Technology Report

Group

MEMS in the Market

Technology Report

Mems in the market

Project Team

Name / E-mail / Backgrounds / Responsibilities
Ryan Dempsey / / Biomedical Engineering
Management of Technology /

Business team leader
Web site design

John Richardson / / Biomedical Engineering
Economics
BioMEMS /

MEMS technology design team leader

Peter Shanahan / / Biomedical Engineering
BioMEMS
Mathematics /

MEMS technology design

Charles Bloom / / Biomedical Engineering
Management of Technology /

Business team assistant
Legal

Rachel Weaver / / Biomedical Engineering
Management of Technology /

MEMS technology design assistant
Photography

Group 25 is composed of Ryan Dempsey, John Richardson, Peter Shanahan, Charles Bloom, and Rachel Weaver. The group was chosen based on a combination of biomedical engineering and business backgrounds. Because the senior design project deals specifically with BioMEMS technology, it is our intention to assemble a group with MEMS experience and biomedical engineering majors. Furthermore, the project includes a business portion, which develops a strategy to market the MEMS device to venture capitalists. Initially, the group entered a business competition called the MRS Challenge, but the group did not qualify for entrance due to a lack of graduate business students in the group.

Mems in the market – Technology report

Table of Contents

abstract...... 2

introduction...... 3

Biomems Background...... 3

Biomems market...... 3

Consumer Demand...... 4

Primary objectives/Goals...... 5

Performance criteria ...... 5

Methodology...... .6

Device Design...... 6

Device Fabrication...... 7

Flow Calibration...... 9

Device Testing...... 10

Equipment ...... 10

Results...... 11

Device Creation and Testing...... 11

Economics...... 13

Safety, health, and Risk...... 13

Conclusion...... 14

Informal Observations...... 14

recommendations...... 15

Changes...... 15

Future Work...... 15

Ethical Issues...... 15

Acknowledgements...... 16

Appendix A; Nanophysiometer proposal...... 17

Appendix B: Equipment...... 20

appendix c:QFD Diagram...... 21

Appendix D: Innovation WorkBench (IWB)...... 22

Appendix E: concept Diagram...... 27

Appendix F: Design Safe...... 28

Appendix G: Project Notebook...... 34

References...... 36

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Mems in the market – Technology report

Section

Abstract

In the proposal stage of our project, it was our intention to develop a tangible product to present in the Materials Research Society’s (MRS) Entrepeneurship Challenge. This is a competition that was designed to help members of MRS develop the entrepreneurial skill of placing laboratory technology in the market.

The MRS website1 states, “Through the Entrepreneurship Challenge, scientists and business students will form “virtual teams” to develop a 12-slide PowerPoint presentation that will present a startup technology to a panel of venture capitalist judges.” We decided upon BioMEMs Nanophysiometer devices as our startup technology. Unfortunately, we discovered that in order to be eligible for the Challenge, at least two graduate business students had to participate in our group. We decided to continue with the idea of the challenge and develop upon the idea of BioMEMs Nanophysiometer devices both technically and economically.

Because our group is larger than others, we found it necessary to go above and beyond the requirements of smaller groups. This report is made up of two sub-reports. The first of the two is the “Technology Report.” Our primary objective for the “Technology Report” is to create a bioMEMs lab-on-chip dual cell culture device at the pico-liter volume scale. The future objective for the “Technology Report” is for the dual-chamber device to allow for automated cell culturing and sensing for the testing of drugs and other perfused substances (also known as a nano-bioreactor). The second of the two is the “Business Strategy Report”. In it, we create a business proposal in order to market our technology to venture capitalists. Our long-term objective is to launch a start-up company based on our bioMEMs device. In order to do so, we must analyze the market for the device and the current demands for it. Also, we must analyze the corporate environment already in place for bioMEMs devices and the financing behind such ventures.

The development and results of our nano-bioreactor fabrication can be found in the “Technology Report”. The results entail the fabrication of an original dual-chamber nano-bioreactor. Included in the fabrication are two cell culture areas (600 μm x 600 μm x 15 μm), an input and output channel for experimental solutions and medium, and an input and output channel for the cells to be tested with pneumatic pressure values that allow for the cells to be trapped in the cell cultures during experimentation. The development and results of the business proposal are detailed in the “Business Strategy Report.” The market was found to be made up of two related industries: 1) major drug manufacturers and 2) drug delivery research. It was found that the bioMEMs drug delivery market will increase from 14.4 billion dollar industry to a 28 billion dollar industry between the years 2002 and 2005. It was estimated that our device will save $1 million per year in reagent, labor and disposal costs for over 10 assays. Furthermore, the Net Present Value (explained further in the “Business Strategy Report”) was estimated near $7 million, an indication for profitability.

With the results from both reports, it is seen that the development of such a technology described in the “Technology Report” has great potential in the drug development industry. Implementing the suggested design updates presented in this lab could change the drug development industry all together.

Section

Introduction

A lab-on-chip (LOC) device is a micro-scale laboratory utilizing a network of micro-channels, electrodes, sensors, and electronic circuits. 2BioMEMS, a type of LOC, are bio-functionalized microelectromechanical systems (MEMS) that are designed for usage in biomedicine and bioengineering. The term MEMS was created in the late 1980s to develop sensors and actuators out of the basic integrated circuitry micro-fabrication technologies, utilizing silicon as the primary substrate and structure material. The term bioMEMS first appeared in the early 1990s as MEMS was applied in medicine and bioinstrumentation.

BioMEMS can be divided into two main categories: (1) in vitro bioMEMS, and (2) in vivo bioMEMS. In vitro bioMEMS deals primarily with samples from the body. For example, blood, tissue, serum, urine, and saliva are among the most common body fluids studied. In vivo bioMEMS deals with the living host anatomy. Applications include long term medical implants, surgical tools, artificial organs, and drug delivery.3

In order to understand the market for BioMEMs devices, several areas of the market must be analyzed. First, the market must be defined. The primary market for our BioMEMS device includes companies involved in one of two related industries: (1) major drug manufacturing, or pharmaceuticals, and (2) drug delivery. The pharmaceutical industry comprises companies primarily engaged in one or more of the following:

manufacturing biological and medicinal products;
processing botanical drugs and herbs;
isolating active medicinal principals from botanical drugs and herbs; and
manufacturing pharmaceutical products intended for internal and external consumption in such forms as tablets, capsules, vials, ointments, powders, or solutions.

The drug delivery industry comprises companies developing systems by which therapeutic agents are introduced into the body, and directed in a controlled way towards a target organ or site of action. Conventional drug delivery forms are simple oral, topical, inhaled or injection formulations.

Currently, the top three drug manufacturing companies, by market capitalization, include Pfizer Inc., Johnson and Johnson, and GlaxoSmithKline. The top three drug delivery companies, by market capitalization, include Hospira Inc., Elan Corporation, and Biovail Corporation4Figure 1 displays all potential market applications for our microfluidic device. The primary applications for our BioMEMS device include high-throughput drug screening, clinical diagnostics, and genetic analysis. Our device will assist scientists by evaluating the effectiveness of a given drug to living cells.

In order to get a grasp on the market potential of our device, we must realize the market size with which we are dealing. Our dual-chamber MEMS device has enormous market potential. BioMEMS is predicted to have the fastest growth rate within the entire MEMS market, particularly biomedical applications such as drug discovery and delivery. BioMEMS applications will consist of approximately 16% of the entire $10.9 billion MEMS market. Research firm UBS Warburg estimates that the BioMEMS drug delivery market in the U.S. alone will go from $14.4 billion in 2002 to $28 billion in 2005. 5

The cause for this high demand is the increase in research and development (R&D) costs incurred by the drug companies. Currently, billions of dollars are spent finding “blockbuster” drugs by major pharmaceutical companies. Because of large amount of money that can be earned in the global healthcare market, these companies are spending more and more money on research and development (R&D) of new drugs. Despite rapid growth in outsourcing R&D activities over the last few decades, pharmaceutical companies have significantly expanded the number of their own employees devoted to the R&D of the company. Applying a real growth rate of 1.76% per year for compensation to a growth rate of 7.4% per year in employment yields a growth rate of 9.3% per year in labor costs for pharmaceutical companies. Given these labor costs, it would be in the best interests of a pharmaceutical company to save money on labor costs by utilizing new, more efficient technologies. Major pharmaceutical companies spend an average of $802 million and 10 to 15 years researching and developing a drug to come to the market9. Comparing this to the 1987 average of $231 million and the 1976 average of $54 million, it is quite obvious that developing new drugs has gotten extremely expensive6.

Lastly, we need to analyze the demand for such a device. In order for our bioMEMS device to have market success, a particular emphasis and effort should be placed on identifying the needs of our customers (i.e. pharmaceutical companies) and offering appropriate solutions. Among the most current demands given by major pharmaceuticals include7:

Cost efficiency
Development of detection technologies (i.e. on-chip sensors)
Interfacing micro and macro scales
Reliable bonding metal electrodes onto polymer substrates.

Further market analysis can be found in the “Business Strategy Report.” In order to capture the market potential for such a device, the consumer demands must be met. Our goal is to offer a dual-chamber LOC nano-bioreactor. A dual-chamber bioMEMS device allows double the experiments to be performed on fewer chips, thus saving time and money. Also, the cell-to-volume ratio of our MEMs device is much greater than the Petri dish or T flask. This means two things: 1) the MEMs device is closer to in vivo cell-to-volume ratios, and 2) more accurate measurements of the cell medium can be obtained. Furthermore, our device will also decrease labor costs and reagent costs, thus promoting cost efficiency. In order to analyze the efficacy of drugs on the cell culture, sensors that enable the user to analyze the consistency of the cell culture medium must be fabricated into the device. This would allow one to detect cell metabolism in response to a drug.

The primary goal of the project was to create a bioMEMs lab-on-chip dual-chamber cell culture device at the pico-liter volume scale and discuss its marketability. The first step in accomplishing this goal was to create design parameters for such a device. The following are the device specs that we wished to accomplish:

Create a dual-chamber LOC cell culture device with each culture chamber at the pico-liter scale
Create separate perfusion channel inputs and outputs that allow for the cell cultures to be independent of one another
Create a pneumatic valve system to both shutoff cell input and prevent cell’s from leaving the cell chamber
Design a mixing system to use diffusion to mix substances
Circular perfusion inlets to allow user-friendly cell and fluid insertion
Design the cell culture chamber so that the cell resides below the perfusion inputs from a cross sectional perspective to contain cells
Addition of Clark oxygen sensor to measure cell metabolism
Addition of a carbon dioxide, lactate, and glucose sensor
Improve the perfusion system

Because of time restraints, we knew that accomplishing all of these design parameters would be difficult. We listed the parameters in order of importance and tangibility in order to accomplish as much as possible in such a little time period. Thus, our primary goal became the creation of a dual-chamber device and to show perfusion and cell input capabilities. Our secondary/future goals are to fabricate a plethora of sensors onto the LOC in order to analyze the metabolism of the cells in culture.

The problem with LOC is that there are several design issues or criteria that must be addressed in order to achieve proper results. First, the liquid filling of the device must avoid entrapment (presence of air bubbles). Three steps must be done carefully in order to avoid entrapment: 1) careful design of the device, 2) proper control of the filling process, and 3) proper selection of materials. In our case, our channels are large enough that entrapment should not be a problem. Secondly, the filling process will be done strictly by gravity, thus avoiding the creation of bubbles due to turbulent flow. Lastly, the device will be made up of a silicon-type material (PDMS) and glass, both of which will not have significant adhesion problems. Also, the nano-bioreactor must allow for cells to be injected into the cell culture area. To achieve this, the cell input and output channels must be large enough to allow for cells to pass through (15μm x 15 μm). Second, the user must be able to capture the cells in the cell culture volume in order to conduct experiments. To achieve this, we will implement pneumatic pressure values for the cell input and output channels. Third, the perfusion input must mix thoroughly in order to achieve consistency when entering the cell culture area. One problem with microfluidic devices is that the fluid flow is strictly laminar with very low Reynold’s numbers (<10). Because of this, the mixing of the solutions is strictly based on diffusion. In order to mix via diffusion, a mixing pattern was designed into the device at the perfusion input and output. Lastly, the output or waste of the two cell culture volumes must remain separate in order to keep the two experiments independent of one another.2

The contents of this report are broken down into two parts. The first part, “Technology Report”, details the design and development of a dual-chamber bioMEMs nano-bioreactor. It details the design steps, the fabrication steps and the testing of the device. The second part, “Business Strategy Report”, details the marketability of such a device. The first section of the “Business Strategy Report” defines the market of bioMEMs by characterizing the market size, strategic positioning, consumer pricing, and market drivers and barriers. Later sections of the “Business Strategy Report” include the technological environment of the device, the corporate environment of bioMEMs, the economic and government policies for such a device and a project valuation.

Section

Methodology

The proposed goal for this project was to create a theoretical device and present its market potential to venture capitalists through the Materials Research Society’s (MRS) Entrepreneurial Challenge. This is a competition that was designed to help members of MRS develop the entrepreneurial skill of placing laboratory technology in the market.

The MRS website1 states, “Through the Entrepreneurship Challenge, scientists and business students will form “virtual teams” to develop a 12-slide PowerPoint presentation that will present a startup technology to a panel of venture capitalist judges..” We decided upon BioMEMs Nanophysiometer devices as our startup technology. Unfortunately, we discovered that in order to be eligible for the Challenge, at least two graduate business students had to participate in our group. We decided to continue with the idea of the challenge and develop upon the idea of BioMEMs Nanophysiometer devices both technically and economically.

Device Design

The primary goal of the project was to create a bioMEMs lab-on-chip dual-chamber cell culture device at the pico-liter volume scale and discuss its marketability. The first step in accomplishing this goal was to create design parameters for such a device.There were several preliminary design goals that we wished to accomplish:

Create a dual-chamber LOC cell culture device with each culture chamber at the pico-liter scale
Create separate perfusion channel inputs and outputs that allow for the cell cultures to be independent of one another
Create a pneumatic valve system to both shutoff cell input and prevent cell’s from leaving the cell chamber
Design a mixing system to use diffusion to mix substances
Circular perfusion inlets to allow user-friendly cell and fluid insertion
Design the cell culture chamber so that the cell resides below the perfusion inputs from a cross sectional perspective to contain cells
Addition of Clark oxygen sensor to measure cell metabolism
Addition of a carbon dioxide sensor
Addition of lactate sensor
Improve the perfusion system
Addition of glucose sensor

The list above was ranked in order of importance. Because of time restraints, we knew that it might not be possible to accomplish all of our preliminary goals. The cross section of our very first design sketch is shown in Figure 2. The aerial view of the first design sketch is shown in Figure 3.This design includes a dual-chamber cell culture fitted with pneumatic pressure valves, perfusion and cell inputs and outputs that allow for independent testing, a “ditched” cell culture chamber, a “mixer” design for input channels and circular perfusion inlets. We also had to calculate the necessary dimensions for the system. The basic requirement was to allow cells to move through the channels. We knew that most fibroblasts that would be used are around 10 μm in diameter. Considering that this diameter was an average, we decided upon using 15 μm as the minimum sizeof the channels and chamber to allow for the cells to pass easily. Next, we decided upon a 600 μmx 600 μm cell culture area. This large area would allow for sensor fabrication in later steps. Each branch seen entering the cell culture areahas a cross-sectional area of 100 μm x 15 μm. The larger input and output branches seen toward the exterior of the view are 200μm x 15 μm. These cross-sectional areas are ample space for the cells and solution mixtures to pass through to the cell culture chamber. The cell culture chamber was calculated to have a volume of 5.4 pL. The next step was to move from design into development.