College of Medicine and Public Health USDA & Nanotech Delivery of (Bio)molecules ? Mauro Ferrari,...

College of Medicine and Public Health

USDA & Nanotech Delivery of (Bio)molecules ?

Mauro Ferrari, Ph.D.Associate Vice President,

Health Sciences, Technology and Commercialization

Edgar C. Hendrickson Professor of Biomedical Engineering

Associate Director,

Dorothy M. Davis Heart and Lung Research Institute

Professor of Internal Medicine & Mechanical Engineering

M.D. student

USDA – November 18, 2002


From a Drug-Delivery Perspective

• Proposed Analogy: – Smart drug-delivery systems & smart delivery

of nutrients?

• Smart = any combination of:– Spatially Directed – Time-Controlled Release Profile– Intelligent Control:

• Remotely regulated• Pre-programmed

• Self-regulated


En route to self-regulated….

• Integration of:

–Sensing of target trigger

–Intelligence onboard

–Release technologyon delivery implant or particulates for oral,

intravascular, transdermal or aerosol delivery


Crucial Bottlenecks *

• Stability of Implanted Sensing Technology: To Develop Antifouling Tech, or Fouling-Insensitive Strategies?

• Availability of Appropriate Disease Markers

• (On-board Logics Linkage Between Sensing and Therapeutic Delivery)

• “SMART” DELIVERY TECHNOLOGY

*From NIH BECON’s Active Disease Management, 6/25/02


Three examples of use of (top-down) nanotech

• Nanopores for controlled release of biomolecules

• Nanopores for immunoprotected implantation of cell bioreactors

• Multifunctional particles for the oral delivery of biological molecules

(from my lab and iMEDD, Inc – please note that I have a financial interest in iMEDD)


Silicon Wafer

Etch Trenches

Deposit SacrificialOxide Layer

Deposit PolySilicon Structural Layer

NanoPORE Fabrication Process


Planarized

Apply Etch Stop

Back Etch

Remove Etch Stop



Remove Sacrificial Oxide



Array of NanoPOREChannels



NanoPUMP Implantable Drug Delivery Device

Iso-osmotic Iso-osmotic electrolyte primer solutionelectrolyte primer solution

Check valve (closed)Check valve (closed)AnodeAnode CathodeCathode PlungerPlunger

VentVentSwitch (open)Switch (open)

Release orificeRelease orifice

Drug/electrolyte solutionDrug/electrolyte solution

Nanopore membrane arrayNanopore membrane array

Battery packBattery packBiocompatible encasementBiocompatible encasement

Check valve (opened)Check valve (opened) Advancing PlungerAdvancing PlungerVentVent

Switch (closed)Switch (closed)

Released DrugReleased Drug

Drug/electrolyte solutionDrug/electrolyte solution


NanoPORE Array

SEM showing top views of parallel 50 nanometer pores (each 45 m long)

Pore

Anchor

Top View

Poly Silicon Beam


Molecular

Dim

ensions

500 nm500 nm

NanoPORE Array

Cross Section View


NanoGATE Glucose Diffusion

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16

Time (days)

Glu

cose

Re

lea

sed

, (m

g)

7nm-#3 13nm-#3 20nm-#1 27nm-#3

Total Amount Loaded


0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

Data(26 nm)Fick (26 nm)Data(13 nm)Fick (13 nm)

Albumin Diffusion Kinetics

Time (Days)

Cum

ulat

ive

Per

cent

Rel

ease


Robotic surgery meets nanotech


BIOCAPSULE/1History of Cell Encapsulation

Active research field for over three decades

Previous focus has been entirely on natural or synthetic polymeric biocapsules [Chang, 1967; Lim & Sun, 1980;

Lacy, 1991; Lanza, 1992; Soon-Shiong, 1993;

Scharp; Hubbell; and many more...]

Limitations associated with premature biodegradation, chemical and mechanical instability, and broad pore size distributions


Animal # 2 (Insulinoma)

050

100150200250300350400450

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days POD

Blo

od G

luco

se

(mg/

dL)

180

190

200

210

220

230

240

250

Bod

y W

eigh

t (g)

Blood Glucose

Body Weight

Figure 11. Non fasting blood glucose concentration and body weight in STZ-diabetic Lewis rat after biocapsule implantation

Cell Transplant BiocapsuleCell Transplant Biocapsule

Implant containing cells Implant containing cells to produce insulin (or to produce insulin (or other therapeutic agent)other therapeutic agent)

Membrane protects Membrane protects transplanted cells from transplanted cells from immune attackimmune attack

Phase 2 SBIR Grant Phase 2 SBIR Grant applicationapplication

Figure 8. IgG Diffusion into biocapsule


The Programmable PillBy Alexandra Stikeman

Technology ReviewMay 2001

Vol. 104/No.4, pp.78-83

Starting with oral…..


Enteric coating protects drug-loaded particles in acidic stomach

Capsule dissolves in intestines releasing drug-loaded particles

Particles adhere to intestinal wall and transport contents into the blood stream

Oral Peptide Delivery:Transport through the GI Tract


Anatomy of Intestinal Mucosa


Intestinal Mucosa: Tight Junction Complex


120 m

120 m

(a) Particles on Substrate

(b) Released Particle

(c) Pores in Particle

Size: 150 – 300 mThick: 25 m Pore Size: 20 – 100 nmPorosity: 70%

Microfabricated Porous Silicon Particles


Porous Silicon Particles

College of Medicine and Public Health NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2 NH2

NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2 NH2 NH2

NH2

NH2

NH2

NH2

H2N

H2N

H2N

NH NH NH NH NH NH NH NH NH NH NH NH

NHNHNHNHNHNHNHNHNHNHNHNH NH NH

NH

NH

NH

NH

HN

HN

HN

Porous Silicon Particles




NH

NH

NH

NH

HN

HN

HN



NH

NH

NH

NH

HN

HN

HN


Vasculature

Intestinal epithelial

cells

Intestinal mucin

Microfabricated Trans-Mucosal Patch

For Delivery ofBiologically Active Peptides and Proteins

Intestinal lumen

NH

NH

NH

NH

NH

NH

NH

NH

NH

1. Lectin mediates binding 1. Lectin mediates binding of particle to mucosaof particle to mucosa

NH

NH

NH

NH

NH

NH

NH

NH

NH


Vasculature


cells

Intestinal mucin



Intestinal lumen

2. Thru-particle hydration 2. Thru-particle hydration releases drug + enhancerreleases drug + enhancer

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH


Vasculature


cells

Intestinal mucin



Intestinal lumen 3. High local 3. High local

concentration of concentration of enhancer + drugenhancer + drug

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .... ... . .. ... . ... ... . .. ... ..

.. ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .N

HNH

NH

NH

NH

NH

NH

NH

NH


Vasculature


cells

Intestinal mucin



Intestinal lumen

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .... ... . .. ... . ... ... . .. ... ..

.. ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

4. Enhancer opens 4. Enhancer opens tight junctionstight junctions

NH

NH

NH

NH

NH

NH

NH

NH

NH


Vasculature


cells

Intestinal mucin


Intestinal lumen

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .... ... . .. ... . ... ... . .. ... ..

.. ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

... ... . .. ... . ... ... . .. ... .... ... . .. ... . ... ... . .. ... . ... ... . .. ... .... ... . .. ... .

5. Drug passes 5. Drug passes between cells between cells and enters and enters blood streamblood stream

.............

.............. .. .. .. .. .. ..

.

. .. .. .. .. .. .. .. .. .. .. .. . .

..... .. .. .. ... .. .. .. .. .. ..

.. .. .. .. .. .. .

.............

.............

.............

.......................................

....................................... .......

................................

.......................................

.............

. ... ...... ...

.............

. ............

.............

. ...................................................

.......................................

.............

.............

.............

.......................................

.......................................

NH

NH

NH

NH

NH

NH

NH

NH

NH



Relative Size of Trans-Mucosal Patch


0

5%

10%

15%

20%

25%

ControlControl OralMEDDSOralMEDDSParticlesParticles

Tra

nsp

ort

of

Insu

linT

ran

spo

rt o

f In

sulin

(% o

f d

os

e/h

r)

(% o

f d

os

e/h

r)

((~2%)~2%)

((~22%)~22%)

Enhanced Transport of InsulinEnhanced Transport of InsulinCACO-2 Intestinal ModelCACO-2 Intestinal Model

Oral MEDDS ParticlesOral MEDDS Particles


Strategy: Need FACILITIESStrategy: Need FACILITIES

Science Village at Ohio State

MicroMD

First Dedicated bioMEMS/Nanotechnology R&D

Facility


Thanks

[email protected]

College of Medicine and Public Health USDA & Nanotech Delivery of (Bio)molecules ? Mauro Ferrari,...

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