Responsive Drug Delivery Systems

Applying micromachining, biosensors, telemetry, and other techniques at the interface of analytical chemistry and bioengineering to revolutionize drug delivery.

Sapna K. Deo, Elissavet A. Moschou, Serban F. Peteu, Leonidas G. Bachas, Sylvia Daunert - University of Kentucky Patricia E. Eisenhardt, ChipRx, Marc J. Madou - University of California Irvine

Akbari Abolfazl nanolife

Overview

Introduction Responsive drug delivery Sensing Delivery Microfabrication Telemetry Future perspectives and challenges

Introduction

Drug absorption, distribution and metabolism vary among individuals Individualized therapy Controlled release low therapeutic index high patient compliance Cannot respond individuals drug therapy

Responsive drug delivery

Located inside patients bodysense-deliver drug ICD (implantable cardio defibrillator) monitors heart beat Sensing: highly sensitive, selective and robust sensors-monitor small volumes of body fluids Protein engineering, molecular biology-bioreagents-biosensors Human physiology, physiological fluids- affect biosensors

Glucowatch- reverse iontophoresisinterstitial fluid. Medtronic MiniMed sensor, MiniMeds 2007 implantable insulin pump- 72 hrs Alpha Dx, the OPTI critical care analyser, the senDX 100, I-Stat point of care blood analysis Advantage of closed loop drug delivery: life sustaining benefit for cardiac serve as alarm angina, stroke, cancer, etc

Limitations: Biocompatability and foreign body response Solutions: use of biomimetic surfaces, polyethylene oxide coatings, NO releasing material Delivery: 2 types of commercial delivery system 1. implantable infusion pump 2. noninvasive reverse iontophoretic devices Piezo actuated silicon micropump using MEMS size 16X12X1.86mm, flow rate 100 l/h.

Types of drug delivery systems.

Main features Commercially available Implantable fusion pumps Noninvasive reverse iontophoresis devices Controlled release Duros implant technology Responsive Closed loop

Preprogrammed to deliver at any release rate through a catheter to a specific body location Electric current applied across skin to extract analyte from within/beneath the skin
Continuous release for pain medication, individually tailored using an osmotic gradient Delivers as a function of sensor signal;includes sensing and release systems

Responsive polymers Release from a smart polymer in response to a stimulus Micro and miniature systems Microfabricated sacrificial Contains nano- to low-microliter volumes of therapeutic agents in valves individually sealed reservoirs; drug is released by electrochemically removing each microvials lid Artificial muscle Based on a soft hydrogel and polymer blend miniature valves that mimics natural muscle functions

Duros controlled release device pain medication 4mm diameter, 44mm length holds 150L drug and deliver at rate 0.4L/day. Responsive delivery release physiological signal Smart polymers deliver drug biological stimulus Antigen-antibody interaction

Detection of S. aureus increased thrombin release antibiotic gentamicin Gentamicin bound-PVA hdrogel-peptide linker Thrombin-Biologically inactiveactive by leucine aminopeptodase Self-relating insulin delivery devices immobilizing glucose oxidase(GOx) in a pH-sensitive hydrogel Problems: Passive drug release, nonphysiological working pH, nonreproducible drug release, slow response time, biocompatability and limited lifetimes

Microfabrication:

Nonconventional MEMS polymeric materials control surface hydrophilicity and minimize protein absorption Microreservoirs store sensing reagents/active drug solid or liquid form Eg. Microchip based device mechanism elecrochemical dissolution of metal cover film Soft hydrogel and polymer valves-mimic natural muscle

Telemetry Wireless transmission of data Integrated with defibrillators, pumps or retinal prosthetics Monitor intrauterine pressure changes,body temperature and heart rate of a fetus Pill sized wireless cameras and image sensors endoscopic capsules

Future perspectives and challenges

Properties of responsive drug delivery device Combination of sensing and delivery Small and easy to implant and remove, patient compliance Long-lived, Biocompatible and inexpensive Inert, mechanically strong, comfortable for patient Safe from accidental release, easy to fabricate and sterilize and allow high drug loading Continuous monitoring, telemetric data transfer and allow physician intervention if needed

Control- circadian rhythm Covera-HS hypertension/angina pectoris Norplant - Subcutaneous implantation contraceptive device Incorporating telemetry access sensor and delivery at all times.