Biomedical subjects

R Langer

Publications and source records attributed to R Langer.

At least 109 records · Page 6Linked to original sources

PubMed1999

[3D-computed tomography for spatial arrangement of the cranial bones of the human fetus].

Aim of the study was to assess the value of in vitro three-dimensional computed tomography (3D-CT) as a new method for the depiction of the fetal skull. 3D-CT images of a fetal head of 24 weeks gestational age were generated with the implemented software on the basis of contiguous CT slices of 1 mm thickness. 3D-CT gave real three-dimensional information about morphology and spatial arrangement of the cranial bones. Using cutting and rotating procedures fast evaluation of all imaged ossified structures in arbitrary views without disturbing superpositions was possible, thus allowing easy identification and accurate description of the cranial bones and making isolated examinations of particular macroscopic sections of the specimens unnecessary. Advantages of 3D-CT over other evaluation techniques for the fetal cranium and its limitations are discussed. In conclusion, 3D-CT promises to be an effective tool for the investigation of fetal cranial development.

Fetus↗

PubMed1999

Microparticles of novel branched copolymers of lactic acid and amino acids: preparation and characterization.

The preparation and characterization of microparticles produced from a new class of functionalized, biodegradable, comblike graft copolymers is presented. The copolymers are polyester-polyamino acid hybrids, composed of a poly(L-lactic acid-co-L-lysine) (PLAL) backbone, and poly(L-lysine), poly(D,L-alanine) or poly(L-aspartic acid) side chains extending from the lysine residues of PLAL. The microparticles have been characterized with regard to their surface properties, morphology, and size. Thus, electron spectroscopy for chemical analysis data and results of Zeta potential measurements suggest that the polyamino acid side chains tend to concentrate at the surface of the particles. Also, analyses by environmental scanning electron microscopy and confocal scanning laser microscopy indicate that particles carrying poly(lysine) chains have an unusual porous structure, most probably due to the combined effects of the amphiphilic, polyelectrolyte, and chemical nature of the composing copolymer, as well as of the particular preparation technique employed. The capabilities of the microparticles to serve as carriers in controlled drug release and delivery devices were demonstrated by encapsulation and release of rhodamine B, a low molecular weight drug model.

Aerosols↗

PubMed1999

PLGA microspheres containing plasmid DNA: preservation of supercoiled DNA via cryopreparation and carbohydrate stabilization.

Biodegradable microspheres containing plasmid DNA have potential uses as mediators of transfection in cells, particularly phagocytic cells such as macrophages. However, the hydrophilic nature and the structural instability of supercoiled DNA preclude its facile encapsulation in polymer matrixes such as poly(d, l-lactic-co-glycolic acid) (PLGA) by traditional methods. We initially studied the microencapsulation of plasmid DNA using the established water-in-oil-in-water double-emulsion solvent-evaporation method and found that (1) the encapsulation efficiency was low (about 20%), (2) the microencapsulation procedure nicked (degraded) the supercoiled DNA, and (3) lyophilization of the microsphere also nicked the DNA. We have therefore designed a new microsphere preparation method (called cryopreparation) to specifically address these concerns. Using the cryopreparation method, the aqueous phase of the primary emulsion containing the plasmid DNA is frozen and then subjected to homogenization. Because there is no shear stress inside a solid, we hypothesized that freezing the aqueous phase of the primary emulsion would help to preserve the supercoiled plasmid DNA during formation of the secondary emulsion. We also hypothesized that the formation of crystals from buffers within the primary emulsion was a causative factor for nicking during freezing or lyophilization, and that disruption of the crystal formation by the addition of saccharides into the primary emulsion would improve the supercoiled-DNA content of the spheres. Our results support the two hypotheses. Not only was the supercoiled-DNA content increased from 39% to over 85%, but the encapsulation efficiency was also elevated from 23% to over 85%.

Carbohydrates↗

PubMed1999

Encapsulation and release of rhodium(II) citrate and its association complex with hydroxypropyl-beta-cyclodextrin from biodegradable polymer microspheres.

Rhodium(II) carboxylates and their derivatives constitute a promising class of second-generation transition metal compounds with anticancer properties. While most transition metal anticancer compounds chelate DNA and cause extensive chromosomal damage, rhodium(II) carboxylates act on the enzyme DNA polymerase alpha and hence cause minimal chromosomal damage. Rhodium(II) citrate, a recent member of the rhodium(II) carboxylate family is highly promising as an antitumor agent. However, due to its high water solubility, a high systemic dose is necessary to achieve efficacy. In this paper, we have explored the complexation of rhodium(II) citrate with hydroxypropyl-beta-cyclodextrin as a means to improve encapsulation and release kinetics from poly(dl-lactic-co-glycolic) acid (PLGA) and poly(anhydride) microspheres. We observed that complexation of rhodium(II) citrate with hydroxypropyl-beta-cyclodextrin significantly increased both the encapsulation efficiency and duration of release in both polymer systems.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1999

Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs.

PURPOSE: To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. METHODS: Large and porous particles, comprising a combination of endogenous or FDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. RESULTS: Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. CONCLUSIONS: The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.

Administration, Inhalation↗

PubMed1999

Formulation and physical characterization of large porous particles for inhalation.

PURPOSE: Relatively large (>5 microm) and porous (mass density <0.4 g/cm3) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. METHODS: Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler device in vitro in both an Andersen cascade impactor and an Aerosizer. RESULTS: By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 microm, and tap densities between 0.04 and 0.6 g/cm3. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the Aerosizer most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1-3 microm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. CONCLUSIONS: Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.

Administration, Inhalation↗

PubMed1999

Photopolymerizable degradable polyanhydrides with osteocompatibility.

We have developed a new family of photopolymerizable, methacrylated anhydride monomers and oligomers that combine high strength, controlled degradation, and photoprocessibility in a singular system. Networks with degradation times ranging from 1 week to nearly 1 year and that retain up to 90% of their tensile modulus at 40% mass loss are attainable. In vivo studies in rats have shown that these networks possess excellent osteocompatibility. These combined properties could offer many advantages in medical applications ranging from dentistry to orthopedics.

Anhydrides↗

PubMed1999

Mechanical shear properties of cell-polymer cartilage constructs.

Cartilaginous constructs were created by using bovine chondrocytes on synthetic, biodegradable scaffolds made of fibrous polyglycolic acid (PGA). The constructs have previously been shown to resemble natural articular cartilage biochemically and histologically. The mechanical properties of articular cartilage mainly depend on the swollen extracellular matrix (ECM), which is a gel consisting of collagen fibers and proteoglycans in a fluid phase of water and electrolytes. The biomechanical properties of the constructs and the build-up of the ECM were studied using dynamic, nondestructive measurements in shear. A small, harmonic strain, lambda < or = 5 x 10(-4), was applied to the sample, and the resulting stress was recorded and used for calculating the complex shear modulus G*. The applied strain was much smaller than that used in confined compression. The shear modulus G* correlated well with both the collagen and glycosaminoglycan content of the constructs but did not reach the same level as in natural cartilage. Collagen is the dominant component contributing to the shear strength of cartilage, and G* was shown to depend approximately quadratically on the collagen content of the constructs. The difference in G* between the constructs and natural cartilage was shown to depend on both the biochemical composition and the microstructure of the constructs. () ()

Animals↗

PubMed1999

Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 sodium channel blockers.

BACKGROUND: Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. METHODS: Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. RESULTS: Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. CONCLUSIONS: Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.

Anesthetics, Local↗

PubMed1999

Transdermal photopolymerization of poly(ethylene oxide)-based injectable hydrogels for tissue-engineered cartilage.

Transdermal photopolymerization, a minimally invasive method for implantation, was used to subcutaneously place a mixture of polymer and isolated chondrocytes to regenerate cartilage tissue in vivo. Semi-interpenetrating networks of varying proportions of poly(ethylene oxide)-dimethacrylate and poly(ethylene oxide) and primary bovine articular chondrocytes were implanted in athymic mice. Four mice (12 implants) were harvested at 2, 4, and 7 weeks. Chondrocytes survived implantation and photopolymerization and formed neocartilage containing 1.5 to 2.9% wet weight collagen and 4 to 7% glycosaminoglycan. Thirty-five percent of the total collagen was type II collagen. Histologic analysis exhibited tissue structure resembling neocartilage, and safranin O staining demonstrated glycosaminoglycan distribution throughout the hydrogels. This study demonstrates the potential use of transdermal photopolymerization for minimally invasive subcutaneous implantation of hydrogels and chondrocytes for in vivo cartilage regeneration.

Animals↗

PubMed1999

Visual performance in giant cell arteritis (temporal arteritis) after 1 year of therapy.

AIMS: To determine if patients with giant cell arteritis (GCA) treated with corticosteroids develop delayed visual loss or drug related ocular complications. METHODS: In a multicentre prospective study patients with GCA (using precise diagnostic criteria) had ophthalmic evaluations at predetermined intervals up to 1 year. The dose of corticosteroid was determined by treating physicians, often outside the study, with the daily dose reduced to the equivalent of 30-40 mg of prednisone within 5 weeks. Subsequently, treatment guidelines suggested that the dose be reduced as tolerated or the patient was withdrawn from steroids in a period not less than 6 months. RESULTS: At presentation, of the 22 patients enrolled, seven patients had nine eyes with ischaemic injury. Four eyes had improved visual acuity by two lines or more within 1 month of starting corticosteroids. No patients developed late visual loss as the steroid dose was reduced. At 1 year the visual acuity, contrast sensitivity, colour vision, and threshold perimetry were not significantly different from the 4-5 week determinations. At 1 year, there were no significant cataractous or glaucomatous changes. At 2 months, there was no difference in systemic complications between patients who received conventional dose (60-80 mg per day) or very high doses (200-1000 mg per day) of corticosteroids at the start or early in the course. CONCLUSIONS: Patients with GCA related visual loss can improve with treatment. Corticosteroids with starting doses of 60-1000 mg per day, with reduction to daily doses of 40-50 mg per day given for 4-6 weeks, and gradual dose reduction thereafter, as clinically permitted, did not result in delayed visual loss. There were no significant drug related ophthalmic complications.

Adrenal Cortex Hormones↗

PubMed1999

Prospective randomized study for an injection protocol for intravenous contrast media in abdominal and pelvic helical CT.

OBJECTIVE: To develop an injection protocol for intravenous administration of contrast media in abdominal and pelvic helical CT which provides optimal contrast enhancement of arterial and venous vessels. MATERIAL AND METHODS: For the study on a Somatom Plus 4 unit, a standard helical CT examination procedure of abdomen and pelvis consisted firstly of a native helical examination of the liver, a second one of the liver after intravenous injection of 120 ml nonionic contrast medium with a constant start delay of 50 s, and subsequently a third helical CT of the lower abdomen and pelvis. 125 patients were randomized for examination under different protocols, varying the injection flow from 2.0-4.0 ml/s and the time delay between the second and the third helical examinations from an additional 20-40 s. The efficacy of the contrast injection was checked by region of interest (ROI) measurements of HUs in aorta, inferior vena cava, and in femoral arteries and veins. The results were compared by t-test statistics. RESULTS: A slow flow rate of 2.0 ml/s led to a higher contrast enhancement in the aorta than a flow rate of 3.0 and 4.0 ml/s. The difference between 2.0 ml/s and 4.0 ml/s was statistically significant. In the inferior vena cava, a flow of 3.0 ml/s caused a better contrast than a flow of 2.0 ml/s or 4.0 ml/s, but the measurements did not reach statistical significance. The measurements in the femoral arteries and veins did not show any significant differences. Maximal enhancement in the pelvic vessels was achieved when the third helical examination was started immediately after the second one had ended. Adding any delay (20 s, 40 s) led to a reduced contrast in the pelvic vessels, with a significant reduction in aorta and femoral arteries. CONCLUSION: For routine abdominal and pelvic helical CT, we recommend an injection of 120 ml contrast medium with a flow rate of 3.0 ml/s. Contrast-enhanced examination of the liver should be started after 50 s, and examination of the lower abdomen and pelvis region should be performed without any further delay. This gives an appropriate contrast in the major vessels.

Abdomen↗

PubMed1999

SPIO-MR imaging versus double-phase spiral CT in detecting malignant lesions of the liver.

PURPOSE: To assess the diagnostic performance of superparamagnetic iron oxide MR (SPIO-MR) imaging compared with double-phase spiral CT in detecting liver metastases and hepatocellular carcinoma. MATERIAL AND METHODS: Thirty-eight patients with a total of 144 malignant lesions of the liver were examined by CT and SPIO-MR. After definition of a gold standard by a panel of experts, the patient images were randomized and presented to a blinded jury of 5 independent observers whose task was to identify as many lesions as possible. The results were tested for statistical significance using multifactorial analysis of variance (alpha=5%). RESULTS: SPIO-MR produced the highest detection rate and was significantly superior (p<0.05) to unenhanced MR imaging and double spiral-phase contrast-enhanced CT (DPS-CECT). Maximum performance in DPS-CECT was obtained during the portal venous contrast phase but was significantly inferior to SPIO-MR imaging. The scores for unenhanced CT and unenhanced MR were significantly lower than for the corresponding enhanced procedures. SPIO-MR imaging produced a higher incidence of false-positive findings (n=39). CONCLUSION: SPIO-MR produced a significantly better detection rate for malignant focal liver lesions compared with double-phase spiral DPS-CECT but was associated with a higher rate of false-positive findings.

Adult↗

PubMed1999

[Erythrocytes after cryopreservation with HES: molecular, structural and functional characteristics].

The use of hydroxyethylstarch (HES) as an alternative to glycerol for cryopreservation of erythrocytes is presented. Immediately after thawing erythrocytes showed alterations in the membrane skeleton and a lowered rigidity of their membrane. However, a few minutes after resuspension in a physiological salt solution the initial poicilocytosis changed back to normocytotic forms. Intravital microscopy of the dog's mesentery revealed a homogeneous distribution of labeled previously cryopreserved erythrocytes in the capillary bed. The lowering of the ATP-level in the erythrocyte by about 20 to 40% was seen to be harmless, because the ATP-turn over rate was unchanged and the glucose support by the GluT 1 carrier was seen to be guaranteed. There was no decrease in the 2,3-DPG level on one hand, but a shift to the right in the O2-association as well as dissociation functions; the saturation capacity of hemoglobin with O2 on the other hand was constant. Free radical oxygen species, generated as a consequence of the freezing/thawing process, were inactivated by the erythrocyte's own antioxidation system. The 24-hour post-transfusion survival in dog amounted to about 95% and the in vivo-life time was normal. The hemolysis of human erythrocytes after thawing was about 5%. Most methodological and scientific problems concerning erythrocyte cryopreservation are considered to be solved. After official permission for use in humans, major benefits to many fields in surgery are expected: no more short-cuts in blood supply, practically complete exclusion of infectious risks, even unlimited use of autologous blood.

Animals↗

PubMed1998

Surface hydrolysis of poly(glycolic acid) meshes increases the seeding density of vascular smooth muscle cells.

A procedure for surface hydrolysis of poly(glycolic acid) (PGA) meshes was developed to increase cell seeding density and improve attachment of vascular smooth muscle cells. Hydrolysis of PGA in 1N NaOH transformed ester groups on the surface of PGA fibers to carboxylic acid and hydroxyl groups. After hydrolysis, the polymer scaffold retained its original gross appearance and dimensions while the fiber diameter decreased. A plot of fiber diameter versus the hydrolysis time showed a linear relationship, with a rate of decrease in fiber diameter of 0.65 microm/min. The molecular weight and thermal properties of the polymer did not change significantly following surface hydrolysis. In cell seeding experiments, surface-hydrolyzed mesh was seeded with more than twice as many cells as unmodified PGA mesh. Vascular smooth muscle cells attached to the surface-hydrolyzed PGA mesh both as individual cells and as cell aggregates while only cell aggregates were observed on the unmodified mesh. Control experiments indicated that adsorption of serum proteins onto the surface-hydrolyzed PGA fibers was correlated with the increase in cell seeding density. These results demonstrate that optimization of biomaterial-cell interactions provides a strategy for increasing the initial cell seeding density for the engineering of tissues of high cell density.

Animals↗

PubMed1998

Collagen in tissue-engineered cartilage: types, structure, and crosslinks.

The function of articular cartilage as a weight-bearing tissue depends on the specific arrangement of collagen types II and IX into a three-dimensional organized collagen network that can balance the swelling pressure of the proteoglycan/water gel. To determine whether cartilage engineered in vitro contains a functional collagen network, chondrocyte-polymer constructs were cultured for up to 6 weeks and analyzed with respect to the composition and ultrastructure of collagen by using biochemical and immunochemical methods and scanning electron microscopy. Total collagen content and the concentration of pyridinium crosslinks were significantly (57% and 70%, respectively) lower in tissue-engineered cartilage that in bovine calf articular cartilage. However, the fractions of collagen types II, IX, and X and the collagen network organization, density, and fibril diameter in engineered cartilage were not significantly different from those in natural articular cartilage. The implications of these findings for the field of tissue engineering are that differentiated chondrocytes are capable of forming a complex structure of collagen matrix in vitro, producing a tissue similar to natural articular cartilage on an ultrastructural scale.

Amino Acids↗

PubMed1998

Oral particulate delivery: status and future trends.

Oral delivery of complex molecules such as peptides and proteins is one of the most intensively studied research subjects. However, its success has been hampered by the degradation of these molecules in the gastrointestinal tract. As a result, various types of particulate systems such as biodegradable microspheres and liposomes have been proposed as potential delivery vehicles to protect these drugs in the gastrointestinal tract. Unfortunately, these particulates generally display low oral absorption efficiencies. This renders most encapsulated drugs ineffective after oral administration and therefore remains as the main obstacle to their practical application as oral delivery vehicles. In attempts to improve particle absorption efficiency, strategies such as using mucoadhesive polymers and targeted delivery systems have been studied in animals. In this chapter, the usefulness of these strategies are briefly reviewed. Potential applications and future prospects of particulates in oral delivery of complex molecules are also highlighted.

Journal Article↗

PubMed1998

Transplantation of cells in matrices for tissue regeneration.

Tissue engineering is a field that has truly emerged in the last decade. It has brought together diverse technologies, e.g. cell culture, polymer chemistry and transplantation. The creation of matrices to guide tissue regeneration allows manipulation at several levels, i.e. the cells employed, the choice of polymer and the design of construct assembly methods. We present experience using such constructs to guide regeneration of diverse tissues, e.g. liver, intestine, urologic tissue, skin, cartilage, bone and cardiovascular structures. Emerging concepts in using cell/polymer constructs include the need for appropriate modeling of the micromechanical environments of different tissues, as well as the necessity of finding new strategies to achieve vascularization of tissues for transplant. Finally, the concept of applying tissue-engineered structures to non-native sites is discussed.

Journal Article↗