Intelligent BiomaterialsProtein Delivery Molecular Imprinting and MicropatterningNicholas A. Peppas

Our Laboratories22 Researchers12 Ph.D. students (8 ChEs, 4 BMEs)3 Visiting scientists (Italy)1 Technician6 Undegraduate studentsAbout 3,800 sq.ft. facilitiesModern equipment including cellular facilitiesBudget of about $ 2MGrants from NIH, NSF, industry

The Changing World of Biomaterials, Drug Delivery and Biomolecular EngineeringFormation and fabrication of supramolecular assemblies comprising natural biological elements, structures or membranes.Synthesis and preparation of modified biological moleculesBiomolecules as the basis of nanostructures, molecular adhesivesMicropatterned and microfabricated arrays

Oral protein delivery

Oral Delivery of ProteinsWhy?Increase patient compliance and comfort over other forms of drug delivery (i.e. injection)Mimic physiologic delivery of proteinsSimple administrationReduce costsPotentially improve efficacyOral delivery of peptides and proteins has long been dubbed the Holy Grail of drug delivery

Challenges of Oral Protein Delivery

Protect the drugAcidic environment in the stomachProteolytic enzymes in the GI tractImprove bioavailabilityIncrease drug transport across intestinal epitheliumLocalize drug at targeted site of absorptionMaintain biologically active and stable drugGI Tract is designed to digest proteins and food.

Transport for Oral Drug AbsorptionTransport MechanismTranscellular pathwayParacellular pathwayTranscytosis and receptor-mediated endocytosisLymphatic absorption through M cellsP-glycoprotein efflux (not shown)

Factors Affecting TransportMolecular mass of drugDrug solubility

In Vivo Study with pH-Responsive Complexation HydrogelsP(MAA-g-EG) microspheres loaded with insulinAdministered to diabetic rats 40% drop in blood glucose levelsPrior work done by Tony Lowman

Carrier Mediated

Biodegradable polymers, lectin modified carriersSites of uptakeM cells (majority of uptake)TranscellularParacellularPoor particle absorption

Goal: Protect drug in the GI tract and be absorbed with drug by epithelial layer.

Florence, A. T. The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual. Pharm Res 1997, 3, 259-266.

MucoadhesionMucosaMucosaDecomplexation

Caco-2 Cells as GI Model AdvantagesSpontaneously differentiateProduce enzymesPosses tight junctionsDevelop microviliiTransport of inorganic molecules correlates well with the in vivo absorptionDisadvantagesDo not produce mucusThe properties are determined by the passage number

Nanodevices of Intelligent Gelsfor Protein ReleaseGOxGOxGlucAGOxGOxGEmpty hydrogel absorbs glucoseleading to gluconic acid productionDecrease in pH leads to gel expansionwhich releases insulinGGGGGGlucAGlucAGOxGOxGGGGGlucAGlucA

Targetting and NanotechnologyTargeted delivery for cancer therapyGene deliveryLong term treatment of chronic diseases

BioMEMS Sensor PlatformPattern environmentally responsive hydrogels onto silicon microcantilevers to create a BioMEMS/MEMS sensor device.

Experimental ProcedureSurface Modification

Micropatterning

Micropatterned Hydrogel on Silicon MicrocantileverTop view images obtained utilizing an optical microscope in Nomarski mode showing a silicon microcantilever patterned with an environmentally responsive hydrogel. In A), the focus is on the substrate, while in B), the focus is on the microcantilever tip. Profilometry indicated that the thickness of the patterned hydrogel is approximately 2.2 mm.Volume shrunk as the polymerization proceeded

Polymer adhered to silicon surface and could not shrink at the interface, resulting in stress formation in the polymer film

This stress in the polymer film resulted in bending the microcantileverA)B)

Confocal Images of MicroarraysAcrylamide-PEG200DMA with 67% Crosslinking Ratio3D Projection of micropatterned recatangular array of a biorecognitive networks obtained utilizing a confocal microscope. Profilometry indicated that the thickness of the micropatterns are approximately 13 mm.

Optical and Confocal Images of MicropatternsAcrylamide-PEG200DMA with 67% Crosslinking RatioMicrocantilever ShapeImages of micropatterned biorecognitive networks. In A), an optical image (Nomarski mode) of recognitive network patterned in shape of cantilever is demonstrated. In B) and C), a confocal microscope slice through middle cantilever pattern of a control and recognitive network, respectively, are shown. Profilometry indicated that the thickness of the micropatterns are approximately 13 mm.RecognitiveControlB)C)