Search PubMed⌕ Search

Biomedical subjects

R Langer

Publications and source records attributed to R Langer.

At least 145 records · Page 8Linked to original sources
PubMed1998

A re-examination of tetrodotoxin for prolonged duration local anesthesia.

BACKGROUND: Highly potent toxins such as tetrodotoxin that block sodium channels with great specificity have been studied for many years and can provide prolonged blockade when coadministered with vasoconstrictors or conventional local anesthetics. Their utility has been constrained, however, by systemic toxicity. The authors examined the efficacy of tetrodotoxin with and without epinephrine or bupivacaine for producing prolonged-duration sciatic nerve blockade in the rat, and they assessed the degree of concomitant toxicity. METHODS: Rats received percutaneous sciatic nerve blockade using tetrodotoxin with and without epinephrine or bupivacaine. A subset received subcutaneous injections at the nuchal midline. Nociceptive, proprioceptive, and motor blockade were quantified using contralateral leg responses as controls for systemic effects. RESULTS: Tetrodotoxin without epinephrine produced sciatic nerve blockade, but with considerable toxicity at most effective doses. Epinephrine reduced the median effective concentration of tetrodotoxin for nociception from 37.6 to 11.5 microM and prolonged its duration, such that reversible blocks lasting > 13 h were achieved. Epinephrine reduced measures of systemic distribution and increased the median lethal dose of tetrodotoxin from 40 to 53.6 nmole/kg, thus more than quadrupling the therapeutic index. Bupivacaine increased the local anesthetic potency of tetrodotoxin, reduced its systemic toxicity, and, when coinjected subcutaneously, increased the median lethal dose from 43.7 to 47.7 nmole/kg. The addition of epinephrine did not further improve the effectiveness of the bupivacaine-tetrodotoxin combination. CONCLUSION: Combinations of epinephrine or bupivacaine with tetrodotoxin or with other high-potency toxins active on sodium channels should be examined for the potential to provide clinically useful, prolonged nerve blockade.

Anesthesia, Local↗
PubMed1998

Recent advances in pulmonary drug delivery using large, porous inhaled particles.

The ability to deliver proteins and peptides to the systemic circulation by inhalation has contributed to a rise in the number of inhalation therapies under investigation. For most of these therapies, aerosols are designed to comprise small spherical droplets or particles of mass density near 1 g/cm3 and mean geometric diameter between approximately 1 and 3 micron, suitable for particle penetration into the airways or lung periphery. Studies performed primarily with liquid aerosols have shown that these characteristics of inhaled aerosols lead to optimal therapeutic effect, both for local and systemic therapeutic delivery. Inefficient drug delivery can still arise, owing to excessive particle aggregation in an inhaler, deposition in the mouth and throat, and overly rapid particle removal from the lungs by mucocilliary or phagocytic clearance mechanisms. To address these problems, particle surface chemistry and surface roughness are traditionally manipulated. Recent data indicate that major improvements in aerosol particle performance may also be achieved by lowering particle mass density and increasing particle size, since large, porous particles display less tendency to agglomerate than (conventional) small and nonporous particles. Also, large, porous particles inhaled into the lungs can potentially release therapeutic substances for long periods of time by escaping phagocytic clearance from the lung periphery, thus enabling therapeutic action for periods ranging from hours to many days.

Administration, Inhalation↗
PubMed1998

Creating biomimetic micro-environments with synthetic polymer-peptide hybrid molecules.

In designing polymers that can act as tissue engineering templates it is beneficial to consider methods of mimicking the natural support structures used by the human body to guide the behavior and development of cells within tissues. The well-known RGD cell adhesion ligand provides a simple mechanism of creating polymer surfaces that mimic the extracellular matrix. This paper considers the methods that have been used to attach such motifs to synthetic polymers. In general there are two strategies: the formation of polymer-peptide hybrid molecules, or the immobilization of the ligand on the fabricated surface of the polymer. The three major synthetic strategies of creating polymer-peptide hybrids are reviewed.

Biocompatible Materials↗
PubMed1998

Deterioration of lyophilized pharmaceutical proteins.

The successful use of proteins in pharmaceutical and other commercial applications requires close examination of their relative fragility. Because of the resultant enhanced stability, proteins are often formulated in the solid state, even though dehydration tends to alter their structure. Even in the solid form, however, proteins may become inactivated due to various deleterious processes, e.g., aggregation. This review focuses on such mechanisms, with an emphasis on case studies conducted in our laboratory. Proteins which have both disulfide bonds and free thiols may aggregate via thiol-disulfide exchange, and this process may be facilitated by lyophilization-induced structural perturbations. For proteins possessing disulfides but not free thiols, aggregation also may occur when native disulfides are beta-eliminated, thus giving rise to thiol species which can catalyze disulfide scrambling. Other deleterious processes have also been uncovered, including a formaldehyde-mediated aggregation of formalinized vaccines. It is illustrated how knowledge of such deterioration pathways makes possible the rational development of stable solid protein formulations.

Drug Stability↗
PubMed1998

[CT-controlled percutaneous drainage of intra-abdominal abscesses with basket catheters].

Today, CT-guided percutaneous drainage for intraabdominal abscesses of various origin and location is well accepted. With this method open surgery and its complications can be often avoided. We report results of such treatment in 47 patients with intraabdominal abscess formation. 66 "basket" catheters were placed into abscess formations of differing sizes and locations. 27 patients had developed abscess formation after surgery, in 2 patients abscesses after tumorembolisation were drained. In 18 cases there was no previous surgery. No complications occurred. Mean drainage time was 8.5 days. Surgical intervention was avoided in 34/47 patients. 9 of 47 patients received only percutaneous drainage. 25 of 47 patients required concomitant antibiotics for successful treatment. Antibiotics were selected according to bacterial culture with resistance determination. 13/47 cases required secondary surgery. About 80% of intraabdominal abscesses are curable with CT guided percutaneous drainage and systemic antibiotic medication. If a percutaneous drainage fails and signs of infection still remain, the procedure can be repeated. If secondary surgery after failing of percutaneous drainage should become necessary, the extent of the surgical intervention can be reduced. Surgery is necessary, if CT guided percutaneous drainage could not reach the abscess formation, if drainage failed or if an additional illness exists, which requires an operation.

Abdominal Abscess↗
PubMed1998

Well-differentiated versus less-differentiated endometrial carcinoma.

The aim of this study was to compare well-differentiated (grade 1) and less-differentiated (grades 2 and 3) endometrial carcinoma, concerning clinical risk factors, presenting symptoms and operative findings. Seventy-one surgically staged endometrial carcinoma cases were reviewed and retrospectively divided according to tumor differentiation into two groups: grade 1 cases (Group I; n=40) and grade 2 and 3 cases (Group II; n=31). No difference was found between the two groups when comparing patient age, gravidity and parity, history of hypertension, diabetes or other malignancies, duration of menopause, number of patients receiving hormonal replacement therapy and histological type of tumor. There was also no difference in presenting symptoms or in duration of uterine bleeding up to the diagnosis of endometrial carcinoma. On the other hand, patients with well-differentiated tumors, as compared to patients with less-differentiated endometrial carcinoma, were significantly more obese (p<0.02), had a smaller uterus (p<0.01) and presented with less advanced stage disease (p<0.0005). The fact that the age of the patients, as well as the duration of uterine bleeding before diagnosis, was similar in both groups may indicate that more advanced cases, as in group II, represent originally a more aggressive tumor rather than progression from a well-differentiated disease. This hypothesis needs further research.

Aged↗
PubMed1998

Action of hydroxyethyl starch (HES) on the activity of plasmatic clotting factors.

Studies were carried out on the effects of different doses of hydroxyethyl starch 200/0.5 (HES) on plasma clotting factors in dogs, as an animal model for the human clotting system. In 8 German shepherd dogs 15% of the total blood was isovolemically substituted either by Ringer's solution with lactate alone (controls) or with 0.6, 1.3, 1.9, 2.5 g HES/kg b.w. Immediately after the infusion, the HES concentration in the recipients' plasma amounted to 8 mg/ml up to 38 mg/ml. In the following 6 h, the HES decreased to 25% in each case. It was found that the higher the plasma HES content was, the lower the haematocrit. Neither the thrombin-nor the batroxobin-time showed any significant change, irrespective of the plasma HES concentration. The prothrombin-time was decreased directly after the infusion in parallel to the haematocrit. The single clotting factors FI, FII, FV, FVII, FVIII, FX, and FXII behaved approximately in the same way: their activities directly after infusion, but also 6 h later, were lowered in proportion to the amount of HES infused. The loss of factor activity correlated with the volume-expanding effect of HES shortly after the infusion, but not 6 h later. It is concluded that there are two different modes of HES action on clotting factors: the dilution by plasma volume expansion and a non-dilutional action. Cautious handling might be required in patients with clotting disturbances as well as in long-term treatment.

Animals↗
PubMed1997

Tissue engineering of cartilage in space.

Tissue engineering of cartilage, i.e., the in vitro cultivation of cartilage cells on synthetic polymer scaffolds, was studied on the Mir Space Station and on Earth. Specifically, three-dimensional cell-polymer constructs consisting of bovine articular chondrocytes and polyglycolic acid scaffolds were grown in rotating bioreactors, first for 3 months on Earth and then for an additional 4 months on either Mir (10(-4)-10(-6) g) or Earth (1 g). This mission provided a unique opportunity to study the feasibility of long-term cell culture flight experiments and to assess the effects of spaceflight on the growth and function of a model musculoskeletal tissue. Both environments yielded cartilaginous constructs, each weighing between 0.3 and 0.4 g and consisting of viable, differentiated cells that synthesized proteoglycan and type II collagen. Compared with the Earth group, Mir-grown constructs were more spherical, smaller, and mechanically inferior. The same bioreactor system can be used for a variety of controlled microgravity studies of cartilage and other tissues. These results may have implications for human spaceflight, e.g., a Mars mission, and clinical medicine, e.g., improved understanding of the effects of pseudo-weightlessness in prolonged immobilization, hydrotherapy, and intrauterine development.

Animals↗
PubMed1997

Long-term engraftment of hepatocytes transplanted on biodegradable polymer sponges.

Hepatocyte transplantation may provide an alternative to orthotopic liver transplantation to treat liver failure. However, suitable systems to transplant hepatocytes and promote long-term engraftment must be developed. In this study, highly porous, biodegradable sponges were fabricated from poly (L-lactic acid) (PLA), and poly (DL-lacticco-glycolic acid) (PLGA), and utilized to transplant hepatocytes into the mesentery of three groups of Lewis rats. The portal vein was shunted to the inferior vena cava in one group of rats (PCS). The second group of animals received a PCS and a 70% hepatectomy on the day of sponge-hepatocyte implantation (PCS + HEP), and the control group (CON) received no surgical stimulation. The sponges were vascularized by ingrowth of fibrovascular tissue over the first 7 days in vivo. Approximately 95-99% of the implanted hepatocytes (determined utilizing computer-assisted image analysis) died in all three experimental groups during this time. The number of engrafted hepatocytes in the CON group further decreased over the next 7 days to 1.3 +/- 1.1% of the original cell number. However, the number of engrafted hepatocytes in the PCS and PCS + HEP increased over this time to 6 +/- 1% and 5 +/- 2%, respectively. The number of engrafted hepatocytes in the PCS group continued to increase over the next 2.5 months to a value of 26 +/- 12% of the initial cell number, and a large number of engrafted hepatocytes was still present at 6 months. These results indicate that stable new tissues can be engineered by transplanting hepatocytes on biodegradable sponges into heterotopic locations if appropriate stimulation is provided.

Animals↗
PubMed1997

Tissue-engineered heart valve leaflets: does cell origin affect outcome?

BACKGROUND: We previously reported the successful creation of tissue-engineered valve leaflet constructs and the implantation of these autologous tissue leaflets in the pulmonary valve position in a lamb model. The optimal cell origin for creating these valve leaflets remains unclear. This study was designed to compare dermal with arterial wall myofibroblasts as the cells of origin for the leaflet constructs. METHODS AND RESULTS: Mixed cell populations of endothelial cells and fibroblasts were isolated from ovine femoral arteries or subdermis and then expanded in vitro. A synthetic biodegradable polymer scaffold was then seeded with the cultured cells. The tissue scaffold was composed of a polyglactin woven mesh sandwiched between two nonwoven polyglycolic acid mesh sheets, which measured 3x3 cm in size and 3.2 mm in thickness. The cell-seeded polymer construct was implanted to replace one pulmonary valve leaflet in the same juvenile animal from which the cells had originally been obtained. Using cardiopulmonary bypass, the right posterior leaflet of the pulmonary valve was completely resected and replaced with an autologous engineered valve leaflet. In group D (n=5), the cells were obtained from subdermis, and in group A (n=4), they were obtained from the arterial wall. Eight to 10 weeks after leaflet implantation, the animals were killed, and the implanted valve leaflets were examined histologically, biochemically, and biomechanically. The dimensions of each tissue-engineered leaflet (TEL) were compared with those of the two remaining native valve leaflets to obtain a growth index. A 4-hydroxyproline assay was performed to evaluate collagen content. Leaflet tensile strength was evaluated in vitro by using a Vitrodyne V-1000 mechanical tester. Factor VIII and elastin stains were performed to histologically assess the presence of endothelial cells and elastin, respectively. In all animals, the TEL persisted in the pulmonary valve position after 8 to 10 weeks, and all polyglycolic acid polymer had been degraded. Group A leaflets had a higher growth index (0.86+/-0.11) than group D (0.41+/-0.08) (P<.05). Macroscopically, the group D leaflets appeared thicker and contracted. Histologically, elastic fibers were more abundant in group A than in group D. Total collagen content and biomechanical testing showed no differences between groups. Leaflets from both groups had positive staining for factor VIII on the surface, confirming growth of endothelial cells to cover the TEL. CONCLUSIONS: Autologous TEL derived from vascular fibroblasts seem to develop functionally and morphologically like the native valve leaflets in the pulmonary circulation. Use of arterial myofibroblasts for the creation of TEL seems preferable to dermal fibroblasts with current tissue culture conditions.

Animals↗
PubMed1997

New advances in microsphere-based single-dose vaccines.

Polymer microspheres have shown great potential as a next generation adjuvant to replace or complement existing aluminum salts for vaccine potentiation. Microsphere-based systems can now be made to deliver subunit protein and peptide antigens in their native form in a continuous or pulsatile fashion for periods of weeks to months with reliable and reproducible kinetics, often obviating the need for booster immunizations in animal models. Microspheres have also shown potential as carriers for oral vaccine delivery due to their protective effects on encapsulated antigens and their ability to be taken up by the Peyer's patches in the intestine. The potency of these optimal depot formulations for antigen may be enhanced by the co-delivery of vaccine adjuvants, including cytokines, that are either entrapped in the polymer matrix or, alternatively, incorporated into the backbone of the polymer itself and released concomitantly with antigen as the polymer degrades. In this article we review the use of polymer microspheres for single-step immunization and discuss future applications for the improvement of vaccines and immunotherapies by utilizing encapsulation technology.

Journal Article↗
PubMed1997

Stimulation of neurite outgrowth using an electrically conducting polymer.

Damage to peripheral nerves often cannot be repaired by the juxtaposition of the severed nerve ends. Surgeons have typically used autologous nerve grafts, which have several drawbacks including the need for multiple surgical procedures and loss of function at the donor site. As an alternative, the use of nerve guidance channels to bridge the gap between severed nerve ends is being explored. In this paper, the electrically conductive polymer--oxidized polypyrrole (PP)--has been evaluated for use as a substrate to enhance nerve cell interactions in culture as a first step toward potentially using such polymers to stimulate in vivo nerve regeneration. Image analysis demonstrates that PC-12 cells and primary chicken sciatic nerve explants attached and extended neurites equally well on both PP films and tissue culture polystyrene in the absence of electrical stimulation. In contrast, PC-12 cells interacted poorly with indium tin oxide (ITO), poly(L-lactic acid) (PLA), and poly(lactic acid-co-glycolic acid) surfaces. However, PC-12 cells cultured on PP films and subjected to an electrical stimulus through the film showed a significant increase in neurite lengths compared with ones that were not subjected to electrical stimulation through the film and tissue culture polystyrene controls. The median neurite length for PC-12 cells grown on PP and subjected to an electrical stimulus was 18.14 micron (n = 5643) compared with 9.5 micron (n = 4440) for controls. Furthermore, animal implantation studies reveal that PP invokes little adverse tissue response compared with poly(lactic acid-co-glycolic acid).

Animals↗
PubMed1997

Large porous particles for pulmonary drug delivery.

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.

Administration, Inhalation↗
PubMed1997

Characterization and development of RGD-peptide-modified poly(lactic acid-co-lysine) as an interactive, resorbable biomaterial.

The design of biomaterials containing specific ligands on the surface offers the possibility of creating materials that can interact with and potentially control mammalian cell behavior. Biodegradable materials further provide the significant advantage that the polymer will disappear in vivo, obviating long-term negative tissue responses as well as the need for retrieval. In earlier studies we synthesized and characterized arginine-glycine-aspartic acid (RGD) peptide-modified poly(lactic acid-co-lysine) (PLAL). In this study, both bulk properties and surface features have been characterized, with a focus on surface analysis as a means of interpreting observed changes in cell behavior. Bulk peptide attachments were performed using 1,1'-carbonyldiimidazole (CDI). Amino groups were measured using colorimetric assays and X-ray photoelectron spectroscopy (XPS). Peptides were measured by incorporating iodine into the peptide as a distinct elemental marker for use with XPS. Typical samples contained 13 +/- 4 pmol/cm2 of amino groups and 4 +/- 0.2 pmol/ cm2 of peptides, as calculated from XPS measurements of nitrogen and iodine. The wettability and crystallinity of the samples were determined by contact angles and differential scanning calorimetry, respectively. Wettability and crystallinity were not altered by the incorporation of lysine or peptides. After incubating bovine aortic endothelial (BAE) cells for 4 h on surfaces with RGD-containing peptides, the mean spread cell area increased from 77 +/- 2 microns2 to 405 +/- 29 microns2 compared to 116 +/- 11 microns2 on poly(lactic acid), 87 +/- 4 microns2 on PLAL, and 105 +/- 4 microns2 on surfaces with RDG-containing (control) peptides. The significance of this work is that the first synthetic interactive, resorbable biomaterial has been developed, and use of this material to control cell behavior has been demonstrated.

Animals↗
PubMed1997

A Film Tension Theory of Phagocytosis

A film tension criterion is derived on the basis of which it is possible to evaluate the probability of a particle or vesicle being phagocytosed by phagocytic cells. Variations of this criterion are arrived at by mechanical and thermodynamical analyses. Specific receptor-ligand binding interactions are included in the analysis, as are electrostatic, steric repulsive, and van der Waals attractive interactions between the surface of the phagocytosed particle and the pseudopods of the host cell membrane. Cytoskeletal forces proximate to the membrane are also implicitly included in the approach. The film tension criterion is shown to reduce to the classical wettability criterion in the limit of purely passive phagocytosis, wherein there are no electrostatic, steric repulsive, or receptor-ligand binding interactions between the cell and the phagocytosed particle. Several formulas characterizing various aspects of phagocytosis are derived. Opsonized particles are demonstrated to be more readily phagocytosed than nonopsonized particles, owing both to the energy of specific binding between opsonins and cell receptors and to the lowering of membrane tension that occurs in the vicinity of spreading pseudopods as a result of spontaneous actin polymerization. It is shown that certain particles or vesicles (those that are most easily phagocytosed) tend to be ingested more readily with increasing particle size, while others (those less easily phagocytosed) tend to be ingested more readily with decreasing size. In the limit of purely passive phagocytosis, formulas are developed for predicting the relative volumetric and particle-number uptake by cells as a function of organic/water partition coefficients. Partition coefficients of polystyrene particles and polymerized liposomes were measured and used to make theoretical predictions of particle uptake by macrophages. These predictions are compared with phagocytic uptake data for hydrophilic and hydrophobic nano- and microparticles. The comparisons show agreement between predicted trends of volumetric and particle-number uptake as a function of particle size, with uptake of hydrophilic nanoparticles diminishing with increasing size and uptake of hydrophobic nanoparticles increasing with increasing size (at least for submicrometer particles that are relatively insensitive to gravitational forces). Additional comparisons between published experimental data and theoretical predictions are also made. The potential use of the theory in characterizing the tendency of drug-loaded polymeric particles to be engulfed by macrophages is emphasized.

Journal Article↗
PubMed1997

The Adsorption of Poly(vinyl alcohol) to Biodegradable Microparticles Studied by X-Ray Photoelectron Spectroscopy (XPS)

The design of biodegradable microparticle drug delivery systems with precisely tailored surface properties requires surface analytical methods that can relate polymer chemistry and fabrication parameters to the final surface chemistry of the microparticles. We demonstrate using X-ray photoelectron spectroscopy (XPS) that it is possible to identify significant variations in the surface chemistry of microparticles composed of poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), or block copolymers of PLA or PLGA with poly(ethylene glycol) (PEG). These variations are related to the mechanism by which the microparticle/water interface is stabilized. This, in turn, is controlled by the interfacial surface tensions of the polymers within aqueous environments. For PEG containing block copolymers, adsorption of a surfactant, poly(vinyl alcohol) (PVA), from the aqueous medium onto the polymer is reduced compared with the PLA and PLGA polymers. This reduction is achieved because the PEG segments, within the copolymer structure, stabilize the polymer/water interface. Estimates of the relative amounts of lactide, lactide-co-glycolide, vinyl alcohol, and ethylene glycol monomer units at the microparticle surfaces are presented based on curve-fitting analysis of the XPS data.

Journal Article↗
PubMed1997

Peritoneal fluid lactate dehydrogenase in ovarian cancer.

In attempt to identify patients with ovarian carcinoma and differentiate them from patients with benign ovarian tumor or other gynecological malignancies, peritoneal fluid and serum lactate dehydrogenase (LDH) levels were measured in 51 patients: 15 with ovarian carcinoma, 15 with endometrial carcinoma, 4 with cervical carcinoma, and 17 with benign ovarian tumor. Peritoneal fluid and serum LDH levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumor (P < 0.001) or other gynecological malignancies (P < 0.001 and P < 0.03, respectively). Yet, peritoneal fluid LDH demonstrated higher diagnostic sensitivity (87%) and greater diagnostic accuracy (90%) than serum LDH (60 and 77%, respectively) or serum CA-125 (73 and 83%, respectively). Comparing the histological types of ovarian cancer, serous cystadenocarcinoma presented higher peritoneal fluid LDH levels than endometrioid or mucinous cystadenocarcinoma. No difference in peritoneal fluid LDH was observed comparing different stages of ovarian cancer. The results suggest that peritoneal fluid LDH may be an efficient biochemical marker in diagnosis of ovarian cancer.

Adolescent↗