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1.  Photo-crosslinked Hybrid Polymer Networks Consisting of Poly(propylene fumarate) (PPF) and Poly(caprolactone fumarate) (PCLF): Controlled Physical Properties and Regulated Bone and Nerve Cell Responses 
Biomacromolecules  2008;9(4):1229-1241.
Aiming to achieve suitable polymeric biomaterials with controlled physical properties for hard and soft tissue replacements, we have developed a series of blends consisting of two photo-crosslinkable polymers: polypropylene fumarate (PPF) and polycaprolactone fumarate (PCLF). Physical properties of both uncrosslinked and UV crosslinked PPF/PCLF blends with PPF composition ranging from 0% to 100% have been investigated extensively. It has been found that the physical properties such as thermal, rheological, and mechanical properties could be modulated efficiently by varying the PPF composition in the blends. Thermal properties including glass transition temperature (Tg) and melting temperature (Tm) have been correlated with their rheological and mechanical properties. Surface characteristics such as surface morphology, hydrophilicity and the capability of adsorbing serum protein from culture medium have also been examined for the crosslinked polymer and blend discs. For potential applications in bone and nerve tissue engineering, in vitro cell studies including cytotoxicity, cell adhesion, and proliferation on crosslinked discs with controlled physical properties have been performed using rat bone marrow stromal cells and SPL201 cells, respectively. In addition, the role of mechanical properties such as surface stiffness in modulating cell responses has been emphasized using this model blend system.
doi:10.1021/bm7012313
PMCID: PMC2888142  PMID: 18307311
Photo-crosslinking; Polymer blends; Poly(propylene fumarate) (PPF); Poly(caprolactone fumarate) (PCLF); Controlled physical properties; Cell responses
2.  Effects of composite formulation on the mechanical properties of biodegradable poly(propylene fumarate)/bone fiber scaffolds 
The objective of our study was to determine the effects of composite formulation on the compressive modulus and ultimate strength of a biodegradable, in situ polymerizable poly(propylene fumarate) (PPF) and bone fiber scaffold. The following parameters were investigated: the incorporation of bone fibers (either mineralized or demineralized), PPF molecular weight, N-vinyl pyrrolidinone (NVP) crosslinker amount, benzoyl peroxide (BP) initiator amount, and sodium chloride porogen amount. Eight formulations were chosen based on a resolution III two level fractional factorial design. The compressive modulus and ultimate strength of these formulations were measured on a materials testing machine. Absolute values for compressive modulus varied from 21.3 to 271 MPa and 2.8 to 358 MPa for dry and wet samples, respectively. The ultimate strength of the crosslinked composites varied from 2.1 to 20.3 MPa for dry samples and from 0.4 to 16.6 MPa for wet samples. Main effects of each parameter on the measured property were calculated. The incorporation of mineralized bone fibers and an increase in PPF molecular weight resulted in higher compressive modulus and ultimate strength. Both mechanical properties also increased as the amount of benzoyl peroxide increased or the NVP amount decreased in the formulation. Sodium chloride had a dominating effect on the increase of mechanical properties in dry samples but showed little effects in wet samples. Demineralization of bone fibers led to a decrease in the compressive modulus and ultimate strength. Our results suggest that bone fibers are appropriate as structural enforcement components in PPF scaffolds. The desired orthopaedic PPF scaffold might be obtained by changing a variety of composite formulation parameters.
doi:10.1155/2010/270273
PMCID: PMC3201805  PMID: 22034584
poly(propylene fumarate); bone fiber; orthopaedic biomaterials; injectable; mechanical properties
3.  Photo-Crosslinked Poly(ε-caprolactone fumarate) Networks: Roles of Crystallinity and Crosslinking Density in Determining Mechanical Properties 
Polymer  2008;49(26):5692-5699.
We present a material design strategy of combining crystallinity and crosslinking to control the mechanical properties of polymeric biomaterials. Three polycaprolactone fumarates (PCLF530, PCLF1250, and PCLF2000) synthesized from the precursor polycaprolactone (PCL) diols with nominal molecular weights of 530, 1250, and 2000 g.mol-1, respectively, were employed to fabricate polymer networks via photo-crosslinking process. Five different amounts of photo-crosslinking initiator were applied during fabrication in order to understand the role of photoinitiator in modulating the crosslinking characteristics and physical properties of PCLF networks. Thermal properties such as glass transition temperature (Tg), melting temperature (Tm), and degradation temperature (Td) of photo-crosslinked PCLFs were examined and correlated with their rheological and mechanical properties.
doi:10.1016/j.polymer.2008.10.021
PMCID: PMC2951835  PMID: 20936057
Polycaprolactone fumarate; Photo-crosslinking; Mechanical Properties
4.  Two-Dimensional Nanostructure- Reinforced Biodegradable Polymeric Nanocomposites for Bone Tissue Engineering 
Biomacromolecules  2013;14(3):900-909.
This study investigates the efficacy of two dimensional (2D) carbon and inorganic nanostructures as reinforcing agents of crosslinked composites of the biodegradable and biocompatible polymer polypropylene fumarate (PPF) as a function of nanostructure concentration. PPF composites were reinforced using various 2D nanostructures: single- and multi-walled graphene oxide nanoribbons (SWGONRs, MWGONRs), graphene oxide nanoplatelets (GONPs), and molybdenum di-sulfite nanoplatelets (MSNPs) at 0.01–0.2 weight% concentrations. Cross-linked PPF was used as the baseline control, and PPF composites reinforced with single- or multi-walled carbon nanotubes (SWCNT, MWCNT) were used as positive controls. Compression and flexural testing show a significant enhancement (i.e., compressive modulus = 35–108%, compressive yield strength = 26–93%, flexural modulus = 15–53%, and flexural yield strength = 101–262% greater than the baseline control) in the mechanical properties of the 2D-reinforced PPF nanocomposites. MSNPs nanocomposites consistently showed the highest values among the experimental or control groups in all the mechanical measurements. In general, the inorganic nanoparticle MSNPs showed a better or equivalent mechanical reinforcement compared to carbon nanomaterials, and 2-D nanostructures (GONP, MSNP) are better reinforcing agents compared to 1-D nanostructures (e.g. SWCNTs). The results also indicate that the extent of mechanical reinforcement is closely dependent on the nanostructure morphology and follows the trend nanoplatelets > nanoribbons > nanotubes. Transmission electron microscopy of the cross-linked nanocomposites indicates good dispersion of nanomaterials in the polymer matrix without the use of a surfactant. The sol-fraction analysis showed significant changes in the polymer cross-linking in the presence of MSNP (0.01–0.2 wt %) and higher loading concentrations of GONP and MWGONR (0.1–0.2 wt%). The analysis of surface area and aspect ratio of the nanostructures taken together with the above results indicates differences in nanostructure architecture (2D vs. 1D nanostructures), as well as the chemical compositions (inorganic vs. carbon nanostructures), number of functional groups, and structural defects for the 2D nanostructures maybe key properties that affect the mechanical properties of 2D nanostructure-reinforced PPF nanocomposites, and the reason for the enhanced mechanical properties compared to the controls.
doi:10.1021/bm301995s
PMCID: PMC3601907  PMID: 23405887
5.  Physical Properties and Cellular Responses to Crosslinkable Poly(Propylene Fumarate)/Hydroxyapatite Nanocomposites 
Biomaterials  2008;29(19):2839-2848.
A series of crosslinkable nanocomposites has been developed using hydroxyapatite (HA) nanoparticles and poly(propylene fumarate) (PPF). PPF/HA nanocomposites with four different weight fractions of HA nanoparticles have been characterized in terms of thermal and mechanical properties. To assess surface chemistry of crosslinked PPF/HA nanocomposites, their hydrophilicity and capability of adsorbing proteins have been determined using static contact angle measurement and MicroBCA protein assay kit after incubation with 10% fetal bovine serum (FBS), respectively. In vitro cell studies have been performed using MC3T3-E1 mouse pre-osteoblast cells to investigate the ability of PPF/HA nanocomposites to support cell attachment, spreading, and proliferation after 1, 4, and 7 days. By adding HA nanoparticles to PPF, the mechanical properties of crosslinked PPF/HA nanocomposites have not been increased due to the initially high modulus of crosslinked PPF. However, hydrophilicity and serum protein adsorption on the surface of nanocomposites have been significantly increased, resulting in enhanced cell attachment, spreading, and proliferation after 4 days of cell seeding. These results indicate that crosslinkable PPF/HA nanocomposites are useful for hard tissue replacement because of excellent mechanical strength and osteoconductivity.
doi:10.1016/j.biomaterials.2008.03.030
PMCID: PMC2430424  PMID: 18403013
Poly(propylene fumarate) (PPF); Hydroxyapatite (HA); Nanocomposite; Protein adsorption; Osteoblast response
6.  The Roles of Matrix Polymer Crystallinity and Hydroxyapatite Nanoparticles in Modulating Material Properties of Photo-crosslinked Composites and Bone Marrow Stromal Cell Responses 
Biomaterials  2009;30(20):3359-3370.
Two poly(ε-caprolactone fumarate)s (PCLFs) with distinct physical properties have been employed to prepare nanocomposites with hydroxyapatite (HA) nanoparticles via photo-crosslinking. The two PCLFs are PCLF530 and PCLF2000, named after their precursor PCL diol molecular weight of 530 and 2000 g.mol-1, respectively. Crosslinked PCLF530 is amorphous while crosslinked PCLF2000 is semi-crystalline with a melting temperature (Tm) of ∼40 °C and a crystallinity of 40%. Consequently, the rheological and mechanical properties of crosslinked PCLF2000 are significantly greater than those of crosslinked PCLF530. Structural characterizations and physical properties of both series of crosslinked PCLF/HA nanocomposites with HA compositions of 0%, 5%, 10%, 20%, and 30% have been investigated. By adding HA nanoparticles, crosslinked PCLF530/HA nanocomposites demonstrate enhanced rheological and mechanical properties while the enhancement in compressive modulus is less prominent in crosslinked PCLF2000/HA nanocomposites. In vitro cell attachment and proliferation have been performed using rat bone marrow stromal cells (BMSCs) and correlated with the material properties. Cell attachment and proliferation on crosslinked PCLF530/HA nanocomposite disks have been enhanced strongly with increasing the HA composition. However, surface morphology and surface chemistry such as composition, hydrophilicity, and the capability of adsorbing protein cannot be used to interpret the cell responses on different samples. Instead, the role of surface stiffness in regulating cell responses can be supported by the correlation between the change in compressive modulus and BMSC proliferation on these two series of crosslinked PCLFs and PCLF/HA nanocomposites.
doi:10.1016/j.biomaterials.2009.03.015
PMCID: PMC2868517  PMID: 19339048
Polycaprolactone fumarate (PCLF); Hydroxyapatite (HA); Nanocomposite; Photo-crosslinking; Bone marrow stromal cell responses
7.  Low density biodegradable shape memory polyurethane foams for embolic biomedical applications 
Acta biomaterialia  2013;10(1):67-76.
Low density shape memory polymer foams hold significant interest in the biomaterials community for their potential use in minimally invasive embolic biomedical applications. The unique shape memory behavior of these foams allows them to be compressed to a miniaturized form, which can be delivered to an anatomical site via a transcatheter process, and thereafter actuated to embolize the desired area. Previous work in this field has described the use of a highly covalently crosslinked polymer structure for maintaining excellent mechanical and shape memory properties at the application-specific ultra low densities. This work is aimed at further expanding the utility of these biomaterials, as implantable low density shape memory polymer foams, by introducing controlled biodegradability. A highly covalently crosslinked network structure was maintained by use of low molecular weight, symmetrical and polyfunctional hydroxyl monomers such as Polycaprolactone triol (PCL-t, Mn 900 g), N,N,N0,N0-Tetrakis (hydroxypropyl) ethylenediamine (HPED), and Tris (2-hydroxyethyl) amine (TEA). Control over the degradation rate of the materials was achieved by changing the concentration of the degradable PCL-t monomer, and by varying the material hydrophobicity. These porous SMP materials exhibit a uniform cell morphology and excellent shape recovery, along with controllable actuation temperature and degradation rate. We believe that they form a new class of low density biodegradable SMP scaffolds that can potentially be used as “smart” non-permanent implants in multiple minimally invasive biomedical applications.
doi:10.1016/j.actbio.2013.09.027
PMCID: PMC4075478  PMID: 24090987
Shape Memory Polyurethane; Polycaprolactone triol; low density foams; degradation rate; FTIR
8.  Photo-Crosslinked Poly(ε-caprolactone fumarate) Networks for Peripheral Nerve Regeneration: Physical Properties and Preliminary Biological Evaluations 
Acta biomaterialia  2009;5(5):1531-1542.
In an effort of achieving suitable biomaterials for peripheral nerve regeneration, we present a material design strategy of combining a crystallite-based physical network and a crosslink-based chemical network. Biodegradable polymer disks and conduits have been fabricated by photo-crosslinking three poly(ε-caprolactone fumarate)s (PCLF530, PCLF1250, and PCLF2000), which were synthesized from the precursor poly(ε-caprolactone) (PCL) diols with nominal molecular weights of 530, 1250, and 2000 g.mol−1, respectively. Thermal properties such as glass transition temperature (Tg), melting temperature (Tm), and crystallinity of photo-crosslinked PCLFs were examined and correlated with their rheological and mechanical properties. Furthermore, in vitro degradation of uncrosslinked and crosslinked PCLFs in PBS crosslinked PCLFs in 1 N NaOH aqueous solution at 37 °C was studied. In vitro cytocompatibility, attachment, and proliferation of Schwann cell precursor line SPL201 cells on three PCLF networks were investigated. Crosslinked PCLF2000 with the highest crystallinity and mechanical properties was found to best support cell attachment and proliferation. Using a new photo-crosslinking method, single-lumen crosslinked PCLF nerve conduits without defects were fabricated in a glass mold. Crosslinked PCLF2000 nerve conduits were selected for evaluation in a 1-cm gap rat sciatic nerve model. Histological evaluation demonstrated that the material was biocompatible with sufficient strength to hold sutures in place after 6 and 17 weeks of implantation. Nerve cable with myelinated axons was found in the crosslinked PCLF2000 nerve conduit.
doi:10.1016/j.actbio.2008.12.015
PMCID: PMC2869216  PMID: 19171506
Poly(ε-caprolactone fumarate); Photo-crosslinking; Peripheral nerve regeneration; Cell responses
9.  Tungsten Disulfide Nanotubes Reinforced Biodegradable Polymers for Bone Tissue Engineering 
Acta biomaterialia  2013;9(9):8365-8373.
In this study, we have investigated the efficacy of inorganic nanotubes as reinforcing agents to improve the mechanical properties of poly(propylene fumarate) (PPF) composites as a function of nanomaterial loading concentration (0.01-0.2 wt%). Tungsten disulfide nanotubes (WSNTs) were used as reinforcing agents in the experimental groups. Single- and multi- walled carbon nanotubes (SWCNTs and MWCNTs) were used as positive controls, and crosslinked PPF composites were used as baseline control. Mechanical testing (compression and three-point bending) shows a significant enhancement (up to 28-190%) in the mechanical properties (compressive modulus, compressive yield strength, flexural modulus, and flexural yield strength) of WSNT reinforced PPF nanocomposites compared to the baseline control. In comparison to positive controls, at various concentrations, significant improvements in the mechanical properties of WSNT nanocomposites were also observed. In general, the inorganic nanotubes (WSNTs) showed a better (up to 127%) or equivalent mechanical reinforcement compared to carbon nanotubes (SWCNTs and MWCNTs). Sol fraction analysis showed significant increases in the crosslinking density of PPF in the presence of WSNTs (0.01-0.2 wt%). Transmission electron microscopy (TEM) analysis on thin sections of crosslinked nanocomposites showed the presence of WSNTs as individual nanotubes in the PPF matrix, whereas SWCNTs and MWCNTs existed as micron sized aggregates. The trend in the surface area of nanostructures obtained by BET surface area analysis was SWCNTs > MWCNTs > WSNTs. The BET surface area analysis, TEM analysis, and sol fraction analysis results taken together suggest that chemical composition (inorganic vs. carbon nanomaterials), presence of functional groups (such as sulfide and oxysulfide), and individual dispersion of the nanomaterials in the polymer matrix (absence of aggregation of the reinforcing agent) are the key parameters affecting the mechanical properties of nanostructure-reinforced PPF composites, and the reason for the observed increases in the mechanical properties compared to the baseline and positive controls.
doi:10.1016/j.actbio.2013.05.018
PMCID: PMC3732565  PMID: 23727293
polymer nanocomposites; carbon nanotubes; tungsten nanotubes; mechanical properties; bone tissue engineering
10.  Human urine-derived stem cells in combination with polycaprolactone/gelatin nanofibrous membranes enhance wound healing by promoting angiogenesis 
Background
Despite advancements in wound healing techniques and devices, new treatments are needed to improve therapeutic outcomes. This study aimed to evaluate the potential use of a new biomaterial engineered from human urine-derived stem cells (USCs) and polycaprolactone/gelatin (PCL/GT) for wound healing.
Methods
USCs were isolated from healthy individuals. To fabricate PCL/GT composite meshes, twin-nozzle electrospinning were used to spin the PCL and gelatin solutions in normal organic solvents. The morphologies and hydrophilicity properties of PCL/GT membranes were investigated. After USCs were seeded onto a PCL/GT, cell adhesion, morphology, proliferation, and cytotoxicity were examined. Then, USCs were seeded on a PCL/GT blend nanofibrous membrane and transplanted into rabbit full-thickness skin defects for wound repair. Finally, the effect of USCs condition medium on proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) were performed in vitro.
Results
USCs were successfully isolated from urine samples and expressed specific mesenchymal stem cells markers and could differentiate into osteoblasts, adipocytes, and chondrocytes. PCL/GT membrane has suitable mechanical properties similar with skin tissue and has good biocompatibility. USCs-PCL/GT significantly enhanced the healing of full-thickness skin wounds in rabbits compared to wounds treated with PCL/GT membrane alone or untreated wounds. USCs-PCL/GT-treated wounds closed much faster, with increased re-epithelialization, collagen formation, and angiogenesis. Moreover, USCs could secrete VEGF and TGF-β1, and USC-conditioned medium enhanced the migration, proliferation, and tube formation of endothelial cells.
Conclusion
USCs in combination with PCL/GT significantly prompted the healing of full-thickness skin wounds in rabbits. USCs based therapy provides a novel strategy for accelerating wound closure and promoting angiogenesis.
doi:10.1186/s12967-014-0274-2
PMCID: PMC4189744  PMID: 25274078
Human urine-derived stem cells (USCs); Angiogenesis; Endothelial cells; Polycaprolactone/gelatin (PCL/GT)
11.  Perfluorocarbon-loaded Shell Crosslinked Knedel-like Nanoparticles: Lessons regarding polymer mobility and self assembly 
Reversible addition-fragmentation chain transfer polymerization was employed to synthesize a set of copolymers of styrene (PS) and 2,3,4,5,6-pentafluorostyrene (PPFS), as well as block copolymers with tert-butyl acrylate (PtBA)-b-PS-co-PPFS, with control over molecular weight and polydispersity. It was found that the copolymerization of styrene and PFS allowed for the preparation of gradient copolymers with opposite levels of monomer consumption, depending on the feed ratio. Conversion to amphiphilic block copolymers, PAA-b-(PS-co-PPFS), by removing the protecting groups was followed by fitting with monomethoxy poly(ethylene glycol) chains. Solution-state assembly and intramicellar crosslinking afforded shell crosslinked (SCK) block copolymer nanoparticles. These fluorinated nanoparticles (ca. 20 nm diameters) were studied as potential magnetic resonance imaging (MRI) contrast agents based on the 19F-nuclei, however, it was found that packaging of the hydrophobic fluorinated polymers into the core domain restricted the mobility of the chains and prohibited 19F-NMR spectroscopy when the particles were dispersed in water without an organic cosolvent. Packing of perflouro-15-crown-5-ether (PFCE) into the polymer micelle was demonstrated with good uptake efficiency, however, it was necessary to swell the core with a good solvent (DMSO) to increase the mobility and observe the 19F-NMR signal of the PFCE.
doi:10.1002/pola.23184
PMCID: PMC2779516  PMID: 20157345
Block copolymers; copolymerization; fluoropolymers; amphiphilic polymers; micelles; nanoparticles; reversible addition-fragmentation chain transfer (RAFT) polymerization; NMR
12.  Synthesis of Poly(Propylene Fumarate) 
Nature protocols  2009;4(4):518-525.
This protocol describes the synthesis of 500 – 4000 Da poly(propylene fumarate) by a two-step reaction of diethyl fumarate and propylene glycol through a bis(hydroxypropyl) fumarate diester intermediate. Purified PPF can be covalently crosslinked to form degradable polymer networks, which have been widely explored for biomedical applications. The properties of crosslinked PPF networks depend upon the molecular properties of the constituent polymer, such as the molecular weight. The purity of the reactants and the exclusion of water from the reaction system are of utmost importance in the generation of high-molecular-weight PPF products. Additionally, the reaction time and temperature influence the molecular weight of the PPF product. The expected time required to complete this protocol is 3 d.
doi:10.1038/nprot.2009.24
PMCID: PMC3076598  PMID: 19325548
biodegradable; biomaterial; injectable material; tissue engineering scaffold
13.  Micromechanical finite element modeling and experimental characterization of the compressive mechanical properties of polycaprolactone:hydroxyapatite composite scaffolds prepared by selective laser sintering for bone tissue engineering 
Acta Biomaterialia  2012;8(8):3138-3143.
Bioresorbable scaffolds with mechanical properties suitable for bone tissue engineering were fabricated from polycaprolactone (PCL) and hydroxyapatite (HA) by selective laser sintering (SLS) and modeled by finite element analysis (FEA). Both solid gage parts and scaffolds having 1-D, 2-D and 3-D orthogonal, periodic porous architectures were made with 0, 10, 20 and 30% HA by volume. PCL:HA scaffolds manufactured by SLS had nearly full density (99%) in the designed solid regions and had excellent geometric and dimensional control. Through optimization of the SLS process, the compressive moduli for our solid gage parts and scaffolds are the highest reported in the literature for additive manufacturing. The compressive moduli of solid gage parts were 299.3, 311.2, 415.5 and 498.3 MPa for PCL:HA loading at 100:0, 90:10, 80:20 and 70:30 respectively. The compressive effective stiffness tended to increase as the loading of HA was increased and the designed porosity was lowered. In the case of the most 3-D porous scaffold, the compressive modulus more than doubled from 14.9 MPa to 36.2 MPa when changing the material from 100:0 to 70:30 PCL:HA. A micromechanical finite element analysis (FEA) model was developed to investigate the reinforcement effect of HA loading on the compressive modulus of the bulk material. Using a first-principles based approach, the random distribution of HA particles in a solidified PCL matrix was modeled for any loading of HA to predict the bulk mechanical properties of the composites. The bulk mechanical properties were also used for FEA of the scaffold geometries. Results of the FEA were found to be in good agreement with experimental mechanical testing. The development of patient and site-specific composite tissue engineering constructs with tailored properties can be seen as a direct extension of this work on computational design, a priori modeling of mechanical properties and direct digital manufacturing.
doi:10.1016/j.actbio.2012.04.022
PMCID: PMC3389275  PMID: 22522129
tissue engineering; scaffolds; polycaprolactone; hydroxyapatite; selective laser sintering; mechanical properties
14.  Curvature-coupled hydration of Semicrystalline Polymer Amphiphiles yields flexible Worm Micelles but favors rigid Vesicles: polycaprolactone-based block copolymers 
Macromolecules  2010;43(23):9736-9746.
Crystallization processes are in general sensitive to detailed conditions, but our present understanding of underlying mechanisms is insufficient. A crystallizable chain within a diblock copolymer assembly is expected to couple curvature to crystallization and thereby impact rigidity as well as preferred morphology, but the effects on dispersed phases have remained unclear. The hydrophobic polymer polycaprolactone (PCL) is semi-crystalline in bulk (Tm = 60°C) and is shown here to generate flexible worm micelles or rigid vesicles in water from several dozen polyethyleneoxide-based diblocks (PEO-PCL). Despite the fact that `worms' have a mean curvature between that of vesicles and spherical micelles, `worms' are seen only within a narrow, process-dependent wedge of morphological phase space that is deep within the vesicle phase. Fluorescence imaging shows worms are predominantly in one of two states – either entirely flexible with dynamic thermal undulations or fully rigid; only a few worms appear rigid at room temperature (T << Tm), indicating suppression of crystallization by both curvature and PCL hydration. Worm rigidification, which depends on molecular weight, is also prevented by copolymerization of caprolactone with just 10% racemic lactide that otherwise has little impact on bulk crystallinity. In contrast to worms, vesicles of PEO-PCL are always rigid and typically leaky. Defects between crystallite domains induce dislocation-roughening with focal leakiness although select PEO-PCL – which classical surfactant arguments would predict make worms – yield vesicles that retain encapsulant and appear smooth, suggesting a gel or glassy state. Hydration in dispersion thus tends to selectively soften high curvature microphases.
doi:10.1021/ma101316w
PMCID: PMC3075012  PMID: 21499509
block copolymer; worm micelle; polymersome; crystallinity
15.  Synthesis and characterization of segmented poly(esterurethane urea) elastomers for bone tissue engineering 
Acta biomaterialia  2007;3(4):475-484.
Segmented polyurethanes have been used extensively in implantable medical devices, but their tunable mechanical properties make them attractive for examining the effect of biomaterial modulus on engineered musculoskeletal tissue development. In this study a family of segmented degradable poly(esterurethane urea)s (PEUURs) were synthesized from 1,4-diisocyanatobutane, a poly(ε-caprolactone) (PCL) macrodiol soft segment and a tyramine-1,4-diisocyanatobutane-tyramine chain extender. By systematically increasing the PCL macrodiol molecular weight from 1100 to 2700 Da, the storage modulus, crystallinity and melting point of the PCL segment were systematically varied. In particular, the melting temperature, Tm, increased from 21 to 61°C and the storage modulus at 37°C increased from 52 to 278 MPa with increasing PCL macrodiol molecular weight, suggesting that the crystallinity of the PCL macrodiol contributed significantly to the mechanical properties of the polymers. Bone marrow stromal cells were cultured on rigid polymer films under osteogenic conditions for up to 14 days. Cell density, alkaline phosphatase activity, and osteopontin and osteocalcin expression were similar among PEUURs and comparable to poly(D,L-lactic-coglycolic acid). This study demonstrates the suitability of this family of PEUURs for tissue engineering applications, and establishes a foundation for determining the effect of biomaterial modulus on bone tissue development.
doi:10.1016/j.actbio.2007.02.001
PMCID: PMC2034277  PMID: 17418651
Polycaprolatone; Tissue engineering; Polyurethane; Osteoblast; Modulus
16.  Mesenchymal Stem Cell Responses to Bone-Mimetic Electrospun Matrices Composed of Polycaprolactone, Collagen I and Nanoparticulate Hydroxyapatite 
PLoS ONE  2011;6(2):e16813.
The performance of biomaterials designed for bone repair depends, in part, on the ability of the material to support the adhesion and survival of mesenchymal stem cells (MSCs). In this study, a nanofibrous bone-mimicking scaffold was electrospun from a mixture of polycaprolactone (PCL), collagen I, and hydroxyapatite (HA) nanoparticles with a dry weight ratio of 50/30/20 respectively (PCL/col/HA). The cytocompatibility of this tri-component scaffold was compared with three other scaffold formulations: 100% PCL (PCL), 100% collagen I (col), and a bi-component scaffold containing 80% PCL/20% HA (PCL/HA). Scanning electron microscopy, fluorescent live cell imaging, and MTS assays showed that MSCs adhered to the PCL, PCL/HA and PCL/col/HA scaffolds, however more rapid cell spreading and significantly greater cell proliferation was observed for MSCs on the tri-component bone-mimetic scaffolds. In contrast, the col scaffolds did not support cell spreading or survival, possibly due to the low tensile modulus of this material. PCL/col/HA scaffolds adsorbed a substantially greater quantity of the adhesive proteins, fibronectin and vitronectin, than PCL or PCL/HA following in vitro exposure to serum, or placement into rat tibiae, which may have contributed to the favorable cell responses to the tri-component substrates. In addition, cells seeded onto PCL/col/HA scaffolds showed markedly increased levels of phosphorylated FAK, a marker of integrin activation and a signaling molecule known to be important for directing cell survival and osteoblastic differentiation. Collectively these results suggest that electrospun bone-mimetic matrices serve as promising degradable substrates for bone regenerative applications.
doi:10.1371/journal.pone.0016813
PMCID: PMC3035635  PMID: 21346817
17.  Poly(Propylene Fumarate) Reinforced Dicalcium Phosphate Dihydrate Cement Composites for Bone Tissue Engineering 
Calcium phosphate cements have many desirable properties for bone tissue engineering, including osteoconductivity, resorbability, and amenability to rapid prototyping based methods for scaffold fabrication. In this study, we show that dicalcium phosphate dihydrate (DCPD) cements, which are highly resorbable but also inherently weak and brittle, can be reinforced with poly(propylene fumarate) (PPF) to produce strong composites with mechanical properties suitable for bone tissue engineering. Characterization of DCPD-PPF composites revealed significant improvements in mechanical properties for cements with a 1.0 powder to liquid ratio. Compared to non-reinforced controls, flexural strength improved from 1.80 ± 0.19 MPa to 16.14 ± 1.70 MPa, flexural modulus increased from 1073.01 ± 158.40 MPa to 1303.91 ± 110.41 MPa, maximum displacement during testing increased from 0.11 ± 0.04 mm to 0.51 ± 0.09 mm, and work of fracture improved from 2.74 ± 0.78 J/m2 to 249.21 ± 81.64 J/m2. To demonstrate the utility of our approach for scaffold fabrication, 3D macroporous scaffolds were prepared with rapid prototyping technology. Compressive testing revealed that PPF reinforcement increased scaffold strength from 0.31 ± 0.06 MPa to 7.48 ± 0.77 MPa. Finally, 3D PPF-DCPD scaffolds were implanted into calvarial defects in rabbits for 6 weeks. Although the addition of mesenchymal stem cells to the scaffolds did not significantly improve the extent of regeneration, numerous bone nodules with active osteoblasts were observed within the scaffold pores, especially in the peripheral regions. Overall, the results of this study suggest that PPF-DCPD composites may be promising scaffold materials for bone tissue engineering.
doi:10.1002/jbm.a.34130
PMCID: PMC3360828  PMID: 22489012
18.  Bone Tissue-Engineering Material Poly(propylene fumarate): Correlation between Molecular Weight, Chain Dimensions, and Physical Properties 
Biomacromolecules  2006;7(6):1976-1982.
Poly(propylene fumarate) (PPF) is an important biodegradable and crosslinkable polymer designed for bone tissue-engineering applications. For the first time we report the extensive characterization of this biomaterial including molecular weight dependences of physical properties such as glass transition temperature Tg, thermal degradation temperature Td, density ρ melt viscosity η0, hydrodynamic radius RH, and intrinsic viscosity [η]. The temperature dependence of η0 changes progressively with molecular weight, while it can be unified when the temperature is normalized to Tg. The plateau modulus GN0 and entanglement molecular weight Me have been obtained from the rheological master curves. A variety of chain microstructure parameters such as the Mark-Houwink-Sakurada constants K and α, characteristic ratio C∞, unperturbed chain dimension r02/M, packing length p, Kuhn length b, and tube diameter a have been deduced. Further correlation between the microstructure and macroscopic physical properties has been discussed in light of recent progress in polymer dynamics to supply a better understanding about this unsaturated polyester to advance its biomedical uses. The molecular weight dependence of Tg for six polymer species including PPF has been summarized to support that Me is irrelevant for the finite length effect on glass transition, while surprisingly these polymers can be divided into two groups when their normalized Tg is plotted simply against Mw to indicate the deciding roles of inherent chain properties such as chain fragility, intermolecular cooperativity, and chain end mobility.
doi:10.1021/bm060096a
PMCID: PMC2530912  PMID: 16768422
19.  Novel chitosan-polycaprolactone blends as potential scaffold and carrier for corneal endothelial transplantation 
Molecular Vision  2012;18:255-264.
Purpose
The aim of this prospective study was to evaluate whether blending two kinds of biomaterials, chitosan and polycaprolactone (PCL), can be used as scaffold and carrier for growth and differentiation of corneal endothelial cells (CECs).
Methods
A transparent, biocompatible carrier with cultured CECs on scaffold would be a perfect replacement graft. In the initial part of experiment, for essential and biocompatible test, chitosan and PCL were evaluated respectively and blended in various proportions by coating. In the later part of this study, for evaluation of potential application, homogenous solutions of 25%, 50%, and 75% PCL compositions were attempted to structure blend membranes.
Results
Chitosan, PCL 25, PCL 50, and PCL 75 blends could maintain transparency of culturing substrata. BCECs were found to be reached confluence successfully after 7 days on PCL 25, PCL 50, and PCL 75. The expression of tight junction and extracellular matrix protein were observed as well. Alternatively, only PCL 25 could make blend membrane with enough strength during preparation for carrier in culture. On this blend membrane, the growth pattern and phenotype of BCECs could be observed well.
Conclusions
A ratio of 75:25 (chitosan:PCL) blends showed enough mechanical properties as well as suitable support for cellular activity in cultivating BCECs. Thus, a novel methodology of biodegradable carrier from chitosan and PCL has potential to be a good replacement scaffold for raising CECs for clinical transplantation.
PMCID: PMC3276373  PMID: 22328821
20.  Degradable poly(2-hydroxyethyl methacrylate)-co-polycaprolactone Hydrogels for Tissue Engineering Scaffolds 
Biomacromolecules  2008;9(12):3370-3377.
Biodegradable poly(2-hydroxyethyl methacrylate) hydrogels for engineered tissue constructs were developed using atom transfer radical polymerization (ATRP), a degradable crosslinker and a macroinitiator. Hydrogels are appropriate materials for tissue engineering scaffolds due to their tissue-like mechanical compliance and mass transfer properties. However, many hydrogels that have seen wide application in medicine are not biodegradable or cannot be easily cleared from the body. Poly(2-hydroxyethyl methacrylate) (pHEMA) was selected for the scaffold material due to its reasonable mechanical strength, elasticity, long history of successful use in medicine and because it can be easily fabricated into numerous configurations. pHEMA was studied at various molecular weights between 2 kDa and 50 kDa. The molecular weight range suitable for renal clearance was an important factor in the experimental design. The fabricated hydrogels contain oligomeric blocks of polycaprolactone (PCL), a hydrolytically and enzymatically degradable polymer, as a crosslinking agent. In addition a degradable macroinitiator also containing oligomeric PCL was used to initiate the ATRP. The chain length, crosslink density, and polymerization solvent were found to greatly affect the mechanical properties of the pHEMA hydrogels. Degradation of the pHEMA hydrogels was characterized using 0.007 M NaOH, lipase solutions and phosphate buffered saline. Mass loss, swelling ratio and tensile modulus were evaluated. Degradation products from the sodium hydroxide were measured using gel permeation chromatography (GPC) to verify the polymer lengths and polydispersity. Erosion was only observed in the sodium hydroxide and lipase solutions. However, swelling ratio and tensile modulus indicate bulk degradation in all PCL containing samples. Degradable hydrogels in enzymatic solutions showed 30% mass loss in 16 weeks. Initial cell toxicity studies indicate no adverse cellular response to the hydrogels or their degradation products. These hydrogels have appropriate mechanical properties, a tunable degradation rate, and are composed of materials currently in FDA approved devices. Thus the degradable pHEMA developed in this study has considerable potential as a scaffold for tissue engineering in cardiac and other applications.
doi:10.1021/bm800686h
PMCID: PMC2650022  PMID: 19061434
PolyHEMA; Polycaprolactone; ATRP; Cardiac Tissue Engineering; Degradation
21.  Folate-targeted polymeric micelles loaded with ultrasmall superparamagnetic iron oxide: combined small size and high MRI sensitivity 
Targeted delivery of contrast agents is a highly desirable strategy for enhancing diagnostic efficiency and reducing side effects and toxicity. Water-soluble and tumor-targeting superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by loading hydrophobic SPIONs into micelles assembled from an amphiphilic block copolymer poly(ethylene glycol)- poly(ɛ-caprolactone) (PEG-PCL) bearing folate in the distal ends of PEG chains. Compared to the water-soluble SPIONs obtained by small molecular surfactant coating, ultrasmall SPION encapsulation with PEG-PCL micelles (PEG-PCL-SPIONs) simultaneously increases transverse (r2) and decreases longitudinal (r1) magnetic resonance (MR) relaxivities of water proton in micelle solution, leading to a notably high r2/r1 ratio up to 78, which makes the PEG-PCL-SPIONs a highly sensitive MR imaging (MRI) T2 contrast agent. The mean size of folate-attached SPION micelles (Fa-PEG-PCL-SPIONs) is 44 ± 3 nm on average, ideal for in vivo MRI applications in which long circulation is greatly determined by small particle size and is highly desirable. Prussian blue staining of BEL-7402 cells over-expressing folate receptors, after incubation with micelle-containing medium, demonstrated that folate functionalization of the magnetic particles significantly enhanced their cell uptake. The potential of Fa-PEG-PCL-SPIONs as a potent MRI probe for in vivo tumor detection was assessed. At 3 hours after intravenous injection of the Fa-PEG-PCL-SPION solution into mice bearing subcutaneous xenografts of human BEL-7402 hepatoma, a 41.2% signal intensity decrease was detected in the T2-weighted MR images of the tumor, indicating the efficient accumulation of Fa-PEG-PCL-SPIONs in the tumor tissue.
doi:10.2147/IJN.S25739
PMCID: PMC3383322  PMID: 22745549
tumor targeting; magnetic resonance imaging; polymeric micelles; superparamagnetic iron oxide
22.  Development of biodegradable polycaprolactone film as an internal fixation material to enhance tendon repair: an in vitro study 
Background
Current tendon repair techniques do not provide sufficient tensile strength at the repair site, and thus early active motion rehabilitation after tendon repair is discouraged. To enhance the post-operative tensile strength, we proposed and tested an internal fixation technique using a polycaprolactone (PCL) biofilm. PCL was chosen for its good biocompatibility, excellent mechanical strength, and an appropriate degradation time scale.
Methods
PCL biofilms were prepared by a modified melt-molding/leaching technique, and the physical and mechanical properties and in vitro degradation rate were assessed. The pore size distribution of the biofilm and the paratenon of native tendons were observed using scanning electron microscopy. Next, we determined whether this biofilm could enhance the tensile strength of repaired tendons. We performed tensile tests on rabbit Achilles tendons that were first lacerated and then repaired: 1) using modified Kessler suture combined with running peripheral suture (‘control’ group), or 2) using biofilm to wrap the tendon and then fixation with sutures (‘biofilm’ group). The influence of different repair techniques on tendon tensile strength was evaluated by mechanical testing.
Results
The novel biofilm had supple texture and a smooth surface. The mean thickness of the biofilm was 0.25 mm. The mean porosity of the biofilm was 45.3%. The paratenon of the rabbit Achilles tendon had pores with diameters ranging from 1 to 9 μm, which were similar to the 4–12 μm diameter pores in the biofilm cross-section. The weight loss of the biofilms at 4 weeks was only 0.07%. The molecular weight of PCL biofilms did not change after immersion in phosphate buffered saline for 4 weeks. The failure loads of the biofilm were similar before (48 ± 9 N) and after immersion (47 ± 7 N, P > 0.1). The biofilm group had ~70% higher mean failure loads and 93% higher stiffness compared with the control group.
Conclusions
We proposed and tested an internal fixation technique using a PCL biofilm to enhance tendon repair. Internal fixation with the biofilm followed by standard suturing can significantly increase the tensile strength of tendon repair sites. This technique has the potential to allow active motion rehabilitation during the early post-operative period.
doi:10.1186/1471-2474-14-246
PMCID: PMC3751937  PMID: 23957758
Tendon injury; Internal fixation; Biomechanics; Microstructure
23.  Fabrication and Characterization of Tough Elastomeric Fibrous Scaffolds for Tissue Engineering Applications 
Development of biodegradable tough elastomeric scaffolds are important for engineering tissues such as myocardium and heart valves that experience dynamic environments in vivo. Biomaterial scaffolds should ideally provide appropriate physical, chemical and mechanical cues to the seeded cells to closely mimic the native ECM. Collagen fibers form an important component of native myocardium as well as heart valve leaflets and provide necessary tensile properties to these tissues. Amongst various polymers, collagen mimicking biodegradable elastomer, Poly-(glycerol-sebacate) (PGS) has shown great promise in microfabricated scaffolds for cardiac tissue engineering. However, its use is limited by its solubility and the ability to cast nano-/microfibrous structures. For its superior mechanical properties, thermal or UV crosslinking of the pre-polymer is required under high temperatures and vacuum limiting fabrication of fibers. In this work, electrospun PGS fibers were fabricated by simply blending it with biodegradable polycaprolactone (PCL) polymer without any post-processing. It was hypothesized that microfibrous PGS-PCL scaffolds would provide appropriate physical (fibrous structure) and chemical (balanced hydrophilicity and hydrophobicity) to the cells in addition to the mechanical properties.
doi:10.1109/IEMBS.2010.5627486
PMCID: PMC3098812  PMID: 21096824
24.  Poly(ε-Caprolactone)-Based Copolymers Bearing Pendant Cyclic Ketals and Reactive Acrylates for the Fabrication of Photocrosslinked Elastomers 
Acta biomaterialia  2013;9(9):8232-8244.
Block copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) with chemically addressable functional groups were synthesized and characterized. Ring opening polymerization of ε-caprolactone (CL) and 1,4,8-trioxaspiro-[4,6]-9-undecanone (TSU) using α-methoxy, ω-hydroxyl poly(ethylene glycol) (mPEG) as the initiator afforded a copolymer with cyclic ketals being randomly distributed in the hydrophobic PCL block. At an initiator/catalyst molar ratio of 10/1 and a TSU/CL weight ratio of 1/4, a ketal-carrying copolymer (ECT2-CK) with Mn of 52 kDa and a ketal content of 15 mol% was obtained. Quantitative side chain deacetalization revealed the reactive ketones without noticeable polymer degradation. In our study, 10 mol% of cyclic ketals were deprotected and the ketone-containing copolymer was designated as ECT2-CO. Reaction of ECT2-CO with 2-(2-(aminooxy)acetoxy)-ethyl acrylate gave rise to an acrylated product (ECT2-AC) containing an estimated 3–5 acrylate groups per chain. UV-initiated radical polymerization of ECT2-AC in dichloromethane resulted in a crosslinked network (xECT2-AC). Thermal and morphological analyses employing Differential Scanning Calorimetry (DSC) and Atomic Force Microscopy (AFM) operated in PeakForce Tapping mode revealed the semicrystalline nature of the network, containing stiff crystalline lamellae dispersed in a softer amorphous interstitial. Macroscopic and nanoscale mechanical characterizations showed that ECT2-CK exhibited a significantly lower modulus than PCL of a similar molecular weight. While ECT2-CK undergoes a plastic deformation with a distinct yield point and a cold drawing region, xECT2-AC exhibited a compliant, elastomeric deformation with a Young’s modulus of 0.5 ± 0.1 MPa at 37 °C. When properly processed, the crosslinked network exhibited shape memory behaviors, with shape fixity and shape recovery values close to 1 and a shape recovery time of less than 4 s at 37 °C. In vitro studies showed that xECT2-AC films did not induce any cytotoxic effects to the cultured mesenchymal stem cells. The crosslinkable polyester copolymers can be potentially used as tissue engineering scaffolds and minimally invasive medical devices.
doi:10.1016/j.actbio.2013.06.005
PMCID: PMC3732508  PMID: 23770222
Poly(ε-caprolactone); Poly(ethylene glycol); Copolymers; Functional Groups; Photocrosslinking; Elastomeric; Shape Memory; Tissue Engineering
25.  Enhanced Cell Ingrowth and Proliferation through Three-Dimensional Nanocomposite Scaffolds with Controlled Pore Structures 
Biomacromolecules  2010;11(3):682-689.
We present enhanced cell ingrowth and proliferation through crosslinked three-dimensional (3D) nanocomposite scaffolds fabricated using poly(propylene fumarate) (PPF) and hydroxyapatite (HA) nanoparticles. Scaffolds with controlled internal pore structures were produced from computer-aided design (CAD) models and solid freeform fabrication (SFF) technique, while those with random pore structures were fabricated by NaCl leaching technique for comparison. The morphology and mechanical properties of scaffolds were characterized using scanning electron microscopy (SEM) and mechanical testing, respectively. Pore interconnectivity of scaffolds was assessed using X-ray micro-computed tomography (micro-CT) and 3D imaging analysis. In vitro cell studies have been performed using MC3T3-E1 mouse preosteoblasts and cultured scaffolds in a rotating-wall-vessel bioreactor for 4 and 7 days to assess cell attachment, viability, ingrowth depth, and proliferation. The mechanical properties of crosslinked nanocomposite scaffolds were not significantly different after adding HA or varying pore structures. However, pore interconnectivity of PPF/HA nanocomposite scaffolds with controlled pore structures has been significantly increased, resulting in enhanced cell ingrowth depth 7 days after cell seeding. Cell attachment and proliferation are also higher in PPF/HA nanocomposite scaffolds. These results suggest that crosslinked PPF/HA nanocomposite scaffolds with controlled pore structures may lead to promising bone tissue engineering scaffolds with excellent cell proliferation and ingrowth.
doi:10.1021/bm901260y
PMCID: PMC2839506  PMID: 20112899
Poly(propylene fumarate) (PPF); Hydroxyapatite (HA); Nanocomposite; Solid freeform fabrication (SFF); Pre-osteoblast responses

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