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  • 1
    Keywords: Medicine ; Neurosciences ; Toxicology ; Biomedicine ; Neurosciences ; Pharmacology/Toxicology ; Springer eBooks
    Pages: : digital
    ISBN: 9780387766430
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  • 2
    ISSN: 1573-904X
    Keywords: protein stability ; protein aggregation ; monoclonal antibodies ; volume exclusion ; poly(vinylpyrrolidone)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract An IgM anti-group B Streptococcus monoclonal antibody (4B9) was found to undergo irreversible heat-induced aggregation at 50°C. A variety of excipients was tested for their ability to inhibit antibody aggregation. The amount of 4B9 aggregation, which was determined by analysis on a size-exclusion HPLC, was significantly reduced in the presence of low concentrations [between 0.1 and 1.0% (w/v)] of poly(vinylpyrrolidone) (PVP) molecules ranging in molecular weight from 10 to 40 kDa. When the PVP concentration was greater than 1.0%, antibody aggregation was enhanced, and with the highest molecular weight PVP, antibody precipitation occurred. HPLC was used to show that more PVP was associated with the 4B9 at 50°C than at 25°C. Differential scanning calorimetry revealed that PVP concentrations greater than 2.0% decreased the antibody thermal transition temperature. Enzyme-linked immunosorbent assays were used to assess the effects of PVP on the antigen binding capacity of 4B9 and on 4B9 quantitation. At 4°C, PVP solutions of up to 5.0% had no effect on either 4B9 quantitation or antigen binding. At 50°C, however, less 4B9 was detected in the 5.0% PVP solution. The heat stabilization of the 4B9 antibody by low concentrations of PVP can be explained by a weak binding of PVP to the native protein. The PVP may sterically interfere with protein–protein interactions, thus reducing aggregation. Higher concentrations of PVP lead to protein aggregation and precipitation, probably by a volume-exclusion mechanism. Low concentrations of less than 1.0% PVP can be used to stabilize proteins against heat-induced aggregation, but care should be exercised, since even slightly higher concentrations of PVP can also lead to protein destabilization.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-904X
    Keywords: IL-1R type I ; microcalorimetry ; protein formulation ; stability ; aggregation ; preservatives ; far-uv circular dichroism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the solution conditions that confer stability of aqueous IL-1R using differential scanning calorimetry (DSC). Methods. Optimal pH conditions were determined by monitoring degradation products encountered during accelerated studies (at elevated temperatures) using SDS-PAGE. At the pH optimum, DSC screened for excipients that enhanced thermal stability by shifting the Tm to higher values. Using SEC the relationship between thermal unfolding and stability was investigated by considering if lower Tm's in the presence of preservatives correlated with degradation products at 37°C over time. The degree of aggregation relative to that of a control determined the level of stability achieved. Results. Circular dichroism (CD) measurements confirmed molecular modeling studies showing IL-1R to be about 39% β-sheet. Two major transitions characterized the DSC data with Tm's observed near 47°C and 66°C. Among 21 excipients screened, NaCl exhibited the greatest stabilizing influences based on shifting the low temperature transition to 53°C. The low temperature transition was later found to comprise two transitions, yielding a total of three melting transitions for IL-1R. High Tm's arising from the presence of preservatives correlated with the order of stability (i.e., 0.065% phenol 〉 0.1% m-Cresol 〉 0.9% benzyl alcohol). Conclusions. The three melting transitions are consistent in origin with the cooperative unfolding of three unique immunoglobulin-like domains of IL-1R. Optimal stability was achieved in 20 mM sodium citrate at pH 6 with sufficient NaCl to attain the tonicity of human serum. A correlation between the predicted ranking of stability and the extent of aggregation was demonstrated using DSC.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-904X
    Keywords: poly(glycolide-co-D,L-lactide) ; poly(D,L-lactide) ; granulocyte-macrophage colony-stimulating factor (GM-CSF) ; biodegradable microspheres ; pharmacokinetics ; resorbable polymer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study describes the preparation and characterization of a controlled release formulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) encapsulated in poly(glycolide-co-D,L-lactide) (PLGA) and poly(D,L-lactide) (PLA) microspheres. Methods. GM-CSF was encapsulated in PLGA/PLA microspheres by a novel silicone oil based phase separation process. Several different blends of PLGA and low molecular weight PLA were used to prepare the microspheres. The microspheres and the encapsulated GM-CSF were extensively characterized both in vitroand in vivo. Results. Steady release of GM-CSF was achieved over a period of about one week without significant 'burst' of protein from the microspheres. Analysis of microsphere degradation kinetics by gel permeation chromatography (GPC) indicated that low molecular weight PLA enhanced the degradation of the PLGA and thereby affected release kinetics. GM-CSF released from the microspheres was found to be biologically active and physically intact by bioassay and chromato-graphic analysis. Analysis of serum from mice receiving huGM-CSF indicated that the GM-CSF was biologically active and that a concentration of greater than 10 ng/mL was maintained for a period lasting at least nine days. MuGM-CSF was not detected followingin vivo administration of muGM-CSF microspheres. The tissues of mice receiving muGM-CSF microspheres were characterized by infiltration of neutrophils, and macrophages which were in significant excess of those found in mice administered with placebo controls (i.e. microspheres without GM-CSF). Conclusions. This study demonstrates the influence of formulation parameters on the encapsulation of GM-CSF in PLGA/PLA microspheres and its controlled release in biologically active form. The intense local tissue reaction in mice to muGM-CSF microspheres demonstrates the importance of the mode of delivery on the pharmacologic activity of GM-CSF.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Bioconjugate chemistry 6 (1995), S. 332-351 
    ISSN: 1520-4812
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Applied Biomaterials 2 (1991), S. 133-139 
    ISSN: 1045-4861
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The field of biomaterials has grown rapidly over the last three decades in the academic, industrial, and regulatory sectors. Beginning as a research thrust, which led to courses at a few universities, biomaterials education has evolved into distinct curriculum in over 60 institutions in the United States and Canada alone.Rapid growth, however, can cause problems. In an effort to determine the present status and future needs in each sector, as well as begin to assess if the needs of industry are being met by present academic programs, two surveys were sent out.As shown by the two surveys, academic programs have been increasing in both size and quality while industry has also been expanding, as indicated by the many small companies involved in biomaterials. The shift toward graduate programs is in keeping with the perceived educational needs of potential employers. The majority of academic programs appear to be providing the training and coursework desired by employers. Further information, however, is needed to determine if the number of graduates trained in biomaterials is adequate, or in fact excessive.It is, therefore, recommended that a more comprehensive survey, sent to the biomaterials companies listed in the FDA registry, be undertaken. In addition, a survey to each academic program that addresses hiring of recent graduates would also be beneficial. It does appear that certain standards for curricula could be agreed upon, although the field has probably not evolved sufficiently for accreditation or professional registration to be addressed yet.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1045-4861
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The ability of transforming growth factor-beta1 (TGF-β1) to stimulate bone healing was evaluated in a rat critical calvarial defect model. Both a low dose and a high dose of TGF-β1 were incorporated into two different types of implants: one made from a composite of poly(lactic-co-glycolic acid) (PLPG) (50:50) and demineralized bone matrix (DBM), and the other from calcium sulfate (CaSO4). Scanning electron microscopy showed that the CaSO4 implants were more porous than the PLPG/DBM samples. Both types of implants released biologically active TGF-β1 for over 300 h in vitro. The samples were implanted in a 9-mm diameter rat calvarial defect for 6 weeks along with contralateral control implants containing no TGF-β1. Microradiography and histological analysis were used to assess the bone healing in the defects. Microradiography revealed that the greatest amount of calcified bone (67.5%) was present in the CaSO4 implants containing a high dose of TGF-β1 while minimal new bone formation occurred in the PLPG/DBM implants. Histologically, the PLPG/DBM implants exhibited an inflammatory response with little mineralization or bone formation. The defects containing the PLPG/DBM implants consisted of a connective tissue stroma with large void spaces. Giant cells and numerous polymorphonuclear leukocytes were present throughout the implants. In contrast, the CaSO4 implants had only a few inflammatory cells and the presence of mineralization and true bone was a more consistent feature. These preliminary studies show that TGF-β1 is capable of inducing new bone formation. Furthermore, the materials used to deliver the growth factor can play a significant role in the bone healing process. © 1994 John Wiley & Sons, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The impaired wound healing associated with aging may reflect inadequate secretion or delivery of cytokines. Transforming growth factor-β1 is a mitogenic polypeptide with beneficial effects on wound healing. In the present study we questioned whether topical administration of transforming growth factor-β1 could improve the wound healing process in aged rats in vivo. Wound repair (from 1 to 14 days) was analyzed in full-thickness incisional wounds from 2-year-old rats with or without a single topical application of transforming growth factor-β1 (1 µg/wound) at the time of wounding. Identical wounds from 3-month-old, untreated rats served as controls. Histologic analysis showed a marked delay in several aspects of wound repair in the aged rats in comparison with that noted in the younger animals. Immunostaining of the wounds for proliferating cell nuclear antigen showed a reduction in the number of cycling fibroblasts in old rats. In addition, the number of capillaries per unit area of the wound as determined by a stain for Griffonin (Bandeiraea) simplicifolia lectin, and the number of inflammatory cells as identified by an antibody specific for macrophages, were also reduced in the wound area in old rats. Treatment with transforming growth factor-β1 resulted in marked enhancement of the following parameters: cell proliferation, inflammatory cell and fibroblast influx, wound closure, and angiogenesis. As seen with in situ hybridization, a similar temporal pattern of expression of messenger RNAs corresponding to type I procollagen and Secreted Protein, Acidic and Rich in Cysteine (osteonectin), known to be prevalent in healing wounds, was observed in both young and aged rats. However, the levels of mRNA corresponding to these secreted proteins appeared to be reduced in wound tissue from aged rats. Treatment with transforming growth factor-β1 subsequently resulted in an increase in the expression of both type I procollagen and Secreted Protein, Acidic and Rich in Cysteine mRNA in the wound tissue from aged rats. In summary, a single topical application of transforming growth factor-β1 to the wounds of aged rats at the time of wounding was associated with a healing response that, in all the parameters of wound repair examined, was similar to that of young rats. Topical transforming growth factor-β1 might therefore be beneficial in the treatment of dermal wounds in the aged.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Surfaces containing poly(ethylene oxide) (PEO) are interesting biomaterials because they exhibit low degrees of protein adsorption and cell adhesion. In this study different molecular weight PEO molecules were covalently attached to poly(ethylene terephthalate) (PET) films using cyanuric chloride chemistry. Prior to the PEO immobilization, amino groups were introduced onto the PET films by exposing them to an allylamine plasma glow discharge. The amino groups on the PET film were next activated with cyanuric chloride and then reacted with bis- amino PEO. The samples were characterized by scanning electron microscopy, water contact angle measurements, gravimetric analysis, and electron spectroscopy for chemical analysis (ESCA). The adsorption of 125I-labeled baboon fibrinogen and bovine serum albumin was studied from buffer solutions. Gravimetric analysis indicated that the films grafted with the low-molecularweight PEO contained many more PEO molecules than the surfaces grafted with higher-molecular-weight PEO. The highmolecular-weight PEO surfaces, however, exhibited greater wettability (lower water contact angles) and less protein adsorption than the low-molecular-weight PEO surfaces. Adsorption of albumin and fibrinogen to the PEO surfaces decreased with increasing PEO molecular weight up to 3500. A further increase in molecular weight resulted in only slight decreases in protein adsorption. Protein adsorption studies as a function of buffer ionic strength suggest that there may be an ionic interaction between the protein and the allylamine surface. The trends in protein adsorption together with the water contact angle results and the gravimetric analysis suggest that a kind of “cooperative” water structuring around the larger PEO molecules may create an “excluded volume” of the hydrated polymer coils. This may be an important factor contributing to the observed low protein adsorption behavior.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
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