school of medical science and technology

From waste to health

A joint research team, including a multidisciplinary team of researchers from IIT Kharagpur, use goat ear [bio-waste] to produce Collagen for cartilage regeneration therapy

Covid-19 is the latest health threat for the aged. Arthritis has been their bane for a long time, affecting the elderly mostly due to inflammation, or wear and tear of their bodies. Even for the younger generation, trauma, degenerative joint diseases, obesity or joint instability could be ample reasons for an unforgiving joint ache or debility. But technological innovations are making it possible to look at early detection of cartilage degeneration and, therefore, regeneration therapy as a long-term solution to these conditions.

The therapy requires the use of Collagen, the protein that helps maintain the structure and functionality of the cartilage. Once Collagen becomes available as oral nutrient supplements or injectable gel, the therapy will receive a big boost. However, isolating the protein in large amounts is a problem and researchers the world over are looking for ways to do that from various sources.

Researchers at IIT Kharagpur have a solution. They have found that copious amounts of Collagen can be isolated and purified in a cost-effective way from the cartilage of disposed goat ears, which is a commonly available bio-waste product. Not only that, they have also prepared a Collagen infused injectable hydrogel that could be used in cartilage regeneration therapy. (Read the research paper here – https://www.nature.com/articles/s42003-019-0394-6)

The isolated Collagen was incorporated in a highly stable Pluronic F127 gel base. The CP (Collagen-Pluronic) hydrogel could be used for cartilage regeneration therapy. In addition, when combined with stem cells derived from the goat ear adipose tissue, this injectable hydrogel was found in laboratory conditions to highly facilitate cartilage formation. It could thus speed up the healing of cartilage injury.

Using a novel addition to the existing process, the researchers, led by Prof. Santanu Dhara of the School of Medical Science and Technology of IIT Kharagpur, have shown that the isolation process could be simple, cost-effective and fast. Whereas the maximum yield from existing process for isolating Collagen from other sources is below 55 per cent, the process used by the research team that included precipitation with a sodium chloride solution for 48 hours, reported more than 55 per cent yield.

Prof. Dhara said, “The blended CP hydrogel has an encouraging result to be used as injectable hydrogel for cartilage regeneration and also to perform as a stem cell delivery vehicle by minimal invasion.” The multi-institutional and multidisciplinary team included researchers from the School of Medical Science and Technology, Department of Biotechnology and Rubber Technology Centre of IIT Kharagpur and from the Centre for Healthcare Science and Technology, IIEST, Shibpur.

The team additionally used a newly developed mass spectrometric analytic method to study the structure of the isolated Collagen. The findings from the MALDI-MS/MS analysis, which showed post-translational modifications in the position and expression of hydroxyproline (Hyp), a crucial part of the triple helix structure of Collagen, will help in the early detection of cartilage disorders, including of arthritis.

The identification and mapping of Hyp position in signature motif plays an important role to correlate molecular alteration of the component chains of cartilage with the progression of arthritis. Prof. Dhara said, “This identification may contribute to early prediction of dysfunctional collagen leading to rheumatoid arthritis as well as molecular identification of Collagen from other sources.”

The team included Priti Prasanna Maity, Debabrata Dutta, Sayan Ganguly, Kausik Kapat, Krishna Dixit, Ramapati Samanti, Prof. Narayan Chandra Das, Prof. Amit Kumar Das and Prof. Dhara from IIT Kharagpur, Prof. Amit Roy Chowdhury and Dr. Pallab Datta from IIEST.

Protecting the Protectors

Making Face Shields for Healthcare Workers During Lockdown

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Professor Santanu Dhara and Professor Sangeeta Das Bhattacharya, researchers at the School of Medical Science and Technology at IIT Kharagpur have made a prototype to make face shields for healthcare workers from home during the lockdown. The face shield is an essential part of the personal protective equipment (PPE) required for healthcare workers taking care of patients with suspected COVID-19.

The basic PPE for healthcare workers include respirator or face masks, eye protection including goggles and face shields, gloves and gowns. The face shield is a transparent plastic protective cover, attached to an elastic head gear. It protects the face from splashes. There is a shortage of all PPE for healthcare workers globally.

Professor Santanu Dhara and Professor Sangeeta Das Bhattacharya have designed a face shield using materials which can be procured even under the nation-wide lockdown. The items include transparency sheet, sponge, folded paper, cardboard or packaging box, elastic, or rubber band, and double-sided tape. A team from the School of Medical Science and Technology produced 14 such face shields in 2 hours and are in the process of making more, while remotely working from their homes.

“At a time when the demand for protective wears has escalated sharply, we have to improvise products using easily sourced materials and simple process to offer some sort of protection for the health workers,” remarked Prof. Santanu Dhara.

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“It is essential to get personal protective equipment for healthcare workers and the faceshield is just one part. We are contributing in a small way, these have not been rigorously tested,” said Prof. Sangeeta Das Bhattacharya.

Face shields like other medical equipment require testing and certification. These are desperate times. There is a dire shortage of PPE globally and health care workers have taken to crowdsourcing. The hashtag #GetMePPE is trending across social media.

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Disclaimer: This release is made in the public interest. Items described herein are only prototypes and caution is warranted during the DIY procedure. Every medical product and equipment requires testing and certification by appropriate authorities before use.

New Repurposed Drugs & Methodology Identified by IIT Kharagpur Researchers

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Researchers from the School of Medical Science & Technology at IIT Kharagpur have identified new drug repurposing candidates for induction of fetal hemoglobin to treat beta-thalassemia patients

Blood disorders or hemoglobinopathies such as beta-thalassemia and sickle cell anemia affect millions. Drug-induced increase in fetal hemoglobin has been shown to improve the condition of those affected with these blood disorders. But these drugs have side-effects. Scientists are exploring if ‘repurposed’ or existing drugs can be used to treat these disorders. To find out which drugs could be used for possible repurposing the researchers at the Regenerative Medicine Lab at School of Medical Science and Technology of IIT Kharagpur studied the working of microRNAs which regulate the pathways along which the production of fetal hemoglobin is stimulated.

The researchers observed Curcumin, found in turmeric, and Ginsenoside, found in the roots of Ginseng, both known for their medicinal properties, could go a long way in treating blood disorders like thalassemia and sickle cell anemia. These two plant ingredients, together with approved drugs such as Valproate and Vorinostat were found to be ‘most suitable for future clinical trials’.

The researchers also studied how miRNAs work, how they regulate gene expressions and also which chemical molecules affect their expression pattern. The team at SMST used several bioinformatics tools to match differentially expressed miRNAs with differentially expressed genes (as found in publicly available datasets) and identify their pathways. The team has also devised a database called “miRwayDB” to provide comprehensive information of experimentally validated microRNA-pathway associations in various diseases. As many as 19 miRNAs were found to be differentially expressed in those who had high fetal hemoglobin levels in their blood. The team also identified some unique small molecules that strongly affected the expression of those 19 miRNAs.

Of the five molecules identified by the research, three – 5’-aza 2’-deoxycytidine, Valproate and Vorinostat – are commonly used to treat other diseases. For example, Valproate is used to treat seizure disorders in childhood and Vorinstat is an anticancer agent.

“These identified markers expand our understanding of fetal hemoglobin regulatory mechanism and may have importance in designing new therapeutic strategies to reactivate its production in patients with hemoglobin disorders,” said Prof. Nishant Chakravorty, who heads the Regenerative Medicine Lab and the team at SMST.

The study was conducted by Prof. Chakravorty, his student at SMST, Mr. Sankha Subhra Das, and Dr. Rashmi Sinha of IIT Kharagpur’s in-house medical facility B.C. Roy Technology Hospital and published in the “Gene” journal.

“Medical practitioners nowadays widely use repurposed drugs. An example is Sildenafil, which is used to treat impotence in males as well as neonatal pulmonary hypertension,” said Dr. Anish Chatterjee (MBBS, DCH, MD-Paediatrics), Professor, Dr. B C Roy Post Graduate Institute of Paediatric Sciences. Dr Chatterjee believes that research into repurposing of drugs is important and could even lower the cost of medical treatment as cheaper drugs, instead of costly ones presently used, could be used to treat diseases.

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SPARC Workshop Explores Critical Challenges of Children’s Healthcare

The School of Medical Science and Technology at IIT Kharagpur recently held an Indo-UK Residential Workshop in collaboration with the University of Manchester, UK, on the “Practical Management of Inherited Pediatric Hematological Disorders”. The focus was on clinical reasoning of cases related to children’s blood and bone marrow disorders using an interactive problem-based learning approach with direct interactions with globally renowned experts.

The areas covered in the workshop included the workup of the child presenting with signs and symptoms of reduction in the number of various blood cells, or cytopenias including pancytopenia or bone marrow failure. Workup included understanding the genetics behind certain syndromes, targeted testing, and treatment planning including an overview of bone marrow transplantation. Other topics covered included understanding cognitive errors in clinical decision making and computerized clinical decision support systems.

Experts from IIT Kharagpur, University of Manchester, Tata Medical Center and Tata Translational Cancer Research Centre, Kolkata, and NRS Medical College participated in this three-day workshop which was sponsored under the Scheme for Promotion of Academic and Research Collaboration (SPARC), an initiative of Ministry of Human Resource Development, Govt. of India.

Among the speakers were Prof. Vaskar Saha from the University of Manchester and Director of the Tata Translational Cancer Research Center a pediatric oncologist and hematologist and an expert in the care of children with leukemia. He worked through cases with participants to guide thinking on how to approach the child with a complex bone marrow disorder to come up with a diagnosis that could then lead to a treatment plan. Dr. Shekhar Krishnan, senior consultant in paediatrics hematology and oncology at TMC-TTCRC discussed bone marrow transplant.

Diagnosis was a focus area of the workshop. Dr. Niharendu Ghara senior paediatric consultant at TMC-TTCRC Kolkata discussed targeted approaches to diagnostic testing making sure to find the right test for the right situation, Dr. Rajib De from NRS Medical College discussed thalassemia in the context of Eastern India and approaches to screening, diagnosis, and management.

Prof. Jayanta Mukhopadhyay from IIT Kharagpur’s Dept. of Computer Science and Engineering discussed automated clinical decision support systems and their role in improving clinical decision making. Prof. Sangeeta Das Bhattacharya of SMST discussed cognitive errors in clinical decision making.

Students from diverse areas such as MBBS, Masters in Medical Science & Technology, MD, postdoctoral fellows, and clinical fellows in hematology participated in the workshop. The participants gained insights from master clinicians in real-time in clinical reasoning through case-based learning.

Opening new vistas

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Curcumin, found in turmeric, and Ginsenoside, found in the roots of Ginseng, both known for their medicinal properties, could go a long way in treating blood disorders like thalassemia and sickle cell anemia. These two plant ingredients, together with approved drugs such as Valproate and Vorinostat were found to be “most suitable for future trials” by a team of genetic scientists at IIT Kharagpur. They are trying to see which drugs induce fetal hemoglobin production – which is known to ameliorate such blood disorders – and whether ‘repurposed drugs’ could be used. Repurposing of drugs, a new and exciting arena of scientific study, seeks to use approved drugs for clinical conditions other than those in which they are usually used for.

Blood disorders or hemoglobinopathies such as beta thalassemia and sickle cell anemia affect millions. They occur due to mutations in the β-globin gene, which leads to low or absent production of adult hemoglobin. Drug-induced increase in fetal hemoglobin – which constitutes a major percentage of the total hemoglobin in newborns, and which gets almost completely replaced by adult hemoglobin by 4 to 6 months of age – has been shown to improve the clinical features of those affected with sickle cell disease and beta thalassemia. Unfortunately, most of these drugs have serious side-effects and are therefore rarely used in therapy. Identifying new drugs could be a time-consuming and uncertain exercise. Hence scientists are trying to see whether ‘repurposed’ or existing drugs can be used to treat these disorders.

To find out which drugs could be investigated for possible repurposing to treat these specific blood disorders, scientists at the Regenerative Medicine lab of the School of Medical Science and Technology of IIT Kharagpur studied the working of microRNAs (miRNAs), and also which chemical molecules affect their expression pattern. MiRNAs, which are a small class of non-coding RNAs, have recently been identified as critical regulators of as much as 70% of the genes in the human genome.

The production of fetal hemoglobin in human body, much like other biological processes, is a “coordinated event under the control of genes and proteins encoded by the human genome”. Since miRNAs regulate the pathways along which the production of fetal hemoglobin is stimulated, how miRNAs work and how they regulate gene expressions have evolved into a major branch of study. Several miRNA databases, tools and algorithms have been designed by scientists all over the world to understand their gene regulatory mechanism. In fact, the Regenerative Medicine Lab at IIT Kharagpur has also devised a database called “miRwayDB” to provide comprehensive information of experimentally validated microRNA-pathway associations in various diseases. Additionally, the lab has also developed an interactive tool known as “miRnalyze” to unlock intuitive microRNA regulation of cell signaling pathways.

‘Messenger RNAs’ and ‘microRNAs’ are two important biomolecules found in our cells which are known to regulate cellular functions. Any abnormality in the production of these molecules may disrupt series of molecular events or pathways, which subsequently may manifest as critical diseases. Our lab has developed “miRwayDB”, a database which records information about the effects of these biomolecules on molecular pathways as observed in various diseases. The resource has many applications such as prediction of in silico models, integrative analysis, validation of computational analysis etc. In addition, we have also developed a prediction tool, “miRnalyze”, which can predict ‘messenger RNA’ targets of ‘microRNA’ in a molecular pathway. The tool can identify common ‘microRNAs’ that have more than one ‘messenger RNA’ targets. miRnalyze is a useful tool for hypothesis generation in ‘microRNA’ mediated molecular pathways. Both resources were published in ‘Database’ journal of Oxford University press.

The team at SMST used several bioinformatics tools to match differentially expressed miRNAs with differentially expressed genes (as found in publicly available datasets) and identify their pathways. As many as 19 miRNAs were found to be differentially expressed in those subjects who had high fetal hemoglobin levels in their blood. Next, using another database (SM2MiR), the team identified 13 unique small molecules that strongly affected the expression of those 19 miRNAs. An exhaustive analysis of these 13 molecules showed that only five were definitely associated with the pathways that reactivated fetal hemoglobin production and can be further investigated for repurposing.

Prof. Nishant Chakravorty, who heads the Regenerative Medicine Lab and the team at SMST, said, “In our study, a number of genes and miRNAs were identified as putative molecular marker for HbF (fetal hemoglobin) regulation. The identified markers expand our understanding of HbF regulatory mechanism and may have importance in designing new therapeutic strategies to reactivate HbF production in patients with hemoglobin disorders.”

Of the five, three – 5’-aza 2’-deoxycytidine, Valproate and Vorinostat – are known pharmacological agents. For example, Valproate is used to treat seizure disorders in childhood and Vorinstat is an anti-cancer agent. However, these have side-effects.

Prof. (Dr.) Anish Chatterjee (MBBS, DCH, MD-Paediatrics), Professor, Dr. B C Roy Post Graduate Institute of Paediatric Sciences, said, “Medical practitioners nowadays widely use repurposed drugs. For example, Sildenafil, which is used to treat impotency in males is used to treat neonatal pulmonary hypertension. Again, Hydralazine which is used to control blood pressure, is also used to treat leprosy.” He adds, “Research in repurposing of drugs, which is being carried out by the Regenerative Medicine Lab of IIT Kharagpur, with which I have been associated with for some time, has immense potential. It might lead to the discovery of new information about existing drugs. Not only that, it could lower the cost of medical treatment as cheaper drugs, instead of the costly ones presently used, could be used to treat diseases.”

The study at the Regenerative Medicine Lab was conducted by Prof. Chakravorty, his student at SMST, Mr. Sankha Subhra Das, and Dr. Rashmi Sinha of the B.C. Roy Technology Hospital. The work, which has been published in the April 2019 “Gene” and is available online, also identified natural compounds, such as Curcumin and Gensenoside, which have proven health benefits with minimal toxicity, which the team expects to be “of critical importance in future clinical trials for HbF induction”.

Mr. Sankha Subhra Das, a research scholar associated with this team, is already working on other facets of thalassemia treatment, and has done several other in silico studies using bioinformatics tools. Other PhD scholars, such as Mr. Motiur Rahaman, is working specifically on beta-thalassemia. “We are trying to classify HbE-beta thalassemia into different categories based on clinical severity and trying to see if there is correlation with HLA haplotypes,” said Prof. Chakravorty. The team is enriched by several scholars such as Dr. Suman Kumar Ray (post-doctoral fellow), who has a background in plant medicine, and helping it to see how plant based phytochemicals can help increase fetal hemoglobin. The researchers at the Regenerative Lab are also engaged in research on repurposing strategies for bone and cartilage regeneration. The team will be moving on to do further experimental in-depth studies particularly on thalassemia patients. An active collaboration with Prof. (Dr.) Tuphan Kanti Dolai’s clinical team at the Department of Hematology, NRS Medical College and Hospital, Kolkata holds promise to this.

From the lab to the hospital

Prof. Suman Chakraborty, Head, School of Medical Science and Technology, talks about the thrust areas, ongoing programmes, research, achievements and long-term goals of one of the youngest and most ambitious departments of IIT Kharagpur

Could you talk about the genesis of SMST?

The department started its journey in 2001 against a background where technology was progressively coming into the domain of medical world. It was felt that a unique school or department should be established that would work at the interface between medicine and technology. A medical school would be bothered about the clinical aspects of the study, not necessarily on the technology that goes behind medical devices. On the other hand, an engineering school classically is not equipped to take up the responsibility. An interdisciplinary department was required. And that is how SMST came to be in 2001.

What are the ongoing academic programs/courses of SMST?

The flagship programme of this school is MMST or the three-year Masters in Medical Science and Technology, an interdisciplinary program, which is first of its kind in India. This is a unique program where medical graduates, i.e. MBBS, take up a course in medical technology. The first few batches ran successfully and this motivated us to expand the scope of the department. Subsequently, an MTech programme started in medical imaging and informatics as a number of Faculty members were working in that area. This programme still continues but we will soon replace this program with one on Biomedical Engineering from next year. The idea is that postgraduate-level education need not be a super-specialization in medical imaging and informatics. There are so many other areas that can be clubbed under Biomedical Engineering. This is a standard, highly recognized Masters programme, considered all around the world as a very lucrative one, including in India, and we felt it was the right time to explore this area.

Apart from this, we have been exploring international tie-ups for developing joint programmes. We are in the final stages of tying up with some top universities with whom we are about to offer the programmes jointly, i.e., joint academic programme plus jointly supervised thesis work. These will be Masters-level programmes.

Over the years, we have felt that medical technology-based work is not complete unless you have a clinical connection. Technological development should go from bench to bedside, that is, from the laboratory to the hospital. We also have to learn a lot from the needs of the clinicians who are actually serving the patients. That is why we have started collaborations with many leading medical colleges and hospitals. One structured programme is the joint education and research programme with Tata Medical Centre (TMC) at Kolkata. From 2018, we started 3 joint MSc-PhD programmes in collaboration with Tata. The entire academics is looked after by IIT KGP, but TMC is providing its expertise in teaching, research and access to the labs and data necessary to do medical research. The three areas are molecular medical microbiology, nuclear medicine and medical physics.

This year we selected students through a highly competitive entrance exam. We are happy with the students and they are exceptionally bright. They are the future generation medical technologists. They are from a wide background like chemistry, physics, biology. They are not necessarily doctors. We have to understand that the entire support system in the medical world is heavily dependent on medical scientists who may not always be medical doctors by training.

Are there courses for qualified doctors other than the MMST?

For qualified doctors, we have started a special programme with Tata Medical Centre – a highly advanced certification programme on clinical oncology. We have selected 10 junior doctors from TMC this year who will be participating in an advanced research program. Doctors usually do MD, DM etc. after graduating. But they can now undertake super-specialization in the niche topic of clinical oncology research with at least one supervisor from IIT KGP and the other from Tata Medical Centre. They are not required to stay on campus. There is a designated time during which they visit IIT KGP and interact with faculty member and team supervisors. This is a dynamic programme and we are trying increase the number of such flexible programmes. Doctors trained by SMST will help us translate our dream of making the transition from lab to hospital.

What are the other programs run by the school?

Apart from this there are the usual research programmes run by the Institute, such as MS and PhD programs where students are drawn from all backgrounds. Medical Science and technology is such an interdisciplinary area that people from all backgrounds can contribute. Even for MTech in Biomedical Engineering we have not put any restrictions on the UG programme. Someone who has done mechanical engineering can take up biomechanics as a scope of research/Masters programme. Someone who has done Computer Science can use big data analytics and machine learning to solve problems in the clinical setting. So we are quite flexible.

Is there a larger vision behind SMST’s programs and activities?

We are trying to internationalize our program as much as possible. Hence we are tying up with hospitals all around the world. We are also at a critical juncture since our own medical college and hospital is about to begin early next year. As the SMST Head, it is my vision is to integrate the ongoing research activities of SMST with that of the hospital. That is where all our hypotheses, technology development, research, scientific understanding will be validated and brought to the benefit of patients. Not only that, we are also bringing a large number of specialist doctors from all around the world to be a part of our hospital. We are going to leverage on their presence on campus.

What are the thrust areas of SMST?

Our faculty is diverse and this is reflected in the research. Some of our faculty members are doctors, others from basic sciences and engineering. We work as a team. The thrust areas a. Microfluidics and Point of Care Diagnostics, b. Multimodal Medical Imaging & Image Processing, c. Tissue Engineering, Regenerative Medicine, d. Stem cells and Bio-Materials, and Signal Transduction, Proteomics and reproductive health, and e. Cancer Biology & Public Health.

They can be broadly divided into diagnostics and therapeutics. Diagnostics is about diagnosing diseases and therapeutics is about delivering the treatment which may require medicines, or medical devices. So development of devices, drugs etc. fall under this category. One particular focus is cancer detection and management. Lots of faculty members and students are working in this area. My own thrust area is affordable diagnostics. Instead of using costly diagnostic methods, we have devised simple, low cost devices essentially made from pieces of paper or plastic where, with a drop of blood, saliva or urine, one can do a large number of tests at low cost almost immediately. Instead of bringing the patient to the hospital, one can bring these handheld medical devices to the hospital to get the diagnostic test done. This is called point-of-care diagnostics.

What are the recent accomplishments of your department?

Our students are engaged in collaborative research and internship programmes with top medical device companies or top universities throughout the globe. And out all other departments, I believe SMST possibly has the strongest visibility internationally. Several international awards have been won by students and the Faculty. Our students are DAAD and Fullbright fellows. Our Faculty members are fellows of the prestigious national academies of science. I have been a recipient of Shanti Swarup Bhatnagar award, am a fellow of all national academies of science and engineering. I am the JC Bose National Fellow Institute Chair Professor and was recently awarded fellowship of the Americal Physical Society as well as the Royal Society of Chemistry.

As a department we are a strong unit, but we need to grow further. We have recently recruited very bright young faculty members, most of them are doing research in the interface of fundamental biology with clinical application – immunology, cardiac sciences for example. I could mention Dr Gayatri Mukherjee, Prafulla Shukla, and Nishant Chakravarty as the latest entrants to the Faculty. Dr Chakravaty is an alumnus of the department and a flag-bearer. He was the MMST topper and did his PhD abroad. He works on research interfacing clinical aspects with medical technology, also on stem cells, maternal and child health.

Since we are not yet a large unit, each Faculty has a lab to his or her own. We are going to aggressively recruit new faculty and want to recruit members who work at the interface of medical science and engineering.

Are there any projects close to your heart?

Our vision is to use deep science leading to sustainable technology for public welfare. There are two Imprint projects under my investigation, both involving affordable diagnostics. Affordable healthcare, as you know, is a mission of our institute. We are in the final stages of getting a large project whereby technology developed by us will be transferred to medium and small scale industries. They will create an ecosystem that will make practical devices implementable in the medical world. SMST will act as the Centre of Research for Technology development that will allow small scale industries to incubate and then transfer what happens in the lab to practical life. There are innumerable Startups that make devices and diagnostics but these are not validated. We are, for the first time, going to bridge this gap by developing a unique tech hub that will be fully funded by the govt.

Are there any notable affordable healthcare products made by SMST?

Yes, there are two. One is paper based microfluidic device which have small channels in the paper. Blood dropped in this device will go through the channels and react with reagents. A change of colour will happen if there is a particular disease. The change of colour signal is recorded by a camera and this information is digitally processed. In case of blood glucose level, haemoglobin, bilirubin, these are calibrated against the image data and the information is transferred to a smart phone. These are inexpensive devices. Anyone with a pricking device can do this. This is ‘colorimetric detection’.

The other uses a similar technology. It is called a Lab on a CD. By centrifugal force, the sample of blood, saliva or urine, whichever is being tested, will go radially outwards and react with certain chemicals. Here we are using electrochemical detection. The change of electrical signals or impedance will signal the result of the test. We are trying to implement this in extreme rural settings – places where there is no power supply or refrigeration. This is called extreme point of care diagnostics.