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Biomedical subjects

Robert Langer

Publications and source records attributed to Robert Langer.

At least 109 records · Page 6Linked to original sources
PubMed2004

Single nanocrystal arrays on patterned poly(ethylene glycol) copolymer microstructures using selective wetting and drying.

Single nanocrystal arrays were fabricated on sub-microwells of poly(ethylene glycol) (PEG) copolymer using selective wetting on the hydrophilic regions of the exposed substrate surface and subsequent drying. Templates were produced by molding a thin film of a PEG-based random copolymer on hydrophilic substrates such as glass or silicon dioxide. The polymeric microstructures provide a topographical barrier around the well, which makes it possible to create nanocrystal arrays with controlled geometrical features. The size of the nanocrystal was found to decrease with decreasing well size and also decrease with decreasing topological height. A simple empirical equation was derived to predict the size of the crystal as a function of the pattern size and height, which is in good agreement with the experimental data.

Journal Article↗
PubMed2004

A soft lithographic approach to fabricate patterned microfluidic channels.

The control of surface properties and spatial presentation of functional molecules within a microfluidic channel is important for the development of diagnostic assays and microreactors and for performing fundamental studies of cell biology and fluid mechanics. Here, we present a simple technique, applicable to many soft lithographic methods, to fabricate robust microchannels with precise control over the spatial properties of the substrate. In this approach, the patterned regions were protected from oxygen plasma by controlling the dimensions of the poly(dimethylsiloxane) (PDMS) stamp and by leaving the stamp in place during the plasma treatment process. The PDMS stamp was then removed, and the microfluidic mold was irreversibly bonded to the substrate. The approach was used to pattern a nonbiofouling poly(ethylene glycol)-based copolymer or the polysaccharide hyaluronic acid within microfluidic channels. These nonbiofouling patterns were then used to fabricate arrays of fibronectin and bovine serum albumin as well as mammalian cells. In addition, further control over the deposition of multiple proteins onto multiple or individual patterns was achieved using laminar flow. Also, cells that were patterned within channels remained viable and capable of performing intracellular reactions and could be potentially lysed for analysis.

Animals↗
PubMed2004

Delivery of therapeutic levels of heparin and low-molecular-weight heparin through a pulmonary route.

Although heparin and low-molecular-weight heparins (LMWH) have been widely used clinically as anticoagulants, their broader use has been limited by the lack of noninvasive delivery methods for this class of molecules. In this study, we demonstrate an efficient, rapid, and reproducible delivery system for heparin through the lungs that is not confined to particles of a certain geometric or aerodynamic diameter. Importantly, blood levels after intrapulmonary administration of either heparin or LMWH were comparable to that of s.c. administration but are characterized by a more rapid onset of action (t(1/2) = 40 min vs. 2.5 h, respectively). Furthermore, we show in animal models, that inhaled heparin species efficiently inhibit diseases such as thrombosis and emphysema, and that the repetitive inhalation of formulated LMWH results in no observable toxicity from the delivery of reproducible systemic levels of heparin or LMWH.

Absorption↗
PubMed2004

Fabrication of gradient hydrogels using a microfluidics/photopolymerization process.

A method of fabricating photo-cross-linked hydrogels with gradients of immobilized molecules and crosslinking densities is introduced. Two macromer/initiator solutions are injected into a unique poly(dimethylsiloxane) channel system that produces a prepolymer gradient that is subsequently polymerized into a water-swollen hydrogel with ultraviolet light exposure. The gradient is controlled by the injection flow rate (optimized to 0.3 microL/min per inlet to produce a linear gradient). The technique is investigated both through fabrication of adhesive ligand gradients that modulate spatial distribution of attached endothelial cells and gradients of cross-linking densities that led to unique hydrogel architectures and spatially dependent swelling.

Cell Adhesion↗
PubMed2004

Poly-beta amino ester-containing microparticles enhance the activity of nonviral genetic vaccines.

Current nonviral genetic vaccine systems are less effective than viral vaccines, particularly in cancer systems where epitopes can be weakly immunogenic and antigen-presenting cell processing and presentation to T cells is down-regulated. A promising nonviral delivery method for genetic vaccines involves microencapsulation of antigen-encoding DNA, because such particles protect plasmid payloads and target them to phagocytic antigen-presenting cells. However, conventional microparticle formulations composed of poly lactic-co-glycolic acid take too long to release encapsulated payload and fail to induce high levels of target gene expression. Here, we describe a microparticle-based DNA delivery system composed of a degradable, pH-sensitive poly-beta amino ester and poly lactic-co-glycolic acid. These formulations generate an increase of 3-5 orders of magnitude in transfection efficiency and are potent activators of dendritic cells in vitro. When used as vaccines in vivo, these microparticle formulations, unlike conventional formulations, induce antigen-specific rejection of transplanted syngenic tumor cells.

Animals↗
PubMed2004

Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells.

Identification of biomaterials that support appropriate cellular attachment, proliferation and gene expression patterns is critical for tissue engineering and cell therapy. Here we describe an approach for rapid, nanoliter-scale synthesis of biomaterials and characterization of their interactions with cells. We simultaneously characterize over 1,700 human embryonic stem cell-material interactions and identify a host of unexpected materials effects that offer new levels of control over human embryonic stem cell behavior.

Biocompatible Materials↗
PubMed2004

Molecular release from a polymeric microreservoir device: Influence of chemistry, polymer swelling, and loading on device performance.

A polymeric microreservoir device for controlled-release drug delivery relies on the degradation of thin poly(lactic-co-glycolic acid) membranes that seal each reservoir to achieve pulsatile drug delivery. In vitro release studies in which the swelling of the reservoir membranes was measured indicate a correlation between the release times of various radiolabeled molecules from the devices and the time at which the maximum membrane swelling was observed. Varying the chemistry (lipophilicity/hydrophilicity) or molecular weight of the molecules loaded into the devices did not appear to affect the degree of membrane swelling that was observed, or the time at which the molecules were released from the devices. The amount of drug that was loaded into the reservoirs also did not appear to affect the observed release time of the drug from the device, a significant departure from the behavior of many matrix-type polymeric drug delivery systems.

Biocompatible Materials↗
PubMed2004

Designing materials for biology and medicine.

Biomaterials have played an enormous role in the success of medical devices and drug delivery systems. We discuss here new challenges and directions in biomaterials research. These include synthetic replacements for biological tissues, designing materials for specific medical applications, and materials for new applications such as diagnostics and array technologies.

Animals↗
PubMed2004

Effect of excipient composition on the biocompatibility of bupivacaine-containing microparticles at the sciatic nerve.

Microparticulate formulations are often used for experimental prolongation of nerve blockade. Here we examine the effect of excipient composition on the biocompatibility of bupivacaine-containing microparticles. Lipid-protein-sugar particles (LPSPs) composed of 3% (1.3-microm diameter) and 60% (4.7-microm diameter) (w/w) dipalmitoylphosphatidylcholine (DPPC) were produced by spray drying, containing 10% (w/w) bupivacaine. Rat sciatic nerve blocks with 75 mg of particles produced statistically similar durations of sensory nerve block [3% (w/w) DPPC particles: 301 min; 60% (w/w) DPPC particles: 321 min]. Examination of tissues 1 day after injection revealed large particle deposits and acute inflammation in animals that received 60% (w/w) DPPC particles. There were no visible deposits in those that received 3% (w/w) DPPC particles, and microscopic inflammation was reduced. The difference between groups was similar 4 days after injection. Two weeks after injection, there was no particulate mass in either group, and inflammation had largely resolved. In both groups, moderately severe myotoxicity was seen 1 and 4 days after injection but had largely resolved by 2 weeks. In summary, reduction in particles' DPPC content greatly improved biocompatibility without compromising duration of nerve blockade; the improvement was probably attributable to the enhanced rate of particle resorption.

Animals↗
PubMed2004

Molecularly engineered poly(ortho ester) microspheres for enhanced delivery of DNA vaccines.

Genetic vaccination using plasmid DNA presents a unique opportunity for achieving potent immune responses without the potential limitations of many conventional vaccines. Here we report the design of synthetic biodegradable polymers specifically for enhancing DNA vaccine efficacy in vivo. We molecularly engineered poly(ortho ester) microspheres that are non-toxic to cells, protect DNA from degradation, enable uptake by antigen-presenting cells, and release DNA rapidly in response to phagosomal pH. One type of microsphere of poly(ortho esters) that releases DNA vaccines in synchrony with the natural development of adaptive immunity, elicited distinct primary and secondary humoral and cellular immune responses in mice, and suppressed the growth of tumour cells bearing a model antigen. This polymer microparticulate system could, with further study, have implications for advancing the clinical utility of DNA vaccines as well as other nucleic-acid-based therapeutics against viral infections and cancer.

Adjuvants, Immunologic↗
PubMed2004

Microparticulate formulations for the controlled release of interleukin-2.

Interleukin 2 (IL-2) is a pleotropic growth factor essential to immune system function. Current methods of administration are limited by the necessity of hospitalization as well as dose-limiting toxicities and side effects. There is also the issue of low therapeutic concentrations at the desired site of action; for instance, in the case of solid tumor treatment. Here we describe the design of controlled-release vehicles for the local administration of IL-2 based on single (SE) and double emulsion (DE) poly(lactic-co-glycolic acid) (PLGA) systems and a newly developed class of spray-dried lipid-protein-sugar systems composed of L-alpha-dipalmitoylphosphatidylcholine (DPPC) and 0.2% Eudragit E 100. All three systems demonstrated the release of therapeutic drug quantities. Totals of 2.0, 0.5, and 2.8 microg of IL-2 (per mg of solid) were encapsulated in the SE, DE, and spray-dried formulations, respectively. The SE and DE released of 30 and 15% of the encapsulated protein, respectively, with delivery of biologically active IL-2 during the first 5 to 10 days. The lipid-protein-sugar-based system demonstrated extended sustained release of biologically active IL-2 for a period of 4 months. These systems provide a potential framework for long-term loco-regional immunotherapeutic treatment regimens.

Animals↗
PubMed2004

Experimental demonstration of the existence of highly permeable localized transport regions in low-frequency sonophoresis.

Recent advances in low-frequency sonophoresis have focused on the existence of hypothesized localized transport regions (LTRs). However, there has been no actual experimental demonstration that the hypothesized LTRs are, in fact, localized regions of high permeability. Through a series of low-frequency sonophoresis experiments conducted with full-thickness pig skin, in the presence of the surfactant sodium lauryl sulfate (SLS), in which we have separately measured the transport of calcein through the LTRs, which have areas ranging from 10 to 40 mm(2), and the surrounding regions of the skin (the non-LTRs) by means of a novel masking technique, we demonstrate that the calcein permeability through the LTRs is approximately 80-fold higher than the calcein permeability through the non-LTRs, suggesting that the LTRs are structurally perturbed to a greater extent than the non-LTRs from the exposure to the ultrasound/SLS system. In addition, we propose basic models to predict the total skin transdermal permeability from the transdermal permeabilities of the LTRs and the non-LTRs, and then compare the predictions to the experimental data obtained from the masking experiments. We also demonstrate that both the LTRs and the non-LTRs exhibit significant decreases in skin electrical resistivity relative to untreated skin ( approximately 5000-fold and approximately 170-fold, respectively), suggesting the existence of two levels of significant skin structural perturbation due to ultrasound exposure in the presence of SLS. Finally, an analysis of the porosity/tortuosity ratio (epsilon/tau) values suggests that trans-cellular transdermal transport pathways are present within the highly permeable, and highly structurally perturbed, LTRs.

Animals↗
PubMed2004

A rapid-curing alginate gel system: utility in periosteum-derived cartilage tissue engineering.

In this study, we have developed a rapid-curing alginate gel system and demonstrated its utility as a scaffold for periosteum-derived chondrogenesis for articular cartilage tissue engineering applications. A homogeneous mechanically stable gel was formulated by inducing gelation of a 2% (w/v) solution of a high G content alginate (65-75% G) with a 75 mM solution of CaCl(2). The gel exhibited near-elastic behavior at low levels of deformation (15%, R(2)=0.996), Young's modulus of 0.17+/-0.01 MPa, and rapid gelation kinetics (<1 min to completion). The in vitro cell culture of chondrocytes in the gel yielded alginate/cell constructs that lacked the continuous, interconnected collagen/proteoglycan network of hyaline cartilage. In addition, we have demonstrated that this gel system is capable of supporting periosteum-derived chondrogenesis. We observed that when whole-tissue explants of periosteum were cultured in vitro within the gel, after 6 weeks, significant quantities (>50%) of the total area of the periosteal explants was composed of cartilage that was hyaline-like in appearance and contained cartilage-specific proteoglycans and type-II collagen. It is envisioned that such explants could be transplanted or regenerated in vivo within the biodegradable alginate matrix for the treatment of partial or full-thickness defects in articular cartilage. Importantly, the injectable delivery of the gel could be used in filling complex defects in the articular surface via minimally invasive procedures.

Alginates↗
PubMed2004

A novel polymeric chlorhexidine delivery device for the treatment of periodontal disease.

An implantable, anti-microbial delivery device for the treatment of periodontal disease has been developed. In this polymer-based delivery system, the encapsulation efficiency, release characteristics, and bioactivity of anti-microbial agent were controlled by the complexation of the drug with cyclodextrins of differing lipophilicity. Microparticles of poly(dl-lactic-co-glycolic acid) (PLGA) containing chlorhexidine (Chx) free base, chlorhexidine digluconate (Chx-Dg) and their association or inclusion complex with methylated-beta-cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) were prepared by single emulsion, solvent evaporation technique. It was observed that encapsulation efficiency and release of the chlorhexidine derivatives from the microparticles was a function of the lipophilicity of the cyclodextrin. Complexation of the poorly water soluble Chx with the more hydrophilic HPBCD resulted in 62% higher encapsulation efficiency and longer duration of sustained release over a 2-week period than complexation with the more lipophilic MBCD. In contrast, the complexation of the more water-soluble derivative of chlorhexidine, Chx-Dg, with the more lipophilic MBCD improved encapsulation efficiency by 12% and prolonged its release in comparison to both the free Chx-Dg and its complex with HPBCD. Furthermore, it was observed that the initial burst effect could be diminished by complexation with CD. Preliminary studies have shown that the chlorhexidine released from PLGA chips is biologically active against bacterial population that is relevant in periodontitis (P. gingivalis and B. forsythus) and a healthy inhibition zone is maintained in agar plate assay over a period of at least a 1-week. The PLGA/CD delivery system described in this paper may prove useful for the localized delivery of chlorhexidine salts and other anti-microbial agents in the treatment of periodontal disease where prolonged-controlled delivery is desired.

Anti-Infective Agents, Local↗
PubMed2004

Layer-by-layer deposition of hyaluronic acid and poly-L-lysine for patterned cell co-cultures.

A novel method for patterning cellular co-cultures that uses the layer-by-layer deposition of ionic biopolymers is described. Non-biofouling hyaluronic acid (HA) micropatterns were used to immobilize cells and proteins to glass substrates. Subsequent ionic adsorption of poly-L-lysine (PLL) to HA patterns was used to switch the HA surfaces from cell repulsive to adherent thereby facilitating the adhesion of a second cell type. The utility of this approach to pattern co-cultures of hepatocytes or embryonic stem cells with fibroblasts was demonstrated. In addition, the versatility of this approach to generate patterned co-cultures irrespective of the primary cell seeding and relative adhesion of the seeded cells was demonstrated. Thus, the proposed method may be a useful tool for fabricating controlled cellular co-cultures for cell-cell interaction studies and tissue engineering applications.

Adsorption↗
PubMed2004

Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid.

Controlled release technology has been applied extensively in providing prolonged duration local anesthesia. Here we used modified hyaluronic acids (HAs; hydrazide and aldehyde) that cross-link upon mixing, as the vehicle for bupivacaine. We assessed the formulations' efficacy and biocompatibility in a rat model of sciatic nerve blockade. We found that 2% (w/v) cross-linked HA doubled the duration of block of 0.1%, 0.25%, and 0.5% (w/v) bupivacaine, without a statistically significant increase in myotoxicity. 1% (w/w) cross-linked HA also prolonged nerve block, but unmodified HA, and both modified HAs did not. HA itself was associated with a mild to moderate inflammatory response with macrophages and lymphocytes. Cross-linked HA is an effective and biocompatible vehicle for enhancing local anesthetic efficacy.

Animals↗