A Cool Way to Start Life

Pluss Advanced Technologies has not always been in the business of saving babies. The India-based materials research and development company built its name making products that are decidedly less heroic sounding: specialty polymers that are used in products like flexible packaging and composite deck material, and designer chemical mixtures that hold heat or cold for the purpose of refrigeration, food delivery or pharmaceutical transport.

It was their expertise in the latter—refrigeration—that led to a serendipitous union between industry and healthcare and unexpectedly thrust the company into the world of manufacturing medical devices.

As it turns out, the products they make to keep food cool for long periods of time are also effective in lowering the body temperatures of sick newborn babies—a proven medical treatment for children born with a condition called birth asphyxia.

Birth asphyxia, or lack of oxygen at birth, is one of the leading causes of infant mortality in low- and middle-income countries. The World Health Organization estimates that 650,000 babies worldwide die from birth asphyxia each year, though the number of annual instances is notoriously underreported, especially for children who survive. The overwhelming majority of cases—more than 95 percent—occur in less-developed parts of the world. Many mothers from these areas lack access to skilled medical care during pregnancy and childbirth. The result is an increase in injuries to newborns during the birth process.

Babies who survive the condition often suffer serious and irreparable brain damage that can result in lifelong physical and mental disabilities. Cerebral palsy is among the most recognized of these.

Permanent damage to the brain can be reduced or prevented simply by cooling the child’s body to sub-normal temperatures immediately after birth. There is a long history of scientific literature demonstrating that temporary, controlled hypothermia can benefit newborns that have suffered from hypoxic conditions. The treatment involves cooling a baby from a normal 37 degrees Celsius (98.6 degrees Fahrenheit) to between 33 and 34 degrees Celsius and maintaining that body temperature over 72 hours. This type of treatment is regularly used on adults who suffer strokes or other ischemic brain injuries, and the rationale is the same: a drop in temperature reduces metabolic activity, thus reducing the body’s overall oxygen requirement. For a brain that has been deprived of oxygen, minimizing the amount of oxygen needed to function mitigates neural cell injury and cell death.

The Treatment Disparity

The technology for inducing controlled hypothermia already exists and is commonly used in top tier global hospitals for both children and adults. These sophisticated temperature control systems operate by wrapping a patient in a blanket perfused with a chilled fluid. The patient’s core temperature is then continuously monitored, and the temperature of the fluid automatically adjusts to fluctuations in body temperature. In such fully-automated systems, a reduction in core temperature is obtained quickly and is accurately and reliably held at the desired level with little to no human intervention.

Physicians in low-resource hospitals resort to crude methods to treat birth asphyxia, like ice packs.

But these systems, while extremely effective, are also very expensive, costing upwards of US$25,000 each. This price renders them far out of reach for many hospitals with limited financial resources.

Out of necessity, physicians in low-resource hospitals and clinics often look to a cruder method for cooling asphyxiated babies: ice. Specifically, frozen gel packs. With some practice, caregivers are able to use the same ice packs that might be used to prevent swelling in a sprained ankle to achieve the same therapeutic benefits that more sophisticated systems for controlled hypothermia accomplish. Hospital and clinical staff freeze or refrigerate the gel packs to below the target body temperature and then layer them between blankets around the baby.

This method has a number of limitations, however. First, it induces cooling more slowly than desired, particularly in warm weather geographies or facilities that are not fully climate controlled. Also, it is difficult to control the set temperature with ice packs, so newborns must be constantly monitored by nursing staff to make sure they do not become overly cold or warm. Common side effects from this method of treatment are ice burns on the skin or allergic-type reactions to cold.

Neonatologist Niranjan Thomas is well aware of the challenges. Dr. Thomas first began experimenting with gel packs as a cooling treatment nearly a decade ago at the Christian Medical College in Vellore, in India’s southern state of Tamil Nadu, where he heads the department of neonatology. Thomas says he first became aware of the benefits of hypothermia for asphyxiated babies while working abroad in Australia and Canada. But when he returned to India in 2007, he discovered that the practice had not been adopted there, despite overwhelming evidence of its effectiveness.

“At the time, no one in India was cooling babies, so we started using the cool gel packs,” Thomas recalls, but adds that he quickly became frustrated with the results. “It was very labor intensive. There were huge swings in temperature. It was not at all ideal.”

“In low-resource countries like India, we do not have the level of nursing that is available in the West. When you are using cool gel packs, you really need to have a nurse there all the time,” he explains.

An Idea is Born

A medical paper about how phase-change materials, or PCMs, had been tested on piglets for body cooling provided a moment of inspiration for Thomas. PCMs are specialty materials that use chemical bonds to store and release heat at specific temperatures. Heat transfer occurs at the compound’s individual melting and freezing points—the temperature at which the material changes between solid and liquid phases. By creating designer compounds that change phase at an intended temperature, manufactures of these materials are able tailor refrigerants that are more effective and long lasting than ice.

Phase-change materials of all types—ice included—are highly effective at maintaining temperatures close to their melting points. For example, ice placed in a four-degree Celsius refrigerator will take much longer to melt than ice sitting on a 22-degree counter top or placed in someone’s 37-degree hand— or next to a 37-degree baby. Thus, if the goal for hypothermic treatment is to bring a baby’s body temperature to 33.5 degrees, then a material with a melting point just below that temperature would be far more effective than ice.

“The heat transfer from the phase-change material will stop after the baby and the material reach the same temperature,” Thomas explains. “It will melt slowly so you won’t have to keep changing ice packs.” That was the idea tested on the piglets, at any rate.

For the babies being treated in his department at Christian Medical College, Thomas imagined that PCMs could be used in a device that would maintain an infant’s body temperature at a steady 33.5 degrees for 72 hours without costly and complicated electronics or around-the-clock monitoring.

Twenty-two hundred kilometers away in a suburb of Delhi, Pluss Advanced Technologies was engineering custom phase-change materials for refrigeration and other industry-specific purposes. Thomas found the company in a Google search and got in touch. “I asked them, ‘Do you have a product that melts at around 32 to 33 degrees?’” he recalls.

“He wrote that he needed three kilograms of a 32-degree material and gave us some dimensions,” recounts Pluss’ spokesman, Ankit Jhanwar. Thomas was looking for just enough of the material to test his hypothesis, but for Pluss, it was an unusual request.

“We really don’t supply in kilograms. We supply in tons,” Jhanwar notes, but adds that his team was intrigued and agreed to fulfill the request.

The company took a complete leap of faith—testing and approving new medical products is murky and challenging for newcomers to navigate.

Thomas set to work building a prototype for his idea: a phase-change material cooling bed for the neonatal intensive care unit. His goal was to come up with a solution that was as reliable and easy to use as more expensive systems, but at price low-resource hospitals could afford.

The first results were disappointing: simply put, the babies’ body temperatures did not come down. Lack of insulation in the bed design eventually proved to be the problem. Heat from the baby’s surroundings rather than its body was being transferred to the material, but it took Thomas two years to identify that as the issue, he admits.

Once the bed was redesigned using a better insulating material, his team began seeing the results they sought. They successfully tested the device on nine asphyxiated babies in the unit, and in December 2012, Thomas’ invention was recognized for its results with an innovation award from the National Neonatology Forum of India.

From Concept to Product

Despite what appeared to be a scientific success, Thomas was unsatisfied. He had found a solution to a prevalent problem, but felt he had limited capacity to ensure that the solution reached the people who needed it.

To take the research forward, Thomas approached Pluss for a second time. He proposed that they use his prototype to build a commercial product that they could sell. He asked for no financial compensation and was willing to waive any intellectual property rights.

Although Pluss had no experience in the medical devices domain, the team was enthusiastic. “We are not a medical device company. We had no idea we could do something like this with this material. But the prospect of partnering with Thomas to create a product that had a social impact was exciting,” Jhanwar says.

Pluss’ engineers were able to develop an inexpensive and improved model that was ready for testing within a few months. One of the key changes they made was switching from a 33-degree material to a 29-degree material, which would help cool a baby’s body temperature more quickly. This was one of the limitations Thomas had struggled to resolve with his model.

Pluss makes its phase-change materials by creating unique mixtures of salts, which are inorganic, and fatty acids, which are organic. By experimenting with different ratios, the team can customize a material’s melting point to an intended application. The materials company also customizes the thermal conductivity for each of its PCM designs, which affects the rate at which heat is exchanged. The entire mixture is then encapsulated in a “polymer matrix” so that even in a liquid state, the material will not leak if punctured.

“When it is frozen, it will feel like a rock, and when it has melted, it just feels like a soft solid. It’s much easier to work with,” Jhanwar explains.

For the neonatal cooling material, Pluss’ engineers based the design on average calculations of how much heat a baby’s body emits, which is about 10 joules per second. They speculated that using a material that could absorb that amount of heat for 72 hours would ensure that the baby’s temperature would remain constant and that the cooling pad would not melt.

The Pluss team also created a special conduction mattress made of a gel-based material to position between the baby and the phase-change material. This addition was included because the 29-degree material becomes “rock solid,” as Jhanwar explains, so the baby cannot be placed directly on top of it. He adds that the mattress’ other purpose is to speed up the transfer of heat between the phase-change material and the baby. “Just using a phase-change material will not cool a baby. You need thermal conductivity as well.”

But Will They Use It?

For such an exact product, Jhanwar describes the process as “basically a shot in the dark.” The team was working off of theoretical calculations when designing the phase-change material, but the only way to know for sure whether they had struck the right formula was to test their device in hospitals’ neonatal units. As the team quickly discovered, the process for testing and approving new medical products in India is murky and challenging for newcomers to navigate. Upon reflection, Jhanwar says the company took a complete leap of faith when it agreed to take the project forward. They had not done a market survey and had no understanding of how clinical trials worked.

Dr. Thomas stepped forward to test the new iteration of his device at Christian Medical College. Together, they tested the cooling bed on 41 babies in the CMC neonatal intensive care unit, and discovered that with a few modifications, the 29-degree material was successful at bringing a 37-degree newborn’s temperature down to 33.5 degrees. Furthermore, it could do it within 45 minutes, and once there, the material was able to maintain thermal equilibrium with the child.

Taking the results as an overwhelming success, Pluss officially launched the device under the name “MiraCradle” in April 2014—just under two years after Dr. Thomas approached them to commercialize the idea.

![Early results of the MiraCradle on newborns’ body temperatures](/content/images/2016/04/Screen-Shot-2016-03-31-at-5-13-22-AM.png)

But the team’s initial optimism was short lived. The hospitals that their sales staff approached responded with severe skepticism, and one after another turned them away. Jhanwar now jokes of being kicked out of about 15 hospitals. “They asked us if we had done a randomized clinical trial,” he recalls, but outside of the limited testing at CMC, there was no formal clinical data for the MiraCradle.

By August, they had gained no traction in the market and elected to try a different approach. Through Dr. Thomas, they approached a number of India’s top neonatologists and invited them to attend a day-long medical education workshop on cooling treatment for birth asphyxia at Christian Medical College in Vellore. Pluss let Thomas and his team lead.

“We stayed completely out of it and let the doctors do the talking. Then, if they wanted to try the product, we gave it to them free of charge and asked for feedback,” Jhanwar says. Fifteen hospitals requested a MiraCradle.

Reaching The Right Markets

Most of the feedback from MiraCradle’s initial beta-testers was positive, and gradually, word of mouth spread. Within 18 months of launch, the neonatal cooling device had treated 170 babies in 54 hospitals in India.

The device has since gone through several additional iterations. The phase-change cooling layer now includes a temperature gauge to inform hospital staff of when it has reached the correct temperature for use. This feature was added because the test hospitals reported mixed results with the speed and accuracy of cooling. In the end, Pluss discovered that its design team had not accounted for different regional and hospital climates that could affect the material’s temperature maintenance. As an added precaution, the engineers also added a second phase-change material with a lower melting point of 21 degrees that can be placed between the 29-degree layer and the conduction mattress if the baby’s body temperature does not drop sufficiently in the initial 45-minute window.

![Map of MiraCradle’s trial sites in India](/content/images/2016/04/Screen-Shot-2016-03-31-at-5-14-03-AM.png)
With these improvements and additional hospital feedback, the MiraCradle has received medical device certification from the International Standards Organization, which validates that Pluss’ methods for making and testing the MiraCradle meet accepted international requirements. Pluss is working to obtain CE Mark certification in Europe for the device as well.

Pluss is also making progress with the product’s distribution. The company continues to be focused on India as its primary market, but also has plans underway to distribute the device to hospitals in Kenya and South Africa; it also sees a market for smaller hospitals and clinics in the U.S. and Europe that are looking for low-cost alter- natives to the pricey hypothermia treatment systems that are currently available.

But if the MiraCradle is gaining traction, Pluss does not anticipate making a significant profit from the device, and expects no profit at all anytime soon. Going back to the original purpose of Dr. Thomas’ design, the MiraCradle is meant for low-resource medical facilities that cannot pay exorbitant prices for new technologies. While its target users are not 10-bed rural clinics that often lack even basic medical machinery—the device is still too complex to function effectively without appropriate monitoring equipment and trained staff—nor are they top tier private hospitals. Jhanwar says that ideal candidates for the MiraCradle are small hospitals with a neonatal intensive care unit.

To reach them, Pluss priced the neonatal cooling bed at 240,000 Indian rupees, or about $4,000. The team understands, however, that although the price is roughly a tenth of alternative technologies, there will be challenges and pushback. Some doctors, including Dr. Thomas initially, have said that the cost is too high given the low-cost of the materials used to make it. Jhanwar counters that the materials are only one factor in the price.

“There are several major factors that account for the cost other than manufacturing. One is development. We spent three years making the product,” Jhanwar explains. “Then there is the the process of obtaining certification in different countries, securing patents and trademarks for intellectual property protection, and marketing—and those costs are really high.”

Pluss learned the hard way how difficult it is to market the product themselves within the medical community, where they do not have long-standing relationships. Instead, they have now turned to working with distributors, who take a commission of 30 percent or more of the sales price. These margins may seem high, but Jhanwar concedes it is standard practice in the industry.

Furthermore, because hypothermic treatment is not a widely recognized intervention for birth asphyxia in places like India and Kenya, these distributors play a critical role in educating medical communities on the usefulness of Pluss’ product. Jhanwar says this is a major reason that sales volumes have been slow to gain momentum.

“The time and effort it takes to educate people about the treatment and market the product is really significant. The conversion cycle for one sale is about three months,” he adds.

Pluss has hosted eight treatment education workshops with doctors around India like the first one it held with Thomas in Vellore. Once informed about the treatment and product, some doctors acknowledged that such a device cannot be sold at a very low price. For one, in order for advances in medical technology to become more widely available, they have to be financially sustainable. Also, they should not be priced so low that they are purchased by facilities that are not equipped to use them.

Education about the treatment will be key to developing a market for the product, and it will take time.

“If it becomes too cheap, everybody will buy it,” Thomas explains. “These babies are sick. If you drop the price too much, people who [cannot provide] the appropriate level of care will be tempted to advertise it and use it.”

Dr. Suman Rao, a neonatologist from St. John’s Medical College in Bangalore agrees. “[The MiraCradle] shouldn’t be marketed as so easy that anyone can use it. You can’t use it everywhere that there is asphyxia—it should only be used in hospitals that are able to deal with the complications of asphyxia as well as the complications of cooling,” she says.

Jhanwar says that as the MiraCradle becomes more widely known, the costs will even out. This means that in places like Kenya, where cooling as a treatment for birth asphyxia is still not widely used, it will take time to develop the market. Even then, hospitals will probably require financial support from funding organizations like the World Health Organization or the Bill and Melinda Gates Foundation to purchase the cradles. But in other places like the U.S., the MiraCradle has the potential to establish itself as a cost-effective alternative to more expensive, active-controlled models. Indeed, the team says it is starting to catch the attention of potential distributors in some parts of the U.S.

Pluss hopes that the MiraCradle will one day help sick babies all over the world. In spite of the team’s steep learning curve upon entering the world of medical devices, support networks for this kind of social impact work are beginning to take notice. The company was a recent winner of the India Innovation Growth Program (IIGP), an international technology development program that helps recipients commercialize their products for the international market.

“They came in with a highly technical, but also simplistic solution that met the practical needs of developing countries, and yet maintained the very high tolerances that are required for treating babies with asphyxia,” states Mike Fields, a business development manager for IIGP.

If anything, that will be the message that takes their innovation forward.

Gretchen Cuda-Kroen

Gretchen is a journalist covering science, technology, medicine and environmental issues for Wired News, Nature Medicine and The New York Times, and on radio for NPR, PRI's Marketplace and others.