Elizabeth L Hedberg

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands

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Publications (11)60.99 Total impact

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    ABSTRACT: Injectable calcium phosphate (Ca-P) cement materials exhibit favorable osteocompatible behavior but are resorbed slowly because of a lack of a bone ingrowth-enabling macroporosity. In this study, poly(DL-lactic-co-glycolic acid) (PLGA) microparticles (average size 66 +/- 25 microm) were incorporated into Ca-P cement to obtain a macroporous Ca-P cement scaffold after PLGA hydrolysis in vivo. Preset PLGA/Ca-P cement composite discs of various weight ratios (0/100, 15/85, 30/70, and 50/50) were implanted subcutaneously and in cranial defects in rats for 12 weeks. Histological analysis revealed that all macropores in the PLGA-containing composites (average pore size 73 +/- 27 microm) were filled with fibrous tissue and blood vessels (subcutaneous implants) and/or bone (cranial implants). Histologically, bone formation appeared most abundant and most consistent in the 30/70 PLGA/Ca-P cement composites. Histomorphometrical evaluation revealed a significant increase in defect fill in the 15/85 and 30/70 PLGA/Ca-P cement composites. Finally, subcutaneous and cranial 50/50 PLGA/Ca-P cement composites had degraded to a large extent, without adequate replacement by bone in the cranial implants. Therefore, we conclude that PLGA/Ca-P cement composites enable tissue ingrowth and show excellent osteocompatibility in weight ratios of 15/85 and 30/70 PLGA/Ca-P cement. In this model, 30/70 PLGA/Ca-P cement composites showed the most favorable biological response.
    Journal of Biomedical Materials Research Part A 10/2005; 74(4):533-44. · 2.83 Impact Factor
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    ABSTRACT: This study investigated the in vivo degradation of poly(propylene fumarate) (PPF)/poly(DL-lactic-co-glycolic acid) (PLGA) composite scaffolds designed for controlled release of osteogenic factors. PPF/PLGA composites were implanted into 15.0mm segmental defects in the rabbit radius, harvested after 12 and 18 weeks, and analyzed using histological techniques to assess the extent of polymer degradation as well as the tissue response within the pores of the scaffolds. Polymer degradation was limited to micro-fragmentation of the scaffold at the ends and edges of the implant at both 12 and 18 weeks. The tissue within the pores of the scaffold consisted of fibrous tissue, blood vessels and some inflammatory cells. In areas where polymer breakdown was evident, an increased inflammatory response was observed. In contrast, areas of bone ingrowth into the polymer scaffold were characterized by minimal inflammatory response and polymer degradation. Our results show that minimal degradation of porous PPF occurs within 18 weeks of implantation in a rabbit model. Further, the in vivo degradation data of porous PPF/PLGA scaffolds are comparable with earlier obtained in vitro data.
    Biomaterials 09/2005; 26(22):4616-23. · 8.31 Impact Factor
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    ABSTRACT: This study investigated the in vitro degradation of porous poly(propylene fumarate) (PPF-based) composites incorporating microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) during a 26-week period in pH 7.4 phosphate-buffered saline at 37 degrees C. Using a fractional factorial design, four formulations of composite scaffolds were fabricated with varying PEG content of the microparticles, microparticle mass fraction of the composite material, and initial leachable porogen content of the scaffold formulations. PPF scaffolds without microparticles were fabricated with varying leachable porogen content for use as controls. The effects of including PLGA/PEG microparticles in PPF scaffolds and the influence of alterations in the composite formulation on scaffold mass, geometry, water absorption, mechanical properties and porosity were examined for cylindrical specimens with lengths of 13 mm and diameters of 6.5 mm. The composite scaffold composition affected the extent of loss of polymer mass, scaffold length, and diameter, with the greatest loss of polymer mass equal to 15+/-5% over 26 weeks. No formulation, however, exhibited any variation in compressive modulus or peak compressive strength over time. Additionally, sample porosity, as determined by both mercury porosimetry and micro-computed tomography did not change during the period of this study. These results demonstrate that microparticle carriers can be incorporated into PPF scaffolds for localized delivery of bioactive molecules without altering scaffold mechanical or structural properties up to 26 weeks in vitro.
    Biomaterials 07/2005; 26(16):3215-25. · 8.31 Impact Factor
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    ABSTRACT: This study was designed to assess the influence of varied release kinetics of the osteogenic thrombin peptide TP508 from osteoconductive poly(propylene fumarate)-based (PPF) composite scaffolds on bone formation in vivo. Four classes of scaffolds were constructed with different TP508 dosages (200, 100, or 0 microg) and release kinetics (large burst release, minimal burst release, or no release) and implanted in 15.0 mm segmental defects in rabbit radii. The animals were euthanized at 12 weeks and the implants were analyzed by light microscopy, histological scoring analysis, and histomorphometric analysis. Samples from all classes displayed bone growth within the pores of the scaffold near the edges of the defect. In areas where bone was not observed, the pores were filled with mostly fibrous tissue and exhibited minimal inflammatory response for all classes. In contrast to other scaffold classes, scaffolds containing a total dose of 200 microg TP508 and exhibiting a large burst release profile showed statistically more bone formation guided along the surface of the scaffold, with these scaffolds averaging 80% of the defect length bridged with bone compared to 10% or less bridged for the other scaffold classes. These results demonstrate that the extent of in vivo bone formation in response to controlled release from PPF-composite scaffolds is determined by the release kinetics of the incorporated osteogenic peptide.
    Journal of Biomedical Materials Research Part A 04/2005; 72(4):343-53. · 2.83 Impact Factor
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    ABSTRACT: The objective of the study presented here was to investigate the bone inductive properties as well as release kinetics of rhTGF-beta1- and rhBMP-2-loaded Ti-fiber mesh and CaP cement scaffolds. Therefore, Ti-fiber mesh and porous CaP cement scaffolds were provided with these growth factors and inserted in subcutaneous and cranial implant locations in rats and rabbits. In vitro, a rapid release of rhTGF-beta1 was observed during the first 2 h of the Ti-fiber mesh scaffolds. During this time, more than 50% of the total dose of rhTGF-beta1 was released. Following this initial peak, a decline in the level of rhTGF-beta1 occurred. After 1 week, the entire theoretical initial dose was observed to have been released. This in contrast to the rhTGF-beta1 and rhBMP-2 release of the porous CaP cement scaffolds. Here, no substantial initial burst release was observed. The scaffolds showed an initial release of about 1% after 1 day, followed by an additional marginal release after 1 week. Histological analysis revealed excellent osteoconductive properties of non-loaded Ca-P material. Inside non-loaded Ti-mesh fiber scaffolds, also bone ingrowth occurred. Quantification of the bone ingrowth showed that bone formation was increased significantly in all scaffold materials by administration of rhTGF-beta1 and rhBMP-2. Consequently, we conclude that the release kinetics of growth factors from porous CaP cement differs from other scaffold materials, like metals and polymers. Nevertheless, orthotopic bone formation in a rabbit cranial defect model was stimulated in rhTGF-beta1- and rhBMP-2-loaded CaP cement and Ti-fiber mesh scaffolds compared with non-loaded implants.
    Journal of Controlled Release 02/2005; 101(1-3):127-36. · 7.63 Impact Factor
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    ABSTRACT: This study focused on the assessment of radiography, microcomputed tomography, and histology for the evaluation of bone formation in a 15.0-mm defect in the rabbit radius after the implantation of a tissue-engineered construct. Radiography was found to be useful as a noninvasive method for obtaining images of calcified tissue throughout the time course of the experiment. With this method, however, image quality was low, making it difficult to obtain precise information about the location and quantity of the bone formed. Microcomputed tomography was used to create three-dimensional reconstructions of the bone (25-microm resolution). These reconstructions allowed for greater spatial resolution than the radiography, but did not allow for imaging of the implanted scaffold material or the surrounding, nonmineralized tissue. To visualize all materials within the defect area at the cellular level, histology was used. Histological analysis, however, is a destructive technique that did not allow for any further analysis of the samples. Each technique examined here has its own advantages and limitations, but each yields unique information regarding bone regeneration. It is only through the use of all three techniques that complete characterization of the bone growth and tissue/construct responses after implantation in vivo.
    Tissue Engineering 01/2005; 11(9-10):1356-67. · 4.25 Impact Factor
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    ABSTRACT: In the present study, biodegradable microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) were explored as a potential carrier for the controlled release of polysaccharide oligomers. To this end, hyaluronan (HY) oligomers of varying molecular weights were incorporated into PLGA/PEG microparticles. Using a two-level fractional factorial experimental design, four microparticle formulation parameters, the amount of PEG included in the microparticles, the initial HY loading of the microparticles, the molecular weight of HY, and the molecular weight of PLGA, were studied for their influence on the incorporation and in vitro release of HY over the period of 28 days. The entrapment efficiencies were found to range between 10+/-1% and 24+/-2% depending on the initial loading and the molecular weight of the HY oligomer used in the fabrication of the microparticles. The HY was released in a multiphasic fashion including an initial burst release, followed by two separate periods of linear release. The normalized cumulative mass released during the burst release ranged from 25.1+/-9.2% to 93.0+/-0.7% and was found to be significantly influenced by the initial HY loading, the HY molecular weight, and the PLGA molecular weight. The initial period of linear release lasted from day 1 to day 14 and displayed normalized cumulative rates of release from 0.1+/-0.0%/day to 1.4+/-0.2%/day. During this period, PEG content of the microparticles and HY molecular weight exerted the greatest influence on the rate of release. Finally, the second period of linear release lasted through the final time-point at day 28. Here, the normalized cumulative rate of release values ranged from 0.2+/-0.1%/day to 3.6+/-0.7%/day and were dependent on all formulation parameters studied. These results demonstrate the potential of PLGA/PEG blend microparticles for the controlled release of HY oligomers.
    Journal of Controlled Release 12/2004; 100(2):257-66. · 7.63 Impact Factor
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    ABSTRACT: Poly(D,L-lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) blend microparticles loaded with the osteogenic peptide TP508 were added to a mixture of poly(propylene fumarate) (PPF), poly(propylene fumarate)-diacrylate (PPF-DA), and sodium chloride (NaCl) for the fabrication of PPF composite scaffolds that could allow for tissue ingrowth as well as for the controlled release of TP508 when implanted in an orthopedic defect site. In this study, PPF composites were fabricated and the in vitro release kinetics of TP508 were determined. TP508 loading within the PLGA/PEG microparticles, PEG content within the PLGA/PEG microparticles, the microparticle content of the PPF composite polymer component, and the leachable porogen initial mass percent of the PPF composites were varied according to a fractional factorial design and the effect of each variable on the release kinetics was determined for up to 28 days. Each composite formulation released TP508 with a unique release profile. The initial release (release through day 1) of the PLGA/PEG microparticles was reduced upon inclusion in the PPF composite formulations. Day 1 normalized cumulative mass release from PPF composites ranged from 0.14+/-0.01 to 0.41+/-0.01, whereas the release from PLGA/PEG microparticles ranged from 0.31+/-0.02 to 0.58+/-0.01. After 28 days, PPF composites released 53+/-4% to 86+/-2% of the entrapped peptide resulting in cumulative mass releases ranging from 0.14+/-0.01 microg TP508/mm(3) scaffold to 2.46+/-0.05 microg TP508/mm(3) scaffold. The results presented here demonstrate that PPF composites can be used for the controlled release of TP508 and that alterations in the composite's composition can lead to modulation of the TP508 release kinetics. These composites can be used to explore the effects varied release kinetics and dosages on the formation of bone in vivo.
    Journal of Controlled Release 01/2003; 84(3):137-50. · 7.63 Impact Factor
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    ABSTRACT: In bone tissue engineering, poly(DL-lactic-co-glycolic acid) (PLGA) microparticles are frequently used as a delivery vehicle for bioactive molecules. Calcium phosphate cement is an injectable, osteoconductive, and degradable bone cement that sets in situ. The objective of this study was to create an injectable composite based on calcium phosphate cement embedded with PLGA microparticles for sustained delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2). (125) I-labeled rhBMP-2 was incorporated in PLGA microparticles. PLGA microparticle/calcium-phosphate cement composites were prepared in a ratio of 30:70 by weight. Material properties were evaluated by scanning electron microscopy, microcomputed tomography, and mechanical testing. Release kinetics of rhBMP-2 from PLGA/calcium-phosphate cement disks and PLGA microparticles alone were determined in vitro in two buffer solutions (pH 7.4 and pH 4.0) for up to twenty-eight days. The entrapment yield of rhBMP-2 in PLGA microparticles was a mean (and standard deviation) of 79% +/- 8%. Analysis showed spherical PLGA microparticles (average size, 17.2 +/-1.3 micro m) distributed homogeneously throughout the nanoporous disks. The average compressive strength was significantly lower (p < 0.001) for PLGA and calcium-phosphate cement composite scaffolds than for calcium-phosphate cement scaffolds alone (6.4 +/- 0.6 MPa compared with 38.6 +/- 2.6 MPa, respectively). Average rhBMP-2 loading was 5.0 +/- 0.4 micro g per 75-mm (3) disk. Release of rhBMP-2 was limited for all formulations. At pH 7.4, 3.1% +/- 0.1% of the rhBMP-2 was released from the PLGA/calcium-phosphate cement disks and 18.0% +/- 1.9% was released from the PLGA microparticles alone after twenty-eight days. At pH 4.0, PLGA/calcium-phosphate cement disks revealed more release of rhBMP-2 than did PLGA microparticles alone (14.5% +/- 6.3% compared with 5.4% +/- 0.7%) by day 28. These results indicate that preparation of a PLGA/calcium-phosphate cement composite for the delivery of rhBMP-2 is feasible and that the release of rhBMP-2 is dependent on the composite composition and nanostructure as well as the pH of the release medium.
    The Journal of Bone and Joint Surgery 01/2003; 85-A Suppl 3:75-81. · 3.23 Impact Factor
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    ABSTRACT: The objective of this research is to develop injectable, in situ polymerizable polymer scaffolds for the controlled release of inductive factors for bone and cartilage tissue engineering. To that end, the novel polymer oligo(poly(ethylene glycol) fumarate) (OPF) was synthesized with varying poly(ethylene glycol) (PEG) chain lengths to create crosslinked networks of varying mesh size. A 23 amino acid peptide, TP508, was incorporated into OPF networks either directly or embedded in poly(DL-lactic-co-glycolicacid) (PLGA) microparticle carriers and the release kinetics of the TP508 was examined. After 30 hours, hydrogels of PEG chains of molecular weight 10,000 (PF10K) had released greater percentages of the total TP508 (53±3 wt% of directly loaded TP508) than those fabricated with PEG chain of molecular weight 1,000 (PF1K) (31±7 wt%). This effect was also observed upon the inclusion of PLGA microparticle carriers. For hydrogels of either PEG chain length, release of TP508 was greatly reduced with the use of microparticle carriers (6±1 and 2±1 wt% for PF10K and PF1K, respectively). Our results demonstrate that TP508 can be incorporated into OPF hydrogels and that the release kinetics of the peptide can be modulated through alterations in the scaffold mesh size and the use of a microparticle carrier.
    01/2002; 1.
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    ABSTRACT: Macroporous poly(2-hydroxyethyl methacrylate) (p(HEMA)) hydrogels were prepared in the presence of a 0.3-0.7 M NaCl solution. The pore morphology of the p(HEMA) hydrogels was dependent on the concentration of NaCl for a constant monomer solution to aqueous solution ratio. Swelling studies showed an increase in equilibrium water content and hydrogel porosity as the NaCl concentration in the polymerization medium increased from 0 to 0.7 M. The equilibrium water content, however, decreased as the NaCl concentration in the swelling medium increased. The frozen water content increased and non-frozen water decreased with an increase in the NaCl concentration in the polymerization medium. Mechanical testing indicated that the elastic modulus of the hydrogels was not affected by the increased porosity until the pores became interconnected. These data suggest that the addition of NaCl to the polymerization medium results in a multi-phase separation during fabrication that produces macroporous hydrogels of controlled morphology.
    Biomaterials 12/2000; 21(21):2163-9. · 8.31 Impact Factor

Publication Stats

443 Citations
60.99 Total Impact Points

Institutions

  • 2005
    • Radboud University Medical Centre (Radboudumc)
      • Department of Biochemistry
      Nymegen, Gelderland, Netherlands
  • 2000–2005
    • Rice University
      • Department of Bioengineering
      Houston, TX, United States