Biomedical subjects

Robert Langer

Publications and source records attributed to Robert Langer.

At least 181 records · Page 10Linked to original sources

PubMed2002

Prediction of steady-state skin permeabilities of polar and nonpolar permeants across excised pig skin based on measurements of transient diffusion: characterization of hydration effects on the skin porous pathway.

The applicability of a two-parameter Fickian diffusion model for predicting the skin steady-state permeability based on measurements of the transient transport of permeants across the skin was tested. Using five model permeants possessing different physicochemical properties and pig skin as the model membrane, the skin permeabilities predicted by the two-parameter Fickian diffusion model were compared with the measured skin permeabilities. Results show that the transient skin permeation profiles of the hydrophobic permeants, estradiol, testosterone, and dolichol, across split-thickness pig skin can be modeled adequately by the two-parameter Fickian diffusion model (with constant parameter values), and therefore, that this model can be utilized to shorten the experimental time required to determine the skin permeabilities of these compounds. However, the skin permeabilities of the highly hydrophilic permeants, mannitol and sucrose, predicted by the two-parameter Fickian diffusion model (with constant parameter values) were significantly lower than the experimentally determined values, indicating that the dominant skin pathway of polar permeants within the excised pig skin undergoes significant structural changes during the in vitro diffusion cell studies. Although the skin permeability values determined experimentally using the traditional steady-state method normally correspond to a highly hydrated skin sample, the two-parameter Fickian diffusion model enables an estimation of the skin permeability of the skin membrane at its less-hydrated state (a condition more representative of in vivo and clinical situations). Using the two-parameter Fickian diffusion model and a recently developed skin porous-pathway theory, the effects of skin hydration on the skin porous pathway within the excised pig skin were characterized. Specifically, we found that hydration leads to induction of new pores/reduction of the tortuosity of existing pores within the excised pig skin during the 48 h diffusion cell studies conducted, while the skin average pore radii remain relatively constant (approximately 26 A) for up to 48 h.

Algorithms↗

PubMed2002

An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport.

PURPOSE: Low-frequency ultrasound (20 kHz) has been shown to increase the skin permeability to drugs, a phenomenon referred to as low-frequency sonophoresis (LFS). Many previous studies of sonophoresis have proposed that ultrasound-induced cavitation plays the central role in enhancing transdermal drug transport. In this study, we sought to definitively test the role of cavitation during LFS, as well as to identify the critical type(s) and site(s) of cavitation that are responsible for skin permeabilization during LFS. METHODS: Pig full-thickness skin was treated by 20 kHz ultrasound and the effect of LFS on the skin permeability was monitored by measuring the increase in the skin electrical conductance. A high pressure LFS cell was constructed to completely suppress cavitation during LFS. An acoustic method, as well as chemical and physical dosimetry techniques, was utilized to monitor the cavitation activities during LFS. RESULTS: The study using the high-pressure LFS cell showed definitively that ultrasound-induced cavitation is the key mechanism via which LFS permeabilizes the skin. By selectively suppressing cavitation outside the skin using a high-viscosity coupling medium, we further demonstrated that cavitation occurring outside the skin is responsible for the skin permeabilization effect, while internal cavitation (cavitation inside the skin) was not detected using the acoustic measurement method under the ultrasound conditions examined. Acoustic measurement of the two types of cavitation activities (transient vs. stable) indicates that transient cavitation plays the major role in LFS-induced skin permeabilization. Through quantification of the transient cavitation activity at two specific locations of the LFS system, including comparing the dependence of these cavitation activities on ultrasound intensity with that of the skin permeabilization effect, we demonstrated that transient cavitation occurring on, or in the vicinity of, the skin membrane is the central mechanism that is responsible for the observed enhancement of skin permeability by LFS. CONCLUSIONS: LFS-induced skin permeabilization results primarily from the direct mechanical impact of gas bubbles collapsing on the skin surface (resulting in microjets and shock waves).

Acoustics↗

PubMed2002

A tough biodegradable elastomer.

Biodegradable polymers have significant potential in biotechnology and bioengineering. However, for some applications, they are limited by their inferior mechanical properties and unsatisfactory compatibility with cells and tissues. A strong, biodegradable, and biocompatible elastomer could be useful for fields such as tissue engineering, drug delivery, and in vivo sensing. We designed, synthesized, and characterized a tough biodegradable elastomer from biocompatible monomers. This elastomer forms a covalently crosslinked, three-dimensional network of random coils with hydroxyl groups attached to its backbone. Both crosslinking and the hydrogen-bonding interactions between the hydroxyl groups likely contribute to the unique properties of the elastomer. In vitro and in vivo studies show that the polymer has good biocompatibility. Polymer implants under animal skin are absorbed completely within 60 days with restoration of the implantation sites to their normal architecture.

3T3 Cells↗

PubMed2002

Moving smaller in drug discovery and delivery.

Advances in new micro- and nanotechnologies are accelerating the identification and evaluation of drug candidates, and the development of new delivery technologies that are required to transform biological potential into medical reality. This article will highlight the emerging micro- and nanotechnology tools, techniques and devices that are being applied to advance the fields of drug discovery and drug delivery. Many of the promising applications of micro- and nanotechnology are likely to occur at the interfaces between microtechnology, nanotechnology and biochemistry.

Drug Delivery Systems↗

PubMed2002

Topographic heterogeneity in transdermal transport revealed by high-speed two-photon microscopy: determination of representative skin sample sizes.

A novel application of high-speed two-photon microscopy was utilized to determine the optimum number of skin sites required to accurately determine the changes in transdermal transport properties incurred globally, over a clinically relevant area of skin. In contrast to the four to six skin sites (100 microm by 100 mirom area per site) examined previously, this study accounted for the fluorescent probe distributions at 400 consecutive skin sites, covering a total skin area of 2 mm by 2 mm. The oleic-acid-induced changes in the transdermal transport properties of the model hydrophobic probe, rhodamine B hexyl ester, and of the model hydrophilic probe, sulforhodamine B, for this 400-skin-site study exhibited different dependencies on sample size for each probe. Whereas the examination of six skin sites captures the relative changes in the global transdermal transport properties of the hydrophobic probe, the valid assessment of these changes for the hydrophilic probe requires a significantly larger sample size of at least 24 skin sites.

Biological Transport↗

PubMed2002

Effectiveness of muscimol-containing microparticles against pilocarpine-induced focal seizures.

PURPOSE: To investigate the efficacy of in situ lipid-protein-sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in rats. METHODS: LPSPs with and without muscimol were produced by spray-drying, sized by Coulter counter, and muscimol content determined by high-pressure liquid chromatography (HLPC). Particles, free muscimol or saline, were injected into the hippocampi of Sprague-Dawley rats before 40 mM pilocarpine, and seizure activity was scored. The trajectories of behavioral scores between groups were compared with two-way repeated measures analysis of variance. Animals were killed after 2 weeks. Brain sections were stained (Timm and thionin) and scored. RESULTS: LPSPs were 4 to 5 microm in diameter, and contained 0 or 2% (wt/wt) muscimol. In vitro, muscimol was released over a 5-day period. Intrahippocampal injections of normal saline and blank LPSPs did not deter seizure activity from pilocarpine. The rise of the trajectory in behavior scores in animals given LPSPs containing 5 microg muscimol was significantly slower than in those receiving saline, blank particles, or 5 microg of unencapsulated muscimol. There was less apparent neuronal injury and CA3 and supragranular mossy fiber sprouting in hippocampi of animals receiving muscimol-containing particles than in animals that did not receive muscimol. Hippocampi of animals that received 5 microg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 microg of unencapsulated muscimol, but showed no difference in cell loss or CA3 sprouting. CONCLUSIONS: Focally delivered biodegradable microparticles loaded with muscimol are effective in reducing seizure activity from pilocarpine in animals and mitigate the histologic effects.

Animals↗

PubMed2002

Differential effects of growth factors on tissue-engineered cartilage.

The effects of four regulatory factors on tissue-engineered cartilage were examined with specific focus on the ability to increase construct growth rate and concentrations of glycosaminoglycans (GAG) and collagen, the major extracellular matrix (ECM) components. Bovine calf articular chondrocytes were seeded onto biodegradable polyglycolic acid (PGA) scaffolds and cultured in medium with or without supplemental insulin-like growth factor (IGF-I), interleukin-4 (IL-4), transforming growth factor-beta1 (TGF-beta1) or platelet-derived growth factor (PDGF). IGF-I, IL-4, and TGF-beta1 increased construct wet weights by 1.5-2.9-fold over 4 weeks of culture and increased amounts of cartilaginous ECM components. IGF-I (10-300 ng/mL) maintained wet weight fractions of GAG in constructs seeded at high cell density and increased by up to fivefold GAG fractions in constructs seeded at lower cell density. TGF-beta1 (30 ng/mL) increased wet weight fractions of total collagen by up to 1.4-fold while maintaining a high fraction of type II collagen (79 plus minus 11% of the total collagen). IL-4 (1-100 ng/mL) minimized the thickness of the GAG-depleted region at the construct surfaces. PDGF (1-100 ng/mL) decreased construct growth rate and ECM fractions. Different regulatory factors thus elicit significantly different chondrogenic responses and can be used to selectively control the growth rate and improve the composition of engineered cartilage.

Animals↗

PubMed2002

Perfusion improves tissue architecture of engineered cardiac muscle.

Cardiac muscle with a certain threshold thickness, uniformity of tissue architecture, and functionality would expand the therapeutic options currently available to patients with congenital or acquired cardiac defects. Cardiac constructs cultured in well-mixed medium had an approximately 100-microm-thick peripheral tissue-like region around a relatively cell-free interior, a structure consistent with the presence of concentration gradients within the tissue. We hypothesized that direct perfusion of cultured constructs can reduce diffusional distances for mass transport, improve control of oxygen, pH, nutrients and metabolites in the cell microenvironment, and thereby increase the thickness and spatial uniformity of engineered cardiac muscle. To test this hypothesis, constructs (9.5-mm-diameter, 2-mm-thick discs) based on neonatal rat cardiac myocytes and fibrous polyglycolic acid scaffolds were cultured either directly perfused with medium or in control spinner flasks. Perfusion improved the spatial uniformity of cell distribution and enhanced the expression of cardiac-specific markers, presumably due to the improved control of local microenvironmental conditions within the forming tissue. Medium perfusion could thus be utilized to better mimic the transport conditions within native cardiac muscle and enable in vitro engineering of cardiac constructs with clinically useful thicknesses.

Animals↗

PubMed2002