Cells Remain Upright in Floating Spherical Shipper
Fragile 3D microtissues for drug development and testing must remain upright in transit. This sphere-on-water system takes cues from boats while keeping products in temperature range.
4-part shipper keeps fragile microtissues in plates upright.
Logistics for fragile products can be hard enough to control, but add in the words “living” and “microtissue” and the shipment is even more challenging. Taking inspiration from boats that remain upright in harrowing conditions, one 3D cell technology company developed a spherical shipper that floats on water to keep cells upright.
Switzerland-based InSphero AG specializes in delivering assay-ready and custom 3D tissue models to pharmaceutical and biotech companies worldwide for investigating, developing, or testing new drugs. They produce a variety of models derived from human liver, pancreatic islet, and tumor cells, to provide insights into liver toxicology, metabolic diseases (e.g., diabetes and liver diseases), and oncology.
The shipping process was already tightly controlled so that these delicate cells arrive safely and on time. “Sterility and temperature must be maintained throughout shipment,” explains Olivier Frey, Ph.D., InSphero head of technology & platforms, a former Olympic-bound pole vaulter, and award-winner for contributions to the advancement of organ-on-a-chip technology. “They are living tissues and need to be maintained at 37 C. They can go a bit lower, but shouldn't go over 40C as too much heat will kill the cells and denature proteins.”
The lifetime of the microtissues is limited, though putting them into a three-dimensional structure extends their lifetime. Any wasted time in shipment would cut into the customer’s experimental window.
Additionally, there are specific consumables—culture media—to consider. “The microtissues are around 200 or 300 microns in diameter (three or four times the thickness of a hair). They’re not anchored in a well, but free-floating in a suspension in a specially designed well,” Frey explains. “If the plate shakes, flips, or sits sideways for too much time, the microtissues can get attached to the plate wall or ceiling. Then if you turn it right-side up again, you have the microtissues outside of the medium and they will die.”
The microtissues are not anchored in a well, but free-floating in a suspension in a specially designed well.
Eureka! moment
The company has been designing their own packaging from the outset due to the specialized nature of the products. InSphero CEO Dr. Jan Lichtenberg was working with his son on a new shipper that would keep the plates oriented properly. He had what the company calls a “eureka!” moment for a spherical shipper, initially performing trials using a sphere inside of another sphere with ball bearings and some lubrication. At a certain point, they thought of how boats are constructed, with a heavy keel at the bottom to keep the boat upright, even in heavy winds.
“They thought, ‘Why can’t we put this on water?’ And that's when we started discussing at the office with materials from the hobby store. We did some early prototyping with styrofoam spheres floating and saw that it worked,” says Frey. “Then we further developed the system with a lot of design iterations in a step-by-step team effort.”
InSphero selected Taracell AG from a short-list of companies they looked at, due in part to their specialty in pharmaceutical packaging. Frey notes, “The reason we chose them ultimately was that they were quickly fascinated and showed enthusiasm. We knew from the beginning it was going to be a challenge, but we had the impression that they also wanted to tackle this and put in extra effort. It was a great collaboration.”
They were also close geographically, only 15 or 20 minutes away. “For such a new shipper, we knew it would require iterations, and that it would be good to quickly meet and discuss next steps,” he adds.
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Sphere on water
The final product, the InFloat Shipping System, is a spherical shipper floating on water inside of a rectangular outer container (not quite a cube as it’s taller in height than width—a rectangular cuboid for geometry fans). Both of the aforementioned parts are composed of expanded polypropylene (EPP). Extruded polystyrene (XPS) was considered but lacked flexibility. “We needed to ensure that the packaging was watertight and the closure required some elasticity of the material. And that's why we chose EPP,” Frey explains.
In total, the system is composed of four main parts.
The 3D microtissues sit in the company’s Akura assay plate technology, sealed with a film in sterile conditions. These plates are wrapped in a small plastic bag to maintain sterility. Depending on the customer’s order, a few plates are then placed in a small paperboard box.
The box sits inside of the sphere, which opens in half. Within the sphere are heating elements added for temperature control. The sphere is secured closed by a single plastic strap.
The sphere sits inside the larger rectangular EPP box, floating on 0.5 liters of water. The EPP box has handles for easy carrying and opening. The box features plastic straps to secure closure.
The EPP box is then housed in a large corrugated shipper.
The shipper was developed to balance watertight design with ease of packout.
“The function of the inner box is branding for the product and keeping everything packaged in a proper, easy-to-handle box. The two black EPP containers keep the micro tissues upright and maintain temperature” says Frey. View a video of the InFloat packout and unboxing here.
Taracell manufacturers the shippers at their facility, and assembly steps are performed during packout at InSphero. During packout, InSphero adds ELPRO temperature data loggers.
Key learnings
There were a couple of challenges Frey points to as learning opportunities. “It seems simple, but it's complex in that from the beginning we wanted to have a solution that functions so that the sphere is floating and stays upright all the time, while keeping the temperature in range. But at the same time we wanted to design something, which is also easy for our team to pack. We wanted it to be intuitive so you show them once how the whole thing is packed and then they always do it properly.”
And on the end user side, they wanted the customer to open it with just a couple of steps so that they can quickly get access to the plates. This meant a lot of discussion and a lot of testing.
The most challenging part was that the water inside has a crucial function. “We had to put quite some effort to really match the correct dimensions so that it was both easy to assemble and leakproof with just a few steps of closure,” says Frey.
During the manufacturing process, there were a few optimization steps regarding the choice of the material and the density of the injection molding process. “We have a lot of thermal elements on the inside that need to be correctly assembled, everything has to match. So from the geometry viewpoint, we had to think about a lot of different things,” he says.
Unique shipping temperature
The product itself is rather unusual in shipping around 37 C. Many similar products in the industry are shipped frozen and need to be placed in the refrigerator upon arrival. InSphero ships live cultures across continents in a condition ready to use in laboratory experiments.
The shipper is qualified for three days, and the company aims to have microtissues at the company in two days for U.S. shipments. (Shipping is three days for Japan.) This is heavily dependent on the lifetime of the microtissue because they are not oxygenated during shipment. Frey notes that one shipper was held up at a logistics center for one week due to a Boston snowstorm. When it arrived at its destination in Brunswick, Maine, the shipment of plates was still intact. These were a different product (not microtissues) but the shipper remained functional.
Commercialization
The systems were launched in Q2 2020, and are already shipping to pharmaceutical sites on a daily basis. The unique structure of the shipper garners attention. “Everyone that sees it is seeing this type of package for the first time, and there tends to be this wow effect that’s transmitted back to our sales representatives,” Frey says. The system recently won the Red Dot Best of the Best award for product design in the category of industrial equipment and automation.
The shipper is disposed of in the regular waste stream. Frey explains, “This is something we’re looking into at the moment. What we observed is that more and more customers write asking how they can ship the system back to us.”
Initially, the team considered reuse and systems that need to be shipped back. “We looked at the whole picture, including the CO2 footprint because shipping a packaging twice over the Atlantic would not be carbon neutral. So we went in the direction of single-use. The size of the new package is not larger than the size we had before, but I think due to the visual it has, people don't want to throw it away. We also want to take care of this and we are currently thinking about how these shippers can be reused without losing function,” he says.
They are also looking at how these shippers can be recycled. Frey notes, “Sustainability is important to us and to our customers. There are specific recycling stations for EPP, so we are thinking about the logistics in order to simplify that.”
An anecdote: When they were testing the prototype shipping system, Dr. Frey and David Fluri put two uncovered glasses filled with wine in the inner box compartment and secured the stems in place. They closed the sphere and the outer box–flipped it over a few times for one full rotation. When they opened the shipping system, the glasses were still full of wine, with no evidence of spills. The team toasted their successful trial run.
Shipping, Regs and Customs
• InSphero’s shipping experts handle customs and paperwork requirements, which can be quite intricate depending on the model. They have cells based on animal models; cynomolgus monkey models, for example, need specific regulatory requirements, as well as some additives.
• Liquid hasn't been an issue. They tested it, shipping prototypes overseas to understand how it’s received. Liquids are shipped all the time and typical thermal shippers have liquid, ice blocks, cold pack, etc.
• There have been occasions where the end user’s lab staff was desperately looking for a box that was stuck in their own mail room. InSphero’s customer service department works closely with the customer to ensure that the urgency is emphasized not only in the lab, but also in the shipping facility.
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The microtissues are not anchored in a well, but free-floating in a suspension in a specially designed well.
