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Traditional Drug Dosing

Medicine or injections

Responsive Drug Delivery Systems Lecture 10

Each person responds uniquely Noticeable symptoms are not sufficient to support timely and accurate dosing Examples- diabetes, cardiovascular disease, acute pain Controlled release frequent exposure, side effects, tolerance



Responsive Drug Delivery System

Applying micromachining, biosensors, telemetry, and other techniques at the interface of analytical chemistry and bioengineering to revolutionize drug delivery Responsive drug delivery: Sensing Delivery Micro-fabrication Telemetry
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Responsive Drug Delivery Systems:

Combination of Biosensors & controlled release system Revolutionized medicine by enabling individualized therapy Sense continuously to manage unpredictable condition Immediate respond with appropriate countermeasure Give the patients more flexibility and less disruption of the daily life
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ICD (implantable cardio defibrillator)

Located inside patients bodysense-deliver drug 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

Insulin Pumps

An insulin reservoir (like a regular syringe) A small battery operated pump A computer chip for control Infusion set- a thin plastic tube to deliver insulin to the body Pump therapy

A basal rate & bolus insulin

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Combination with Glucose sensors

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Reverse iontophoresis (a.k.a. Electromotive Drug Administration (EMDA))- interstitial fluid. Biographer: non-invasive, watch-like device that measures glucose AutoSensor: a plastic part that snaps into the Biographer and sticks to the skin. Noninvasive & automatic reading every 10 mins up to 13h
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How does Glucowatch work?

Based on reverse iontophoresis A low electric current pulls glucose through the skin. Glucose is accumulated in two gel collection discs in the AutoSensor. Another electrode in the AutoSensor measures the glucose.
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Enzymatic pathway
Glucose oxidase catalyze oxidization of glucose in hydrogel Hydrogen peroxide reacts on the platinum electrode, providing electrons Current is proportional to glucose

Comparison of Glucose Readings






The Importance of Control

Advantage of closed loop drug delivery: life sustaining benefit for cardiac serve as alarm angina, stroke, cancer, etc Alpha Dx, the OPTI critical care analyser, the senDX 100, I-Stat point of care blood analysis Medtronic MiniMed sensor, MiniMeds 2007 implantable insulin pump- 72 hrs Programmed release controlled by microchips More flexibility & less pain Reduced the risk of side effects More than 200,000 people in the US wear insulin pumps








Types of responsive drug delivery systems

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.
02:22 Biosensors 13 Commercially available Implantable fusion pumps Noninvasive reverse iontophoresis devices Controlled release Duros implant technology Responsive Closed loop Responsive polymers Micro and miniature systems Microfabricated sacrificial valves Artificial muscle miniature valves 02:22 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 Release from a smart polymer in response to a stimulus

Contains nano- to low-microliter volumes of therapeutic agents in individually sealed reservoirs; drug is released by electrochemically removing each microvials lid Based on a soft hydrogel and polymer blend 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
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Controlled-release device

Affecting factors: Compositions of osmotic agent Thickness of semipermeable membrane Surface area

Antigen-antibody interaction smart polymers

A semi-interpenetrating polyacrylamide (PAAm) hydrogel Antigenrabbit immunoglobulin G (rabbit IgG) Antibodygoat antirabbit IgG (GAR IgG)

Antigen-antibody interaction smart polymers

Effect of free antigen concentration on the hydrogen swelling ration

Antigen recognition by antigen-antibody semi-IPN hydrogel

Takashi Miyata et al., Nature, vol 399 ,766 02:22 Biosensors 17 02:22 Biosensors 18


Antigen-antibody interaction smart polymers

Reversible swelling changes Antigen-responsive permeation (a model protein drug haemoglobin through a membrane fabricated from hydrogel )
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Schematic of a Self Regulating Responsive Therapeutic System

Nonconventional MEMS polymeric materials control surface properties 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

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

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
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Control- circadian rhythm Norplant - Subcutaneous implantation contraceptive device Incorporating telemetry access sensor and delivery at all times.