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Robert Langer

Publications and source records attributed to Robert Langer.

At least 37 records · Page 2Linked to original sources
PubMed2006

Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells.

The optic nerve, like most mature CNS pathways, does not regenerate after injury. Through unknown mechanisms, however, macrophage activation in the eye stimulates retinal ganglion cells (RGCs) to regenerate long axons beyond the site of optic nerve injury. Here we identify the calcium (Ca(2+))-binding protein oncomodulin as a potent macrophage-derived growth factor for RGCs and other neurons. Oncomodulin binds to rat RGCs with high affinity in a cyclic AMP (cAMP)-dependent manner and stimulates more extensive outgrowth than other known trophic agents. Depletion of oncomodulin from macrophage-conditioned media (MCM) eliminates the axon-promoting activity of MCM. The effects of oncomodulin involve downstream signaling via Ca(2+)/calmodulin kinase and gene transcription. In vivo, oncomodulin released from microspheres promotes regeneration in the mature rat optic nerve. Oncomodulin also stimulates outgrowth from peripheral sensory neurons. Thus, oncomodulin is a new growth factor for neurons of the mature central and peripheral nervous systems.

Animals↗
PubMed2006

Application of micro- and nano-electromechanical devices to drug delivery.

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an "artificial pancreas" implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.

Administration, Cutaneous↗
PubMed2006

Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo.

Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximately 300 mm3), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.

Animals↗
PubMed2006

Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models.

We have designed a new dextran-peptide-methotrexate conjugate to achieve tumor-targeted delivery of chemotherapeutics. The dextran carrier was selected to allow passive targeting and enhanced permeation and retention (EPR). The peptide linker has also been optimized to allow drug release in the presence of matrix-metalloproteinase-2 (MMP-2) and matrix-metalloproteinase-9 (MMP-9), 2 important tumor-associated enzymes. The new conjugate was assessed for its in vivo antitumor efficacy and systemic side effects. It was compared with free methotrexate (MTX) and a similar conjugate, differing by an MMP-insensitive linker, at equivalent intraperitoneal dosages. The MMP-sensitive conjugate demonstrated tolerable in vivo side effects and effective inhibition of in vivo tumor growth by 83% in each of the 2 separate tumor models that overexpress MMP (HT-1080 and U-87). The antiproliferative effect of the drug contributed to the inhibition of tumor growth. In contrast, free MTX resulted in no significant tumor reduction in the same models. Neither free MTX nor the conjugate caused any tumor inhibition in the mice bearing RT-112, a slower growing model that does not overexpress MMP. MMP-insensitive conjugates, though able to inhibit tumor growth, caused toxicity in the small intestine and bone marrow.

Animals↗
PubMed2006

Microscale technologies for tissue engineering and biology.

Microscale technologies are emerging as powerful tools for tissue engineering and biological studies. In this review, we present an overview of these technologies in various tissue engineering applications, such as for fabricating 3D microfabricated scaffolds, as templates for cell aggregate formation, or for fabricating materials in a spatially regulated manner. In addition, we give examples of the use of microscale technologies for controlling the cellular microenvironment in vitro and for performing high-throughput assays. The use of microfluidics, surface patterning, and patterned cocultures in regulating various aspects of cellular microenvironment is discussed, as well as the application of these technologies in directing cell fate and elucidating the underlying biology. Throughout this review, we will use specific examples where available and will provide trends and future directions in the field.

Animals↗
PubMed2006

Oxygen gradients correlate with cell density and cell viability in engineered cardiac tissue.

For clinical utility, cardiac grafts should be thick and compact, and contain physiologic density of metabolically active, differentiated cells. This involves the need to control the levels of nutrients, and most critically oxygen, throughout the construct volume. Most culture systems involve diffusional transport within the constructs, a situation associated with gradients of oxygen concentration, cell density, cell viability, and function. The goal of our study was to measure diffusional gradients of oxygen in statically cultured cardiac constructs, and to correlate oxygen gradients to the spatial distributions of cell number and cell viability. Using microelectrodes, we measured oxygen distribution in a disc-shaped constructs (3.6 mm diameter, 1.8 mm thickness) based on neonatal rat cardiomyocytes cultured on collagen scaffolds for 16 days in static dishes. To rationalize experimental data, a mathematical model of oxygen distribution was derived as a function of cell density, viability, and spatial position within the construct. Oxygen concentration and cell viability decreased linearly and the live cell density decreased exponentially with the distance from the construct surface. Physiological density of live cells was present only within the first 128 microm of the construct thickness. Medium flow significantly increased oxygen concentration within the construct, correlating with the improved tissue properties observed for constructs cultured in convectively mixed bioreactors.

Animals↗
PubMed2006

Evaluation of chemical enhancers in the transdermal delivery of lidocaine.

The effect of various classes of chemical enhancers was investigated for the transdermal delivery of the anesthetic lidocaine across pig and human skin in vitro. The lipid disrupting agents (LDA) oleic acid, oleyl alcohol, butenediol, and decanoic acid by themselves or in combination with isopropyl myristate (IPM) showed no significant flux enhancement. However, the binary system of IPM/n-methyl pyrrolidone (IPM/NMP) improved drug transport. At 2% lidocaine dose, this synergistic enhancement peaked at 25:75 (v/v) IPM:NMP with a steady state flux of 57.6 +/- 8.4 microg cm(-2) h(-1) through human skin. This observed flux corresponds to a four-fold enhancement over a 100% NMP solution and over 25-fold increase over 100% IPM at the same drug concentration (p < 0.001). NMP was also found to co-transport through human skin with lidocaine free base and improve enhancement due to LDA. These findings allow a more rational approach for designing oil-based formulations for the transdermal delivery of lidocaine free base and similar drugs.

Administration, Cutaneous↗
PubMed2006

Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum.

Drug delivery to the peritoneum is hampered by rapid clearance, and could be improved by application of controlled release technology. We investigated the suitability for peritoneal use of micro- and nanoparticles of poly(lactic-co-glycolic) acid (PLGA), a biodegradable polymer with generally excellent biocompatibility commonly used for controlled drug release. We injected 90 kDa PLGA microparticles, 5-250 microm in diameter, into the murine peritoneum, in dosages of 10-100 mg (n=3-5 per group). We found a high incidence of polymeric residue and adhesions 2 weeks after injection (e.g., 50 mg of 5-microm microparticles caused adhesions in 83% of animals). Histology revealed chronic inflammation, with foreign body giant cells prominent with particles>5 microm in diameter. Five micrometer microspheres made from 54, 57, and 10 kDa PLGA (gamma irradiated) caused fewer adhesions (16.7%) with a similar incidence of residue. Nanoparticles (265 nm) of 90 kDa PLGA also caused much fewer adhesions (6.3% of animals), possibly because they were cleared from the peritoneum within 2 days, and sequestered in the spleen and liver, where foamy macrophages were noted. The effect of sterilization technique on the incidence of adhesion formation is also studied.

Animals↗
PubMed2006

Evaluation of chondrogenesis within PEGT: PBT scaffolds with high PEG content.

Porous poly(ethylene glycol) terephthalate:poly (butylene terephthalate) (PEGT:PBT) scaffolds with high PEG molecular weight (1000 g/mole) and PEGT content (60%) were fabricated using two different processes-paraffin templating and compression molding-for cartilage engineering applications. This polymer composition has previously been shown to enable chondrocyte adhesion and maintain differentiated phenotype in 2D monolayer culture. The influence of 3D polymer scaffold processing on the formation of cartilaginous tissue was studied by seeding primary immature bovine chondrocytes within cylindrical scaffolds in mixed flask reactors for 3 days, followed by cultivation in culture plates for a total of 10 or 24 days. Tissue-polymer constructs were evaluated morphologically by SEM and histology, and quantitatively for cellularity, total collagen, and glycosaminoglycan content, all of which remained statistically equivalent for each time point tested, irrespective of fabrication method. These data demonstrate that the polymers engineered for this study were able to support chondrogenesis independent of scaffold fabrication process, with the influence of pore architecture lessened by the highly hydrated scaffold microenvironments induced by high PEG content.

Animals↗
PubMed2006

Investigation of targeting mechanism of new dextran-peptide-methotrexate conjugates using biodistribution study in matrix-metalloproteinase-overexpressing tumor xenograft model.

We conducted a biodistribution study in HT-1080 bearing mice to investigate the drug targeting mechanism and the cause of side effects of the new dextran-peptide-methotrexate conjugates. HT-1080 is a human fibrosarcoma cell line that is known to overexpress matrix-metalloproteinases (MMPs). The experiments compared conjugates carrying MMP sensitive peptide linkers, conjugates carrying MMP insensitive linkers, and free methotrexate. Passive targeting was evidenced by the prolonged plasma circulation and higher tissue accumulations of both types of the conjugates compared to free methotrexate. Independent of the peptide sequence of the linker, the ratio of drug accumulation at the tumor versus drug accumulation at the major site of side effects (small intestine) for either conjugate was increased by the effect of enhance permeation and retention (EPR). The conjugate released a sufficient amount of peptidyl methotrexate to cause inhibition of tumor growth. There was no significant difference in drug accumulation at the tumor site between the MMP-sensitive and the MMP-insensitive conjugates. We concluded that the tumor targeting effect of the dextran-peptide-methotrexate conjugate was dominantly due to passive targeting and EPR. The difference in the systemic side effects observed for conjugates with different linkers could probably be attributed to their varying susceptibility towards enzymes in normal tissues.

Animals↗
PubMed2006

Modulation of chondrocyte phenotype for tissue engineering by designing the biologic-polymer carrier interface.

Therapeutic strategies based on cell and tissue engineering can be advanced by developing material substrates that effectively interrogate the biological compartment, with or without the complimentary local release of growth factors. Poly(ether ester) segmented copolymers were engineered as model material systems to elucidate the interfacial molecular events that govern the function of adhered cells. Surface chemistry was modulated by varying poly(ethylene glycol) (PEG) length and mole fraction with poly(butylene terephthalate) (PBT), leading to differential competitive protein adsorption of fibronectin and vitronectin from serum and consequently to different cell attachment modes. Adhesion within the hydrogel-like milieu of longer surface PEG was mediated via binding to the CD44 transmembrane receptor, rather than the RGD-integrin mechanism, whereas greater substrate-bound fibronectin resulted in cell adhesion via integrins. These adhesion modalities differentially impacted morphological cell phenotype (spread or spheroid) and the subsequent expression of mRNA transcripts (collagen types II, I) characteristic of phenotypically differentiated or dedifferentiated chondrocytes, respectively. These results demonstrate that materials can be designed to directly elicit the membrane bound receptor apparatus desired for downstream cellular response, without requiring exogenous biological growth factors to enable differentiated potential.

Blotting, Western↗
PubMed2006

Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration.

Vocal fold scarring disrupts the viscoelastic properties of the lamina propria that are critical for normal phonation. There is a clinical need for the development of advanced biomaterials that approximate the mechanical properties of the lamina propria for in vivo vocal fold regeneration. We have developed hyaluronic acid (HA)-based microgels and cross-linked microgel networks with tunable degradation and mechanical properties. HA microgels were prepared by cross-linking HA derivatives carrying hydrazide (HAADH) and aldehyde (HAALD) functionalities within the inverse emulsion droplets. Alternatively, poly(ethylene glycol) dialdehyde (PEGDiALD) was employed in place of HAALD. Microgels based on HAADH/HAALD are more resistant to enzymatic degradation than those generated from HAADH/PEGDiALD. In vitro cytotoxicity studies using vocal fold fibroblasts indicate that microgels synthesized from HAADH/HAALD are essentially nontoxic, whereas microgels derived from HAADH/PEGDiALD exhibit certain adverse effects on the cultured cells at high concentration (> or =2 mg/mL). These microgels exhibit residual functional groups that can be used as reactive handles for covalent conjugation of therapeutic molecules. The presence of residual functional groups also allows for subsequent cross-linking of the microgels with other reactive polymers, giving rise to doubly cross-linked networks (DXNs) with tunable viscoelasticity. Mechanical measurements using a torsional wave apparatus indicate that HA-based DXNs exhibit elastic moduli that are similar to those of vocal fold lamina propria at frequencies close to the range of human phonation. These HA-based microgel systems are promising candidates for the treatment of vocal fold scarring, not just as biocompatible filler materials, but as smart entities that can repair focal defects, smooth the vocal fold margin, and potentially soften and dissolve scar tissue.

Aldehydes↗
PubMed2006

Direct confinement of individual viruses within polyethylene glycol (PEG) nanowells.

Individual M13 viruses were spatially confined within wells fabricated from nanomolding of a PEG-based random copolymer. The viruses were selectively adhered to the region pretreated with an antibody against the virus, resulting in individual virus arrays. The polymer surface was found to be highly resistant to the attachment of the virus (approximately 0.02 microm-2), approximately 2 orders of magnitude lower than that on a bare silicon surface. The physical height of the template provided an additional barrier to the attachment of the virus due to entropic penalty in bending of a semi-flexible M13 virus. The effects of pattern size and barrier height were investigated, revealing that a certain critical height is needed to ensure successful confinement within the template for a given pattern size.

Bacteriophage M13↗
PubMed2006

Biomimetic approach to cardiac tissue engineering: oxygen carriers and channeled scaffolds.

We report that the functional assembly of engineered cardiac muscle can be enhanced by oxygen supply provided by mechanisms resembling those in normal vascularized tissues. To mimic the capillary network, cardiomyocytes and fibroblasts isolated from the neonatal rat hearts were cultured on a highly porous elastomer with a parallel array of channels that were perfused with culture medium. To mimic oxygen supply by hemoglobin, culture medium was supplemented with a perfluorocarbon (PFC) emulsion; constructs perfused with unsupplemented culture medium served as controls. In PFC-supplemented medium, the decrease in the partial pressure of oxygen in the aqueous phase was only 50% of that in control medium (28 mmHg vs. 45 mmHg between the construct inlet and outlet at a flow rate of 0.1 mL/min). Consistently, constructs cultivated in the presence of PFC contained higher amounts of DNA and cardiac markers (troponin I, connexin-43) and had significantly better contractile properties as compared to control constructs. In both groups, electron microscopy revealed open channels and the presence of cells at the channel surfaces as well as within constructs. Improved properties of cardiac constructs could be correlated with the enhanced supply of oxygen to the cells, by a combined use of channeled scaffolds and PFC.

Animals↗
PubMed2006

Interplay of biomaterials and micro-scale technologies for advancing biomedical applications.

Micro-scale technologies have already dramatically changed our society through their use in the microelectronics and telecommunications industries. Today these engineering tools are also useful for many biological applications ranging from drug delivery to DNA sequencing, since they can be used to fabricate small features at a low cost and in a reproducible manner. The discovery and development of new biomaterials aid in the advancement of these micro-scale technologies, which in turn contribute to the engineering and generation of new, custom-designed biomaterials with desired properties. This review aims to present an overview of the merger of micro-scale technologies and biomaterials in two-dimensional (2D) surface patterning, device fabrication and three-dimensional (3D) tissue-engineering applications.

Base Sequence↗
PubMed2006

Quantitative and comparative studies of the vocal fold extracellular matrix. I: Elastic fibers and hyaluronic acid.

OBJECTIVES: This study examines the elastic fiber and hyaluronic acid (HA) content of the midmembranous vocal fold laminae propriae (LPs) of humans, dogs, pigs, and ferrets. METHODS: Lamina propria elastin was quantified by measuring the amino acid desmosine, and HA was measured by an enzyme-linked immunosorbent assay-based technique. Quantitative histology was used to evaluate elastin and HA levels in specific LP regions. The distributions of fibrillin-1, a primary microfibrillar component of elastic fibers, and of tropoelastin, an indicator of elastin synthesis, were immunohistochemically analyzed. RESULTS: Elastin and HA constituted 8.5% +/- 2.1% and 0.82% +/- 0.11% of human LP, respectively, relative to tissue total protein. Although the mean LP desmosine levels were similar across species, the mean HA levels in canine (p < 3.1 x 10(-5)), porcine (p < 1.5 x 10(-5)), and ferret (p < 6.6 x 10(-4)) LPs were 3 to 4 times higher than that in humans. Marked interspecies differences in elastin, fibrillin-1, tropoelastin, and HA distributions were observed histologically. CONCLUSIONS: The elastin content of the human LP is roughly twice that of the dermis, whereas the HA content of the human LP is similar to that of the dermis. Although all species had similar levels of desmosine, histologic evaluation indicates that the porcine elastin distribution is most similar to that of the human LP. Fibrillin-1 staining suggests that stress in the human LP may be particularly high in the superior superficial layer, and tropoelastin staining indicates that the rate of LP elastin turnover may vary spatially.

Animals↗