Showing papers by "Nicholas A. Peppas published in 2003"

Advances in Biomaterials, Drug Delivery, and Bionanotechnology

Abstract: Biomaterials are widely used in numerous medical applications. Chemical engineering has played a central role in this research and development. Polymers as biomaterials, materials and approaches used in drug and protein delivery systems, materials used as scaffolds in tissue engineering, and nanotechnology and microfabrication techniques applied to biomaterials are reviewed.

Dynamic swelling behavior of pH-sensitive anionic hydrogels used for protein delivery

Abstract: There have been many attempts to use anionic hydrogels as oral protein delivery carriers because of their pH-responsive swelling behavior. The dynamic swelling behavior of poly(methacrylic acid-co-methacryloxyethyl glucoside) and poly(methacrylic acid-g-ethylene glycol) hydrogels was investigated to determine the mechanism of water transport through these anionic hydrogels. The exponential relation Mt/M∞ = ktn (where Mt is the mass of water absorbed at time t and M∞ is the mass of water absorbed at equilibrium) was used to calculate the exponent (n) describing the Fickian or non-Fickian behavior of swelling polymer networks. The mechanism of water transport through these gels was significantly affected by the pH of the swelling medium. The mechanism of water transport became more relaxation-controlled in a swelling medium of pH 7.0, which was higher than pKa of the gels. The experimental results of the time-dependent swelling behaviors of the gels were analyzed with several mathematical models. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1606–1613, 2003

Ultrasensitive Biomems Sensors Based on Microcantilevers Patterned with Environmentally Responsive Hydrogels

Abstract: An innovative platform was developed for ultrasensitive microsensors based on microcantilevers patterned with crosslinked copolymeric hydrogels. A novel UV free-radical photolithography process was utilized to precisely align and pattern environmentally responsive hydrogels onto silicon microcantilevers, after microcantilevers were fabricated and released. Specifically, a crosslinked poly(methacrylic acid) network containing high amounts of poly(ethylene glycol) dimethacrylate was prepared and investigated. Hydrogels were patterned onto the silicon microcantilevers utilizing a mask aligner to allow for precise positioning. The silicon surface was modified with γ-methacryloxypropyl trimethoxysilane to gain covalent adhesion between the polymer and the silicon. The hydrogels sensed and responded to changes in environmental pH resulting in a variation in surface stress that deflected the microcantilever. The bending response of patterned cantilevers with a change in environmental pH was observed, showing the possibility to construct MEMS/BioMEMS sensors based on microcantilevers patterned with environmentally responsive hydrogels. An extraordinary maximum sensitivity of 1 nm/5×10−5ΔpH was observed, demonstrating the ultrasensitivity of this microsensor platform.

Novel complexation hydrogels for oral peptide delivery: In vitro evaluation of their cytocompatibility and insulin‐transport enhancing effects using Caco‐2 cell monolayers

Abstract: Poly(methacrylic acid-grafted-poly(ethylene gly- col)) (P(MAA-g-EG)) is a complexation hydrogel molecu- larly designed for oral peptide delivery. In this work, the cytotoxicity and insulin-transport enhancing effect of P(MAA-g-EG) microparticles on intestinal epithelial cells were evaluated using Caco-2 cell monolayers. A series of P(MAA-g-EG) microparticles with different polymer com- positions were prepared by a photo-initiated free radical solution polymerization and subsequent pulverization. The hydrogel microparticles were preswollen in either Ca 2 - containing (CM )o r Ca 2 -free medium (CM; pH 7.4) and applied to the apical side of the Caco-2 monolayers. No significant cytotoxic effects, as determined by a calorimetric assay with P(MAA-g-EG) microparticles preswollen in the CM, were observed at doses ranging from 3 to 31 mg/cm 2 of cell monolayer. Transepithelial electrical resistance (TEER) measurements showed that the P(MAA-g-EG) mi- croparticles induced a Ca 2 concentration-dependent low- ering in TEER values. The reduction effect in CM media was greater than that in CM media (17 2% reduction in CM and 45 3% reduction in CM, respectively). Insulin transport in the presence of the preswollen P(MAA-g-EG) microparticles was also strongly depended on the Ca 2 concentration in the medium. The respective estimated per- meability for insulin alone and the insulin with hydrogels in CM were 0.77 and 1.16 10 8 cm/s, whereas those in CM were 1.18 and 24.78 10 8 cm/s. The results demon- strate that the P(MAA-g-EG) hydrogel microparticles could be used as a cytocompatible carrier possessing the transport- enhancing effect of insulin on the intestinal epithelial cells. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 609 - 617, 2003

Poly(ethylene glycol)-containing Hydrogels for Oral Protein Delivery Applications

Abstract: Novel pH-sensitive hydrogels were developed as suitable candidates for carriers in bioMEMS devices as well as for oral delivery of therapeutic peptides and proteins due to their ability to respond to environmental pH change. Macromonomers containing various PEG molecular weights were synthesized and used to prepare P(MAA-g-EG) hydrogels were by photopolymerization. P(MAA-g-EG) hydrogels showed a drastic change of the equilibrium swelling ratio between pH 2.2 and 7.0. At pH 7.0, hydrogels with PEGMA2000 exhibited higher swelling ratio than hydrogels with PEGMA1000. For both hydrogels with PEGMA1000 and PEGMA2000, the swelling mechanism became more relaxation-controled as the environmental pH changed from 2.2 to 7.0 due to the ionization of the functional groups in polymer networks at high pH. In vitro release studies of insulin were conducted. P(MAA-g-EG) hydrogels exhibited drastic increase of insulin release as the pH of the medium was changed from acidic to basic. Insulin release from P(MAA-g-EG) hydrogels with PEGMA2000 was slower than from hydrogels with PEGMA1000 at both low and high pH. These results were used to design and improve protein release behavior from these carriers.

Monodisperse nanoparticles of poly(ethylene glycol) macromers and N-isopropyl acrylamide for biomedical applications

Abstract: Poly(ethylene glycol)-based nanoparticles have received significant attention in the field of biomedicine. When they are copolymerized with pH- or temperature-sensitive comonomers, their small size allows them to respond very quickly to changes in the environment, including changes in the pH, ionic strength, and temperature. In addition, the high surface-to-volume ratio makes them highly functionalized. In this work, nanoparticles composed of temperature-sensitive poly(N-isopropylacrylamide), poly(ethylene glycol) 400 dimethacrylate, and poly(ethylene glycol) 1000 methacrylate were prepared by a thermally initiated, free-radical dispersion polymerization method. The temperature-responsive behavior of the hydrogel nanoparticles was characterized by the study of their particle size with photon correlation spectroscopy. The size of the nanoparticles varied from 200 to 1100 nm and was a strong function of the temperature of the system, from 5 to 40°C. The thermal, structural, and morphological characteristics were also investigated. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1678–1684, 2003

Microscale sensor element and related device and method of use

Abstract: A monitoring apparatus useful in detecting viability of biological cells. A substrate defines a microscopic chamber. One or more microcantilevers extend from the substrate into the chamber. A detector is operatively connected to the microcantilevers for sensing a state of deformation thereof. On each microcantilevers is deposited a layer of an environmentally sensitive hydrogel polymer having a configuration changing in accordance with presence of an environmental parameter.

Time-dependent mechanical properties of polymeric coatings used in rupturable pulsatile release dosage forms.

Abstract: The mechanical properties of polymer films used in pharmaceutical coatings of pulsatile drug delivery systems were evaluated in the dry and the wet state by a newly developed puncture test, which allowed the time-dependent measurement of the mechanical properties on the same film specimen Force, puncture strength, energy at break, modulus, and strain were investigated as a function of water exposure time with respect to the type of polymer and the type and concentration of plasticizer and pore former (hydroxypropyl methylcellulose, HPMC) Eudragit RS films were very flexible, had a high strain, and broke upon puncture with only small cracks In contrast, ethylcellulose films were more brittle with a lower strain and showed complete film rupture Increased amounts of the hydrophilic pore former, HPMC, resulted in a reduced puncture strength and in an increase in water uptake and weight loss of the films The puncture strength decreased with increasing plasticizer concentration and was lower with the lipophilic dibutyl sebacate than with the hydrophilic triethyl citrate

Effect of monomer type and dangling end size on polymer network synthesis

Abstract: The design of novel biomaterials for applications in biological recognition, drug delivery, or diagnostics requires a judicious choice of preparation conditions and methods for the production of well-characterized 3-dimensional structures, preferably by benign processes. In this work, the polymerization of poly(ethylene glycol) (PEG) methacrylates was examined by kinetic gelation modeling and kinetic analysis in order to ascertain the factors affecting the resulting structure. The kinetics of the polymerization and structure of the final polymer network are strongly affected by the length of the PEG graft chain. The propagation of the polymer chains becomes increasingly diffusion limited with the incorporation of longer PEG grafts. In addition, a more heterogeneous network consisting of numerous microgel regions is produced as the length of the PEG graft is increased. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 3506–3519, 2003

Preparation and properties of poly(ethylene oxide) star polymers

Abstract: Poly(ethylene oxide) (PEO) star polymers were prepared by anionic polymerization of methacryloyl chloride and glyceryl trimethacrylate with sec-butyllithium in cyclohexane. The ensuing polymers were grafted with poly(ethylene glycol) of molecular weight 400. The final product was washed with methylene chloride and analyzed with infrared spectroscopy, differential scanning calorimetry, and thermogravimetry. Star polymers of PEO were also prepared by anionic polymerization of glycidol with sec-butyllithium in cyclohexane. The initiator was chosen so as to yield a polymer of 10,000 molecular weight. The resulting polymers were analyzed by nuclear magnetic resonance, infrared spectroscopy, and thermogravimetry. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 322–327, 2003

Microscale sensor element and related device and method of manufacture

Abstract: A monitoring apparatus useful in detecting viability of biological cells (112). A substrate defines a microscopic chamber. One or more microcantilevers (106) extend from the substrate (102) into the chamber (104). A detector is operatively connected to the microcantilevers for sensing a state of deformation thereof. On each microcantilevers is deposited a layer of an environmentally sensitive hydrogel polymer having a configuration changing in accordance with presence of an environmental parameter.

New biomaterials for intelligent biosensing, recognitive drug delivery and therapeutics

Abstract: Engineering the molecular design of intelligent biomaterials by controlling recognition and specificity is the first step in coordinating and duplicating complex biological and physiological processes. We address design and synthesis characteristics of artificial molecular structures capable of specific molecular recognition of biological molecules. Recent developments in protein delivery have been directed towards the preparation of targeted formulations for protein delivery to specific sites, use of environmentally-responsive polymers to achieve pHor temperature-triggered delivery, usually in modulated mode, and improvement of the behavior of their mucoadhesive behavior and cell recognition. Molecular imprinting and microimprinting techniques, which create stereo-specific threedimensional binding cavities based on a biological compound of interest can lead to preparation of biomimetic materials for intelligent drug delivery, drug targeting, and tissue engineering. We have been successful in synthesizing novel glucose-binding molecules based on non-covalent directed interactions formed via molecular imprinting techniques within aqueous media.

Molecular Simulations of Recognitive Polymer Networks Prepared by Biomimetic Configurational Imprinting as Responsive Biomaterials

Abstract: Proteins, enzymes, and antibodies have the ability to discern specific molecules out of a whole host of species and selectively bind them with remarkable affinity. A route that would enable the creation of synthetic polymers with this binding ability would be a great advance with subsequent applications in chemical sensors, single-molecule separations, and even artificial enzymes. In this work we study the molecular imprinting process whereby a controlled nanostructure consisting of distinct binding sites is created in a polymer network through a templating procedure. Simulations were done to better understand the underlying network structure that gives rise to the increased uptake. An all-atom molecular dynamics simulation was coupled with a kinetic gelation approach to study network formation in the presence of a template. The monomers used were first studied with density-functional theory in order to parameterize a force field for various methacrylates. Simulation results showed three key functional group interactions that lead to successful imprinting and subsequent rebinding.

Novel biomimetic polymer networks: development and application as selective recognition elements for biomolecules at the micro-/nanoscale

Abstract: Novel biomimetic polymer networks were developed that are entirely synthetic and tailored to have various properties and function. These artificial networks have numerous applications such as sensing elements in biosensors, intelligent drug delivery devices, and immunoassays. In comparison to biological entities, biomimetic polymer networks are advantageous because they can be designed to mimic biological recognition pathways and at the same time exhibit other abiotic properties that are more favorable, such as greater stability in harsh environments. For many applications, it is necessary to integrate these polymeric networks at the micro-/nano-scale. In our laboratory, procedures have been developed to facilitate this micro-/nano-scale application. A mask aligner was utilized to enable precise micropatterning of ultra-thin polymers films via UV freeradical polymerization. For the case where these organic polymer networks were patterned onto inorganic silicon substrates, an organosilane coupling agent was utilized to gain covalent adhesion between the dissimilar polymer network and the silicon surface. As an example application, a glucose microsensor was developed based on a patterned biomimetic polymer network designed to selectively recognize D-glucose among similar molecules via non-covalent complexation. Novel copolymer networks containing poly(ethylene glycol) dimethacrylate and functional monomers such as acrylic acid, methacrylic acid, and acrylamide were synthesized in polar, aprotic solvent (dimethyl sulfoxide). Results qualitatively and quantitatively demonstrate that these recognitive macromolecular networks are specific for the target molecule and can be effectively micropatterned in fine dimensions. These results are encouraging for the further development of functionalized micro-biosensors and diagnostic devices and are