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1.
Acta Biomater ; 18: 9-20, 2015 May.
Article in English | MEDLINE | ID: mdl-25575855

ABSTRACT

Various calcium phosphate based coatings have been evaluated for better bony integration of metallic implants and are currently being investigated to improve the surface bioactivity of polymeric scaffolds. The aim of this study was to evaluate the role of calcium phosphate coating and simultaneous delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the in vivo bone regeneration capacity of biodegradable, porous poly(propylene fumarate) (PPF) scaffolds. PPF scaffolds were coated with three different calcium phosphate formulations: magnesium-substituted ß-tricalcium phosphate (ß-TCMP), carbonated hydroxyapatite (synthetic bone mineral, SBM) and biphasic calcium phosphate (BCP). In vivo bone regeneration was evaluated by implantation of scaffolds in a critical-sized rabbit calvarial defect loaded with different doses of rhBMP-2. Our data demonstrated that scaffolds with each of the calcium phosphate coatings were capable of sustaining rhBMP-2 release and retained an open porous structure. After 6weeks of implantation, micro-computed tomography revealed that the rhBMP-2 dose had a significant effect on bone formation within the scaffolds and that the SBM-coated scaffolds regenerated significantly greater bone than BCP-coated scaffolds. Mechanical testing of the defects also indicated restoration of strength in the SBM and ß-TCMP with rhBMP-2 delivery. Histology results demonstrated bone growth immediately adjacent to the scaffold surface, indicating good osteointegration and osteoconductivity for coated scaffolds. The results obtained in this study suggest that the coated scaffold platform demonstrated a synergistic effect between calcium phosphate coatings and rhBMP-2 delivery and may provide a promising platform for the functional restoration of large bone defects.


Subject(s)
Bone Morphogenetic Protein 2/pharmacology , Bone Regeneration/drug effects , Calcium Phosphates/pharmacology , Coated Materials, Biocompatible/pharmacology , Fumarates/pharmacology , Polypropylenes/pharmacology , Skull/drug effects , Tissue Scaffolds/chemistry , Transforming Growth Factor beta/pharmacology , Animals , Delayed-Action Preparations , Female , Humans , Imaging, Three-Dimensional , Kinetics , Porosity , Rabbits , Recombinant Proteins/pharmacology , Skull/diagnostic imaging , Spectrometry, X-Ray Emission , X-Ray Microtomography
2.
J Biomed Mater Res A ; 103(8): 2549-57, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25504776

ABSTRACT

In tissue engineering, development of an osteoconductive construct that integrates with host tissue remains a challenge. In this work, the effect of bone-like minerals on maturation of pre-osteoblast cells was investigated using polymer-mineral scaffolds composed of poly(propylene fumarate)-co-poly(caprolactone) (PPF-co-PCL) and nano-sized hydroxyapatite (HA). The HA of varying concentrations was added to an injectable formulation of PPF-co-PCL and the change in thermal and mechanical properties of the scaffolds was evaluated. No change in onset of degradation temperature was observed due to the addition of HA, however compressive and tensile moduli of copolymer changed significantly when HA amounts were increased in composite formulation. The change in mechanical properties of copolymer was found to correlate well to HA concentration in the constructs. Electron microscopy revealed mineral nucleation and a change in surface morphology and the presence of calcium and phosphate on surfaces was confirmed using energy dispersive X-ray analysis. To characterize the effect of mineral on attachment and maturation of pre-osteoblasts, W20-17 cells were seeded on HA/copolymer composites. We demonstrated that cells attached more to the surface of HA containing copolymers and their proliferation rate was significantly increased. Thus, these findings suggest that HA/PPF-co-PCL composite scaffolds are capable of inducing maturation of pre-osteoblasts and have the potential for use as scaffold in bone tissue engineering.


Subject(s)
Biocompatible Materials , Bone and Bones , Durapatite , Nanocomposites , Polymers , Tissue Scaffolds , Animals , Cell Line , Cell Proliferation , Collagen Type I/metabolism , Materials Testing
3.
Ann Plast Surg ; 73(4): 405-11, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24317246

ABSTRACT

BACKGROUND: Video-assisted gait kinetics analysis has been a sensitive method to assess rat sciatic nerve function after injury and repair. However, in conduit repair of sciatic nerve defects, previously reported kinematic measurements failed to be a sensitive indicator because of the inferior recovery and inevitable joint contracture. OBJECTIVE: This study aimed to explore the role of physiotherapy in mitigating joint contracture and to seek motion analysis indices that can sensitively reflect motor function. METHODS: Data were collected from 26 rats that underwent sciatic nerve transection and conduit repair. Regular postoperative physiotherapy was applied. Parameters regarding step length, phase duration, and ankle angle were acquired and analyzed from video recording of gait kinetics preoperatively and at regular postoperative intervals. RESULTS: Stride length ratio (step length of uninjured foot/step length of injured foot), percent swing of the normal paw (percentage of the total stride duration when the uninjured paw is in the air), propulsion angle (toe-off angle subtracted by midstance angle), and clearance angle (ankle angle change from toe off to midswing) decreased postoperatively comparing with baseline values. The gradual recovery of these measurements had a strong correlation with the post-nerve repair time course. CONCLUSIONS: Ankle joint contracture persisted despite rigorous physiotherapy. Parameters acquired from a 2-dimensional motion analysis system, that is, stride length ratio, percent swing of the normal paw, propulsion angle, and clearance angle, could sensitively reflect nerve function impairment and recovery in the rat sciatic nerve conduit repair model despite the existence of joint contractures.


Subject(s)
Contracture/prevention & control , Gait , Physical Therapy Modalities , Postoperative Care , Postoperative Complications/prevention & control , Sciatic Nerve/surgery , Task Performance and Analysis , Animals , Biomechanical Phenomena , Contracture/etiology , Female , Hindlimb , Nerve Regeneration , Range of Motion, Articular , Rats , Recovery of Function , Sciatic Nerve/injuries , Sciatic Nerve/physiology , Video Recording
4.
Tissue Eng Part A ; 19(5-6): 634-48, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23215980

ABSTRACT

Treatment of large segmental bone defects remains an unsolved clinical challenge, despite a wide array of existing bone graft materials. This project was designed to rapidly assess and compare promising biodegradable osteoconductive scaffolds for use in the systematic development of new bone regeneration methodologies that combine scaffolds, sources of osteogenic cells, and bioactive scaffold modifications. Promising biomaterials and scaffold fabrication methods were identified in laboratories at Rutgers, MIT, Integra Life Sciences, and Mayo Clinic. Scaffolds were fabricated from various materials, including poly(L-lactide-co-glycolide) (PLGA), poly(L-lactide-co-ɛ-caprolactone) (PLCL), tyrosine-derived polycarbonate (TyrPC), and poly(propylene fumarate) (PPF). Highly porous three-dimensional (3D) scaffolds were fabricated by 3D printing, laser stereolithography, or solvent casting followed by porogen leaching. The canine femoral multi-defect model was used to systematically compare scaffold performance and enable selection of the most promising substrate(s) on which to add cell sourcing options and bioactive surface modifications. Mineralized cancellous allograft (MCA) was used to provide a comparative reference to the current clinical standard for osteoconductive scaffolds. Percent bone volume within the defect was assessed 4 weeks after implantation using both MicroCT and limited histomorphometry. Bone formed at the periphery of all scaffolds with varying levels of radial ingrowth. MCA produced a rapid and advanced stage of bone formation and remodeling throughout the defect in 4 weeks, greatly exceeding the performance of all polymer scaffolds. Two scaffold constructs, TyrPC(PL)/TCP and PPF4(SLA)/HA(PLGA) (Dip), proved to be significantly better than alternative PLGA and PLCL scaffolds, justifying further development. MCA remains the current standard for osteoconductive scaffolds.


Subject(s)
Bone Regeneration , Femur/pathology , Tissue Scaffolds/chemistry , Animals , Bone Regeneration/drug effects , Caproates/pharmacology , Disease Models, Animal , Dogs , Female , Femur/diagnostic imaging , Femur/drug effects , Implants, Experimental , Lactones/pharmacology , Male , Organ Size/drug effects , Polycarboxylate Cement/pharmacology , Transplantation, Homologous , X-Ray Microtomography
5.
Acta Biomater ; 8(2): 511-8, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22019759

ABSTRACT

Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulator. Controlled release of such stimulators may enhance and guide the vascularization process, and when applied in a nerve conduit may play a role in nerve regeneration. We report the fabrication and in vitro characterization of poly-lactic-co-glycolic acid (PLGA) microspheres encapsulating VEGF and the in vivo application of nerve conduits supplemented with VEGF-containing microspheres. PLGA microspheres containing VEGF were prepared by the double emulsion-solvent evaporation technique. This yielded 83.16% of microspheres with a diameter <53 µm. VEGF content measured by ELISA indicated 93.79±10.64% encapsulation efficiency. Release kinetics were characterized by an initial burst release of 67.6±8.25% within the first 24h, followed by consistent release of approximately 0.34% per day for 4 weeks. Bioactivity of the released VEGF was tested by human umbilical vein endothelial cell (HUVEC) proliferation assay. VEGF released at all time points enhanced HUVEC proliferation, confirming that VEGF retained its bioactivity throughout the 4 week time period. When the microsphere delivery system was placed in a biosynthetic nerve scaffold robust nerve regeneration was observed. This study established a novel system for controlled release of growth factors and enables in vivo studies of nerve conduits conditioned with this system.


Subject(s)
Guided Tissue Regeneration/methods , Lactic Acid/chemistry , Microspheres , Nerve Regeneration/drug effects , Polyesters/chemistry , Polyglycolic Acid/chemistry , Tissue Scaffolds/chemistry , Vascular Endothelial Growth Factor A/pharmacology , Animals , Cell Proliferation/drug effects , Delayed-Action Preparations , Drug Compounding , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Kinetics , Microscopy, Electron, Scanning , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer , Rats
6.
Acta Biomater ; 8(1): 133-43, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21911087

ABSTRACT

Polycaprolactone fumarate (PCLF) is a cross-linkable derivative 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 PCLF (PCLF(DEG)) 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 (PCLF(PPD)) or glycerol (PCLF(GLY)). PCLF(PPD) is linear and resembles the previously studied PCLF(DEG), while PCLF(GLY) 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 PCLF(PPD) has material properties similar to the previously studied PCLF(DEG). The branched PCLF(GLY) 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 Food and Drug Administration approvable sterilization method is addressed. This study shows that autoclave sterilization of PCLF materials is an acceptable sterilization method for cross-linked PCLF and has minimal effect on the PCLF thermal and mechanical properties.


Subject(s)
Ethylene Glycols/toxicity , Polyesters/chemistry , Polyesters/chemical synthesis , Polyesters/metabolism , Polymers/chemistry , Sterilization/methods , Animals , Biocompatible Materials/chemistry , Biocompatible Materials/metabolism , Elasticity , Ethylene Glycols/chemistry , Glycerol/chemistry , Materials Testing , Molecular Structure , PC12 Cells , Polymers/chemical synthesis , Polymers/metabolism , Propylene Glycol/chemistry , Rats , Stress, Mechanical , Temperature
7.
Acta Biomater ; 7(3): 944-53, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20965280

ABSTRACT

The mechanical and electrical properties of polycaprolactone fumarate-polypyrrole (PCLF-PPy) scaffolds were studied under physiological conditions to evaluate their ability to maintain the material properties necessary for application as conductive nerve conduits. PC12 cells cultured on PCLF-PPy scaffolds were stimulated with regimens of 10 µA of either a constant or a 20 Hz frequency current passed through the scaffolds for 1h per 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 2 kΩ and the scaffolds were electrically stable during the application of electrical stimulation (ES). In vitro studies showed significant increases in the percentage of neurite bearing cells, number of neurites per cell and neurite length in the presence of ES compared with 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 the material properties necessary for application as nerve conduits. Additionally, the capability to significantly enhance and direct neurite extension by passing an electrical current through PCLF-PPy scaffolds renders them even more promising as future therapeutic treatments for severe nerve injuries.


Subject(s)
Biocompatible Materials , Electric Stimulation , Neural Conduction , Polyesters/chemistry , Polymers/chemistry , Pyrroles/chemistry , Adsorption , Animals , Calorimetry, Differential Scanning , PC12 Cells , Proteins/chemistry , Rats
8.
J Biomater Sci Polym Ed ; 22(4-6): 489-504, 2011.
Article in English | MEDLINE | ID: mdl-20566042

ABSTRACT

In this work, a series of co-polymers 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 co-polymer (PCL feed ratio) on the maximum cross-linking temperature, gelation time and mechanical properties of the cross-linked co-polymers were investigated. The maximum cross-linking 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/m(3). Our data suggest that the cross-linking and mechanical properties of PPF-co-PCL can be modulated by varying the composition. Therefore, the PPF-co-PCL co-polymers may offer increased versatility as an injectable, in situ polymerizable biomaterial than the individual polymers of PPF and PCL.


Subject(s)
Biocompatible Materials/chemistry , Fumarates/chemistry , Injections , Polyesters/chemistry , Polymers/chemistry , Polypropylenes/chemistry , Biocompatible Materials/chemical synthesis , Biocompatible Materials/metabolism , Compressive Strength , Cross-Linking Reagents/chemistry , Fumarates/chemical synthesis , Fumarates/metabolism , Humans , Materials Testing , Molecular Structure , Molecular Weight , Polyesters/chemical synthesis , Polyesters/metabolism , Polymers/chemical synthesis , Polymers/metabolism , Polypropylenes/chemical synthesis , Polypropylenes/metabolism , Temperature
9.
Biomacromolecules ; 11(11): 2845-53, 2010 Nov 08.
Article in English | MEDLINE | ID: mdl-20942380

ABSTRACT

Electrically conductive hydrogel composites consisting of oligo(polyethylene glycol) fumarate (OPF) and polypyrrole (PPy) were developed for applications in nerve regeneration. OPF-PPy scaffolds were synthesized using three different anions: naphthalene-2-sulfonic acid sodium salt (NSA), dodecylbenzenesulfonic acid sodium salt (DBSA), and dioctyl sulfosuccinate sodium salt (DOSS). Scaffolds were characterized by ATR-FTIR, XPS, AFM, dynamic mechanical analysis, electrical resistivity measurements, and swelling experiments. OPF-PPy scaffolds were shown to consist of up to 25 mol % polypyrrole with a compressive modulus ranging from 265 to 323 kPa and a sheet resistance ranging from 6 to 30 × 10(3) Ohms/square. In vitro studies using PC12 cells showed OPF-PPy materials had no cytotoxicity and PC12 cells showed distinctly better cell attachment and an increase in the percent of neurite bearing cells on OPF-PPy materials compared to OPF. The neurite lengths of PC12 cells were significantly higher on OPF-PPyNSA and OPF-PPyDBSA. These results show that electrically conductive OPF-PPy hydrogels are promising candidates for future applications in nerve regeneration.


Subject(s)
Hydrogels/chemistry , Nerve Regeneration , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , Pyrroles/chemistry , Animals , Electric Conductivity , Molecular Structure , PC12 Cells , Rats
10.
Biomaterials ; 31(23): 5916-26, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20483452

ABSTRACT

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 preformed PCLF scaffolds (M(n) 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.


Subject(s)
Electric Conductivity , Nerve Regeneration , Polyesters/chemistry , Polymers/chemistry , Pyrroles/chemistry , Animals , Microscopy, Atomic Force , Microscopy, Electron, Transmission , PC12 Cells , Rats , Spectroscopy, Fourier Transform Infrared
11.
Macromol Rapid Commun ; 30(16): 1392-8, 2009 Aug 18.
Article in English | MEDLINE | ID: mdl-21638396

ABSTRACT

High molecular weight tri- and tetrablock copolymers were synthesized from the commercially available Grubbs first generation catalyst for the first time. These polymers had degrees of polymerization from 430 to 1 100, molecular weights up to 419 000 g · mol(-1) , and narrow polydispersities. Oxanorbornene monomers were chosen due to their fast rates of polymerization and slow rates of cross metathesis. Polystyrene arms were grown from selected blocks by atom transfer radical polymerization to yield architecturally complex comb tri- and tetrablock copolymers. These polymers self-assembled in the solid state into ordered morphologies that were characterized by scanning electron microscopy.

12.
Chemistry ; 14(22): 6780-8, 2008.
Article in English | MEDLINE | ID: mdl-18563767

ABSTRACT

The development of a method for site-isolation of Grubbs second-generation catalyst from MCPBA is described. In these reactions, Grubbs catalyst was dissolved in a solvent consisting of a mixture (1:1 v/v) of 1-butyl-3-methylimidazolium hexafluorophosphate and methylene chloride and completely encapsulated within a thimble fabricated from polydimethylsiloxane (PDMS). A series of molecules that react by cross metathesis or ring-closing metathesis were added to the interior of the thimble and allowed to react. In the last step, m-chloroperoxybenzoic acid (MCPBA) dissolved in MeOH/H(2)O (1:1 v/v) was added to the exterior of the PDMS thimble. Small organic molecules diffused through the PDMS to react with MCPBA to form epoxides, but the Grubbs catalyst remained encapsulated. This result is important because Grubbs catalyst catalytically decomposes MCPBA at ratios of MCPBA to Grubbs of 3000 to 1. The yields for this two-step cascade sequence ranged from 67 to 83 %. The concept behind this sequence is that small organic molecules have high flux through PDMS but large molecules--such as Grubbs catalyst--and ionic reagents--such as MCPBA--have much lower flux through PDMS. Small molecules can thus react both outside and inside PDMS thimbles, whereas incompatible catalysts and reagents remain site-isolated from each other. This method does not require alteration of structures of the catalysts or reagents, so it may be applied to a wide range of homogeneous catalysts and reagents. To demonstrate further that the catalyst was encapsulated, the Grubbs catalyst was successfully recycled within the cascade sequence.

14.
J Am Chem Soc ; 129(34): 10551-60, 2007 Aug 29.
Article in English | MEDLINE | ID: mdl-17685524

ABSTRACT

This Article describes a simple two-step synthesis of comb block copolymers with molecular weights exceeding 1,000,000 g mol(-1) and their assembly into ordered morphologies in the solid state. This work is exciting because these polymers assembled into morphologies with domain sizes exceeding 100 nm and, in some examples, 200 nm without the use of additives. These materials reflected selected wavelengths of visible light, and these wavelengths could be affected by swelling with methylene chloride vapor. A comparison between the structures of comb block copolymers and linear block copolymers is presented with a discussion of important parameters affecting their assembly in the solid state. This Article will first describe the synthesis of comb block copolymers using ring opening metathesis polymerization and atom transfer radical polymerization and their subsequent characterization. The comb block copolymers, backbone polymers, and polystyrene arms were all characterized independent of each other and had low polydispersities. The comb block copolymers were assembled by dissolving in methylene chloride and allowing the solvent to evaporate. After thermal annealing, the polymers were characterized by scanning electron and optical microscopy. These polymers assembled into spherical, lamellar, and cylindrical arrays with domain sizes from 132 to 258 nm. This work extends the molecular architectures of polymers that can be assembled in the solid state, the molecular weights of block copolymers that were assembled, and the domain sizes that can be realized without the use of additives.

15.
J Am Chem Soc ; 128(45): 14434-5, 2006 Nov 15.
Article in English | MEDLINE | ID: mdl-17090007

ABSTRACT

The Grubbs' first and second generation catalysts were occluded into cross-linked slabs of polydimethylsiloxane with volumes from 1 mm3 to 1 cm3 by swelling the polymer with catalyst and methylene chloride. Methylene chloride was evaporated under vacuum to yield occluded catalysts where their solvent was polydimethylsiloxane. These occluded catalysts were reacted with alkenes dissolved in H2O or H2O/MeOH mixtures that diffused into the polydimethylsiloxane to react by ring-closing metathesis and cross metathesis. Control experiments revealed that the catalysts remained occluded and metathesis did not occur in the solvent. Occlusion of these catalysts allowed commercially available Grubbs' catalysts to be used with H2O as the solvent while isolating the H2O sensitive ruthenium methylidene from exposure to H2O. Functional group selective experiments were carried out where the polydimethylsiloxane was an "active" membrane to exclude salts. Polydimethylsiloxane is a hydrophobic polymer, so the deprotonated salt of diallylmalonic acid did not diffuse into it while a diallylether diffused into it and reacted by metathesis. Thus, by controlling the polarity of reagents their reactivity can be controlled owing to the properties of polydimethylsiloxane rather than those of the Grubbs' catalysts. Occlusion of catalysts in polydimethylsiloxane has been shown to add new selectivities to mature catalysts.


Subject(s)
Dimethylpolysiloxanes/chemistry , Membranes, Artificial , Silicones/chemistry , Catalysis , Water/chemistry
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