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Biomedical subjects

R Langer

Publications and source records attributed to R Langer.

At least 37 records · Page 2Linked to original sources
PubMed2002

Laminaria dilatation and evacuation for pregnancies with mid-trimester premature rupture of membranes: a retrospective cohort study.

OBJECTIVE: To assess the efficacy and risk of chorioamnionitis with laminaria tents and uterine evacuation in patients with mid-trimester premature rupture of membrane (MPROM). STUDY DESIGN: A retrospective cohort study of 34 women, admitted between January 1995 and May 1999 with confirmed mid-trimester (14-23 weeks) PROM and 34 controls matched for gestational age, undergoing elective termination. All women underwent cervical dilatation by the use of laminaria tents followed by uterine evacuation (D approximately equals E). Perioperative complications were retrieved from the medical records and long-term ones by telephone questionnaire. RESULTS: Apart from one case requiring a change in antibiotic, no short- or long-term complications were reported. Although, in 8 out of 19 study cases (42%) endocervix culture was positive. The number of laminaria tents used was similar in both groups. The future pregnancy rate was higher in the study group but included four early spontaneous abortions and one ectopic pregnancy. CONCLUSION: Evacuation of uterus following cervical dilatation by laminaria tents in patients presenting with MPROM is safe, and probably not associated with future adverse pregnancy outcome.

Abortion, Induced↗
PubMed2002

A biodegradable composite scaffold for cell transplantation.

Cell transplantation is rapidly becoming a therapeutic option to treat disease and injury. However, standard techniques for cell seeding on non-woven polymer meshes or within gels may not be suitable for immediate implantation or surgical manipulations of freshly isolated cells. Therefore, a biodegradable composite system was developed as a way to rapidly entrap cells within a support of predefined shape to potentially facilitate cell delivery into a target site (e.g. meniscal tears in the avascular zone). The composite construct consisted of freshly isolated cells, in this case pig chondrocytes, entrapped in a fibrin gel phase and dispersed throughout the void volume of a polyglycolic acid (PGA) non-woven mesh. Composites were cultured for up to 4 weeks. In vitro degradation of fibrin gel was evaluated via gel-entrapped urokinase. At 28 days in culture, glycosaminoglycan (GAG) content per cell in the composite scaffolds was 2.6 times that of the PGA-only cell construct group and 88% that of native pig cartilage. Total collagen content per cell in the composite scaffolds was not significantly different from the PGA-only cell construct group (P > 0.02) and represented 40% of the value determined for native cartilage. Varying the concentration of entrapped urokinase could effect controlled degradation of fibrin gel.

Absorbable Implants↗
PubMed2002

Uterine papillary serous carcinoma (pure and mixed type) compared with moderately and poorly differentiated endometrioid carcinoma. A clinicopathologic study.

OBJECTIVE: The aim of this study was to investigate the clinicopathologic features and the outcome in patients with pure and mixed type uterine papillary serous carcinoma (UPSC), and to compare these parameters with those observed in patients with moderately and poorly differentiated endometrioid endometrial carcinoma (MPD-EEC). METHODS: The charts of 34 patients with UPSC and 30 patients with MPD-EEC, operated on between January 1995 and December 2000, were retrospectively reviewed. The UPSC group included ten cases of pure and 24 cases of mixed type UPSC (admixed with endometrioid component). All patients had undergone full surgical staging. Clinical features, surgicopathological findings, recurrence rate and recurrence-free interval were compared between the study groups. RESULTS: Significantly more patients with MPD-EEC than with UPSC were operated on in FIGO stage I and II (p = 0.001). MPD-EEC patients were significantly older and more obese (p = 0.03 and p = 0.01, respectively) as compared with the UPSC patients. Significantly more patients with MPD-EEC presented with postmenopausal bleeding (p = 0.02), had a second primary cancer in the past (p = 0.03) and had a first degree relative with history of malignant disease (p = 0.0001). Conversely, the rates of positive abdominal cytology and cervical involvement were significantly higher in the group of UPSC (p = 0.02 and p = 0.02, respectively). Significantly more patients with UPSC were treated with adjuvant therapy (p = 0.01). No significant difference between the two study groups was observed comparing the recurrence rate, the recurrence free interval and the 3-year survival. There was also no significant difference between the pure and the mixed type UPSC, considering the clinical features and the follow-up data. CONCLUSION: The current study presented no significant difference in the outcome of MPD-EEC as compared with the pure and the mixed type UPSC, yet prospective studies are needed to evaluate the role of adjuvant therapy in each study group.

Aged↗
PubMed2001

Inhalation delivery of proteins from ethanol suspensions.

To circumvent inherent problems associated with pulmonary administration of aqueous-solution and dry-powder protein drugs, inhalation delivery of proteins from their suspensions in absolute ethanol was explored both in vitro and in vivo. Protein suspensions in ethanol of up to 9% (wt/vol) were readily aerosolized with a commercial compressor nebulizer. Experiments with enzymic proteins revealed that nebulization caused no detectable loss of catalytic activity; furthermore, enzyme suspensions in anhydrous ethanol retained their full catalytic activity for at least 3 weeks at room temperature. With the use of Zn(2+)-insulin, conditions were elaborated that produced submicron protein particles in ethanol suspensions. The latter (insulin/EtOH) afforded respirable-size aerosol particles after nebulization. A 40-min exposure of laboratory rats to 10 mg/ml insulin/EtOH aerosols resulted in a 2-fold drop in the blood glucose level and a marked rise in the serum insulin level. The bioavailability based on estimated deposited lung dose of insulin delivered by inhalation of ethanol suspension aerosols was 33% (relative to an equivalent s.c. injection), i.e., comparable to those observed in rats after inhalation administration of dry powder and aqueous solutions of insulin. Inhalation of ethanol in a relevant amount/time frame resulted in no detectable acute toxic effects on rat lungs or airways, as reflected by the absence of statistically significant inflammatory or allergic responses, damage to the alveolar/capillary barrier, and lysed and/or damaged cells.

Administration, Inhalation↗
PubMed2001

Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA.

The purpose of the present work was to produce and characterize poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) nanoparticles (size lower than 300 nm) containing a high loading of plasmid DNA in a free form or co-encapsulated with either poly(vinyl alcohol) (PVA) or poly(vinylpyrrolidone) (PVP). The plasmid alone or with PVA or PVP was encapsulated by two different techniques: an optimized w/o/w emulsion-solvent evaporation technique as well as by a new w/o emulsion-solvent diffusion technique. Particle size, zeta potential, plasmid DNA loading and in vitro release were determined for the three plasmid-loaded formulations. The influence of the initial plasmid loadings (5, 10, 20 microg plasmid DNA/mg PLA-PEG) on those parameters was also investigated. The plasmid loaded into the nanoparticles and released in vitro was quantified by fluorimetry and the different molecular forms were identified by gel electrophoresis. PLA-PEG nanoparticles containing plasmid DNA in a free form or co-encapsulated with PVA or PVP were obtained in the range size of 150-300 nm and with a negative zeta potential, both parameters being affected by the preparation technique. Encapsulation efficiencies were high irrespective of the presence of PVA or PVP (60-90%) and were slightly affected by the preparation technique and by the initial loading. The final plasmid DNA loading in the nanoparticles was up to 10-12 microg plasmid DNA/mg polymer. Plasmid DNA release kinetics varied depending on the plasmid incorporation technique: nanoparticles prepared by the w/o diffusion technique released their content rapidly whereas those obtained by the w/o/w showed an initial burst followed by a slow release for at least 28 days. No significant influence of the plasmid DNA loading and of the co-encapsulation of PVP or PVA on the in vitro release rate was observed. In all cases the conversion of the supercoiled form to the open circular and linear forms was detected. In conclusion, plasmid DNA can be very efficiently encapsulated, either in a free form or in combination with PVP and PVA, into PLA-PEG nanoparticles. Additionally, depending on the processing conditions, these nanoparticles release plasmid DNA either very rapidly or in a controlled manner.

Chemical Phenomena↗
PubMed2001

A simple synthetic route to the formation of a block copolymer of poly(lactic-co-glycolic acid) and polylysine for the fabrication of functionalized, degradable structures for biomedical applications.

This article documents the formation of a block copolymer of poly(lactic-co-glycolic acid) and polylysine via a simple coupling technique using dicyclohexyl carbodiimide (DCC). The resulting polymer has been characterized via UV-Vis spectroscopy, GPC, (1)H NMR, and elemental analysis, is soluble in a wide variety of solvents, and is easily processable, making the technique a simple and practical one for the formation of functionalized, degradable block copolymers for the fabrication of functionalized structures for biomedical applications.

Biocompatible Materials↗
PubMed2001

Responsive polymeric delivery systems.

This paper discusses the state of the art in a relatively new approach in the field of controlled drug delivery-responsive polymeric drug delivery systems. Such systems are capable of adjusting drug release rates in response to a physiological need. The fundamental principles of externally and self-regulated delivery systems are examined. Special attention is paid to specific clinical settings such as diabetes, presenting the advantages and disadvantages of different approaches.

Animals↗
PubMed2001

Effects of mixing intensity on tissue-engineered cartilage.

Mechanical forces regulate the structure and function of many tissues in vivo; recent results indicate that the mechanical environment can decisively influence the development of engineered tissues cultured in vitro. To investigate the effects of the hydrodynamic environment on tissue-engineered cartilage, primary bovine calf chondrocytes were seeded on fibrous polyglycolic acid meshes and cultured in spinner flasks either statically or at one of nine different turbulent mixing intensities. In medium from unmixed flasks, CO(2) accumulated and O(2) was depleted, whereas in medium from mixed flasks the concentrations of both gases approached their equilibrium values. Relative to constructs exposed to nonmixed conditions, constructs exposed to mixing contained higher fractions of collagen, synthesized and released more GAG, but contained lower fractions of GAG. Across the wide range of mixing intensities investigated, the presence or absence of mixing, but not the intensity of the mixing, was the primary determinant of the GAG and collagen content in the constructs. The all-or-none nature of these responses may provide insight into the mechanism(s) by which engineered cartilage perceives changes in its hydrodynamic environment and responds by modifying extracellular matrix production and release. 2001 John Wiley & Sons, Inc.

Animals↗
PubMed2001

Prospects for organ and tissue replacement.

Damage or loss of a tissue or organ is common, costly, and tragic. Advances in mechanical artificial organs and organ transplantation have improved the treatment of organ failure, and advances in molecular immunology, tissue engineering, and stem cell biology offer the promise of even better therapeutic modalities for treating organ failure in the future. Enhancement of immune tolerance of transplanted tissues, improved understanding of cellular differentiation and tissue development, and advances in biomaterials may enable the de novo creation of implantable tissue and organs for transplantation. Innovative techniques for prevention and treatment of tissue loss and organ failure should improve the quality and length of life.

Animals↗
PubMed2001

Plasmid DNA encapsulation and release from solvent diffusion nanospheres.

The first step toward hydrophobic polymer-based nanospheres for gene delivery is to encapsulate and release plasmid DNA. However, encapsulating large hydrophilic molecules in very small nanospheres has been difficult, and only a few examples exist in the literature. For example, maximizing protein and peptide as well as small molecule encapsulation requires adjustments in pH or addition of excipients to charge neutralize, and make less hydrophilic, the compound to be encapsulated. Following this model, we have used a cationic lipid to load and release plasmid DNA from nanospheres made by the phase inversion/solvent diffusion method.

DNA↗
PubMed2001

Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini.

Protein expression after delivery of plasmid DNA to the cell nucleus depends on the processes of transcription and translation. Cytotoxic gene-delivery systems may compromise these processes and limit protein expression. This situation is perhaps most prevalent in current nonviral polycationic gene-delivery systems in which the polycationic nature of the delivery system can lead to cytotoxicity. To approach the problem of creating nontoxic but effective gene-delivery systems, we hypothesized that by optimizing the balance between polymer cationic density with endosomal escape moieties, effective gene transfer with low cytotoxicity could be created. As a model system, we synthesized a series of polymers whose side-chain termini varied with respect to the balance of cationic centers and endosomal escape moieties. Specifically, by polymer-analogous amidation we conjugated imidazole groups to the epsilon-amines of polylysine in varying mole ratios (73.5 mol % imidazole, 82.5 mol % imidazole, and 86.5 mol % imidazole). The primary epsilon-amine terminus of polylysine served as a model for the cationic centers, whereas the imidazole groups served as a model for the endosomal escape moieties. These polymers condensed plasmid DNA into nanostructures <150 nm and possessed little cytotoxicity in vitro. Transfection efficiency, as measured by luciferase protein expression, increased with increasing imidazole content of the polymers in a nonlinear relationship. The polymer with the highest imidazole content (86.5 mol %) mediated the highest protein expression, with levels equal to those mediated by polyethylenimine, but with little to no cytotoxicity.

Animals↗
PubMed2001

AB-polymer networks based on oligo(epsilon-caprolactone) segments showing shape-memory properties.

Although shape-memory metal alloys have wide use in medicine and other areas, improved properties, particularly easy shaping, high shape stability, and adjustable transition temperature, are realizable only by polymer systems. In this paper, a polymer system of shape-memory polymer networks based on oligo(epsilon-caprolactone) dimethacrylate as crosslinker and n-butyl acrylate as comonomer was introduced. The influence of two structural parameters, the molecular weight of oligo(epsilon-caprolactone) dimethacrylate and the weight content of n-butyl acrylate, on macroscopic properties of polymer networks such as thermal and mechanical properties has been investigated. Tensile tests above and below melting temperature showed a decrease in the elastic modulus with increasing comonomer weight content. The crystallization behavior of the new materials has been investigated, and key parameters for the programming procedure of the temporary shape have been evaluated. Shape-memory properties have been quantified by thermocyclic experiments. All samples reached uniform deformation properties with recovery rates above 99% after 3 cycles. Whereas strain recovery increased with increasing n-butyl acrylate content, strain fixity decreased, reflecting the decreasing degree of crystallinity of the material.

Journal Article↗
PubMed2001

The different behaviors of skeletal muscle cells and chondrocytes on PEGT/PBT block copolymers are related to the surface properties of the substrate.

The attachment, proliferation, morphology, and differentiation of two cell types-skeletal muscle cells and chondrocytes-were investigated on different compositions of poly(ethylene glycol) and poly(butylene terephthalate) segmented block copolymers. Four weight percentages (40, 55, 60, and 70%) and two different molecular weights (300 and 1000 Da) of poly(ethylene glycol) were tested. Varying the weight percentage and molecular weight of poly(ethylene glycol) resulted in different behaviors for skeletal muscle cells and chondrocytes. The attachment of skeletal muscle was the highest (similar to tissue culture polystyrene) when copolymers containing 55 wt % of poly(ethylene glycol) were used, regardless of the poly(ethylene glycol) molecular weight. Maximum proliferation and differentiation of skeletal muscle cells was achieved when copolymers containing 55 wt % and 300 Da molecular weight of poly(ethylene glycol) were used. In contrast, the weight percentage and molecular weight of poly(ethylene glycol) had no significant effect on chondrocyte attachment and proliferation; the attached chondrocytes retained a differentiated phenotype only when a 70 wt % of poly(ethylene glycol) was used. Cell behavior was correlated with the surface properties of the copolymer films, as indicated by contact-angle measurements. These results suggest that an optimized wt % and molecular weight of poly(ethylene glycol) will be useful depending on the specific cell type.

Animals↗
PubMed2001

Selective differentiation of mammalian bone marrow stromal cells cultured on three-dimensional polymer foams.

Bone marrow stromal cells (BMSC) are pluripotent progenitor cells that can regenerate different skeletal tissues in response to environmental signals. In this study, we used highly porous, structurally stable three-dimensional polymer foams in conjunction with specific regulatory molecules to selectively differentiate mammalian BMSC into either cartilaginous or bone-like tissues. Bovine BMSC were expanded in monolayers and cultured on 5-mm-diameter, 2-mm-thick foams made of poly(lactic-co-glycolic acid) and poly(ethylene glycol). Constructs maintained their original size and shape for up to 4 weeks of culture and supported BMSC growth and production of extracellular matrix (ECM). By proper use of chondrogenic (dexamethasone, insulin, transforming growth factor-beta1) or osteogenic (dexamethasone, beta-glycerophosphate) medium supplements, we could control whether the generated ECM was cartilaginous (containing collagen type II and sulfated glycosaminoglycans) or bone-like (containing osteocalcin, osteonectin, and mineralized foci). After 4 weeks of cultivation, cartilaginous and bone-like ECM were uniformly distributed throughout the construct volume and respectively represented 34.2 +/- 9.3% and 12.6 +/- 3.2% of the total available area. BMSC culture on poly(lactic-co-glycolic acid)/poly(ethylene glycol) foams provides a three-dimensional model system to study the development of mesenchymal tissues in vitro and has potential applications in engineering autologous grafts for skeletal tissue repair.

Animals↗
PubMed2001

Theoretical description of transdermal transport of hydrophilic permeants: application to low-frequency sonophoresis.

Application of ultrasound enhances transdermal transport of drugs (sonophoresis). The enhancement may result from enhanced diffusion due to ultrasound-induced skin alteration and/or from forced convection. To understand the relative roles played by these two mechanisms in low-frequency sonophoresis (LFS, 20 kHz), a theory describing the transdermal transport of hydrophilic permeants in both the absence and the presence of ultrasound was developed using fundamental equations of membrane transport, hindered-transport theory, and electrochemistry principles. With mannitol as the model permeant, the role of convection in LFS was evaluated experimentally with two commonly used in vitro skin models- human cadaver heat-stripped skin (HSS) and pig full-thickness skin (FTS). Our results suggest that convection plays an important role during LFS of HSS, whereas its effect is negligible when FTS is utilized. The theory developed was utilized to characterize the transport pathways of hydrophilic permeants during both passive diffusion and LFS with mannitol and sucrose as two probe molecules. Our results show that the porous pathway theory can adequately describe the transdermal transport of hydrophilic permeants in both the presence and the absence of ultrasound. Ultrasound alters the skin porous pathways by two mechanisms: (1) enlarging the skin effective pore radii, or (2) creating more pores and/or making the pores less tortuous. During passive diffusion, both HSS and FTS exhibit the same skin effective pore radii (r = 28 +/- 13 A). In contrast, during LFS, r within HSS is greatly enlarged (r > 125 A), whereas r within FTS does not change significantly (23 +/- 10 A). The observed different roles of convection during LFS across HSS and FTS can be attributed to the different degrees of structural alteration that these two types of skin undergo during LFS.

Administration, Cutaneous↗
PubMed2001

Cell-killing potential of a water-soluble radical initiator.

The diazo compound, 2,2'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPC), is a water-soluble radical initiator that can be activated at mild temperatures (37 degrees -40 degrees C). Potential biomedical applications of this compound include the fabrication of hydrogels by radical polymerization (e.g., cell encapsulation or drug delivery) and the thermal sensitization of cancerous cells to induce localized cell death. In this study we evaluated whether this compound could induce cell death at 37 degrees C in vitro and in vivo using a tumor animal model. Cytotoxicity was quantitated with a sulfo-rhodamine B colorimetric assay by monitoring growth inhibition of human glioma cells in vitro. AIPC was entrapped in fibrin gel and exposed to cells in culture as a potential way to localize the compound in a controlled release environment. The mechanism of action for cell death was evaluated by quantitating caspase-3 activity in cells. In vivo studies included human glioma tumors that were grown subcutaneously in rats to study the effect of intra-tumor injections of AIPC. AIPC was also injected subcutaneously into normal tissue. Concentrations of 0.2% and 0.02% (w/v in RPMI medium) showed 93% and 84% inhibition of cell growth in vitro, respectively. Cell-growth inhibition using gel-entrapped AIPC was comparable to that obtained with AIPC in solution after 48 hr (86% inhibition at 0.2% w/v). Exposure to AIPC resulted in a significant increase of caspase activity (up to 163 units after 20 min), suggesting induced apoptosis as a possible mechanism of action of the AIPC. Histological pictures showed that, relative to normal tissue, cancerous tissue was more sensitive to the effects of AIPC.

Animals↗