1. Intelligent Biomaterials Protein Delivery Molecular Imprinting and Micropatterning
Nicholas A. Peppas

2. Our Laboratories 22 Researchers 12 Ph.D. students (8 ChEs, 4 BMEs)
3 Visiting scientists (Italy)
1 Technician
6 Undegraduate students
About 3,800 sq.ft. facilities
Modern equipment including cellular facilities
Budget of about $ 2M
Grants from NIH, NSF, industry

3. The Changing World of Biomaterials, Drug Delivery and Biomolecular Engineering
Formation and fabrication of supramolecular assemblies comprising natural biological elements, structures or membranes.
Synthesis and preparation of modified biological molecules
Biomolecules as the basis of nanostructures, molecular adhesives
Micropatterned and microfabricated arrays

4. Oral protein delivery

5. Oral Delivery of Proteins
“Oral delivery of peptides and proteins has long been dubbed the ‘Holy Grail’ of drug delivery…”
Why?
Increase patient compliance and comfort over other forms of drug delivery (i.e. injection)
Mimic physiologic delivery of proteins
Simple administration
Reduce costs
Potentially improve efficacy

6. Challenges of Oral Protein Delivery
GI Tract is designed to digest proteins and food.
Protect the drug
Acidic environment in the stomach
Proteolytic enzymes in the GI tract
Improve bioavailability
Increase drug transport across intestinal epithelium
Localize drug at targeted site of absorption
Maintain biologically active and stable drug

7. Transport for Oral Drug Absorption
Transport Mechanism
Transcellular pathway
Paracellular pathway
Transcytosis and receptor-mediated endocytosis
Lymphatic absorption through M cells
P-glycoprotein efflux (not shown)
Factors Affecting Transport
Molecular mass of drug
Drug solubility

8. In Vivo Study with pH-Responsive Complexation Hydrogels
P(MAA-g-EG) microspheres loaded with insulin
Administered to diabetic rats 40% drop in blood glucose levels
Prior work done by Tony Lowman

9. Carrier Mediated
Goal: Protect drug in the GI tract and be absorbed with drug by epithelial layer.
Biodegradable polymers, lectin modified carriers
Sites of uptake
M cells (majority of uptake)
Transcellular
Paracellular
Poor particle absorption
Florence, A. T. The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual. Pharm Res 1997, 3,

10. Mucoadhesion Upper small Intestine Stomach Mucosa Mucosa
Decomplexation
Mucosa
Mucosa

11. Blood Glucose Response in Healthy and Diabetic Wistar Rats

13. Caco-2 Cells as GI Model Spontaneously differentiate Produce enzymes
Advantages
Spontaneously differentiate
Produce enzymes
Posses tight junctions
Develop microvilii
Transport of inorganic molecules correlates well with the in vivo absorption
Disadvantages
Do not produce mucus
The properties are determined by the passage number

14. Nanodevices of Intelligent Gels for Protein Release
Empty hydrogel absorbs glucose
leading to gluconic acid production I
GOx I
GOx I I I G
GlucA
GOx I G G I G I
GlucA
GOx G
GlucA G I I
GlucA
GOx G G I G
GOx
Decrease in pH leads to gel expansion
which releases insulin
GlucA G I

15. Targetting and Nanotechnology
Targeted delivery for cancer therapy
Gene delivery
Long term treatment of chronic diseases

16. BioMEMS Sensor Platform
Pattern environmentally responsive hydrogels onto silicon microcantilevers to create a BioMEMS/MEMS sensor device.
Polymer
Silicon
Laser beam θ
φ > θ
Laser beam φ
Change in pH, temperature, etc.  hydrogel swells

17. Experimental Procedure
Surface Modification
Micropatterning

18. Micropatterned Hydrogel on Silicon Microcantilever
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 microcantilever A) B)
Top 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.

19. Confocal Images of Microarrays Acrylamide-PEG200DMA with 67% Crosslinking Ratio
3D 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.

20. Optical and Confocal Images of Micropatterns Acrylamide-PEG200DMA with 67% Crosslinking Ratio Microcantilever Shape B)
25 m
Control C)
Recognitive
50 m
Silicon
Polymer A)
Images 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.