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我们的2009新年音乐会获得了巨大成功，今天来自各界的好评如潮。整个晚会的各个方面我觉得都没有任何遗憾，完全显示了我们强大团队的超强实力。晚会那天我场内场外穿梭，看到大家都那么认真那么团结的在一起工作，心里好感动！演出的时候我们有不少成员在Reception坚守岗位，不少人在后台忙碌而无法欣赏精彩的节目。希望有机会我可以单独弹琴给你们听。

从音乐会的筹备到举办有数个月的时间，各个方面我们都付出了诸多努力。我们顶着很大压力，背负高强度的work load，还有苛刻的director和coordinator等施以淫威，大家都吃了不少苦，受了不少委屈。但是这一切都是值得的，因为我们的努力可以让几十甚至上百位在国内贫困地区的失学儿童重返校园。我们在还没有走出校园的时候就已经可以为社会作出这样的贡献，可以回报我们的祖国，可以改变很多孩子们的未来，我相信我们每一个人都应该为自己感到骄傲。

我在这里还要特别提到三个人：Max，Han，和诺。

Max作为整个音乐会的coordinator，他的付出有目共睹，他几乎已经把音乐会和杂志社当做自己的full-time job。他有很强的工作能力和执行力，并且敢于承担责任和风险，这一点我很钦佩。同时我也很欣赏工作就像打仗一样的人。他虽然有时候挺生猛的，但是我们看到当500个人涌进小小的auditorium时，场内秩序井井有条。他是在2月7日忙碌了超过20个小时的人。请大家给Max热烈的掌声！

Han为了音乐会节目单的制作、海报和Thank-You Card的设计、以及我们最新的2009春季刊杂志的排版，可谓是呕心沥血鞠躬尽瘁死而后已。他的电脑烧坏了，于是每天都在下班后留在办公室忙杂志的事。一直以来，杂志的排版对于整个美编组都是巨大的工作量，而Han这次一个人在短时间内完成了全部工作，而且做得如此好，我必须承认他是超人。请大家给Han热烈的掌声！

诺在音乐会节目编排上给了我很多宝贵的意见。他和我组织的team在4天内为音乐会卖了85张票。2月7日当天他被我9点就弄到了现场，整整一上午都站在podium里制作晚会开场前播放的slide show，而下午则在场内场外跑堂。演出时，他成为了前台后台沟通的中流砥柱，舞台的灯光一直是他控制，还不断用自己的手机跟二楼通信确保spot light完美运作。他当天接近20个小时的工作完善了晚会很多细节，解决了大量麻烦。请大家给诺热烈的掌声！

音乐会的成功举办离不开我们每一位的努力和汗水。我们再次以实际行动和事实证明了International Student Center的Director Mr. Ben Yang的话——我们是多大20年以来最成功的学生组织。

让我们再接再厉，办好接下来的企业家论坛，办好今后的每一期杂志和每一个活动，因为EXCELLENCE is our STANDARD，SUCCESS is our RULE。

　
附：诺写的音乐会主持人开场白（雷）

黑暗中迸发出光芒，于是远方的孩子能被启迪
寂静里流淌出乐音，于是黄河的子孙低声歌吟
我们的所在此刻月色朗朗，夜幕低垂
而遥远却又熟悉的彼岸正迎来黎明前的曙光
他们的心灵此时稚嫩透亮，嗷嗷待哺
而真实却又残忍的贫穷正要夺去他们的未来
今夜我们聚在这里，手心中燃烧着火焰，要将光和热传递
今夜我们聚在这里，心灵中盛开着花朵，要将美和爱播种
越过这深蓝的海水，有那样一种情感在向着心的方向起航
跨过这深邃的天空，有那样一份思念在朝着爱的目标飞翔

详细信息请访问多大中文官方网站：http://www.utchinese.org

Speakers: Eva Furczon, Thomas O’Sullivan, Gavin Ouyang, Gurdeep S. Shah

Breast cancer is the second most common type of cancer and the fifth most common cause of cancer death worldwide. Treatments of the disease include radiation therapy, chemotherapy, hormone therapy, and immunotherapy. The cancer cells are usually found over express markers including estrogen receptor, progesterone receptor, and HER2+, which have been used as targets of hormone therapy and immunotherapy. An example of a humanized monoclonal antibody used in immunotherapy is Herceptin (trastuzumab), an antibody which binds to the HER2+ receptor and leads to G1 growth arrest of the cell.

Traditionally, monoclonal antibodies for the treatment of breast cancer are made from mammalian cell cultures. This process is expensive, time intensive, and has a limited global capacity which is approaching its threshold. It is clear that the pharmaceutical industry must consider alternative production methodologies.

PlantFORM, established in early 2008, is currently investigating the production of monoclonal antibodies using tobacco plants as bioreactors. Plants can offer advantages such as lower cultivation and scalability costs, high yields, and low capital investments. By creating recombinant humanized antibodies in transgenic tobacco plants, PlantFORM aims to cost effectively generate biosimilars.

This seminar will evaluate the regulatory, manufacturing, and technical hurdles PlantFORM is currently facing, and make recommendations based on our analysis. The BioIntelligence Group believes that a paradigm shift towards plant bioreactors is necessary such that commercial production of monoclonal antibodies remains viable, available and affordable to patients.

Date and Time: 6:30pm, Tuesday, January 27, 2009
Location: CCT 3150, University of Toronto Mississauga

For webcast information please click here.

A Different Concert for a Different Future

演出时间
7PM (Doors Open @ 6:15PM)
Saturday, February 7th, 2009

演出地点
J. J. R. Macleod Auditorium (MS 2158)
Medical Sciences Building, University of Toronto
1 King’s College Circle, Toronto ON M5S 1A8

Logo设计说明
1、图形由两个音乐符号构成（左边是4/4节拍号，右边是低音谱号）
2、两个音乐符号形似09
3、两个音乐符号组合出爱心的形状，体现音乐会慈善的性质
4、颜色使用多大中文标志性的红色

查看多大中文2009新年音乐会详细信息

详细信息请访问多大中文官方网站：http://www.utchinese.org

Interview with Dr. A. T. and Dr. M. H.

Please describe a “typical” day at work. What do you do all day?

Dr. A. T.: I don’t have a “typical” day, everyday can be quite different. But what they have in common is traveling a lot. For example, visiting companies and universities to find out what they have, what they need, and what we can offer to them.

Dr. M. H.: At 20% of the time I deal with human resource issues and manage employees. 40% of my time would be spent on telephones, for example, talking to clients, talking about our projects, talking about our products and services, etc. 20% of the time would be related to financial, business development and project management issues. The remaining 20% of the time would be spent on strategic planning, technology review, and long-term development of the company.

What are the most critical problems you face as a manager?

Dr. A. T.: The major problems are “human problems”. You have to have strong communication skills and interpersonal skills. Different people have different personalities, and this can cause a variety of issues. It’s not like the old days that a company reinforces strict hierarchical structures; nowadays we should work with people in a team. The “people skill” becomes critical.

Dr. M. H.: The first problem is the consistency of technical talents and dealing with employee turnovers. It has always been very difficult to find the “perfect person”. We are not just looking at their skill sets, but also their personalities. The second problem is the changing economic conditions which can have significant impact on the sales cycles and our business development.

What are the most critical skills needed to be a successful manager in your line of work? Why?

Dr. A. T.: Communication skills and interpersonal skills. Leadership skills are also very important, and the manager needs to be able to inspire and motivate other people in the team.

Dr. M. H.: Leadership skills, performance management skills, and human skills (both internal and external) are all important. Internal human skills allow one to work well in the team, and external human skills allow one to work well with our clients and customers. Communication, negotiation and interpersonal skills are a few examples of the human skills. Moreover, a successful manager should be able to recognize and define the goals, coordinate oneself, and coordinate the team very well.

What are the main reasons managers fail in positions like yours?

Dr. A. T.: Lack of the ability to deal with “human issues”, as I explained earlier.

Dr. M. H.: Lack of focus, not focusing on the key targets and objectives, not thinking strategically, not recognizing economic changes, lack of risk management, inability to deal with various random events.

What are the outstanding skills or abilities of other effective managers that you’ve known?

Dr. A. T.: I’ve known managers that can build the level of trust and integrity in the team. This ability is what I’d like to stress.

Dr. M. H.: Managers has different styles, but what they share in common are the skills and abilities I mentioned earlier. They are able to get people listen to them.

If you had to train someone to replace you in your current job, what key abilities would you focus on?

Dr. A. T.: Like what we have discussed earlier, I will focus on the communication skills and the interpersonal skills. The ability of interacting with people effectively makes management effective.

Dr. M. H.: Ability to learn, patience, ability to manage various changes effectively, and general intelligence would be the main focus. Also the person should be able to get along with people very well.

Is there a particular book, magazine or article about management you have found useful in your career?

Dr. A. T.: There are hundreds. I’m currently reading “The Trusted Advisor”. There is an old book called “How to Pick Men”, which teaches you how to conduct job interviews and pick the “right” people.

Dr. M. H.: Many books written by Jack Welch are highly recommended. Also I read “Harvard Business Review” magazines and various articles on the Internet.

Discussion

Dr. A. T. and Dr. M. H. are from companies with completely different objectives, businesses and market niches. It is therefore interesting to learn the opinions from Dr. A. T. and Dr. M. H. who have very different backgrounds and work in very different environments.

The daily activities of the managers depend on the businesses of the companies. Although Dr. A. T. and Dr. M. H. have very different “typical” days, they share two similarities. Firstly, they did not indicate that they participated in the execution of specific tasks, and secondly, they spent significant amount of time on human interactions. In other words, communication with people represents an important portion of their daily activities.

Dr. A. T. indicated that the most frequently used skills and engaged behaviors including delegating, listening actively, empowering others, consensus building, and negotiating, followed by managing personal time and stress, facilitating group decision-making, creative problem solving, managing conflict, attending or conducting meetings, motivating others, making analytical decisions. Most of these were related to team work issues of which communication played a central role. In other words, much of the effort had been put into facilitating team function and productivity. Dr. A. T. also emphasized on consensus building, illustrating the point that a team functions when its members agree with the same goals/objectives.

Dr. M. H. indicated that the most frequently used skills and engaged behaviors including creative problem solving, listening actively, and negotiating, followed by managing conflict, facilitating group decision-making, articulating an energizing vision, delegating, managing teams, attending or conducting meetings, giving oral presentations, empowering others, doing email, motivating others, setting specific goals and targets, and making analytical decisions. Most of these are also related to team work issues, again illustrating the importance of team rather than individual work.

Moreover, Dr. A. T. and Dr. M. H. both indicated that they didn’t like gaining and using power. Dr. A. T. said it “probably the worst thing to do” and considered it a disruption of team work. In addition, it was out of my expectation that holding interviews wasn’t rated as a very frequent daily activity. It’s probably because they are in the senior management team and have more important issues to deal with, and the general interviews are to be carried out by junior managers and human resource staffs.

Although Dr. A. T. and Dr. M. H. face different sets of problems in management, human issues have been common to both. It suggests that as a manager, one should not only able to deal with “human problems” within a team and/or company, but also able to find the right person for the right place. My father has been a very successful entrepreneur in the printing and packaging industry in China, and he told me that a good leader naturally attracts others to work for him. Such attraction may be due to some “intrinsic” characters and/or personalities of the leader, but to work with people efficiently and to make people willing to work with him are nevertheless of the most critical problems in management.

The next four interview questions further address the abilities and skills that are necessary to become an effective manager. The answers from Dr. A. T. and Dr. M. H. can be classified into two categories: business-related skills and organizational skills. The former is straight-forward and industrial context-dependent such that a successful manager in the line of work must be able to understand the business, the industry, the competitors, the customers, and the products and services of the company. The organizational skills have many sub-categories which include but not limited to, communication skills, interpersonal skills, and team work skills. The emphasis is on the team work, as Dr. A. T. said, effective management can only be achieved when the manager and the employees working together as a team, rather than working in a hierarchical fashion. Dr. M. H. also indicated that it would be essential for a manager to recognize and define the objectives, and everyone in the team works towards the common goals.

In addition, Dr. M. H. suggested that an effective manager must be a fast-learner, must possess critical and strategic thinking skills, and must be able to adapt to dynamic environments quickly and deal with changes and random events wisely. These skills are essential to help the company survive in highly competitive situations.

* Further analysis is omitted from this online version.

Speakers: Eva Furczon, Thomas O’Sullivan, Gavin Ouyang, Gurdeep S. Shah

Biodiesel is a biodegradable fuel that is made from a variety of seed oils, recycled vegetable oil, waste animal fat, and grease. Decreasing petroleum reserves and increasing environmental awareness has made biodiesel an attractive renewable alternative to petroleum diesel. Until recently, biodiesel was not competitive with petroleum products due to the slow and expensive production process which is highly dependent on feedstock type. In fact, raw materials comprise 80% of the final cost.

BIOX is the largest producer of biodiesel in Canada, producing over 60 million liters per year mainly from inedible tallow. The company possesses proprietary technology and a patented production process that is significantly faster and more efficient than traditional methods. The competitive strength of the BIOX process lies in its flexibility of converting a wide variety of low-cost feedstock to produce biodiesel. Feedstock prices are highly dependant on free fatty acid (FFA) content and availability. Traditionally, FFA contents of less than 1% are used. BIOX is able to achieve conversion yields greater than 99% and can use feedstock with high FFA content.

However, in order for BIOX to remain competitive in this industry, the company must capitalize on its flexible technology by evaluating alternative raw materials and other geographic locations. Jatropha and algae are two very promising raw materials for biodiesel production. Jatropha seeds contain up to 40% oil, and are being promoted as a cost effective and easily grown biofuel crop in hundreds of projects throughout developing countries. Similarly, algae have been shown to produce far more oil per acre than soybeans, with some genetically modified strains accumulating up to 60% oil by mass. These alternative raw materials coupled with green energy incentives and mandates found in emerging markets, can generate scenarios of particular interest to BIOX and the investors.

Date and Time: 6:30pm, Tuesday, November 18, 2008
Location: CCT 3150, University of Toronto Mississauga

For webcast information please click here.

 
1 VALUE PROPOSITION

The most widely used superabsorbent polymer (SAP) in baby diapers is sodium polyacrylate. Increasing concerns over the environment, baby safety, and production costs have created a need for continued development of SAP’s. We will acquire the license for the development and manufacturing of sacran from the Japanese researchers who discovered the polysaccharide. Compared to current polyacrylate diapers, our product sacran offers the following advantages:

1.1 Superior Absorbency

One gram of sacran absorbs 6100 mL of pure water and 2600 mL of urine (approximately 77 times the absorbency of sodium polyacrylate). Using sacran, we will be able to reduce the amount of SAP and cellulose pulp fluff used in diapers by 26%, yielding a thinner and lighter diaper with a higher absorbency potential.

1.2 Environmental Benefits

An estimated 27.4 billion disposable diapers are used in the U.S. per year, resulting in the addition of 3.4 million tonnes of used diapers to landfills each year. The major advantage of sacran is that it is a 100% biodegradable polymer which is able to completely decompose in approximately two weeks, while polyacrylate-filled diapers occupy landfills for hundreds of years.

1.3 Safety

SAP’s currently used in diapers are chemically synthesized, and have two major safety concerns: skin irritation and toxicity. Urine contains high amounts uric acid and thus causes irritation upon contacting with the skin. Sacran diapers will overcome this safety concern by keeping babies dryer for longer. Furthermore, the toxicity of polyacrylate is a growing concern. SAP as currently used in diapers has been linked to toxic shock syndrome and discontinued as an absorbent in feminine hygiene products. Sacran on the other hand is edible, and therefore does not have such problem.

1.4 Cost Reduction

The superabsorbency of sacran in diapers will reduce the amount of absorbent material used, in turn decreasing the size of the diaper by 26%. This decrease in volume will be extremely advantageous as it will lower the costs of raw material, packaging, transportation, and distribution.

 
2 MARKET ANALYSIS

Diaper manufacturers are our primary target market. The Real Diaper Association, an advocacy group founded in 2004, estimates that 27.4 billion disposable diapers are used in the U. S. each year. Given that each diaper requires 0.37 grams of sacran at a cost of $0.02, the annual sacran diaper market is valued at $630 million. We are planning to enter the market initially by partnering with the diaper giant Procter and Gamble (P&G).

According to statistics, P&G occupies the majority of the diaper market with Pampers and Luvs diapers which generates 42% of global sales. Once established, we will expand into our secondary target markets consisting of adult incontinence, feminine hygiene, and other miscellaneous markets. The annual market size for our secondary target markets is approximately $111 million (15% of the SAP market). The growing trend toward natural and 100% biodegradable “green” products will produce a high demand for sacran diapers by our customers. Furthermore, our potential partners will benefit from extra incentives in the form of green tax rebates, carbon tax credits, and other government incentives.

 
3 COMPETITOR ANALYSIS

Major competitors include SAP manufacturers. The top producers are Stockhausen, Nippon Shokubai, and AMCOL. AMCOL is the major supplier of SAP to P&G with an annual contract of $99 million.

 
4 BASIC SCIENCE

Isolated from the extracellular matrix (ECM) of Aphanothece sacrum (a mass-aquacultured edible freshwater unicellular cyanobacterium from Japan), sacran consists of polysaccharides with over 100,000 sugar subunits, and has an ultra-high molecular weight (>104kDa). The polymer contains both anionic and cationic sugars in an imbalanced ratio of approximately 30:1, and contains sulfated muramic acids which have not been found in polysaccharides before. Sacran is hydrophilic and can readily dissolve in hot water and form physical hydrogels when cooled down. It is the unique features of sacran that are believed to contribute to their incredible pure water absorbency of 6100 mL/g, significantly higher than hyaluronic acid (1200 mL/g) and any other water-absorbents (average is 500 mL/g).

The ability of other absorbents to absorb saline falls drastically (less than 240 mL/g), while one gram of sacran can absorb 2700 mL of saline, or 2600 mL of artificial urine containing various salts. It has been suggested that the underlying absorbency mechanism is a result of crosslinking amongst the sugar units, and their polarity; investigating this mechanism is a goal of our future R&D.

 
5 PILOT PROJECT PLAN

Mass production of sacran will involve a large bioreactor process to efficiently grow algae in industrially significant quantities. Necessary production considerations include bioreactor size, feed and nutrient streams, lighting cycles, and harvesting. As an added environmental bonus, CO2 emissions from manufacturing facilities can be sequestered and fed to the carbon-fixing algae in an effort to minimize the carbon footprint. Sacran can be extracted from A. Sacrum in 80% yields. This is accomplished by eluting the ECM of A. sacrum using hot water and ultracentrifugation, followed by precipitating the sacran fibers from the supernatant using an alkaline solution (0.1 N NaOH) or isopropanol. The finished product can be stored as a dry powder or compressed into various shapes. Details of successful sacran production by large scale cell harvesting and product extraction will be carefully guarded as a trade secret, until a partnership agreement is reached and the process is patented.

 
6 BUSINESS MODEL

6.1 Current Status

The production of sacran has been patented and has only been demonstrated on a laboratory scale. We must therefore, buy a license to produce sacran and invest in the infrastructure required to produce it on a larger scale. The process will initially be proven through the pilot project. Once industrial scale manufacturing has been achieved, further R&D will investigate process efficiencies and the feasibility of in vitro sacran production.

6.2 Future Funding Plan

Production of sacran on a small scale (1% of that required by P&G) will gain customer interest. To this end, we need private investors to contribute a total of $3 million, payable by milestone achievement. This money will be used to finance the plant and equipments for our pilot project, and further research activities.

6.3 Partnership Strategy

Once we have achieved the scale of manufacturing outlined for the pilot project, we will approach P&G in order to establish a partnership. Benefits to partnering include funding for increased production capacity, and the opportunity for P&G to exclusively use sacran in all of their absorbent products for a three-year period. The benefit for P&G lies in their assortment of absorbent products which include adult incontinence, feminine hygiene, cat litter, industrial cleaning materials, and various others which can profit from increased absorbency, biodegradability and lower production cost of sacran.

6.4 Growth Strategy

R&D will improve process efficiencies, and the possibility of in vitro sacran production to achieve lower unit costs and increased profits.

 
7 ESTIMATED PRODUCTION COST

AMCOL produces 160,000 tonnes of SAP each year and generates sales of $99 million from Procter and Gamble. According to AMCOL and assuming a 30% manufacturing cost, year end total production cost is $77 million. One kilogram of SAP ($1.6) will produce 36 diapers at a cost of $0.04 each, based on a 27.7% SAP usage per diaper. Large scale commercial processes for growing and harvesting algae average $50 per dry kg. One kilogram of sacran costs $62.5, and based on equal absorbency, we can produce 2702 diapers per kilogram at a cost of $0.02 per diaper.

 
8 FINANCIAL PROJECTIONS

Predicted production cost of supplying P&G with 1% of SAP required for one year (9 tonnes) is estimated at $500,000. The $3 million venture capitalist investment will fund the initial three year long pilot project. The goal of the pilot project is to initiate production of sacran on a large enough scale to secure a contract with P&G. The sacran manufacturing process is well established, and the development of our product does not require any clinical trials. Furthermore, we anticipate quick regulatory approval because our product is generally recognized as safe. Sacran will be commercialized and generating revenue within three years. For the above mentioned reasons we consider our project a low risk venture with high financial return. Thus our net present value of $124 million is calculated based on a 10% discount rate.

 
9 PROJECT TIMELINE AND GOALS

A three-year pilot project is our aim. The first two years will be focused on building a production facility. R&D aims to improve the efficiency and cost-effectiveness of the extraction process. At the end of year one, the plant would be set up and production underway. By the end of the second year, production will have reached full capacity and have met quality standards. In the third year we will approach P&G for partnership.

* Figures, tables, and references are omitted from this online version.

 
1 INTRODUCTION

1.1 The CortiCheck Diagnostic Device

The assessment of cortisol levels in those presenting symptoms of Cushing’s disease, Addison’s disease, and other hormone-related disorders is critical to treatment algorithms. We propose a cortisol-measuring biosensor, CortiCheck, a tool that detects the fluctuation of current following a redox reaction. It works on the principle of an amperometric biosensor in which 11β-hydroxysteroid dehydrogenase I (11β-HSD) performs a redox reaction on cortisol to produce cortisone, an oxidized cofactor and a single electron. Based on the change in current, it is possible to quantify the amount of salivary cortisol, and therefore evaluate the level of the free hormone in serum.

1.2 Mechanism of Cortisol

Cortisol is a corticosteroid hormone produced by the adrenal gland. It is synthesized from cholesterol and its production is stimulated by pituitary adrenocorticotropic hormone (ACTH) which is regulated by hypothalamic corticotropin releasing factor. Cortisol is often referred to as the “stress hormone” because it is released during stress to help restore homeostasis. In addition to controlling stress, it is responsible for regulating blood pressure, glucose metabolism and immune response. The level of cortisol in blood is tightly regulated and fluctuates on a circadian rhythm, with highest levels present in early morning (6-8 am) and lowest level present around midnight (3-5 hours after the onset of sleep).

When the amount of cortisol in blood is adequate, the hypothalamus and pituitary release less CRH and ACTH. This ensures that the amount of cortisol released by the adrenal glands is precisely balanced to meet the body’s daily needs. However, if a malfunction occurs in the adrenals or their regulating switches in the pituitary gland or the hypothalamus, cortisol production will be deregulated, causing adverse effects such as Cushing’s syndrome or Addison’s disease. Currently, laboratory tests using blood, urine and saliva samples are most frequently used to evaluate levels of cortisol production.

1.3 Product Description

The CortiCheck salivary cortisol biosensor consists of a disposable test strip housing a sample collector with a defined chamber volume, capillaries which transport the sample to a buffer chamber that moderates the sample’s pH, a transducer that detects the redox reaction, and a display system that shows the quantitative results. The entire unit is powered by rechargeable batteries.

The detection procedure is as follows. The sample is loaded into the sample chamber on the strip. Excessive sample will be excluded because of the strictly defined volume of the sample well. The opening can also be covered with a porous membrane to physically filter out large particles such as food from the saliva. Once the sample is loaded, buffer solution flows from its chamber by capillary action into the sample chamber. The buffer ensures the pH of the sample falls within the optimal pH range of the enzyme on the biosensor strip. Once the buffer is fully mixed with the sample, the solution flows into the biosensor chamber. The enzymes used in the biosensor are embedded in a polyacrylamide microgel. The whole system is linked to the detector and data processor device, and the signals from the biosensor will be transmitted into the Data Processor. A quantitative digital output results and will be displayed on the LCD screen. All components except the Detector and Data Processor are disposable.

 
2 VALUE PROPOSITION

2.1 Device Utility

Key opinion leaders and practicing endocrinologists have agreed that it is advantageous in patient diagnosis to view trends in cortisol concentrations versus values obtained at a single time point. Also, a discussion with endocrinologist Dr. Vishnu Bahari of New Orleans, offered insight into the greater value of CortiCheck in post treatment therapy of Cushing’s disease. He stated “there is clear utility for this device, used in the hands of professionals and patients alike to monitor and modify dosing regiments at multiple points throughout the day.” Much like glucose biosensors, it will be possible to store data from previous tests in order to identify patterns in cortisol production and aid in the diagnosis of related diseases. There are approximately 18,000 cortisol tests requested in laboratories across the U. S. every day, not including follow up or post treatment analysis. This tool, as Dr. Bahari explained, will allow for many more cortisol tests to be performed each day, either by a physician or the patient, in an effort to provide more effective treatment algorithms. Research conducted by Cohen & Schwarts revealed that the minimal number of samples needed for an accurate assessment of cortisol production is five. The researchers recommend that samples are obtained immediately upon wakening, 45 minutes after awakening; at 4-6 pm; at 6-9 pm and at bedtime. Furthermore they suggested that the five-sample test be performed for 4-5 days for optimal results. The advantage of monitoring cortisol daily is that it provides greater confidence than the data obtained in one day, which is typically affected by several external factors such as unanticipated stress.

2.2 Sampling and Testing Simplicity

Cortisol production follows a circadian rhythm and is also affected by stimulatory events such as stress or nutrient intake, yet traditionally, cortisol tests mostly involved a single sampling of serum. The invasive nature of blood collection can be an unpleasant experience (especially for children), and the analysis of cortisol through an enzyme-linked immunoassay (ELISA) or radio-immunoassay (RIA) is costly, time intensive, and can only be performed by trained technicians. Over the past five years, endocrinologists have come to further trust the results obtained from salivary cortisol tests. It has been demonstrated through clinical research that testing salivary cortisol to diagnose Cushing’s syndrome is as effective as other diagnostic tools which also include urine sampling.

2.3 Cost Effectiveness

CortiCheck will provide a rapid and cost effective solution for regular monitoring of cortisol levels. The technology is built upon the disposable test strip platform of the glucose biosensor which can be mass produced using silk screen manufacturing techniques. Using the same razorblade methodology as glucose biosensors, the device can be provided free of charge and the test strips priced at a nominal fee. Considering that costs to traditionally evaluate cortisol concentration in saliva, serum, or urine using ELISA or RIA have been established at an average of $80 per test, our disposable test strip is a significantly cheaper alternative. With an average selling cost of $6 per test, this alternative will also be more readily available. Cortisol biosensors, like blood glucose biosensors, will typically be provided to customers free of charge, and the cost of test strips will vary dependent on the size of the kit.

 
3 MARKET ANALYSIS

The low cost of CortiCheck makes it an appealing diagnostic tool in the U. S., where there is not a universal health insurance program. The target market for CortiCheck is found in patients experiencing symptoms that suggest Cushing’s syndrome or Addison’s disease, patients who are currently, or have been treated for Cushing’s syndrome or Addison’s disease, and patients on glucacordicoid medication for rheumatoid arthritis and asthma. Given the importance of ongoing cortisol testing, a near real-time method for monitoring cortisol in saliva using CortiCheck is necessary.

Monitoring the level of cortisol on an ongoing basis would enable physicians to diagnose Cushing’s and Addison’s disease, as well as monitor treatment effects and adjust dosing regimes of patients undergoing treatment with glucacordicoid medication. The total patient population that would benefit from CortiCheck is estimated to be 19 million, yielding a market size of approximately $9 billion. Given the current statistics penetrating even 1% of this market would generate revenue of $90 million annually.

3.1 Annual Cortisol Tests: Referrals by Endocrinologists

Currently there are more than 3,623 registered endocrinologists in the U. S. According to Dr. Vishnu Bahari of New Orleans, on average endocrinologists refer 5 patients per day for cortisol tests. Based on this statistic, the total number of cortisol tests prescribed by endocrinologists is approximately 6.6 million each year in the U.S. alone. The price of the test kit required for a one time diagnosis (CortiCheck AM, Mid-day, PM (1day) – 6 Specimen) is $55. Taken together if all tests were performed with CortiCheck, the annual cortisol diagnostic market, comprising of patients who referred by endocrinologist to take at least one test is valued at approximately $363 million.

3.2 Cushing’s Syndrome

Based on the current available data, the annual cortisol test market comprising of patients who suffer form Cushing’s syndrome is valued at approximately $136K. Cushing’s syndrome, also known as hypercortisolism occurs when the body’s tissues are exposed to excessive levels of cortisol. The syndrome is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol, or by the overproduction of cortisol in the body. Typical treatment of Cushing’s syndrome involves returning the hypothalamic-pituitary-adrenal axis to homeostasis by suppressing cortisol secretion with drugs. In severe cases, surgical removal of the adrenal glands (bilateral adrenalectomy) followed by life long administration of synthetic corticosteroids is necessary. In both cases, dosing must be guided by monitoring cortisol levels to ensure they are maintained within the normal range. Ongoing cortisol monitoring with CortiCheck will significantly improve the treatment of this syndrome.

3.3 Addison’s Disease

The annual cortisol diagnostic market comprising of patients who suffer form Addison’s disease is valued at approximately $3 million every year. Addison’s disease, also known as chronic adrenal insufficiency or hypocortisolism, occurs when the adrenal glands do not produce enough cortisol. Treatment of Addison’s disease involves administration of synthetic glucocorticoids to achieve cortisol homeostasis which can be challenging; under dosing of glucocorticoids results in continued adrenal insufficiency, while overdosing of glucocorticoids results in weight gain, increased blood pressure, and osteoporosis. Monitoring glucocorticoid replacement therapy with CortiCheck is necessary to control the treatment dosing to adequately supplement the adrenal insufficiency while minimizing any adverse effects.

3.4 Patients on Medication for Autoimmune Diseases

The annual cortisol diagnostic market comprising of patients who are undergoing corticosteroid treatment for rheumatoid arthritis and asthma is valued at approximately $9 billion each year. Corticosteroids are drugs closely related to cortisol, they are prescribed as first line treatment for many autoimmune disorders such as rheumatoid arthritis and asthma. If administered within proper guidelines, these drugs have strong anti-inflammatory effects. However, it is known that high doses of exogenous corticosteroid administration over a prolonged period lead to hypercorticolism and the subsequent development of Cushing’s syndrome. Given the sensitive range of cortisol homeostasis it is important for patients to monitor their cortisol level while undergoing treatment with corticosteroids. CortiCheck would allow patients to monitor and report their cortisol levels to physicians on an ongoing basis using a memory storage function. This would enable physicians to correct dosing regimes as appropriate, thereby reducing the chance of these patients developing Cushing’s syndrome.

 
4 COMPETITOR ANALYSIS

There are a number of cortisol test kits commercially available. These kits are based on radioimmunoassay (RIA), immunoassays such as ELISA, or liquid chromatography with tandem mass spectrometry (LC-MS/MS) technology, and can measure cortisol levels in serum, urine, and saliva. When cortisol concentrations are used as a diagnostic tool, patients have to either visit their doctor, or collect the samples themselves, then send them to the laboratory. Below are brief descriptions of the leading competitors in the market, including Siemens, Abbott, Orion Diagnostica, Immunodiagnostic Systems Inc., ARUP Laboratories, and Salimetrics.

Siemens Healthcare Diagnostics has developed cortisol test kits based on ELISA and immunoassay technologies. The IMMULITE® 2000 Cortisol, for example, is a high-throughput immunoassay analyzer that measures serum cortisol levels in 30 minutes. The system is suitable for diagnostic uses by medium- to high-volume immunoassay laboratories.

Abbott Laboratories is a global health care company which has developed the AxSYM™ (Automated Immunoassay Instrument System) that tests thyroid hormones including cortisol. The test kit is suitable for diagnostic uses, and it can process up to 80 to 120 tests per hour.

Orion Diagnostica Oy has developed the Spectria Cortisol RIA. The test consists of a coated-tube RIA-based system for quantitative measurements of cortisol concentration in human serum, urine or saliva. The test kit is suitable for diagnostic uses by laboratories; however, the product is not registered in U. S.

Immunodiagnostic Systems Inc. (IDS Inc.) has developed a number of cortisol test kits based on enzyme immunoassay technology. The DRG Salivary Cortisol ELISA Kit for example, is suitable for diagnostic uses with a sensitivity of 1.14ng/mL.

ARUP Laboratories has developed Cortisol Urine Free, a test kit based on the LC-MS/MS technology to measure cortisol levels in human urine samples, and the product is suitable for diagnostic uses.

Salimetrics, LLC. has developed an ELISA-based system specifically designed and validated for the quantitative measurement of salivary cortisol. It is intended for diagnostic or research use in humans and some animals with a serum correlation of 0.91.

As outlined in the Value Proposition (Section 2), the CortiCheck biosensor which measures salivary cortisol has many advantages over conventional diagnostic tests.

 
5 PRE-CLINICAL AND CLINICAL VALIDITY

5.1 Principle of the Procedure

Salivary cortisol measurement with CortiCheck is based on the fluctuation of electrical current when cortisol participates in a redox reaction with specific enzymes embedded on the test strip. The saliva sample is placed on the strip and only a defined sample volume enters the collection chamber. Through capillary action, saliva is drawn to the reaction site where the enzyme is attached to an electrode. Electrons generated through the redox reaction produce a current proportional to concentration of cortisol in the saliva. The pre-calibrated device then allows for the display of free cortisol concentration found in serum.

5.2 Mechanism of Action

The 11β-hydroxysteroid dehydrogenase [11β-HSD; EC: 1.1.1.146 (Acinetobacter sp. ADP1)] catalyses the interconversion of the 11β-hydroxy group of cortisol into its oxidized keto form. This reaction requires NADP as cofactor as cortisol is oxidized to cortisone and loses a proton, which then reduces NADP to NADPH⁺.

5.3 Surface Chemistry and Enzyme Modification

The test strip would consist of 11β-HSD (Acinetobactor sp.), potassium ferricyanide (oxidizing agent), phosphate buffer (to maintain pH) and non-reactive ingredients such as a polyacrylamide. 11β-HSD is modified to ferrocene-11β-HSD through a series of steps using sodium periodate and ferrocenecarboxylic acid to achieve maximum adsorption and conductivity on the strip. The ferrocene amendment occurs at the sugar groups of the enzymes.

The modified 11β-HSD would also be immobilized in a thin-layer cross-linked polyacrylamide microgel using the concentrated emulsion polymerization method. The degree of cross linking determines water uptake, pore size and the molecular exclusion limit.

5.4 Validation and FDA Approval

5.4.1 Pre-clinical Validation

Pre-clinical validation establishes documented evidence that the device will produce a quality result, providing a high degree of assurance that specifications are met. The most important goal is to document that the device consistently does what it is intended to do. The pre-clinical validation plan consists of the following steps:

a) System Design: Includes all specification information about the device, and describes its mechanism of action.

b) Functional Requirements: Describes how to use the device, its purpose, and user requirements.

c) Installation Qualification: Documents all key aspects of the device fabrication, using good manufacturing practices, such that the design specifications are standardized.

d) Operational Qualification: Test the device and demonstrate that the system performs as intended throughout all anticipated operating ranges (temperature, humidity, shelf life).

e) Performance Qualification: Verifies the device’s precision in terms of its reliable and accurate operation.

Pre-clinical validation will be accomplished through laboratory experiments which involve testing ranges of temperature and humidity with standard cortisol concentrations.

5.4.2 Clinical Validation

Medical devices do not require clinical trials, but do however, need clinical evaluation as noted above for their successful validation. Test data will be compared by testing multiple samples with both a conventional method and CortiCheck. Device functionality and usage techniques will be compared to the device most similar to CortiCheck, the glucose biosensor.

5.4.3 FDA Approval

According to the FDA’s classification of medical devices, CortiCheck is a low risk Class 1 medical device. Due to their low risk, premarket approval (PMA) is not required. However, the Premarket Notification form, also known as the 510(K) form is required in order to compare the device to similar legally marketed devices, and support the substantial equivalency claims of the 510(k) form.

Filing the 510(k) requires submission of the device’s trade name, classification, mechanism of action, design photographs, statement of similarities and/or differences with other marketed devices, and other legal documents which assert accountability. The entire review process takes between 20 and 90 days depending on the complexity of the application. Final decisions are made on the basis of the safety and efficacy of the device. After approval, CortiCheck can be marketed in the U. S.

 
6 DEFENSIBILITY

Protecting the device from imitation is important, and CortiCheck is eligible for patenting based on the following criteria:

a) Utility: CortiCheck has commercial value as a portable biosensing device used for the detection of salivary cortisol in a large patient population. Sample collection is non-invasive, and key opinion leaders agree that the convenience of multiple testing is of high value. Biosensor production is also inexpensive, and the cost of test strips is nominal when compared to ELISA and RIA. Further, there is no special training required in order to operate the device making it very user friendly, and available to all patient populations.

b) Non-obvious: Similar biosensors are used to detect glucose concentration in blood samples. Instead, CortiCheck detects salivary cortisol levels and therefore, has a completely different diagnostic value.

c) Prior Art: Information is available in the public domain regarding the basic mechanistic principle of a biosensor, but CortiCheck’s design relies on a novel mechanism of action in which modified enzymes react with cortisol. In the case of infringing on intellectual property, the owner will be offered a down payment and royalties.

d) Enablement: Complete and detailed descriptions of the design, including drawings and detailed assembly instructions will be provided with the application to the U.S. Patent Office.

 
7 RISK ASSESSMENT

7.1 Barriers to Entry

Physicians often work with traditional procedures which involve sample submission by patients and experiments in laboratories. Our proposed device is suitable for use at home and the complete testing procedure can be performed by the patient. The inherent risk therefore is that the device may not be readily accepted and trusted by doctors and patients. Should this be the case then the target market can focus on laboratories which currently employ expensive technologies for cortisol measurements. However, this strategy may create the risk of switching costs.

7.2 Surface Chemistry and Sensitivity

A particular area of concern involves the immobilization of the enzyme to the test strip while maintaining its activity. There are a number of methods to immobilize enzymes for biosensors. Should our proposed strategy fail, then we can attempt other methods such as attaching our enzyme to a nanoparticle for layer by layer printing. Enzyme modification with streptavidin would also allow for high affinity binding to biotinylated layered silicate.

We acknowledge the fact that the salivary cortisol is found in low concentrations, and biosensors generally have lower sensitivity compared to RIA and ELISA. This yields a risk that salivary cortisol is outside of the detection limit of our biosensor. In the case that it becomes an issue, we can circumvent the problem by pre-concentrating the samples. Pre-concentration is currently an area of scientific research, and a number of methods have been developed for this purpose. Evaporating the water from the sample by heating is a feasible solution in our case. The heating system would be powered by on-board rechargeable batteries, and because the sample volume is very small (in micro-liters), the process would be very quick.

Other components in the saliva sample may interfere with signal transduction; to reduce this risk, and also eliminate noisy signals, molecular wiring can be embedded into the enzyme which provides a direct path for electron flow from the redox reaction site to the conductor of the transducing mechanism. Including control strips or segmenting the strip to have both control and sample testing would further assure the user of the device’s reliability. Depending on the technology chosen for this task, the production costs are likely to increase.

Although using saliva sampling is preferred due to its non-invasive nature, if CortiCheck were not suitable for this application, the device can be adapted to testing cortisol in serum or urine, and the required calibration would be integrated for each sample type.

7.3 Sales and Distribution

While the market for the device has been established, a small company would not be well recognized. By pairing up with a large and well established company, it would be possible to take advantage of brand loyalty and allow the device to enter all facets of the industry.

 
8 BUDGET AND TIMELINE

The first year of our project would be focused on research and development (R&D) of our product. At the end of the year, we expect the design of our product to become mature, and the applications for patent would be submitted. It would take approximately one year for the patent to be approved. At the same time, small-scale manufacture of the product would begin, and a few samples would be sent for FDA approval which would take around 90 days. At the end of the second year when our products have been granted patent and FDA approval, marketing would begin, followed by distribution and sales. We expect revenue generation starting at the third year.

The budget for R&D and manufacture is not included. $80K will be spent on a down payment to reduce incurred royalty fees; the Millennium Research Group quoted $25K on an initial market research analysis project, and a further $30K on marketing materials. A consultant at Scientific Insights Consulting Group estimated the cost of their scientific evaluation service regarding the sensor and strip’s fundamental design at $25K. Validation and proof of concept will be tested in house and run on a budget of $10K. Filing a patent will incur costs of approximately $5K and the legal fees consume an additional $25K, for a grand total of $200K.

* Figures, tables, and references are omitted from this online version.