, 19, 941–955.
nol. Bioeng. 2006, 93, 581–591. 778 Richards, M.; Dahiyat, B. I.; Arm, D. M.; Brown, P. R.;
759 Olmez, S. S.; Korkusuz, P.; Bilgili, H.; Senel, S. Die Pharm. Leong, K. W. J. Biomed. Mater. Res. 1991, 25, 1151–1167.
2007, 62, 423–431. 779 Huang, S.-W.; Wang, J.; Zhang, P.-C.; Mao, H.-Q.; Zhuo, R.-
760 Wittmer, C. R.; Phelps, J. A.; Lepus, C. M.; Saltzman, W. X.; Leong, K. W. Biomacromolecules 2004, 5, 306–311.
M.; Harding, M. J.; Tassel, P. R. V. Biomaterials 2008, 29, 780 Chapman, T. M. J. Polym. Sci. Part A: Polym. Chem. 1989,
4082–4090. 27, 1993–2005.

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Biomedical Applications of Biodegradable Polymers

Bret D. Ulery,1,2 Lakshmi S. Nair,1,2,3 Cato T. Laurencin1,2,3

HYDROLYTICALLY DEGRADABLE POLYMERS

Hydrolytically degradable polymers are materials that pos-

Polyphosphazenes Tissue Engine- Synthetic Flexibility; Complex 4.5 102 – 1.4

Polyanhydrides Drug Delivery; Significant Monomer Low-molecular 1.9 103 – 9.4

Polyphosphoesters Drug Delivery; Biomolecule Compat- Complex 1.4 106

pleted in order for PLLA to be more widely used for short-

name FixsorbV, PLLA has been used as a bone fixator.54

has been converted to a poly(L-lactide) base for better long-

has a higher LA/GA ratio (90:10) than VicrylV causing it to

commercial contraceptive PCL product that is able to deliver

becomes solid during crosslinking; therefore, it has found

in the academic community. Although four classes of poly(or-

superior mechanical and degradation properties for delivery of

that have a degradation rate similar to polyesters and polycar-

Laboratories), and OrCelV (Ortec International) for this appli-

Elastin and Elastin-Like Polypeptides approved for vascular surgery.535

HA has also shown promise as a payload delivery vehicle

gesics,626 siRNA,621 and proteins.623,627,628 Composites of HA

for all biomedical applications has shifted to using polymers,

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