Development of Medical Devices for Cardiovascular Applications.
Gundu H. R. Rao, CEO, Indus Biomedical Associates.
Although definitive numbers on the size of the total medical device market are not available, it has to have surpassed 200 billion dollars in annual revenue in the US, as the top 20 medical device companies generated almost 140 billion dollars in sales in 2005. Even if just look a the total revenue of top five of them; Johnson and Johnson (20 billion), GE Health Care (15 billion), Medtronic (11 billion), Baxter Health Care (10 billion), and Tyco Health Care (10 billion), the market is phenomenal. The US companies clearly dominate this business with 16 of the top 20 firms. This group of companies grew a very solid 10% last year. The Midwest States of the US dominate in medical device companies with 10 of the top located in this area.
Contribution of revenue from Indian medical device firms compared to Indian Pharma companies, is very negligible. It is time, that we start working on the development of cost-effective medical devices in India. We have excellent IT capabilities, manufacturing facilities, trained engineers and specialty hospitals. If we create a platform using the technologies available in India, I am positive; we can develop better medical devices at affordable cost.
South Asians (Indians, Pakistanis, Bangladeshis, and Sri Lankans) have the highest incidence of coronary artery disease, compared to any other ethnic group in the world (Coronary Artery Disease in South Asians: Epidemiology, Risk Factors and Prevention. Gundu H. R. Rao and Vijay Kakkar, Jaypee Medical Publishers, New Delhi 2001. Coronary Artery Disease: Risk Promoters, Pathophysiology and Prevention. Gundu H. R. Rao and S Thanikachalam, Jaypee Medical Publishers, New Delhi, 2005. Hypertension and abdominal obesity are also unique risk factors in this ethnic group. According to World Health Organization (WHO) India ranks number one in the number of individuals with Type-2 Diabetes Mellitus (Diabetes Type-2 in South Asians: Epidemiology, Risk Factors and Prevention. V. Mohan and Gundu H. R. Rao, Jaypee Medical Publishers, New Delhi, 2006). WHO also estimates that incidence of Diabets Type-2 in India will increase by 200% in the next two decades. Currently there are 30 million individuals with Type-2 Diabetes in India. There are another 30 million pre-diabetics. In view of this large number of individuals suffering with diabetes type-2, we consider that development of a cost effective Glucometer in India is of immediate need.
Glucose monitoring world-wide is a 6.5 billion dollar business. Since the market opportunity is very large in Asia, it will be of great interest to develop indigenous technology to monitor blood glucose as well as glycated hemoglobin, as an added feature in such instrument.
Glucometers:
Joint Venture with QuestStar, Eden Prairie, MN:
Transfer of technology (US-FDA approved) to KHMD, Bangalore to develop Glucometers as well as test strips in Bangalore for world-side distribution. Future collaborations to substitute current test strips with fiber-based (NASA-Technology) test tips for monitoring blood glucose.
Value Added Product:
1. Modify the currently available glucometers, so that they monitor not only glucose but also Hemoglobin A1c. Collaborate with Prof. Sampath of Indian Institute of Sciences, Bangalore on this project and develop proof of concept.
2. Modify the detection system to include capability to monitor all the blood chemistry that is done currently in bench-top instruments.
3. Add blue tooth capability, data collection, data collation, transmittal of data to personal physician or to a distance health care provider.
(NS: To add some appropriate figures for illustration)
Blood Pulse Flow Monitors:
Brachial artery imaging with high-resolution ultrasound during reactive hyperaemia is now used to test peripheral vascular endothelial function. In response to luminal physical and chemical stimuli, blood vessels have the capacity to adjust blood flow. This ability to self-regulate vasomotor tone, allows the vessels to respond to changes in the local environment. In flow-mediated dilation (FMD), typically forearm or hand ischemia is induced by interrupting blood supply with a Blood Pressure cuff inflated to suprasystolic pressure. Release of tourniquet induces reactive hyperaemia caused by dilation of distal microcirculation. The magnitude of change in vessel diameter from the baseline period to the peak observed during reactive hyperaemia, is indication of the degree of endothelial function.
FMD detects endothelial dysfunction in local vascular beds, while pulse wave analysis provides a non-invasive method for assessing global endothelial function. The arterial pulse wave is recorded at proximal artery such as carotid as well as distal artery such as femoral. The time delay between the arrivals of predetermined part of pulse wave such as foot at the 2 points is obtained either by the simultaneous measurement or by gating to the peak of R wave of ECG. The distance traveled by the pulse wave is measured over the body surface and pulse wave velocity is then calculated as distance by time (m/sec). ( Reference In: Diabetes Type-2: Epidemiology, Risk Factors and Prevention. V. Mohan and Gundu H. R. Rao, Jaypee Medical Publishers, New Delhi 2006)
Hand Held Platelet Function Monitor:
Framingham studies in USA in the early 50s discovered risk factors that promote vascular disease leading to acute vascular events such as heart attack and stroke. Based on these observations, various drugs were developed to lower these risks. Developmetn of these drugs and ability to monitor these risks have significantly lowered the risk of developing acute vascular events. Although anti-platelet drugs have been in use for more than 50 years, no simple methods are available for monitoring anti-platelet therapy. Aspirin and Plavix are the drugs of choice for anti-platelet therapy. Recently there is considerable concern about patients developing resistance to the action of these drugs.
Platelets release ATP from there dense granules when activated by various agonists such as Epinephrine, ADP collagen, Thrombin and arachidonic acid (AA). Aspirin irreversibly inhibits platelet cycooloxygenase (COX-1) enzymes and formation of prostaglandins by this enzyme. In the absence of these bioactive metabolites, platelets do not release ATP when stimulated by weak agonists such as ADP, Epi, or AA. We would like to take advantage of this phenomenon and develop a rapid detection system for monitoring aspirin resistance. The basic method uses lucferin and luciferase to monitor luminescent generated by ATP in presence of this enzyme-substrate complex. We can build a small hand held monitor with either light emitting diodes or sensitive luminometers and use it for detection of ATP from platelets stimulate with agonists.
It is possible monitor anti-platelet therapies by monitoring expression of activation dependent markers such as expression of P-selectin on the cell membrane. In such a system instead of monitoring luminescence, we will have to monitor the fluorescence using a laser.
One can also develop an electrical impedance based hand-held detector for monitoring platelet aggregation on the surface of an electrode or a coated surface. This could in essence operate similar to whole blood aggregometer except that it is miniaturized. Once could use monolayer of carbon or gold to increase the electrical conductivity. It is worthwhile exploring whether or not surface Plasmon resonance could be used for detecting the change in electrical conductance.
Hand Held Monitors for Determining Global Hemostasis:
Hemostasis is the mechanism by which the body controls bleeding after injury. The definition of hemostasis includes the chemical responses of the blood-vessels, platelet activation, and the biochemical reactions that lead to clot formation and dissolution.
In the USA alone, more than 80,000 adults undergo surgical procedures to repair or replace damaged heart valves every year. Use of these types of heart valves require that patients to take anti-coagulating agents for the rest of their life. Currently there are no simple methods to monitor anti-coagulation therapy at home. Our aim is to develop a cost-effective simple hand-held devise that monitors global hemostasis.
At it s simplest design it could be just a glass capillary tube of 100ul volume. If the blood is drawn to fill half of its length, the blood should clot by surface activation, in a reasonable length of time. By using appropriate light or pressure sensors, we should be able to time the length of time required for surface activation and clot formation. We should be able to develop a “Pen that can house the monitoring set up and disposable glass capillary tubes for performing the tests. Advance test could prepared with AA coate, or ADP coated or Collagen coated glass tubes for further evaluation.