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1.  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.
PMCID: PMC2869216  PMID: 19171506
Poly(ε-caprolactone fumarate); Photo-crosslinking; Peripheral nerve regeneration; Cell responses
2.  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.
PMCID: PMC2868517  PMID: 19339048
Polycaprolactone fumarate (PCLF); Hydroxyapatite (HA); Nanocomposite; Photo-crosslinking; Bone marrow stromal cell responses
3.  Preparation and evaluation of poly (caprolactone fumarate) nanoparticles containing doxorubicin HCI 
Background and the purpose of the study
Biodegradable Poly(caprolactone fumarate) (PCLF) has been used as bioresorbable sutures. In this study, doxorubicin HCl (Dox) loaded PCLF nanoparticles were prepared and characterized.
Material and methods
PCLFs were synthesized by polycondensation of PCL diols (Mws of 530, 1250 and 2000) with fumaryl chloride. The degradation of PCLF in NaOH, water and phosphate buffer saline (PBS), was determined in terms of changes in Mw. Nanoparticles (NPs) were prepared by two methods. In microemulsion polymerization method, dichloromethane containing PCLF and photoinitiator were combined with the water containing surfactants and then the mixture was placed under light for crosslinking. In nanoprecipitation method, the organic solvent containing PCLF was poured into the stirring water. The effect of several variables including concentration of PCLF, polyvinyl alcohol (PVA), Dox and Trypan blue (Trb) and the Mw of PCLF and PVA on NP size and loading were evaluated.
PCLF 530, 1250 and 2000 in PBS or water were not degraded over 28 days. Nanoprecipitaion method gave spherical (revealed by SEM images) stable NPs of about 225 with narrow size distribution and a zeta potential of −43 mV. The size of NP increased significantly by increase in Mw or concentration of PCLF. Although PVA was not necessary for formation of NPs, but it decreased with NP size. Dox loading and EE were 2.5–6.8% and 15–20%, respectively. Increasing the drug concentration increased the drug loading (DL) and NP size. The entrapment efficiency (EE) for Trb ranged from 1% for PCLF530 to 6% for PCLF2000. An increase in PCLF concentration resulted in an increase in EE. Dox and Trb release showed a burst followed by 80% and 78% release during 3 and 4 days respectively.
PCLF possessed suitable characteristics for preparation of nanoparticulate drug delivery system such as desired NP size, stability and degradation time. Although PCLF530 NPs were the smallest, but their DL were lower than PCLF1250 and 2000 NPs.
PMCID: PMC3232073  PMID: 22615635
PCLF nanoparticles; Copolymer molecular weight; Nanoprecipitation method
4.  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.
PMCID: PMC2888142  PMID: 18307311
Photo-crosslinking; Polymer blends; Poly(propylene fumarate) (PPF); Poly(caprolactone fumarate) (PCLF); Controlled physical properties; Cell responses
5.  Reformulating Polycaprolactone Fumarate to Eliminate Toxic Diethylene Glycol: Effects of Polymeric Branching and Autoclave Sterilization on Material Properties 
Acta biomaterialia  2011;8(1):133-143.
Polycaprolactone fumarate (PCLF) is a cross-linkable derivate of polycaprolactone diol that has been shown to be an effective nerve conduit material that supports regeneration across segmental nerve defects and has warranted future clinical trials. Degradation of the previously studied PCLF (PCLFDEG) releases toxic small molecules of diethylene glycol used as the initiator for the synthesis of polycaprolactone diol. In an effort to eliminate this toxic degradation product we present a strategy for the synthesis of PCLF from either propylene glycol (PCLFPPD) or glycerol (PCLFGLY). PCLFPPD is linear and resembles the previously studied PCLFDEG, while PCLFGLY is branched and exhibits dramatically different material properties. The synthesis and characterization of their thermal, rheological, and mechanical properties are reported. The results show that the linear PCLFPPD has material properties similar to the previously studied PCLFDEG. The branched PCLFGLY exhibits dramatically lower crystalline properties resulting in lower rheological and mechanical moduli, and is therefore a more compliant material. In addition, the question of an appropriate FDA approvable sterilization method is addressed. This study shows that autoclave sterilization on PCLF materials is an acceptable sterilization method for cross-linked PCLF and has minimal effect on the PCLF thermal and mechanical properties.
PMCID: PMC3226927  PMID: 21911087
Polycaprolactone fumarate; polyester; sterilization; nerve regeneration
6.  The Development of Electrically Conductive Polycaprolactone Fumarate-Polypyrrole Composite Materials for Nerve Regeneration 
Biomaterials  2010;31(23):5916-5926.
Electrically conductive polymer composites composed of polycaprolactone fumarate and polypyrrole (PCLF-PPy) have been developed for nerve regeneration applications. Here we report the synthesis and characterization of PCLF-PPy and in vitro studies showing PCLF-PPy materials support both PC12 cell and dorsal root ganglia (DRG) neurite extension. PCLF-PPy composite materials were synthesized by polymerizing pyrrole in pre-formed PCLF scaffolds (Mn 7,000 or 18,000 g mol−1) resulting in interpenetrating networks of PCLF-PPy. Chemical compositions and thermal properties were characterized by ATR-FTIR, XPS, DSC, and TGA. PCLF-PPy materials were synthesized with five different anions (naphthalene-2-sulfonic acid sodium salt (NSA), dodecylbenzenesulfonic acid sodium salt (DBSA), dioctyl sulfosuccinate sodium salt (DOSS), potassium iodide (I), and lysine) to investigate effects on electrical conductivity and to optimize chemical composition for cellular compatibility. PCLF-PPy materials have variable electrical conductivity up to 6 mS cm−1 with bulk compositions ranging from 5 to 13.5 percent polypyrrole. AFM and SEM characterization show microstructures with a root mean squared (RMS) roughness of 1195 nm and nanostructures with RMS roughness of 8 nm. In vitro studies using PC12 cells and DRG show PCLF-PPy materials synthesized with NSA or DBSA support cell attachment, proliferation, neurite extension, and are promising materials for future studies involving electrical stimulation.
PMCID: PMC2893281  PMID: 20483452
Electrically Conductive; Polypyrrole; Nerve; PCLF
7.  Synthesis, Material Properties and Biocompatibility of a Novel Self-Crosslinkable Poly(caprolactone fumarate) as an Injectable Tissue Engineering Scaffold 
Biomacromolecules  2005;6(5):2503-2511.
A novel self-crosslinkable and biodegradable macromer poly(caprolactone fumarate) (PCLF) has been developed for guided bone regeneration. This macromer is a copolymer of fumaryl chloride, which contains double bonds for in-situ crosslinking, and poly(ε-caprolactone) that has a flexible chain to facilitate self-crosslinkability. PCLF was characterized with Fourier transform infrared (FTIR) spectroscopy, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and gel permeation chromatography (GPC). Porous scaffolds were fabricated with sodium chloride particles as the porogen and a chemical initiation system. The PCLF scaffolds were characterized with scanning electron microscopy (SEM) and micro-computed tomography (micro-CT). The cytotoxicity and in vivo biocompatibility of PCLF were also assessed. Our results suggest that this novel copolymer, PCLF, is an injectable, self-crosslinkable, and biocompatible macromer that may be potentially used as a scaffold for tissue engineering applications.
PMCID: PMC2530909  PMID: 16153086
8.  Material properties and electrical stimulation regimens through polycaprolactone fumarate-polypyrrole scaffolds as potential conductive nerve conduits 
Acta biomaterialia  2010;7(3):944-953.
Mechanical and electrical properties of polycaprolactone fumarate-polypyrrole (PCLF-PPy) scaffolds were studied under physiological conditions to evaluate their ability to maintain material properties necessary for application as conductive nerve conduits. PC12 cells cultured on PCLF-PPy scaffolds were stimulated with regimens of 10 μA of constant or 20 Hz frequency current passed through the scaffolds for 1 h/day. PC12 cellular morphologies were analyzed by fluorescence microscopy after 48 h. PCLF-PPy scaffolds exhibited excellent mechanical properties at 37°C which would allow suturing and flexibility. The surface resistivity of the scaffolds was 2kΩ and the scaffolds were electrically stable during application of electrical stimulation (ES). In vitro studies showed significant increases in percentage of neurite bearing cells, number of neurites per cell and neurite length in the presence of ES compared to no ES. Additionally, extending neurites were observed to align in the direction of the applied current. This study shows that electrically conductive PCLF-PPy scaffolds possess material properties necessary for application as nerve conduits. Additionally, the capability to significantly enhance and direct neurite extension by passing electrical current through PCLF-PPy scaffolds renders them even more promising as future therapeutic treatments for severe nerve injuries.
PMCID: PMC3031729  PMID: 20965280
Electrical Stimulation; Polypyrrole; Nerve; PCLF; PC12 cells
9.  Crosslinking Characteristics and Mechanical Properties of an Injectable Biomaterial Composed of Polypropylene fumarate and Polycaprolactone Copolymer 
In this work, a series of copolymers of polypropylene fumarate-co-polycaprolactone (PPF-co-PCL) were synthesized via a three-step polycondensation reaction of oligomeric polypropylene fumarate (PPF) with polycaprolactone (PCL). The effects of PPF precursor molecular weight, PCL precursor molecular weight, and PCL fraction in the copolymer (PCL feed ratio) on the maximum crosslinking temperature, gelation time, and mechanical properties of the crosslinked copolymers were investigated. The maximum crosslinking temperature fell between 38.2±0.3 and 47.2±0.4 °C, which increased with increasing PCL precursor molecular weight. The gelation time was between 4.2±0.2 and 8.5±0.7 min, and decreased with increasing PCL precursor molecular weight. The compressive moduli ranged from 44±1.8 to 142±7.4 MPa, with enhanced moduli at higher PPF precursor molecular weight and lower PCL feed ratio. The compressive toughness was in the range of 4.1±0.3 and 17.1±1.3 KJ/m3. Our data suggest that the crosslinking and mechanical properties of PPF-co-PCL can be modulated by varying the composition. Therefore the PPF-co-PCL copolymers may offer increased versatility as an injectable, in situ polymerizable biomaterial than the individual polymers of PPF and PCL.
PMCID: PMC3062160  PMID: 20566042
Polypropylene fumarate; polycaprolactone; injectable biomaterials; in situ polymerizable
10.  Comparison of polymer scaffolds in rat spinal cord: A step toward quantitative assessment of combinatorial approaches to spinal cord repair 
Biomaterials  2011;32(32):8077-8086.
The transected rat thoracic (T9/10) spinal cord model is a platform for quantitatively compa0ring biodegradable polymer scaffolds. Schwann cell-loaded scaffolds constructed from poly (lactic co-glycolic acid) (PLGA), poly(ε-caprolactone fumarate) (PCLF), oligo(polyethylene glycol) fumarate (OPF) hydrogel or positively charged OPF (OPF+) hydrogel were implanted into the model. We demonstrated that the mechanical properties (3-point bending and stiffness) of OPF and OPF+ hydrogels closely resembled rat spinal cord. After one month, tissues were harvested and analyzed by morphometry of neurofilament-stained sections at rostral, midlevel, and caudal scaffold. All polymers supported axonal growth. Significantly higher numbers of axons were found in PCLF (P < 0.01) and OPF+ (P < 0.05) groups, compared to that of the PLGA group. OPF+ polymers showed more centrally distributed axonal regeneration within the channels while other polymers (PLGA, PCLF and OPF) tended to show more evenly dispersed axons within the channels. The centralized distribution was associated with significantly more axons regenerating (P < 0.05). Volume of scar and cyst rostral and caudal to the implanted scaffold was measured and compared. There were significantly smaller cyst volumes in PLGA compared to PCLF groups. The model provides a quantitative basis for assessing individual and combined tissue engineering strategies.
PMCID: PMC3163757  PMID: 21803415
OPF; PLGA; PCLF; axon regeneration; spinal cord injury; Schwann cell
11.  Three-Dimensional Porous Biodegradable Polymeric Scaffolds Fabricated with Biodegradable Hydrogel Porogens 
We have developed a new fabrication technique to create three-dimensional (3D) porous poly(ε-caprolactone fumarate) (PCLF) scaffolds using hydrogel microparticle porogens, as an alternative to overcome certain limitations of traditional scaffold fabrication techniques such as a salt leaching method. Both natural hydrogel, gelatin, and synthetic hydrogel, poly(ethylene glycol) sebacic acid diacrylate, were used as porogens to fabricate 3D porous PCLF scaffolds. Hydrogel microparticles were prepared by a single emulsion technique with the particle size in the range of 100–500 μm after equilibrium in water. The pore size distribution, porosity, pore interconnectivity, and spatial pore heterogeneity of the 3D PCLF scaffolds were assessed using micro-computed tomography and imaging analysis. Scaffolds fabricated with the hydrogel porogens had higher porosity and pore interconnectivity as well as more homogeneous spatial pore distribution, compared to the scaffolds made from the salt leaching process. Compressive moduli of the scaffolds were also measured and showed that lower porosity yielded greater modulus of the scaffolds. Overall, the new fabrication technology using hydrogel porogens may be beneficial for certain tissue engineering applications.
PMCID: PMC2819712  PMID: 19216632
12.  Osteoblast Growth and Bone Healing Response to Three Dimensional Poly(ε-caprolactone fumarate) Scaffolds 
Poly(ε-caprolactone fumarate) (PCLF) scaffold formulations were assessed as a delivery system of recombinant human bone morphogenetic protein (rhBMP-2) for bone tissue engineering. The formulations included PCLF with combinations of poly(vinyl alcohol) (PVA) and hydroxyapatite (HA). The assessments included in vitro and in vivo assays. In vitro assays validated cell attachment using a pre-osteoblast cell line (MC3T3-E1). Additionally, in vitro release profiles of rhBMP-2 from PCLF scaffolds were determined up to 21 days. Data suggested PCLF incorporated with PVA and HA accelerated rhBMP-2 release and the released protein was bioactive. For the in vivo study, a critical sized defect (CSD) model in a rabbit calvaria was used to test PCLF scaffolds. At 6 weeks post-implantation, significantly more bone formation was measured in PCLF scaffolds containing rhBMP-2 than in scaffolds without rhBMP-2. In conclusion, we demonstrated PCLF delivered biologically active rhBMP-2, promoted bone healing in a CSD and has potential as a bone tissue engineering scaffold.
PMCID: PMC3213277  PMID: 21744511
poly(ε-caprolactone fumarate); three-dimensional scaffold; rabbit calvarial critical sized defect; rhBMP-2; bone tissue engineering
13.  Development of Photocrosslinkable Urethane-Doped Polyester Elastomers for Soft Tissue Engineering 
Finding an ideal biomaterial with the proper mechanical properties and biocompatibility has been of intense focus in the field of soft tissue engineering. This paper reports on the synthesis and characterization of a novel crosslinked urethane-doped polyester elastomer (CUPOMC), which was synthesized by reacting a previously developed photocrosslinkable poly (octamethylene maleate citrate) (POMC) prepolymers (pre-POMC) with 1,6-hexamethylene diisocyanate (HDI) followed by thermo- or photo-crosslinking polymerization. The mechanical properties of the CUPOMCs can be tuned by controlling the molar ratios of pre-POMC monomers, and the ratio between the prepolymer and HDI. CUPOMCs can be crosslinked into a 3D network through polycondensation or free radical polymerization reactions. The tensile strength and elongation at break of CUPOMC synthesized under the known conditions range from 0.73±0.12MPa to 10.91±0.64MPa and from 72.91±9.09% to 300.41±21.99% respectively. Preliminary biocompatibility tests demonstrated that CUPOMCs support cell adhesion and proliferation. Unlike the pre-polymers of other crosslinked elastomers, CUPOMC pre-polymers possess great processability demonstrated by scaffold fabrication via a thermally induced phase separation method. The dual crosslinking methods for CUPOMC pre-polymers should enhance the versatile processability of the CUPOMC used in various conditions. Development of CUPOMC should expand the choices of available biodegradable elastomers for various biomedical applications such as soft tissue engineering.
PMCID: PMC3615254  PMID: 23565318
Biodegradable Elastomer; Polyester; Soft Tissue Engineering; Thermo-Crosslinking; UV-Crosslinking
14.  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.
PMCID: PMC2530912  PMID: 16768422
15.  Photo-crosslinked Alginate Hydrogels Support Enhanced Matrix Accumulation by Nucleus Pulposus Cells In Vivo 
Intervertebral disc (IVD) degeneration is a major health concern in the United States. Replacement of the nucleus pulposus (NP) with injectable biomaterials represents a potential treatment strategy for IVD degeneration. The objective of this study was to characterize the extracellular matrix assembly and functional properties of NP cell-encapsulated, photo-crosslinked alginate hydrogels in comparison to ionically crosslinked alginate constructs.
Methacrylated alginate was synthesized by esterification of hydroxyl groups with methacrylic anhydride. Bovine nucleus pulposus cells were encapsulated in alginate hydrogels by ionic crosslinking using CaCl2 or through photo-crosslinking upon exposure to long-wave UV light in the presence of a photoinitiator. The hydrogels were evaluated in vitro by gross and histological analysis and in vivo using a murine subcutaneous pouch model. In vivo samples were analyzed for gene expression, extracellular matrix localization and accumulation, and equilibrium mechanical properties.
Ionically crosslinked hydrogels exhibited inferior proteoglycan accumulation in vitro and were unable to maintain structural integrity in vivo. In further studies, photo-crosslinked alginate hydrogels were implanted for up to 8 weeks to examine NP tissue formation. Photo-crosslinked hydrogels displayed temporal increases in gene expression and assembly of type II collagen and proteoglycans. Additionally, hydrogels remained intact over the duration of the study and the equilibrium Young’s modulus increased from 1.24 ± 0.09 kPa to 4.31 ± 1.39 kPa, indicating the formation of functional matrix with properties comparable to those of the native NP.
These findings support the use of photo-crosslinked alginate hydrogels as biomaterial scaffolds for NP replacement.
PMCID: PMC2753687  PMID: 19427928
Nucleus pulposus; alginate; hydrogel; proteoglycan; type II collagen; Young’s modulus
16.  Effect of Photoinitiator System and Water Content on Dynamic Mechanical Properties of a Light-cured bisGMA/HEMA Dental Resin 
The selection of an appropriate photoinitiator system is critical for efficient polymerization of dental resins with satisfactory mechanical and physical properties. The purpose of this study was to evaluate the influence of adding an iodonium salt to two-component photoinitiator systems. Four photoinitiator systems were included in a model bisGMA/HEMA resin and used to prepare samples at different water contents; the dynamic mechanical properties and the final degree of conversion of the samples were then characterized. Addition of the iodonium salt to the two-component photoinitiator systems increased the final degree of conversion, glass transition temperature, rubbery modulus, and crosslink density. The photoinitiator system containing ethyl-4-(dimethylamino) benzoate as a co-initiator and the iodonium salt exhibited the highest rubbery modulus. The enhanced properties in the presence of the iodonium salt can be attributed to the production of an active phenyl radical with regeneration of the original camphorquinone, which may increase the compatibility between monomers and initiators, especially in the presence of water. The results support the hypothesis that a photoinitiator system containing an iodonium salt can increase both mechanical properties and final conversion of model resin polymerized in the presence of water.
PMCID: PMC2860647  PMID: 19827107
photoinitiator; dynamic mechanical properties; dentin adhesive; degree of conversion; iodonium salt
17.  The taming of the cell: shape-memory nanopatterns direct cell orientation 
International Journal of Nanomedicine  2014;9(Suppl 1):117-126.
We report here that the direction of aligned cells on nanopatterns can be tuned to a perpendicular direction without use of any biochemical reagents. This was enabled by shape-memory activation of nanopatterns that transition from a memorized temporal pattern to the original permanent pattern by heating. The thermally induced shape-memory nanopatterns were prepared by chemically crosslinking semi-crystalline poly(ε-caprolactone) (PCL) in a mold to show shape-memory effects over its melting temperature (Tm = 33°C). Permanent surface patterns were first generated by crosslinking the PCL macromonomers in a mold, and temporary surface patterns were then embossed onto the permanent patterns. The temporary surface patterns could be easily triggered to transition quickly to the permanent surface patterns by a 37°C heat treatment, while surface wettability was independent of temperature. To investigate the role of dynamic and reversible surface nanopatterns on cell alignment on the PCL films before and after a topographic transition, NIH 3T3 fibroblasts were seeded on fibronectin-coated PCL films with a temporary grooved topography (grooves with a height of 300 nm and width of 2 μm were spaced 9 μm apart). Interestingly, cells did not change their direction immediately after the surface transition. However, cell alignment was gradually lost with time, and finally cells realigned parallel to the permanent grooves that emerged. The addition of a cytoskeletal inhibitor prevented realignment. These results clearly indicate that cells can sense dynamic changes in the surrounding environments and spontaneously adapt to a new environment by remodeling their cytoskeleton. These findings will serve as the basis for new development of spatiotemporal tunable materials to direct cell fate.
PMCID: PMC4024980  PMID: 24872707
shape-memory surface; poly(ε-caprolactone); nanopatterns; temperature-responsive polymers; cell orientation
18.  Post-Polymerization Crosslinked Polyurethane Shape-Memory Polymers 
Journal of applied polymer science  2011;121(1):144-153.
Novel urethane shape-memory polymers (SMPs) of significant industrial relevance have been synthesized and characterized. Chemically crosslinked SMPs have traditionally been made in a one-step polymerization of monomers and crosslinking agents. However, these new post-polymerization crosslinked SMPs can be processed into complex shapes by thermoplastic manufacturing methods and later crosslinked by heat exposure or by electron beam irradiation. Several series of linear, olefinic urethane polymers were made from 2-butene-1,4-diol, other saturated diols, and various aliphatic diisocyanates. These thermoplastics were melt-processed into desired geometries and thermally crosslinked at 200°C or radiation crosslinked at 50 kGy. The SMPs were characterized by solvent swelling and extraction, differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), tensile testing, and qualitative shape-recovery analysis. Swelling and DMA results provided concrete evidence of chemical crosslinking, and further characterization revealed that the urethanes had outstanding mechanical properties. Key properties include tailorable transitions between 25 and 80°C, tailorable rubbery moduli between 0.2 and 4.2 MPa, recoverable strains approaching 100%, failure strains of over 500% at Tg, and qualitative shape-recovery times of less than 12 seconds at body temperature (37°C). Because of its outstanding thermo-mechanical properties, one polyurethane was selected for implementation in the design of a complex medical device. These post-polymerization crosslinked urethane SMPs are an industrially relevant class of highly processable shape-memory materials.
PMCID: PMC3092441  PMID: 21572577
19.  Computational Analysis of Viscoelastic Properties of Crosslinked Actin Networks 
PLoS Computational Biology  2009;5(7):e1000439.
Mechanical force plays an important role in the physiology of eukaryotic cells whose dominant structural constituent is the actin cytoskeleton composed mainly of actin and actin crosslinking proteins (ACPs). Thus, knowledge of rheological properties of actin networks is crucial for understanding the mechanics and processes of cells. We used Brownian dynamics simulations to study the viscoelasticity of crosslinked actin networks. Two methods were employed, bulk rheology and segment-tracking rheology, where the former measures the stress in response to an applied shear strain, and the latter analyzes thermal fluctuations of individual actin segments of the network. It was demonstrated that the storage shear modulus (G′) increases more by the addition of ACPs that form orthogonal crosslinks than by those that form parallel bundles. In networks with orthogonal crosslinks, as crosslink density increases, the power law exponent of G′ as a function of the oscillation frequency decreases from 0.75, which reflects the transverse thermal motion of actin filaments, to near zero at low frequency. Under increasing prestrain, the network becomes more elastic, and three regimes of behavior are observed, each dominated by different mechanisms: bending of actin filaments, bending of ACPs, and at the highest prestrain tested (55%), stretching of actin filaments and ACPs. In the last case, only a small portion of actin filaments connected via highly stressed ACPs support the strain. We thus introduce the concept of a ‘supportive framework,’ as a subset of the full network, which is responsible for high elasticity. Notably, entropic effects due to thermal fluctuations appear to be important only at relatively low prestrains and when the average crosslinking distance is comparable to or greater than the persistence length of the filament. Taken together, our results suggest that viscoelasticity of the actin network is attributable to different mechanisms depending on the amount of prestrain.
Author Summary
The actin cytoskeleton provides structural integrity to a cell, is highly dynamic, and plays a central role in a wide variety of phenomena such as migration and the sensation of external forces. For years, researchers have studied the mechanics of the cytoskeleton by creating actin gels in the laboratory in combination with proteins that bridge between and reinforce the actin gel found inside cells. These gels, however, failed to replicate many aspects of cell behavior. Recent studies have shown that tension within the cytoskeleton contributes to the observed stiffness of cells. Still, our understanding of cytoskeletal mechanics is incomplete, and many observed phenomena cannot be explained by existing models. Here, we simulate a three-dimensional network containing actin filaments linked together by other proteins. We studied the relative contributions of thermal fluctuations of the network and the stiffness of filaments and linking proteins. Under conditions that replicate those in a cell, properties of the linking proteins are surprisingly significant, as is the stiffness of the actin filament to stretching. Thermal fluctuations are relatively unimportant, but become more so at low levels of resting tension. At high tensions, a small fraction of filaments support a majority of the load.
PMCID: PMC2703781  PMID: 19609348
20.  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.
PMCID: PMC2034277  PMID: 17418651
Polycaprolatone; Tissue engineering; Polyurethane; Osteoblast; Modulus
21.  Enzyme-catalyzed protein crosslinking 
The process of protein crosslinking comprises the chemical, enzymatic, or chemoenzymatic formation of new covalent bonds between polypeptides. This allows (1) the site-directed coupling of proteins with distinct properties and (2) the de novo assembly of polymeric protein networks. Transferases, hydrolases, and oxidoreductases can be employed as catalysts for the synthesis of crosslinked proteins, thereby complementing chemical crosslinking strategies. Here, we review enzymatic approaches that are used for protein crosslinking at the industrial level or have shown promising potential in investigations on the lab-scale. We illustrate the underlying mechanisms of crosslink formation and point out the roles of the enzymes in their natural environments. Additionally, we discuss advantages and drawbacks of the enzyme-based crosslinking strategies and their potential for different applications.
PMCID: PMC3546294  PMID: 23179622
Cross-linking; Conjugation; Ligation; Fusion proteins; Transglutaminase; Sortase A
22.  Thermo-Mechanical Properties of Semi-Degradable Poly(β-amino ester)-co-Methyl Methacrylate Networks under Simulated Physiological Conditions 
Polymer  2011;52(21):4920-4927.
Poly(β-amino ester) networks are being explored for biomedical applications, but they may lack the mechanical properties necessary for long term implantation. The objective of this study is to evaluate the effect of adding methyl methacrylate on networks' mechanical properties under simulated physiological conditions. The networks were synthesized in two parts: (1) a biodegradable crosslinker was formed from a diacrylate and amine, (2) and then varying concentrations of methyl methacrylate were added prior to photopolymerizing the network. Degradation rate, mechanical properties, and glass transition temperature were studied as a function of methyl methacrylate composition. The crosslinking density played a limited role on mechanical properties for these networks, but increasing methyl methacrylate concentration improved the toughness by several orders of magnitude. Under simulated physiological conditions, networks showed increasing toughness or sustained toughness as degradation occurred. This work establishes a method of creating degradable networks with tailorable toughness while undergoing partial degradation.
PMCID: PMC3181125  PMID: 21966028
Poly(β-amino ester); Degradable; Toughness
23.  Covalent Adaptable Networks (CANs): A Unique Paradigm in Crosslinked Polymers 
Macromolecules  2010;43(6):2643-2653.
Polymer networks possessing reversible covalent crosslinks constitute a novel material class with the capacity for adapting to an externally applied stimulus. These covalent adaptable networks (CANs) represent a trend in polymer network fabrication towards the rational design of structural materials possessing dynamic characteristics for specialty applications. Herein, we discuss the unique attributes of CANs that must be considered when designing, fabricating, and characterizing these smart materials that respond to either thermal or photochemical stimuli. While there are many reversible reactions which to consider as possible crosslink candidates in CANs, there are very few that are readily and repeatedly reversible. Furthermore, characterization of the mechanical properties of CANs requires special consideration owing to their unique attributes. Ultimately, these attributes are what lead to the advantageous properties displayed by CANs, such as recyclability, healability, tunability, shape changes, and low polymerization stress. Throughout this perspective, we identify several trends and future directions in the emerging field of CANs that demonstrate the progress to date as well as the essential elements that are needed for further advancement.
PMCID: PMC2841325  PMID: 20305795
24.  Continuous Digital Light Processing (cDLP): Highly Accurate Additive Manufacturing of Tissue Engineered Bone Scaffolds 
Highly accurate rendering of the external and internal geometry of bone tissue engineering scaffolds effects fit at the defect site, loading of internal pore spaces with cells, bioreactor-delivered nutrient and growth factor circulation, and scaffold resorption. It may be necessary to render resorbable polymer scaffolds with 50 μm or less accuracy to achieve these goals. This level of accuracy is available using Continuous Digital Light processing (cDLP) which utilizes a DLP® (Texas Instruments, Dallas, TX) chip. One such additive manufacturing device is the envisionTEC (Ferndale, MI) Perfactory®. To use cDLP we integrate a photo-crosslinkable polymer, a photo-initiator, and a biocompatible dye. The dye attenuates light, thereby limiting the depth of polymerization. In this study we fabricated scaffolds using the well-studied resorbable polymer, poly(propylene fumarate) (PPF), titanium dioxide (TiO2) as a dye, Irgacure® 819 (BASF [Ciba], Florham Park, NJ) as an initiator, and diethyl fumarate as a solvent to control viscosity.
PMCID: PMC3466612  PMID: 23066427
continuous Digital Light Processing (cDLP); Bone Tissue Engineering; poly(propylene fumarate) (PPF); titanium dioxide (TiO2); Additive Manufacturing
25.  Hydrogels for Osteochondral Repair Based on Photo-crosslinkable Carbamate Dendrimers 
Biomacromolecules  2008;9(10):2863.
First generation, photo-crosslinkable dendrimers consisting of natural metabolites (i.e. succinic acid, glycerol, and β-alanine) and non-immunogenic poly(ethylene glycol) (PEG) were synthesized divergently in high yields using ester and carbamate forming reactions. Aqueous solutions of these dendrimers were photo-crosslinked with an eosin-based photo-initiator to afford hydrogels. The hydrogels displayed a range of mechanical properties based on their structure, generation size, and concentration in solution. All of the hydrogels showed minimal swelling characteristics. The dendrimer solutions were then photo-crosslinked in situ in an ex vivo rabbit osteochondral defect (3 mm diameter and 10 mm depth), and the resulting hydrogels were subjected to physiologically relevant dynamic loads. Magnetic resonance imaging (MRI) showed the hydrogels to be fixated in the defect site after the repetitive loading regimen. The ([G1]-PGLBA-MA)2-PEG hydrogel was chosen for the 6 month pilot in vivo rabbit study because this hydrogel scaffold could be prepared at low polymer weight (10wt%) and possessed the largest compressive modulus of the 10% formulations, a low swelling ratio, and contained carbamate linkages which are more hydrolytically stable than the ester linkages. The hydrogel treated osteochondral defects showed good attachment in the defect site and histological analysis showed the presence of collagen II and glycosaminoglycans (GAGs) in the treated defects. By contrast, the contralateral unfilled defects showed poor healing and negligible GAG or collagen II production. Good mechanical properties, low swelling, good attachment to the defect site, and positive in vivo results illustrate the potential of these dendrimer-based hydrogels as scaffolds for osteochondral defect repair.
PMCID: PMC2819483  PMID: 18800810
Osteochondral defects; Cartilage; Tissue Engineering; Scaffolds; Hydrogel; Dendrimer; Dendritic Polymer

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