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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
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↗
PubMed2001

Long-Term (10-15 years) follow-up after Burch colposuspension for urinary stress incontinence.

The study group comprised 127 patients who underwent a Burch colposuspension for urinary incontinence. All had undergone urodynamic investigation both pre- and postoperatively. All patients had a mean follow-up of 12.4 years (range 10-15); 109 patients had an additional urodynamic investigation at least 10 years after the operation. Following surgery there was an improvement in symptoms of frequency (P<0.001), urgency (P<0.01) and urge incontinence (P<0.001). The cure rate was 93.7%. The only significant changes found on urodynamics were the measurements of the pressure transmission ratio, which were higher postoperatively (P<0.001) and remained so after 10 years. The most frequent postoperative complications were de novo detrusor instability (16.6%) and anatomical defects (18.7%). All failed cases were found during the first postoperative year. De novo detrusor instability appeared in 12/17 patients during the first year of follow-up. Postoperative anatomical defects were found only in 4/24 patients after 5 years. Ten years postoperatively most of the anatomical defects had been detected (20/24), stressing the need for long-term follow-up.

Adult↗
PubMed2001

Drug delivery to tumors of the central nervous system.

Contemporary treatment of malignant brain tumors has been hampered by problems with drug delivery to the tumor bed. Inherent boundaries of the central nervous system, such as the blood-brain barrier or the blood-cerebrospinal fluid barrier, and a general lack of response to many chemotherapeutic agents have led to alternative treatment modalities. In general, all these modalities have sought to either disrupt or bypass the physiologic brain barriers and deliver the drug directly to the tumor. This article reviews past, as well as current, methods of drug delivery to tumors of the central nervous system. Special emphasis is placed on biodegradable polymers that can release chemotherapeutic agents against malignant gliomas. A variety of other nonchemotherapeutic drugs, including antiangiogenesis and immunotherapeutic agents, are presented in the context of new polymer technology. Finally, future directions in drug delivery are discussed with an overview on new advances in emerging biotechnology.

Antineoplastic Agents↗
PubMed2001

Balloon cervical ripening with extra-amniotic infusion of saline or prostaglandin E2: a double-blind, randomized controlled study.

OBJECTIVE: To compare extra-amniotic infusion of diluted prostaglandin (PG) E2 solution with saline infusion in balloon cervical ripening and labor induction. METHODS: Women with pregnancy complications and Bishop scores of 3 or lower (n = 116) were assigned randomly to receive extra-amniotic infusion (1 mL/minute) of normal saline or PGE2 in saline (0.5 microg/mL) through a Foley catheter with a 30-mL inflated balloon. We induced labor using intravenous oxytocin only when labor had not developed by 6 hours after balloon expulsion. Analysis was by intent-to-treat. We assessed ripening efficiency and course of labor in women who had spontaneous balloon expulsion (n = 110) and trial of labor (n = 107), respectively. RESULTS: Ripening with PGE2 was associated with significantly shorter mean (+/- standard error of the mean [SEM]) time for balloon expulsion (4.7 +/- 0.4 versus 6.5 +/- 0.6 hours) and with significantly higher Bishop scores (P <.002), compared with ripening with saline. In the PGE2 group, rates of labor induction (15%) and oxytocin use (37%) were significantly lower than in the saline group (51% and 72%, respectively). The groups did not differ significantly in other labor abnormalities, labor duration, mode of delivery, birth weight, Apgar scores, and puerperal morbidity. CONCLUSION: Cervical ripening by extra-amniotic balloon and PGE2 infusion is faster and more effective than by balloon and saline infusion, resulting in a higher rate of spontaneous labor and a lower rate of oxytocin use.

Adult↗
PubMed2001

Controlled-release of IGF-I and TGF-beta1 in a photopolymerizing hydrogel for cartilage tissue engineering.

Photopolymerizing hydrogel systems provide a method to encapsulate cells and implant materials in a minimally invasive manner. Controlled release of growth factors in the hydrogels may enhance the ability to engineer tissues. IGF-I and TGF-beta1 were loaded in PLGA microspheres using a double emulsion technique. 125 ng and 200 pg of active IGF-I and TGF-beta, respectively, as measured by ELISA, were released over 15 days. The growth factor containing microspheres were photoencapsulated with bovine articular chondrocytes in PEO-based hydrogels and incubated in vitro for two weeks. Statistically significant changes in glycosaminoglycan (GAG) production compared to control gels either without microspheres or with blank spheres were observed after a 14 day incubation with IGF-I and IGF-I/TGF-beta microspheres combined, with a maximum density of 8.41+/-2.5% wet weight GAG. Total collagen density was low and decreased with the IGF-I/TGF-beta microspheres after two weeks incubation, but otherwise remained unchanged in all other experimental groups. Cell content increased 10-fold to 0.18+/-0.056 x 10(6) cells/mg wet weight and extracellular matrix (ECM) staining by H&E increased in hydrogels with IGF-I/TGF-beta microspheres. In conclusion, photoencapsulation of microspheres in PEO-based hydrogels provides a method to deliver molecules such as growth factors in porous hydrogel systems.

Animals↗
PubMed2001

In vitro visualization and quantification of oleic acid induced changes in transdermal transport using two-photon fluorescence microscopy.

In a novel application of two-photon scanning fluorescence microscopy, three-dimensional spatial distributions of the hydrophilic and hydrophobic fluorescent probes, sulforhodamine B and rhodamine B hexyl ester, in excised full-thickness human cadaver skin were visualized and quantified. Both sulforhodamine B and rhodamine B hexyl ester were observed to lie primarily in the lipid multilamellae region surrounding the corneocytes within the stratum corneum. From the two-photon scanning fluorescence microscopy scans, the changes in the concentration gradient and the vehicle to skin partition coefficient of each probe induced by the oleic acid enhancer action were calculated relative to the control sample (not exposed to oleic acid), and subsequently applied to theoretically derived mathematical expressions of transdermal transport to quantitatively characterize the oleic acid-induced relative changes in the skin diffusion coefficient and the skin barrier diffusion length of the permeant. For the hydrophobic probe rhodamine B hexyl ester, the permeability enhancement was primarily driven by an increase in the vehicle to skin partition coefficient, leading to an increase in the steepness of the concentration gradient across the skin. The primary oleic acid-induced changes in the transport properties of the hydrophilic probe sulforhodamine B included increases in the vehicle to skin partition coefficient and the skin diffusion coefficient. These findings utilizing the two-photon scanning fluorescence microscopy methodology and data analysis described here demonstrate that, in addition to providing three-dimensional images that clearly delineate probe distributions in the direction of increasing skin depth, the subsequent quantification of these images provides additional important insight into the mechanistic changes in transdermal transport underlying the visualized changes in probe distributions across the skin.

Biological Transport↗
PubMed2001

A novel immunoadsorption device for removing beta2-microglobulin from whole blood.

BACKGROUND: High plasma levels of beta2-microglobulin (beta2m) have been implicated in the formation of the severely destructive and potentially fatal amyloid deposits that are characteristic of dialysis-related amyloidosis (DRA). Conventional renal replacement technologies remove insufficient quantities of beta2m to normalize plasma levels. This limitation arises because of nonspecific adsorptive qualities and reliance on size exclusion, which can also remove other middle molecular weight proteins. These nonspecific approaches also make it difficult to evaluate the role and contribution of middle molecular weight molecules to the pathology of DRA and other morbidities of end-stage renal disease. A high-affinity and biologically specific approach could target a protein, prevent a significant loss of other important molecules, and improve the apparent adsorption rate within an extracorporeal device. METHODS: Agarose-immobilized murine anti-human beta2m monoclonal antibodies were used in a Vortex Flow Plasmapheretic Reactor (VFPR) to remove donor baseline and controlled amounts of recombinant beta2m from human blood in vitro. The extracorporeal circuit was hemoperfused at 200 mL/min for two hours. RESULTS: The immunoadsorptive media had a binding site density of 30 microg beta2m per mL of settled gel. The VFPR cleared baseline quantities of donor beta2m below detectable limits of the assay. The experiments with higher initial beta2m concentrations reached an equilibrium concentration within 20 minutes, corresponding to a 92% clearance. No deleterious hemocompatibility issues were observed (complete blood count, total protein, and plasma free hemoglobin). CONCLUSIONS: The adsorptive kinetics of the VFPR are optimal for the conditions used and support the use of immunoadsorption for the removal of beta2m.

Blood Component Removal↗
PubMed2001

Intracellular calcium in the isolated rat liver: correlation to glucose release, K(+) balance and bile flow.

This study correlates whole organ measurements of intracellular calcium concentration ([Ca(2+)](i)) with hormone-induced (epinephrine, vasopressin) changes of liver functions (glucose release, K(+) balance and bile flow). [Ca(2+)](i) was measured in the isolated perfused rat liver using the sensor Fura-2 and applying liver surface fluorescence spectroscopy. The technique was improved by (i) minimizing biliary elimination of the sensor by employing a rat strain deficient in canalicular organic anion transport (TR(-) mutation) and (ii) by correcting for changes of interfering intrinsic organ fluorescence that was shown to depend on the oxidation-reduction state (NAD(P)H content) of the organ. Epinephrine (50 nM) elicits an instantaneous peak rise of [Ca(2+)](i) to approx. 400 nM, followed by a sustained elevation that depends on the presence of extracellular Ca(2+). The rise of [Ca(2+)](i) coincides with initiation of glucose release, transient K(+) uptake, and transient stimulation of bile flow. Vasopressin (2 nM) exerts qualitatively similar effects. The transient rise of bile flow is attributed to Ca(2+)-mediated contraction of the pericanalicular actin-myosin web of hepatocytes.

Animals↗
PubMed2001

Morphologic and mechanical characteristics of engineered bovine arteries.

OBJECTIVE: The ideal small-caliber arterial graft remains elusive despite several decades of intense research. A novel approach to the development of small-caliber arterial prostheses with a biomimetic system for in vitro vessel culture has recently been described. In this study we examined the effects of culture time and tissue culture scaffolding on engineered vessel morphology and function and found that these parameters greatly influence the function of engineered vessels. METHODS: This report describes the effects of culture time and scaffold type on vessel morphology, cellular differentiation, and vessel mechanical characteristics. Engineered vessels were cultured from bovine aortic smooth muscle cells (SMCs) and endothelial cells that were seeded onto biodegradable polymer scaffolds and cultured under physiologically pulsatile conditions. Engineered vessels were subjected to histologic, ultrastructural, immunocytochemical, and mechanical analyses. RESULTS: Vessel morphology and mechanical characteristics improved as time in culture increased to 8 weeks. SMCs in the engineered vessel wall were organized into a highly lamellar structure, with cells separated by alternating layers of collagen fibrils. Polymer scaffold remnants were present in vessels cultured for 8 weeks, and SMCs that were in proximity to polymer remnants exhibited a dedifferentiated phenotype. CONCLUSIONS: These findings aid in the systematic understanding of the effects of in vitro parameters on engineered vessels and will be useful for the translation of vessel culture techniques to human cells for the development of autologous human vascular grafts.

Animals↗
PubMed2001

Visual function and quality of life among patients with giant cell (temporal) arteritis.

OBJECTIVE: To investigate patient perception of visual and systemic disability associated with giant cell arteritis (GCA) and whether the perceived disability can be correlated with visual performance measures. METHODS: We prospectively evaluated and compared the visual performance and quality of life survey for 20 patients with GCA after 4 to 5 weeks of corticosteroid therapy and after one year of therapy. We measured visual acuity, contrast sensitivity, and threshold perimetry and patients completed the Activities of Daily Vision Scale (ADVS) and the short-form of the Health Survey (SF-36). The results were grouped by GCA affected or unaffected eye or by better or worse eye and reported as a decimal and percent impairment for acuity, log units for contrast, mean deviation and the Advanced Glaucoma Intervention Study (AGIS) score for perimetry. The results for patients with and without visual loss were compared. Correlation analyses between ADVS categories and visual performance measures, SF-36 categories and the presence of visual loss, total corticosteroid dose, systemic symptoms, secondary hypertension or diabetes mellitus, the presence of vertebral fracture, and visual performance were performed. RESULTS: Day driving was the only ADVS category significantly reduced at baseline in patients with visual loss (62.5) compared with those without visual loss (96.3, P = 0.04). Modest to moderate correlations between ADVS categories were most frequent for percent binocular acuity impairment with day driving (r = -0.62, P = 0.017), with distance vision (r = -0.5, P = 0.02), and with glare (r = -0.59, P = 0.006); and the AGIS score of the worse eye with day driving (r = -0.66, P = 0.01), with near vision (r = -0.49, P = 0.03), and with glare (r = -0.48, P = 0.04). The baseline SF-36 scores did not correlate with the presence of vision loss at baseline or systemic complications. The ADVS and SF-36 scores were similar at one year. The total dose of corticosteroids only had a modest correlation with the one-year mental health score (r = -0.45, P = 0.05), but there was no correlation between SF-36 scores and other systemic side effects of steroid therapy. CONCLUSION: Except for the day driving score, the ADVS did not differ between patients with and without visual loss. The SF-36 did not distinguish between patients with and without visual loss and did not reveal significant trends. The ADVS and SF-36 did not reveal significant disability in GCA patients and there were no strong correlations with any visual performance or systemic measures.

Activities of Daily Living↗
PubMed2001

Tissue engineering of functional cardiac muscle: molecular, structural, and electrophysiological studies.

The primary aim of this study was to relate molecular and structural properties of in vitro reconstructed cardiac muscle with its electrophysiological function using an in vitro model system based on neonatal rat cardiac myocytes, three-dimensional polymeric scaffolds, and bioreactors. After 1 wk of cultivation, we found that engineered cardiac muscle contained a 120- to 160-microm-thick peripheral region with cardiac myocytes that were electrically connected through gap junctions and sustained macroscopically continuous impulse propagation over a distance of 5 mm. Molecular, structural, and electrophysiological properties were found to be interrelated and depended on specific model system parameters such as the tissue culture substrate, bioreactor, and culture medium. Native tissue and the best experimental group (engineered cardiac muscle cultivated using laminin-coated scaffolds, rotating bioreactors, and low-serum medium) were comparable with respect to the conduction velocity of propagated electrical impulses and spatial distribution of connexin43. Furthermore, the structural and electrophysiological properties of the engineered cardiac muscle, such as cellularity, conduction velocity, maximum signal amplitude, capture rate, and excitation threshold, were significantly improved compared with our previous studies.

Animals↗
PubMed2000

Microchips as Controlled Drug-Delivery Devices.

Controlled-release systems are common in a number of product areas, including foods, cosmetics, pesticides, and paper. Microencapsulated systems, for example, are used for the release of flavors and vitamins in foods, fragrances in perfumes, and inks in carbonless copy paper. Controlled-release systems for drug delivery first appeared in the 1960s and 1970s. In the past three decades, the number and variety of controlled release systems for drug-delivery applications has increased dramatically. Many of these use polymers having particular physical or chemical characteristics such as biodegradability, biocompatibility, or responsiveness to pH or temperature changes. However, recent advances in the field of microfabrication have created the possibility of a new class of controlled-release systems for drug delivery, namely, that of small, programmable devices. Their small size, potential for integration with microelectronics, and ability to store and release chemicals on demand could make controlled-release microchips useful in a number of areas, including medical diagnostics, analytical chemistry, chemical detection, industrial process monitoring and control, combinatorial chemistry, microbiology, and fragrance delivery. More importantly, drug-delivery microchips resulting from this convergence of controlled release and microfabrication technologies may provide new treatment options to clinicians in their fight against disease.

Journal Article↗
PubMed2000

Macroporous polymer foams by hydrocarbon templating.

Porous polymeric media (polymer foams) are utilized in a wide range of applications, such as thermal and mechanical insulators, solid supports for catalysis, and medical devices. A process for the production of polymer foams has been developed. This process, which is applicable to a wide range of polymers, uses a hydrocarbon particulate phase as a template for the precipitation of the polymer phase and subsequent pore formation. The use of a hydrocarbon template allows for enhanced control over pore structure, porosity, and other structural and bulk characteristics of the polymer foam. Polymer foams with densities as low as 120 mg/cc, porosity as high as 87%, and high surface areas (20 m(2)/g) have been produced. Foams of poly(l-lactic acid), a biodegradable polymer, produced by this process have been used to engineer a variety of different structures, including tissues with complex geometries such as in the likeness of a human nose.

Biocompatible Materials↗
PubMed2000

Design of imidazole-containing endosomolytic biopolymers for gene delivery.

The development of safe and effective gene delivery agents poses a great challenge in the quest to make human gene therapy a reality. Cationic polymers represent one important class of materials for gene delivery, but to date they have shown only moderate efficiency. Improving the efficiency will require the design of new polymers incorporating optimized gene delivery properties. For example, inefficient release of the DNA/polymer complex from endocytic vesicles into the cytoplasm is one of the primary causes of poor gene delivery. Here we report the synthesis of a biocompatible, imidazole-containing polymer designed to overcome this obstacle. DNA/polymer polyplexes incorporating this polymer were shown to have desirable physico-chemical properties for gene delivery and are essentially nontoxic. Using this system, mammalian cells in vitro were transfected in the absence of any exogenous endosomolytic agent such as chloroquine.

Animals↗
PubMed2000

Determination of threshold energy dose for ultrasound-induced transdermal drug transport.

Low-frequency (20 kHz) ultrasound has been shown to enhance transdermal transport of drugs, a phenomenon referred to as sonophoresis. In this paper, we report the threshold energy dose for ultrasound-induced transdermal drug transport. The threshold was determined by in vitro measurements of the dependence of sonophoretic enhancement on ultrasound parameters, including intensity, duty cycle, and exposure time. While the enhancement varies linearly with ultrasound intensity and exposure times, it is independent of the duty cycle in the range of parameters studied. The enhancement is also directly proportional to the ultrasound energy density once the threshold value is crossed. For full thickness pig skin, the threshold value is about 222 J/cm(2). The overall dependence of transport enhancement on ultrasound parameters is similar to that of cavitation measured in a model system, pitting of aluminum foil. Specifically, the extent of pitting is proportional to ultrasound intensity and exposure time and is independent of duty cycle. Furthermore, the extent of pitting is also proportional to the ultrasound energy density. The similarity between the parametric dependence of transport enhancement and cavitation is consistent with previous findings that cavitation plays the dominant role in sonophoresis.

Administration, Cutaneous↗
PubMed2000

Photoencapsulation of chondrocytes in poly(ethylene oxide)-based semi-interpenetrating networks.

A photopolymerizing hydrogel system provides an efficient method to encapsulate cells. The present work describes the in vitro analysis of bovine and ovine chondrocytes encapsulated in a poly(ethylene oxide)-dimethacrylate and poly(ethylene glycol) semi-interpenetrating network using a photopolymerization process. One day after encapsulation, (3-[4,5-dimethylthiazol-2-y1]-2, 5-diphenyl-2H-tetrazolium bromide) (MTT) and light microscopy showed chondrocyte survival and a dispersed cell population composed of ovoid and elongated cells. Biochemical analysis demonstrated proteoglycan and collagen contents that increased over 2 weeks of static incubation. Cell content of the gels initially decreased and stabilized. Biomechanical analysis demonstrated the presence of a functional extracellular matrix with equilibrium moduli, dynamic stiffness, and streaming potentials that increased with time. These findings suggest the feasibility of photoencapsulation for tissue engineering and drug delivery purposes.

Animals↗
PubMed2000

Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport.

Application of low-frequency ultrasound has been shown to enhance transdermal transport of drugs (low-frequency sonophoresis). In this paper, we show that the efficacy of low-frequency ultrasound in enhancing transdermal transport can be further increased by its combination with sodium lauryl sulfate (SLS), a well-known surfactant. The dependence of the ultrasound-SLS-mediated transport on ultrasound parameters, including intensity, net exposure time, and duty cycle, is discussed. The transdermal transport enhancement is proportional to ultrasound intensity as well as to exposure time, and is independent of duty cycle as long as the net exposure time is the same. The synergistic effect of SLS and ultrasound on transdermal transport increases linearly with SLS concentration. The enhancement is also proportional to the ultrasound energy density beyond a threshold value, which suggests that a certain minimum amount of energy density is required before noticeable changes in skin permeability occur. A similar dependence of the transdermal transport enhancement on energy density is observed in the case of the enhancement induced by ultrasound alone. Although the threshold energy density value in the presence of SLS is about 10 times lower than that in the case of ultrasound alone, the relationship between enhancement and energy density in the presence and in the absence of SLS is otherwise similar. Possible mechanisms for the synergistic effect of ultrasound and SLS are also discussed.

Aluminum↗