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Biomedical subjects

R Langer

Publications and source records attributed to R Langer.

At least 73 records · Page 4Linked to original sources
PubMed2000

In vitro and in vivo degradation of porous poly(DL-lactic-co-glycolic acid) foams.

This study investigated the in vitro degradation of porous poly(DL-lactic-co-glycolic acid) (PLGA) foams during a 20-week period in pH 7.4 phosphate-buffered saline (PBS) at 37 degrees C and their in vivo degradation following implantation in rat mesentery for up to 8 weeks. Three types of PLGA 85 : 15 and three types of 50 : 50 foams were fabricated using a solvent-casting, particulate-leaching technique. The two types had initial salt weight fraction of 80 and 90%, and a salt particle size of 106-150 microm, while the third type had 90% initial weight fraction of salt in the size range 0-53 microm. The porosities of the resulting foams were 0.82, 0.89, and 0.85 for PLGA 85 : 15, and 0.73, 0.87, and 0.84 for PLGA 50 : 50 foams, respectively. The corresponding median pore diameters were 30, 50, and 17 microm for PLGA 85: 15, and 19, 17, and 17 microm for PLGA 50 : 50. The in vitro and in vivo degradation kinetics of PLGA 85: 15 foams were independent of pore morphology with insignificant variation in foam weight, thickness, pore distribution, compressive creep behavior, and morphology during degradation. The in vitro foam half-lives based on the weight average molecular weight were 11.1 +/- 1.8 (80%, 106-150 microm), 12.0 +/- 2.0 (90%, 106-150 microm), and 11.6 +/- 1.3 (90%, 0-53 microm) weeks, similar to the corresponding values of 9.4 +/- 2.2, 14.3 +/- 1.5, and 13.7 +/- 3.3 weeks for in vivo degradation. In contrast, all PLGA 50 : 50 foams exhibited significant change in foam weight, water absorption, and pore distribution after 6-8 weeks of incubation with PBS. The in vitro foam half-lives were 3.3 +/- 0.3 (80%, 106-150 microm), 3.0 +/- 0.3 (90%, 106-150 microm), and 3.2 +/- 0.1 (90%, 0-53 microm) weeks, and the corresponding in vivo half-lives were 1.9 micro 0.1, 2.2 +/- 0.2, and 2.4 +/- 0.2 weeks. The significantly shorter half-lives of PLGA 50: 50 compared to 85: 15 foams indicated their faster degradation both in vitro and in vivo. In addition, PLGA 50: 50 foams exhibited significantly faster degradation in vivo as compared to in vitro conditions due to an autocatalytic effect of the accumulated acidic degradation products in the medium surrounding the implants. These results suggest that the polymer composition and environmental conditions have significant effects on the degradation rate of porous PLGA foams.

Animals↗
PubMed2000

In vitro degradation of porous poly(L-lactic acid) foams.

This study investigated the in vitro degradation of porous poly(L-lactic acid) (PLLA) foams during a 46-week period in pH 7.4 phosphate-buffered saline at 37 degrees C. Four types of PLLA foams were fabricated using a solvent-casting, particulate-leaching technique. The three types had initial salt weight fraction of 70, 80, and 90%, and a salt particle size of 106-150 microm, while the fourth type had 90% initial weight fraction of salt in the size range 0-53 microm. The porosities of the resulting foams were 0.67, 0.79, 0.91, and 0.84, respectively. The corresponding median pore diameters were 33, 52, 91, and 34 microm. The macroscopic degradation of PLLA foams was independent of pore morphology with insignificant variation in foam weight, thickness, pore distribution, compressive creep behavior, and morphology during degradation. However, decrease in melting temperature and slight increase in crystallinity were observed at the end of degradation. The foam half-lives based on the weight average molecular weight were 11.6+/-0.7 (70%, 106-150 microm), 15.8+/-1.2 (80%, 106-150 microm), 21.5+/-1.5 (90%, 106-150 microm), and 43.0+/-2.7 (90%, 0-53 microm) weeks. The thicker pore walls of foams prepared with 70 or 80% salt weight fraction as compared to those with 90% salt weight fraction contributed to an autocatalytic effect resulting in faster foam degradation. Also, the increased pore surface/volume ratio of foams prepared with salt in the range 0-53 microm enhanced the release of degradation products thus diminishing the autocatalytic effect and resulting in slower foam degradation compared to those with salt in the range 106-150 microm. Formation and release of crystalline PLLA particulates occurred for foams fabricated with 90% salt weight fraction at early stages of degradation. These results suggest that the degradation rate of porous foams can be engineered by varying the pore wall thickness and pore surface/volume ratio.

Biocompatible Materials↗
PubMed2000

In vitro generation of osteochondral composites.

Osteochondral repair involves the regeneration of articular cartilage and underlying bone, and the development of a well-defined tissue-to-tissue interface. We investigated tissue engineering of three-dimensional cartilage/bone composites based on biodegradable polymer scaffolds, chondrogenic and osteogenic cells. Cartilage constructs were created by cultivating primary bovine calf articular chondrocytes on polyglycolic acid meshes; bone-like constructs were created by cultivating expanded bovine calf periosteal cells on foams made of a blend of poly-lactic-co-glycolic acid and polyethylene glycol. Pairs of constructs were sutured together after 1 or 4 weeks of isolated culture, and the resulting composites were cultured for an additional 4 weeks. All composites were structurally stable and consisted of well-defined cartilaginous and bone-like tissues. The fraction of glycosaminoglycan in the cartilaginous regions increased with time, both in isolated and composite cultures. In contrast, the mineralization in bone-like regions increased during isolated culture, but remained approximately constant during the subsequent composite culture. The integration at the cartilage/bone interface was generally better for composites consisting of immature (1-week) than mature (4-week) constructs. This study demonstrates that osteochondral tissue composites for potential use in osteochondral repair can be engineered in vitro by culturing mammalian chondrocytes and periosteal cells on appropriate polymer scaffolds.

Animals↗
PubMed2000

Biodegradable photo-crosslinked poly(ether-ester) networks for lubricious coatings.

Biodegradable poly(ether-ester) networks were synthesized by UV photopolymerization and their lubrication performances were evaluated. Polyethers such as poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and poly(tetramethylene glycol) (PTMG) were copolymerized with oligomers of D,L-lactic acid and terminated with acrylate groups to form photopolymerizable macromers. 1H NMR and IR spectra confirmed the chemical structures of copolymers and diacrylated macromers. Crosslinked polymer networks were formed upon UV-initiated free-radical polymerization. Gel contents, water contents, and contact angles were measured to characterize the crosslinked networks. In vitro degradation times of the crosslinked networks at 37 degrees C in 1 N NaOH varied from 20 min to 7 days depending on the crosslinking density (molecular weight of macromer) and the hydrophilic susceptibility (types of polyethers). The crosslinked polymers were coated on stainless-steel needles to investigate the lubrication properties by measuring penetration and drag forces through rubber stoppers. The maximum improvement in penetration force over control was 41% in the needle coated with PPG-based polymer networks (molecular weight of PPG = 4000). These materials can potentially be used as biodegradable lubricants for coating various medical products to replace the existing non-degradable silicone-based materials currently used.

Biodegradation, Environmental↗
PubMed2000

Biomaterials in drug delivery and tissue engineering: one laboratory's experience.

This Account reviews our laboratory's research in biomaterials. In one area, drug delivery, we discuss the development of materials that are capable of releasing macromolecules such as proteins and peptides, intelligent delivery systems based on magnetism or microchip technology, new degradable materials such as polyanhydrides, and noninvasive approaches for delivering molecules through the skin and lungs. A second area, tissue engineering, is also discussed. New polymer systems for creating cartilage, blood vessels, nerves, and other tissues are examined.

Animals↗
PubMed2000

Transdermal extraction of analytes using low-frequency ultrasound.

PURPOSE: Transdermal extraction of clinically relevant analytes offers a potentially non-invasive method of diagnostics. However, development of such a method is limited by the low skin permeability. In this paper, we report a potential method for non-invasive diagnostics based on ultrasonic skin permeabilization and subsequent extraction of interstitial fluid (ISF) across the skin. METHODS: In vivo experiments were performed using Sprague Dawley rats to assess ultrasound-induced skin permeabilization and subsequent extraction of various analytes. Serum and ISF concentrations of various analytes were measured. RESULTS: Application of low-frequency ultrasound rapidly increased skin permeability. Skin remained in a state of high permeability for at least three hours. During this period, application of vacuum extracted ISF across rat skin in vivo at a rate of 25.7 microl/cm2/hr. We measured concentrations of various analytes including glucose, albumin, calcium, urea, triglycerides, lactate, and dextran in transdermally extracted fluid. The composition of the fluid extracted transdermally is similar to that of ISF. CONCLUSIONS: Application of low-frequency ultrasound allows skin permeabilization and extraction of ISF across the skin.

Animals↗
PubMed2000

Visual evidence of acidic environment within degrading poly(lactic-co-glycolic acid) (PLGA) microspheres.

PURPOSE: In the past decade, biodegradable polymers have become the materials of choice for a variety of biomaterials applications. In particular, poly(lactic-co-glycolic acid) (PLGA) microspheres have been extensively studied for controlled-release drug delivery. However, degradation of the polymer generates acidic monomers, and acidification of the inner polymer environment is a central issue in the development of these devices for drug delivery. METHODS: To quantitatively determine the intrapolymer acidity, we entrapped pH-sensitive fluorescent dyes (conjugated to 10,000 Da dextrans) within the microspheres and imaged them with confocal fluorescence microscopy. The technique allows visualization of the spatial and temporal distribution of pH within the degrading microspheres (1). RESULTS: Our experiments show the formation of a very acidic environment within the particles with the minimum pH as low as 1.5. CONCLUSIONS: The images show a pH gradient, with the most acidic environment at the center of the spheres and higher pH near the edges, which is characteristic of diffusion-controlled release of the acidic degradation products.

Drug Delivery Systems↗
PubMed2000

Sciatic nerve blockade with lipid-protein-sugar particles containing bupivacaine.

PURPOSE: To assess the efficacy of lipid-protein-sugar particles (LPSPs) in providing prolonged duration local anesthesia by percutaneous injection. METHODS: Bupivacaine-containing LPSPs were characterized and optimized in vitro. Male Sprague-Dawley rats were given sciatic nerve blocks with bupivacaine-containing LPSPs. Sensory and motor nerve blockade were measured in the hindpaw, as were contralateral functional deficits (a measure of systemic drug distribution). Poly(lactic-co-glycolic) acid (PLGA) microspheres were used as a reference. RESULTS: 10% (w/w) bupivacaine LPSPs (60% dipalmitoylphosphatidylcholine) were 4.4+/-0.39 microm in diameter, with a tap density of 0.11 +/-0.04 g/ml. These LPSPs and 50% (w/w) PLGA microspheres had comparable durations of sensory blockade (468+/-210 min vs. 706+/-344 min, p = 0.08), although the LPSPs produced a much lesser duration of motor blockade (508+/-258 min vs. 1062+/-456 min, p = 0.005). Systemic toxicity was minimal in both groups. CONCLUSIONS: LPSPs provide sensory blockade durations comparable to those from PLGA microspheres, with a smaller amount of drug loading. Motor blockade is shorter with LPSPs than with PLGA microspheres. LPSPs appear to be suitable for extended nerve blockade. Given their size and low density, they may be useful for topical anesthesia of the airway.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Analysis of ultrasonically extracted interstitial fluid as a predictor of blood glucose levels.

Transdermal extraction of clinically relevant analytes offers a potentially noninvasive method of diagnostics. However, development of such a method is limited by the low permeability of skin. In this paper, we present a potential method for noninvasive diagnostics based on ultrasonic skin permeabilization and subsequent extraction of interstitial fluid (ISF) across the skin using vacuum. ISF extracted by this method was collected and analyzed for glucose and other analytes. Glucose concentration in the extracted fluid correlates well with blood glucose concentration over a range of 50-250 mg/dl. A mathematical model describing vacuum-induced transport of ISF through ultrasonically permeabilized skin is presented as well. The model accounts for convective, as well as diffusive, transport processes across blood capillaries, epidermis, and the stratum corneum. The overall predictions of the model compare favorably with the experimental observations.

Animals↗
PubMed2000

Hypertension and its treatment in postmenopausal women: baseline data from the Women's Health Initiative.

Little is known about the patterns of treatment and adequacy of blood pressure control in older women. The Women's Health Initiative, a 40-center national study of risk factors and prevention of heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women, provides a unique opportunity to examine these issues in the largest, multiethnic, best-characterized such cohort. Baseline data from the initial 98 705 women, aged 50 to 79 years, enrolled were analyzed to relate prevalence, treatment, and control of hypertension to demographic, clinical, and risk-factor covariates, and logistic regression analyses were performed to estimate odds ratios after adjusting for multiple potential confounders. Overall, 37.8% of the women had hypertension, which is defined as systolic blood pressure >/=140 mm Hg and/or diastolic blood pressure >/=90 mm Hg or being on medication for high blood pressure; 64.3% were treated with drugs, and blood pressure was controlled in only 36.1% of the hypertensive women, with lower rates of control in the oldest group. After adjustment for multiple covariates, current hormone users had higher prevalence than did nonusers (odds ratio 1.25). Hypertensive women had more comorbid conditions than did nonhypertensive women, and women with comorbidities were more likely to be treated pharmacologically. Diuretics were used by 44.3% of hypertensives either as monotherapy or in combination with other drug classes. As monotherapy, calcium channel blockers were used in 16%, angiotensin-converting enzyme inhibitors in 14%, beta-blockers in 9%, and diuretics in 14% of the hypertensive women. Diuretics as monotherapy were associated with better blood pressure control than any of the other drug classes as monotherapy. In conclusion, hypertension in older women is not being treated aggressively enough because a large proportion, especially those most at risk for stroke and heart disease by virtue of age, does not have sufficient blood pressure control.

Age Factors↗
PubMed2000

Printing patterns of biospecifically-adsorbed protein.

The advancement of elastomeric patterning techniques in recent years has significantly enhanced our ability to spatially control biomaterial surface chemistry at the micrometre level. The application of this technology to the patterning of biomolecules onto solid surfaces has created many potential applications including the development of advanced biosensors, combinatorial library screening and the formation of tissue engineering templates. In this paper, we describe the direct patterning of protein by microcontact printing. An important consideration for the fabrication of protein micropatterns intended for these applications is the nature of the protein immobilization to a substrate. To date, the patterning of proteins by direct microcontact printing (microCP) has relied on the non-covalent adsorption to a substrate. Ideally, the proteins need to be firmly anchored onto a surface without adversely effecting their activity. Here, the high affinity avidin-biotin receptor-ligand interaction has been exploited to form arrays of avidin molecules onto a polymeric substrate expressing biotin moieties. This has created a generic technique by which any biotinylated species can be subsequently immobilized into defined patterns. Utilizing atomic force microscopy (AFM), the patterned surfaces have been characterized to molecular resolution. The micropatterned sample supported cell adhesion when biotin-(G)11-GRGDS was bound to the avidin bearing arrays.

3T3 Cells↗
PubMed2000

Modulation of the mechanical properties of tissue engineered cartilage.

Cartilaginous constructs have been grown in vitro using chondrocytes, biodegradable polymer scaffolds, and tissue culture bioreactors. In the present work, we studied how the composition and mechanical properties of engineered cartilage can be modulated by the conditions and duration of in vitro cultivation, using three different environments: static flasks, mixed flasks, and rotating vessels. After 4-6 weeks, static culture yielded small and fragile constructs, while turbulent flow in mixed flasks induced the formation of an outer fibrous capsule; both environments resulted in constructs with poor mechanical properties. The constructs that were cultured freely suspended in a dynamic laminar flow field in rotating vessels had the highest fractions of glycosaminoglycans and collagen (respectively 75% and 39% of levels measured in native cartilage), and the best mechanical properties (equilibrium modulus, hydraulic permeability, dynamic stiffness, and streaming potential were all about 20% of values measured in native cartilage). Chondrocytes in cartilaginous constructs remained metabolically active and phenotypically stable over prolonged cultivation in rotating bioreactors. The wet weight fraction of glycosaminoglycans and equilibrium modulus of 7 month constructs reached or exceeded the corresponding values measured from freshly explanted native cartilage. Taken together, these findings suggest that functional equivalents of native cartilage can be engineered by optimizing the hydrodynamic conditions in tissue culture bioreactors and the duration of tissue cultivation.

Animals↗
PubMed1999

Mammalian chondrocytes expanded in the presence of fibroblast growth factor 2 maintain the ability to differentiate and regenerate three-dimensional cartilaginous tissue.

The differentiated phenotype of chondrocytes from hyaline cartilage is gradually lost during expansion in monolayers. Chondrocytes can reexpress their differentiated phenotype by transfer into an environment that prevents cell flattening, but serially passaged cells never completely recover their chondrogenic potential. We report that chondrocytes expanded (up to 2000-fold) in the presence of fibroblast growth factor 2 (FGF-2) dedifferentiated, but fully maintained their potential for redifferentiation in response to environmental changes. After seeding onto three-dimensional polymer scaffolds, chondrocytes expanded in the presence of FGF-2 formed cartilaginous tissue that was histologically and biochemically comparable to that obtained using primary chondrocytes, in contrast to chondrocytes expanded to the same degree but in the absence of FGF-2. The presence of FGF-2 inhibited the formation of thick F-actin structures, which otherwise formed during monolayer expansion, were maintained during tissue cultivation, and were associated with reduced ability of chondrocytes to reexpress their differentiated phenotype. This study provides evidence that FGF-2 maintains the chondrogenic potential during chondrocyte expansion in monolayers, possibly due to changes in the architecture of F-actin elements and allows more efficient utilization of harvested tissue for cartilage tissue engineering.

Actins↗
PubMed1999

Improved immunogenicity of a core-coated tetanus toxoid delivery system.

A new microparticulate delivery system composed of a stabilizing gelatin/poloxamer microcore surrounded by a PLGA coat was designed to improve the stability of tetanus toxoid (TT) encapsulated in PLGA microspheres. Microcores were prepared by a spray-congealing technique and encapsulated within PLGA using an oil-in-oil (o/o) solvent evaporation technique. SEM analysis of the cross-sections of the microcapsules revealed the adequate encapsulation of the cores, showing an intimate contact between the core and the coating. This structure was responsible for an osmotic phenomenon observed in vitro, which led to the release of the encapsulated TT in a short period of time. Nevertheless, it was observed that the release was affected by the presence of the poloxamer in the core: microspheres without poloxamer in the core exhibit a faster release (2 h) than those that incorporate the surfactant (24 h). The in vivo evaluation of this system showed that the encapsulated toxoid induced a low but continuous levels of neutralizing antibodies (Nt), whereas those obtained for the control (aluminum phosphate-adsorbed toxoid) decreased after reaching the maximum level at 14 weeks. Moreover, the administration of a mixture of encapsulated and adsorbed TT led to significant higher and more prolonged Nt levels than those measured for the adsorbed toxoid.

Animals↗