Making Moly 99: Sandia technology licensed to produce US supply of widely used, in-demand medical rad source
by Nancy Salem
An Albuquerque startup company has licensed a Sandia technology that offers a way to make molybdenum-99, a radioactive isotope needed for diagnostic imaging in nuclear medicine, in the United States. Known as moly 99 for short, it is currently made in aging, often unreliable nuclear reactors outside the country, raising concerns about future shortages.
Eden Radioisotopes LLC was founded last year and licensed the Sandia moly 99 reactor conceptual design in November. It hopes to build the first US reactor for the isotope and become a global supplier. “One of the pressing reasons for starting this company is the moly 99 shortages that are imminent in the next few years,” says Chris Wagner, Eden’s chief operating officer and a 30-year veteran of the medical imaging industry. “We really feel this is a critical time period to enter the market and supply replacement capacity for what is going offline.”
Moly 99 is the precursor for the radioactive isotope technetium-99m used extensively in medical diagnostic tests because it emits a gamma ray that can be tracked in the body, letting physicians image the spread of a disease. And it decays quickly so patients are exposed to little radiation.
Moly 99 is made in commercial nuclear reactors using weapon-grade uranium and 50 to 100 megawatts of power. Neutrons bombard the uranium-235 target. The uranium fissions and produces a moly 99 atom about 6 percent of the time. Moly 99 is extracted from the reactor through a chemical process in a hot cell facility and used by radiopharmaceutical manufacturers worldwide to produce moly 99/technetium-99m generators. The moly 99, with a 66-hour half-life, decays to technetium-99m, with a six-hour half-life. The generators are then shipped to hospitals, clinics, and radiopharmacies, which make individual unit doses for a variety of patient imaging procedures.
“It’s a $4 billion a year market,” Wagner says. “There are 30 million diagnostic procedures done worldwide each year and 80 percent use technetium-99m. More than 50 percent of the procedures are done in the United States, and 60 percent of those are cardiac related. This issue is very important to US health care because there is no domestic production supplier on US soil.”
Meeting the moly demand
The world’s five primary moly 99 production reactors, in Canada, the Netherlands, South Africa, Belgium, and Australia, are often unpredictably closed for repairs, causing periodic shortages that can last months, Wagner says. Two of the largest, the Canadian and Dutch, could either stop producing moly 99 or be decommissioned in the next 10 years. “They represent more than 60 percent of the global supply,” Wagner says. “There is a new reactor due in France, but at the end of the day, if the two go offline and new replacement capacity comes on, Eden still predicts a 20 to 30 percent global shortage to meet today’s demand.”
A search has been on for a number of years for a way to make moly 99 in the United States without using weapon-grade uranium. Several companies have explored new kinds of reactors and different methods to produce the isotope but are not yet in commercial production. “Eden would be the first reactor in the US specifically for medical isotope production,” Wagner says. “We feel that science-wise, this has the most potential for success in the market.”
Dick Coats, Eden’s chief technology officer, is a retired Sandian who helped develop the moly 99 reactor concept at the Labs in the 1990s. “I’ve been involved in reactors my entire career,” says Coats, who has a PhD in engineering sciences from the University of Oklahoma and worked at Sandia 35 years.
Based on technology developed in the DOE-funded Sandia medical isotope production program of the 1990s, the team created a reactor concept tailored to the business of producing moly 99. “This reactor is very small, less than 2 megawatts in power, about a foot-and-a-half in diameter and about the same height, but very efficient,” Coats says.
The reactor sits in a pool of cooling water 28 to 30 feet deep. It has an all-target core of low-enriched uranium — less than 20 percent U-235 — fuel elements. “The targets are irradiated and every one can be pulled out and processed for moly 99. The entire core is available for moly 99 production,” Coats says. “Every fission that occurs produces moly. The reactor’s only purpose is medical isotope production. This is what is new and unique. Nobody thought about approaching it that way.”
Ed Parma (1384), who was on the original Sandia team, says the world demand for moly 99 can be met with a small, all-target reactor processed every week. He says larger reactors aren’t cost effective because they use so much power to drive the targets. “They’re using 150 megawatts to drive a 1 megawatt system,” he says. “When you add in fuel costs, operations, and maintenance, it’s hard to make money.”
He says there has never been a reactor system designed just to make moly 99. “They all started as something else,” he says. “Our design is scaled down to just the production of moly. The reactor is only the size you need. It’s more efficient and economically viable.”
Completing a mission
The Eden reactor is based on a Sandia reactor concept that was envisioned but not designed. The Sandia team went on to other projects in the late 1990s. After he retired in 2011, Coats was asked to join Eden by company partners including CEO Bennett Lee, who learned of the technology while an intern in the Sandia licensing group.
“The reactor had been on my mind for many years,” Coats says. “It’s very exciting to be part of the effort to commercialize it. I don’t view this so much as trying to produce a successful business venture as to complete a mission. There’s more an emotional aspect than economic. It’s something we can do for the country.”
Eden is raising investment capital. The cost for initial funding through production is about $75 million.
It hopes to be in production in about four years. During that time it will build the reactor and facilities and seek licensing from the Nuclear Regulatory Commission and approval of the manufacturing process from the Food and Drug Administration. Wagner says the preferred location is Hobbs, N.M., which has a workforce familiar with nuclear activities due to the nearby URENCO USA uranium enrichment facility. Eden would employ about 140 people.
“Our intent is not to make something just for the United States,” Wagner says. “We will be US-based so US health care has domestic coverage. But our production capacity will be enough to meet the entire global demand.”
All the bases covered
On the business side, two companies provide 100 percent of US production and distribution of moly 99/technetium-99m generators: Mallinckrodt Pharmaceuticals in Missouri and Lantheus Medical Imaging in Massachusetts. Wagner is a former Mallinckrodt vice president and Eden advisory board member Peter Card is a former Lantheus VP. On the technical side, Coats is joined in the company by Milt Vernon, also a retired Sandian who worked on the technology. “We have all the bases covered to be successful,” Wagner says.
Bob Westervelt (7932) says Sandia pursued an exclusive license for the technology. “We didn’t want multiple people trying to build it,” he says. “We wanted one company that could actually commercialize it.”
The licensing department advertised it last summer, and interested parties had to demonstrate they had the financial resources and technical capabilities to build the reactor and get regulatory and environmental approvals.
“There were 10 responses and only one, Eden, came with a full package proposal,” Bob says. Eden was given an exclusive license for the term of the patent, which is pending.
“It’s very exciting to be part of a project that could be commercialized,” Ed says. “I think this is the future. There’s no doubt in my mind.”
-- Nancy Salem
IED detector developed at Sandia being transferred to Army to support combat troops
Detecting improvised explosive devices in Afghanistan requires constant, intensive monitoring using rugged equipment. When Sandia researchers first demonstrated a modified miniature synthetic aperture radar (MiniSAR) system to do just that, some experts didn’t believe it.
But those early doubts are long gone. Sandia’s Copperhead — a highly modified MiniSAR system mounted on unmanned aerial vehicles (UAVs) — has been uncovering IEDs in Afghanistan and Iraq since 2009. Now, Sandia is transferring the technology to the US Army to support combat military personnel, says Sandia senior manager Jim Hudgens (5340).
The technology was developed with the Defense Department’s Joint Improvised Explosive Device Defeat Organization (JIEDDO), the US Army Engineer Research and Development Center/Cold Regions Research and Engineering Laboratory (CRREL), the Naval Air Systems Command (NAVAIR), Johns Hopkins University’s Applied Physics Laboratory, the Naval Research Laboratory, and Florida-based force protection company AIRSCAN.
“JIEDDO tested a number of technologies and ours emerged as one that was viable,” Jim says. “Today, we’re acknowledged as the most successful airborne IED detection capability out there.”
Department of Energy Secretary Ernest Moniz honored the team that developed Copperhead with an Achievement Award at a ceremony in Washington, D.C., this spring.
Copperhead detects disturbances in the earth, for example, those made when IEDs are buried. It can find them day or night and in many weather conditions, including fog and dust storms. Extremely fine-resolution images are processed onboard UAVs and transmitted in real-time to analysts on the ground. Those analysts pass the information to soldiers charged with destroying IEDs.
Though fewer IED have detonated in Afghanistan since a peak of more than 2,000 in June 2012, IEDs account for 60 percent of US casualties, according to Department of Defense reports.
MiniSAR legacy enables Copperhead’s rapid development
Sandia is a world leader in the development of SAR systems, a history that grew out of Sandia’s mission to develop radars for nuclear weapons. Recent SAR systems have vastly improved radar images from aircraft flying at great heights.
SAR and its descendent MiniSAR, the first system of its size to successfully transmit real-time images from UAVs in 2006, use small antennae that capture reflections of microwaves returned from objects on the ground, transmitting and receiving many radar pulses as the aircraft flies. The received pulses are integrated by signal processing techniques to synthesize a fine-resolution image, hence the name “synthetic aperture.”
Jim and Sandia manager Bill Hensley say had it not been for Sandia’s research and development process to reduce the size of the SAR that led to MiniSAR, Copperhead might never have been ready in time to help the Army.
“If we wouldn’t have made that investment, we wouldn’t have been in position to be ready. Otherwise it would have taken us years,” Jim says. “So what we were able to focus on were the radar modes and the enhanced processing that we needed to do.”
But MiniSAR was still limited when it came to the real-world problem of IEDs. As Americans heard more reports of soldiers killed or maimed by IEDs in Afghanistan and Iraq, Sandia researcher Bryan Burns (5300) wanted to help.
“People were getting blown up driving along the road and I said, ‘We can help solve this problem,’” Bryan says.
A few different demonstrations and tests were conducted to demonstrate the fundamental capability. Though some experts expressed doubt that any coherent change-detection system could detect IEDs, in 2007, the Sandia team connected with Mark Moran, director of the special projects office at CRREL. Moran’s team was running a series of scientific investigations to predict the operational ability of various technologies for JIEDDO. During one of those tests, the team showed the value of the MiniSAR technology.
JIEDDO then became interested in the technology and assigned Moran’s team at CRREL as the developing and fielding program office. JIEDDO needed Copperhead developed in nine months, about half Sandia’s normal development period, Bill says.
“Sandia does this advance research and development because there’s a significant number of customers who come to us, they’ve exhausted their other possibilities, they need something and they need it now,” he says. “If we haven’t gotten out ahead of that with the technology, if we’ve got an 18-month technology development cycle out ahead of us, we can’t help them.”
Focusing on mountaintops, valley floors simultaneously is solved
Just as cameras are limited by depth of field — where a near object is in focus but the background is blurry or vice versa — MiniSAR needed a way to keep the entire height of the terrain in an image in focus, for example, the top of a mountain and the valley floor.
So Bryan created advanced image-processing algorithms that focused the high and low terrain simultaneously while continuing to provide fine-resolution imagery. The new capability, which has been proven effective on slopes of more than 40 degrees, made Copperhead useful in the wide variety of terrain present in places like Afghanistan.
To make Copperhead a reality, more than 300 people each spent at least three months on the project during development, including researchers with diverse areas of expertise and Labs staff who helped with logistics, foreign travel, and contracting, Bill says.
“The team is awesome,” he says.
Sandia and its partners had to quickly adapt and enhance the 30-pound MiniSAR so it could fly on NAVAIR’s 17-foot Tiger Shark UAV and accomplish the mission JIEDDO had set.
Completing the modifications and getting them mature enough for operational use in nine months stressed Sandia’s capabilities and the Copperhead team gave their best to meet an urgent mission need, Bill says.
“There were many late nights and long weekends. Key individuals spent months at Yuma Proving Ground,” Bill says.
In the ensuing years, an additional 200 Sandians have applied their talents to make the program successful. “I wish we had room to list all their names,” Bill says.
When the modifications were made Copperhead’s MiniSAR technology weighed about 65 pounds and was about 1 foot wide, it could do all its image processing on board, and it was rugged enough for the environments it would face, Jim says.
Then the modified MiniSAR was integrated into the operational system known as Copperhead, which includes hardware and software tools to help radar analysts on the ground understand the data coming from the aircraft and a training program for them.
“We developed a flight planner and an exploitation tool that the analysts use in the ground station, and we had to develop all the concepts of operations to make it work and tactics, techniques, and protocols for utilizing the system,” Jim says. “While MiniSAR was a radar that we flew and used to collect data, Copperhead is an entire system, everything from communications to analyzing imagery to providing information useful to people who defeat IEDs.”
Wartime conditions test a success
In 2009, JIEDDO sponsored a 30-day evaluation of the technology in wartime conditions and — despite doubts raised that all the images could have such fine resolution — Copperhead has been fielded in Afghanistan ever since, Bill says.
Copperhead uses a technology called coherent change detection, which compares a pair of extremely detailed SAR images taken of the same scene but at different times. The process allows analysts to detect minute physical changes on the surface.
“There are other approaches to change detection out there, but this is the only one that’s all-weather,” Jim says.
An earlier version of coherent change detection developed at Sandia showed images of a lawn taken 20 minutes apart from an aircraft flying 10,000 feet up and three miles away. The images revealed the path of a lawn mower due to the bending of the blades of grass.
Bryan and the team are working with the Army to ensure that Copperhead continues to solve current problems. “We’re helping them to use it in better and more effective ways, even when things change,” he says. “The system is continuously adapting.”
Sandia’s transfer of the technology to the Army will take years to complete, but the Sandia team members say they are happy that they’ve provided the Army with a needed tool to detect IEDs.
Of the transfer to the Army, Bill says, “We’re making a positive, measureable impact right now on the security of US people. This acknowledgement that it needs to be kept in the Army is very satisfying.”-- Heather Clark
Novel nanoparticle production method could lead to better lights, lenses, solar cells
Sandia has come up with an inexpensive way to synthesize titanium dioxide nanoparticles, and is seeking partners who could demonstrate the process at industrial scale for use in everything from solar cells to light-emitting diodes (LEDs).
Titanium dioxide (TiO2) nanoparticles show great promise as fillers to tune the refractive index of anti-reflective coatings on signs and optical encapsulants for LEDs, solar cells, and other optical devices. Optical encapsulants are coverings or coatings, usually made of silicone, that protect a device.
Industry has largely shunned TiO2 nanoparticles because they’ve been difficult and expensive to make, and current production methods produce particles that are too large.
Sandia became interested in TiO2 for optical encapsulants because of its work in LED materials for solid-state lighting.
Current production methods for TiO2 often require high-temperature processing and/or costly surfactants — molecules that bind to something to make it soluble in another material, like dish soap does with fat. Those methods produce less-than-ideal nanoparticles that are very expensive, can vary widely in size, and show significant particle clumping, called agglomeration.
Sandia’s technique, on the other hand, uses readily available low-cost materials and results in nanoparticles that are small and roughly the same size with no agglomeration.
“We wanted something that was low cost and scalable, and that made particles that were very small,” says researcher Todd Monson (1114), who along with principal investigator Dale Huber (1132) patented the process in mid-2011 (Patent 7,943,116, “High-yield synthesis of brookite TiO2 nanoparticles”).
Technique produces small enough nanoparticles
Their method produces nanoparticles roughly 5 nanometers in diameter, approximately 100 times smaller than the wavelength of visible light, so there’s little light scattering, Todd says.
“That’s the advantage of nanoparticles — not just nanoparticles, but small nanoparticles,” he says.
Scattering decreases the amount of light transmission. Less scattering also can help extract more light, as in the case of an LED, or capture more light, in the case of a solar cell.
TiO2 can increase the refractive index of materials such as silicone in lenses or optical encapsulants. Refractive index is the ability of material to bend light. Eyeglass lenses, for example, have a high refractive index.
Practical nanoparticles must be able to handle different surfactants so they’re soluble in a wide range of solvents. Different applications require different solvents for processing.
“As an example, different polymers are soluble in different solvents. If someone wants to use TiO2 nanoparticles in a range of different polymers and applications, it’s convenient to have your particles be suspension-stable in a wide range of solvents as well,” Todd says. “Some biological applications may require stability in aqueous-based solvents, so it could be very useful to have surfactants available that can make the particles stable in water.”
The researchers came up with their synthesis technique by pooling their backgrounds — Dale’s expertise in nanoparticle synthesis and polymer chemistry and Todd’s knowledge of materials physics. The work was done under a Laboratory Directed Research and Development project Dale began in 2005.
Commercial applications were obvious
“The original project goals were to investigate the basic science of nanoparticle dispersions, but when this synthesis was developed near the end of the project, the commercial applications were obvious,” Dale says. The researchers subsequently refined the process to make particles easier to manufacture.
Existing synthesis methods for TiO2 particles were too costly and difficult to scale up production. In addition, chemical suppliers ship titanium dioxide nanoparticles dried and without surfactants, so particles clump together and are impossible to break up. “Then you no longer have the properties you want,” Todd says.
The researchers tried various types of alcohol as an inexpensive solvent to see if they could get a common titanium source, titanium isopropoxide, to react with water and alcohol.
The biggest challenge, Todd says, was figuring out how to control the reaction, since adding water to titanium isopropoxide most often results in a fast reaction and large chunks of TiO2, rather than nanoparticles. “So the trick was to control the reaction by controlling the addition of water to that reaction,” he says.
Some textbooks dismissed the titanium isopropoxide-water-alcohol method as a way of making TiO2 nanoparticles. Dale and Todd, however, persisted until they discovered how to add water very slowly by putting it into a dilute solution of alcohol. “As we tweaked the synthesis conditions, we were able to synthesize nanoparticles,” Todd says.
The next step is to demonstrate synthesis at an industrial scale, which will require a commercial partner. Todd, who presented the work at Sandia’s fall Science and Technology Showcase, says Sandia has had inquiries from companies interested in commercializing the technology.
“Here at Sandia we’re not really set up to produce the particles on a commercial scale,” he says. “We want them to pick it up and run with it and start producing these on a wide enough scale to sell to the end user.”
Sandia would synthesize a small number of particles, then work with a company to form composites and evaluate them to see if they can be used as better encapsulants for LEDs, flexible high-index refraction composites for lenses, or solar concentrators. “I think it can meet quite a few needs,” Todd says.
-- Sue Major Holmes
Prototype electrolyte sensor provides immediate results
by Neal Singer
Soldiers on long missions, encased in tactical armor, could monitor their electrolytes with a diagnostic tool worn on the wrist and immediately detect and remedy deficiencies, thanks to a prototype device that Sandia researchers are patenting.
Electrolyte levels are key to optimizing health, strength, and awareness, not only for soldiers but for anyone who subjects the body to extremes. The ability to predict and upgrade the performance of long-distance runners or competitors in other strenuous sports would improve significantly if coaches could learn what's happening physiologically while the athlete is exercising. The knowledge would help the self-aware athlete as well.
Electrolytes are crucial in carrying electrical impulses that tell the heart and other muscles when to contract or relax. Even non-athletes who feel poorly and try to navigate today’s complex medical system with its costly laboratory analyses might prefer a pain-free home diagnostic device that can analyze and continuously record electrolyte levels.
The Sandia researchers used various miniaturization techniques to shrink laboratory-scale equipment that analyzes various electrolyte levels on the spot down to a model that can fit in a palm or be worn on a wrist. The device, when commercially available, could decrease the time patients must spend in emergency rooms, lab testing facilities, or doctors' offices.
Painless, noninvasive, long-term use
The device is painless because it employs micro-needles so tiny they can't traumatize nerves when pressed into the skin, and samples only interstitial fluid (i.e. fluid between cells). Thus the device has the potential for long-term, noninvasive use.
“We're proposing a minimally invasive way to move away from centralized laboratory testing,” says Ronen Polsky (1714), lead Sandia researcher on the project.
In a paper to be published as a cover feature in the June issue of Advanced Healthcare Materials (Wylie) and available online, Ronen, Sandia colleagues, and University of North Carolina/North Carolina State University graduate student Phil Miller describe using a fast-pulsed laser to create strong hollow microneedles that suck infinitesimal amounts of colorless fluid from just beneath the skin's surface. The paper demonstrates that tiny amounts of potassium passed unhindered through the microneedle pores into a fluidic cartridge containing carbon electrodes. These measured the amount of this key electrolyte without being confused by the presence of other electrolytes in the fluid.
Miller says it’s easy to change the selectivity of the carbon electrodes to detect and measure other such electrolytes as sodium or calcium in the same device. “We want to make the device wearable, non-invasive, and with real-time readout to constantly measure things a doctor might normally order for laboratory tests,” he said.
University of New Mexico physician and researcher Justin Baca, who will lead human testing of the device, adds, “Development of this benchtop device into a handheld model for consumers and patients will be a true partnership between a clinician and an engineer.”
Sometimes sensor technologies work well, but problems arise when they are adapted to living systems, Baca said. “We're trying to get at this problem from the beginning to develop the best needle geometry.”
Baca, with a background in physical chemistry and a practice in emergency medicine, says he has initial approval from UNM's Human Research Protection Office review board to start tests. He’s interested, he says, because “it's hard, using traditional methods, to take blood samples continuously.” Using only interstitial fluids is another matter entirely, he said.
The initial sensor work was funded by Sandia’s Laboratory Directed Research and Development program and the US Defense Threat Reduction Agency. Others working on the project include University of North Carolina/North Carolina State professor Roger Narayan.
“This is the future of personalized health care,” says Ronen. “These wearable technologies are just starting to come out in different forms. It’s inevitable that people will go there.”
-- Neal Singer