Xenobiotic polymers as vaccine vehicles.
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Animals↗
Biomedical subjects
R Langer
Publications and source records attributed to R Langer.
Hepatocyte transplantation in biodegradable polymer scaffolds using the Dalmatian dog model of hyperuricosuria.
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Analysis of Variance↗
Continence mechanism after colpo-needle suspension for stress urinary incontinence.
OBJECTIVE: To determine the mechanism by which continence is restored following the colpo-needle suspension procedure. STUDY DESIGN: During 1990-1991, 37 women underwent colpo-needle suspension for stress urinary incontinence. Urodynamic investigation was performed preoperatively and 6-12 months postoperatively, and the results of these tests were compared in order to define the changes that might be responsible for the restoration of continence. RESULTS: In comparing the preoperative and postoperative cystometric and uroflowmetric measurements, we found no significant differences in the values for bladder capacity, residual volume pressure rise on filling or standing, maximal urethral voiding pressure or peak flow rates. The urethral pressure profiles at rest did not result in statistically significant differences regarding urethral length or urethral pressure. The only such differences postoperatively were elevation of pressure. Transmission ratios on coughing and in the proximal half of the urethra were Q1, 100.3 (P < .001), and Q2, 100.4 (P < .002), respectively. CONCLUSION: Colposuspension appears to correct genuine stress incontinence by repositioning the proximal urethra in the intraabdominal pressure zone, causing restoration of positive pressure transmission to the proximal urethra.
Female↗
Human immunodeficiency virus-associated squamous cell carcinomas of the head and neck presenting as oral and primary intraosseous squamous cell carcinomas.
Six cases of squamous cell carcinoma arising in the head and neck of patients infected with the human immunodeficiency virus are described. This article reports the first two cases of primary intraosseous squamous cell carcinoma associated with infection with human immunodeficiency virus. Clinical presentation, results of imaging studies, histologic characteristics, therapies applied, and the clinical follow-up are described in detail for each of the six cases. These data are evaluated through a review of the current literature.
Acquired Immunodeficiency Syndrome↗
A study on the functional subunits of phospholipases A2 by enzyme immobilization.
Pancreatic and venom phospholipases A2 have complex and distinct oligomerization behaviour. Pancreatic enzymes are monomeric in solution, but their quaternary structure at interfaces is unknown. On the other hand, certain crotalid venom phospholipases A2 are dimeric in solution, and different reports have proposed either the monomer or the dimer as the catalytically functional subunit. In this study, enzyme immobilization was used as a tool for determining the functional subunits of these enzymes. The dimeric Crotalus atrox phospholipase A2 was covalently attached to agarose beads, via either the amine or the carboxylic groups of the protein. In the first case immobilization led to an 80% loss of activity as compared with the soluble form, and measured by using micellar diheptanoylphosphocholine. Inclusion of micellar protectants in the coupling media did not improve the activity. Enzyme immobilized via carboxylic groups was 2-3-fold more active than the amine-coupled form. In a second approach, Crotalus atrox enzyme was immobilized with single-subunit attachment. The removal, with denaturating washes, of the non-covalently bound units involved in monomer-monomer interactions, caused a large decrease in specific activity of the support-bound enzyme. This suggests the dimeric form as the fully active one. Similar procedures were also carried out with pig pancreatic and Naja naja phospholipases A2. The results indicated that these enzymes are active as monomers.
Animals↗
Carbodiimide modification enhances activity of pig pancreatic phospholipase A2.
Pig phospholipase A2, pig iso-phospholipase A2 and bovine pancreatic phospholipase A2 were reacted in solution with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, in the presence of N-hydroxysulfosuccinimide, at pH 7. The influence of micellar protectants was analyzed. In the presence of n-hexadecylphosphocholine, the losses of activity in micellar diheptanoyl-lecithin were 80, 35, and 10% in bovine phospholipase A2, pig iso-phospholipase A2, and pig phospholipase A2, respectively. With 1-oleoylglycerophosphocholine, the bovine enzyme lost 40% activity, but the pig enzyme was activated sevenfold. The modified pig enzyme showed pre-micellar activation on monomeric diheptanoyl-lecithin, and either reduced or increased activities on mixed micelles of bile salt with egg phosphatidylcholine, depending on the composition of the micelles. This activation is consistent with previous protein-engineering studies of pig pancreatic phospholipase A2. In this study, we present new information concerning the specificity and interfacial recognition behaviour of this enzyme in relation to this activation.
Animals↗
A stereochemical approach to pyranose ring flexibility: its implications for the conformation of dermatan sulfate.
Glycosaminoglycans, such as heparin, heparan sulfate, and dermatan sulfate, are characterized by a disaccharide repeating unit of a uronate and a hexosamine and are increasingly understood to be important physiologically as soluble components of the extracellular matrix. The secondary structure of this class of acidic polysaccharides is believed to play a key role in determining the wide range of biological specificities. Central to the structural diversity of the glycosaminoglycans is the experimentally documented conformational flexibility of the iduronate residue. Here, we outline an approach to explore the iduronate conformational flexibility by imposing stereochemical criteria of nonbonded contact distances. By performing a complete search of all possible torsions that define the iduronate ring geometry, we eliminate any prior bias with regard to minimum energy conformers. The approach led to alternative feasible conformers for the iduronate ring that are stereochemically satisfactory and are consistent with the available physico-chemical data.
Carbohydrate Conformation↗
Electrically conducting polymers can noninvasively control the shape and growth of mammalian cells.
Electrically conducting polymers are novel in that their surface properties, including charge density and wettability, can be reversibly changed with an applied electrical potential. Such properties might render conducting polymers unique for biological applications. However, the majority of research on conducting polymers has been carried out under nonbiological conditions. We synthesized optically transparent polypyrrole thin films and studied them in environments suitable for protein adsorption and mammalian cell culture. In vitro studies demonstrated that extracellular matrix molecules, such as fibronectin, adsorb efficiently onto polypyrrole thin films and support cell attachment under serum-free conditions. When aortic endothelial cells were cultured on fibronectin-coated polypyrrole (oxidized) in either chemically defined medium or the presence of serum, cells spread normally and synthesized DNA. In contrast, when the polymer was switched to its neutral state by applying an electrical potential, both cell extension and DNA synthesis were inhibited without affecting cell viability. Application of a similar electrical potential to cells cultured on indium tin oxide surfaces had no effect on cell shape or function. These data suggest that electrically conducting polymers may represent a type of culture substrate which could provide a noninvasive means to control the shape and function of adherent cells, independent of any medium alteration.
Animals↗
New challenges in biomaterials.
Significant opportunities and challenges exist in the creation and characterization of biomaterials. Materials have been designed for contact with blood, as replacements for soft and hard tissues, as adhesives, and as dental materials. Current methods of synthesis and characterization of these materials are outlined. Approaches for controlling the interface between tissue and biomaterials and ways in which the engineered materials may contribute to medicine are considered.
Amino Acid Sequence↗
Biodegradable long-circulating polymeric nanospheres.
Injectable nanoparticulate carriers have important potential applications such as site-specific drug delivery or medical imaging. Conventional carriers, however, cannot generally be used because they are eliminated by the reticulo-endothelial system within seconds or minutes after intravenous injection. To address these limitations, monodisperse biodegradable nanospheres were developed from amphiphilic copolymers composed of two biocompatible blocks. The nanospheres exhibited dramatically increased blood circulation times and reduced liver accumulation in mice. Furthermore, they entrapped up to 45 percent by weight of the drug in the dense core in a one-step procedure and could be freeze-dried and easily redispersed without additives in aqueous solutions.
Animals↗
Heparinase inhibits neovascularization.
Neovascularization is associated with the regulation of tissue development, wound healing, and tumor metastasis. A number of studies have focused on the role of heparin-like molecules in neovascularization; however, little is known about the role of heparin-degrading enzymes in neovascularization. We report here that the heparin-degrading enzymes, heparinases I and III, but not heparinase II, inhibited both neovascularization in vivo and proliferation of capillary endothelial cells mediated by basic fibroblast growth factor in vitro. We suggest that the role of heparinases in inhibition of neovascularization is through depletion of heparan sulfate receptors that are critical for growth factor-mediated endothelial cell proliferation and hence neovascularization. The differences in the effects of the three heparinases on neovascularization could be due to different substrate specificities for the enzymes, influencing the availability of specific heparin fragments that modulate heparin-binding cytokines involved in angiogenesis.
Allantois↗
In vivo versus in vitro degradation of controlled release polymers for intracranial surgical therapy.
Intracranial studies to analyze the degradation kinetics of the bioerodible polymer poly[bis(p-carboxyphenoxy)propane-sebacic acid] [p(CPP-SA) 20:80] copolymer wafers were conducted in a rat model. Rats were separated into four groups: those receiving 1) polymer, 2) polymer loaded with the chemotherapeutic agent BCNU, 3) drug-loaded polymer with previous tumor implantation, and 4) polymer and an absorbable hemostatic material. A polymer wafer was surgically implanted into the brain of each animal. Residual polymer was harvested at varying times for chromatographic analysis. In vitro effects of pH, mixing, and water availability on degradation were also studied. The results of in vitro and in vivo studies were compared to understand the behavior of polymers in a clinical setting. We found that degradation of p(CPP-SA) initially occurred more slowly in vivo than in vitro. The presence of BCNU, tumor, and absorbable hemostatic material did not affect the ultimate time of polymer degradation in vivo, and the intrinsic polymer degradation time of 1 mm thick p(CPP-SA) 20:80 disks in vivo was 6-8 weeks.
Animals↗
Joint resurfacing using allograft chondrocytes and synthetic biodegradable polymer scaffolds.
Cartilage implants which could potentially be used to resurface damaged joints were created using rabbit articular chondrocytes and synthetic, biodegradable polymer scaffolds. Cells were serially passaged and then cultured in vitro on fibrous polyglycolic acid (PGA) scaffolds. Cell-PGA constructs were implanted in vivo as allografts to repair 3-mm diameter, full thickness defects in the knee joints of adult rabbits, and cartilage repair was assessed histologically over 6 months. In vitro, chondrocytes proliferated on PGA and regenerated cartilaginous matrix. Collagen and glycosaminoglycan (GAG) represented 20 to 8% of the implant dry weight (dw), respectively, at the time of in vivo implantation; the remainder was PGA and unspecified components. Implants based on passaged chondrocytes had 1.7-times as much GAG and 2.6-times as much collagen as those based on primary chondrocytes. In vivo, cartilaginous repair tissue was observed after implantation of PGA both with and without cultured chondrocytes. Six month repair was qualitatively better for cell-PGA allografts than for PGA alone, with respect to: 1) surface smoothness, 2) columnar alignment of chondrocytes, 3) spatially uniform GAG distribution, 4) reconstitution of the subchondral plate, and 5) bonding of the repair tissue to the underlying bone. These pilot studies demonstrate that it is feasible to use cell-polymer allografts for joint resurfacing in vivo.
Animals↗
Erosion of a new family of biodegradable polyanhydrides.
Studies investigating the erosion mechanism of the newly developed poly (fatty acid dimer: sebacic acid) polyanhydride (p:[FAD:SA]) are described. The overall erosion of different monomer compositions of p(FAD:SA) copolymers was examined to determine whether and to what extent copolymer properties affected polymer erosion. Increasing the hydrophobic monomer (FAD) content up to 50 wt% in the copolymer resulted in longer erosion, whereas further increases up to 70 wt% decreased the erosion period. Polymer crystallinity depended on copolymer FAD content. Copolymer degradation was studied by examining anhydride bond hydrolysis using infrared spectroscopy. Much faster hydrolysis was found in p(FAD:SA) 70:30 compared with more crystalline copolymers of higher SA content. Light microscopy indicates the presence of an erosion zone, a distinct area where mass loss occurs. This erosion zone moves from the outside toward the interior of the polymer matrix. It plays an important role in erosion because any water or monomer must diffuse through this eroded layer.
Biodegradation, Environmental↗
Purification and characterization of two collagenase inhibitors from mouse sarcoma 180 conditioned medium.
We have previously shown that mouse sarcoma 180 cells produce vascular endothelial growth factor [VEGF; Rosenthal et al., 1990, Growth Factors, 4: 53-59], an endothelial mitogen that stimulates angiogenesis. Recent reports have implicated metalloproteinases and their inhibitors in the regulation of vascular morphogenesis, tumor invasion, and metastasis. We report here that mouse sarcoma 180 cells produce two collagenase inhibitors. These inhibitors were purified by heparin-Sepharose affinity chromatography, gel filtration, and C4 reverse phase h.p.l.c. Analytical gel electrophoresis of the purified inhibitors (MS-22 and MS-31) revealed molecular masses of 22,000 and 31,000 Da under reducing conditions, and 20,000 and 30,000 Da under nonreducing conditions, respectively. The NH2-terminal amino acid sequence of MS-22 was identical to that of tissue inhibitor of metalloproteinases type 2 (TIMP-2) produced by human melanoma cells [Stetler-Stevenson et al., 1989, J. Biol. Chem. 264: 17374-17378) over the first 30 amino acids. The NH2-terminal amino acid sequence of MS-31 was identical to that of murine TIMP-1 [Gewert et al., 1989, EMBO J 6:651-657]. Statistical analysis of the amino acid composition data of these two mouse sarcoma 180-derived collagenase inhibitors confirms the identification of MS-22 as TIMP-2 and MS-31 as TIMP-1.
Amino Acid Sequence↗
Injectable polyanhydride granules provide controlled release of water-soluble drugs with a reduced initial burst.
A method for preparing polyanhydride granules of an injectable size was developed. The resulting granules permitted a nearly constant release of low-molecular-weight, water-soluble drugs without an initial burst. The polyanhydrides used were poly(fatty acid dimer), poly(sebacic acid), and their copolymers. The dyes acid orange 63 and p-nitroaniline were used as model compounds for drugs. Polymer degradation and drug release for disks and variously sized granules of copolymers containing drugs, prepared by a water-in-oil (W/O) emulsion method, were compared with those for devices prepared by the usual compression method. In the W/O emulsion method, a mixture of aqueous drug solution and polymer-chloroform solution was emulsified by probe sonication to prepare a very fine W/O emulsion. The powder obtained by freeze-drying of the W/O emulsion was pressed into circular disks. In the compression method, the drug was mechanically mixed with the polymer, and the mixture was compressed into circular disks. The resulting disks were ground to prepare granules of different sizes. The granules encapsulated more than 95% of the drug, irrespective of the preparation method. Both methods were effective in preparing polymer disks capable of controlled drug release without any initial burst. However, as the granule size decreased to an injectable size (diameter, < 150 microns), a large difference in the drug release profile was observed between the two preparation methods. The injectable granules obtained by the W/O emulsion method showed nearly constant drug release without any large initial burst, in contrast to those prepared by the compression method, irrespective of the drug type.(ABSTRACT TRUNCATED AT 250 WORDS)
Delayed-Action Preparations↗
A linear theory of transdermal transport phenomena.
A theory of charge, fluid-mass, and solute (including macromolecular) transport through porous media is applied to describe transport phenomena across the external layer of mammalian skin. Linear relationships are derived between transport fluxes and applied fields. These relationships introduce six effective transdermal transport coefficients. Formulas for each of these coefficients are provided. The practical relevance of these parameters is emphasized in the specific context of transdermal drug delivery. By employing typical physiological values for the various geometrical and physicochemical parameters that appear in the formulas for the transdermal transport coefficients, predictions are made for transport rates of charge, fluid mass, and solute species across a uniform-thickness skin sample contained within a diffusion-cell apparatus. These results are used to explore transdermal phenomena involving forced convection, current flow, electroosmosis, iontophoresis, and molecular diffusion (including convective dispersion). Comparisons with existing transdermal drug delivery data are made. On the basis of these comparisons, the theory suggests that transdermal transport in the presence of an electrical field may occur through corneocytes of the stratum corneum. The theory confirms the importance of a shunt route for small ion transport, as well as an intercellular route of transport for passive diffusion of noncharged substances. These latter conclusions, also based on comparisons with experimental data, are consistent with previous statements in the literature. A new form of solute transport enhancement, termed transdermal convective dispersion, is included in the theory, and methods for its measurement are described. Generalizations and future applications of the theory are discussed.
Administration, Cutaneous↗