THE BRIEF: The current practices for in vitro fertilization (IVF) and embryo culture differ dramatically from human physiological systems. Can we leverage the latest microfluidics and material science technologies to deliver a more effective way to culture developing human embryos and ultimately improve the likelihood of successful pregnancy?
DURATION: 02.2007 through 02.2010 (3 years)
ROLE: Product development and marketing strategy lead
OUTCOME: SmartFlo embryo culture system enters human clinical trials; company is acquired
Video: introducing IVF device start-up company Incept BioSystems
THE INSIGHT: There is an increasing trend towards professional adults in the U.S. and globally waiting to have children until later in life. As a result, many couples are faced with infertility or lowered fertility and are seeking medical treatment to help conceive a child. Fertility treatment is expensive, costing nearly $15,000 per cycle and sometimes requiring a patient to undergo multiple cycles before finding success. This process can be physically challenging for the woman as she is required to undergo a regimen of hormone injections and doctor visits. And, of course, these costs, pains, and stress can cause great emotional difficulty for any couple struggling with infertility.
The standard practice for IVF involves the culture of a fertilized embryo in a static droplet of growth medium that is preiodically refreshed over the course of days. Within that single droplet, the environmental conditions change dramatically as the developing embryo consumes nutrients and releases waste products. In the natural physiological environment found within the human reproductive system, however, the conditions are quite different: the physical environment is dynamic and the embryo experiences micro-scale stimulation and movement among villi coating the endometrium; nutrients are constantly being replenished and wastes being removed; pH is regulated to maintain a safe and comfortable environment for development.
Does the difference in these conditions result in sub-optimal development and lead to less robust embryos? Can we create a dynamic environment similar to that within the human body to improve in vitro development and increase the likelihood of successful implantation and pregnancy?
Investigation included study of clinical laboratory setting with incubators, microscope stations, and chemical processing hoods
THE PROCESS: We conducted in-depth investigation of current IVF practices and visited a number of IVF clinics to understand the laboratory conditions, staffing, equipment, and processes in that environment. We closely studied IVF protocol to understand its nuances and design a compatible product that could deliver improved results while minimizing the changes required of laboratory equipment and processes. Incept co-founder Dr. Gary Smith is also an industry expert in reproductive medicine, and his expertise and guidance helped greatly to inform and shape our product design.
(left) Braille reader devices allow a user to place their fingers atop a mechanical unit that changes the position of plastic pins to form words. (right) Dye fills microfluidic channels to demonstrate the pulsatile pumping behavior of Braille pins pressing against thin flexible membrane.
PROOF OF CONCEPT: Our lab specialized in the use of polydimethylsiloxane (PDMS) for rapid prototyping. PDMS is an inert, biocompatible silicone polymer that can be cast over molds to create structures with microscale features. We began with the hypothesis that micro-pulses of fluid could be used to create a biomimetic environment similar to the dynamic physiological conditions we find within the human body. Our lab had been working on proof-of-concept applications using off-the-shelf braille reader units to apply small pulsed force to a thin, flexible membrane to move fluids within a device. This became the foundational technology upon which we built Incept's pulsatile embryo culture system.
Early prototypes: (left, bottom) A microfluidic device molded in PDMS features two embryo culture wells connected to growth medium reservoirs by micro-channels. (left, top) Pump constructed of machined aluminum housing with braille reader units that pulse medium through device channels. (right) Device mounted on pump.
RAPID PROTOTYPING: Once we clearly demonstrated proof of concept the pumping of fluids in PDMS channels using Braille devices, we began designing devices which we could quickly fabricate in PDMS to test cell culture. Mechanical engineers on my team designed and constructed molds based on our device concept designs. We tested a number of variables including: cell culture surface area (affects growth environment), channel geometry (affects dosing), reservoir size (affects fluid mechanics). Meanwhile, we also developed pump hardware to create a consistent mechanical interface between the Braille pins and the channel membrane.
Our test methodology was to culture early-stage mouse embryos on the prototype devices to test for usability and effectiveness. Through these tests, we were able to identify the device design parameters that demonstrate most successful mouse embryo cell culture. These parameters would then inform next-generation device design from commercial-grade materials and high-volume manufacturing process which would be used for commercial application.
3-D renderings and cutaway view of device design shows embryos in vitro in culture wells
PRODUCT DESIGN / USER EXPERIENCE: Based on our PDMS prototypes, we developed cartridge and pump designs that could be feasibly manufactured at scale with biocompatible materials. I partnered with my mechanical engineering counterpart to design digital 3-D models using the parameters defined from our earlier prototype studies. We designed an ergonomic plastic cartridge that was easy to manipulate with one hand with a cell culture area large enough to allow for the growth of multiple embryos. We took into consideration the usability factors of the device and fabricated batches of pre-production devices to demonstrate to clinicians and physicians and gather their initial feedback on ease of use and appearance. This allowed us to iterate on the design and make improvements based on user input before investing in large quantity production of the devices.
Schematic of device assembly illustrates multi-layer construction of cartridge and membrane materials
DEVICE CONSTRUCTION: We also conducted material science studies to explore a variety of plastics and polymers that were inert and compatible with the culture of human embryos. We were forced to consider a variety of flexible polymers that were compliant with regulatory standards for biocompatibility, thermal tolerances, shelf life, clarity, and other requirements for medical devices. In the process of refining the device design and selecting the best materials for the application, we were required to develop a proprietary bonding process to make the construction of the cartridge device possible.
The resulting design and processes developed for assembling the devices lead to the issue of multiple patents.
Prototype SmartFlo clinical system included SmartWell embryo culture cartridge, SmartFlo microfluidic pump, and SmartPak power supply
THE LAUNCH: Incept BioSystems announced the SmartFlo embryo culture system to the reproductive medicine community in anticipation of human clinical trials and subsequent product launch pending regulatory approvals. The system consisted of three components: 1) the SmartWell embryo culture cartridge, 2) the SmartFlo microfluidic pump, and 3) the SmartPak power supply and controller unit. The system was presented as an alternative to traditional IVF static embryo culture practices and was compatible with standard equipment for cell handling and incubation. The SmartFlo system was designed to be installed in most standard cell culture incubators, with the pump unit sitting on incubator shelves and the SmartPak mounted magnetically to the outside wall of the incubator. As with traditional culture dishes, the SmartWell cartridge could be handled easily by lab technicians and simply placed on a SmartFlo pump atop the incubator shelf.
The system posed minimal paradigm shift for clinicians while promising improved outcomes, making it a well-received innovation in the industry.
Clinical SmartFlo system publicly demonstrated at exhibit booth at American Society for Reproductive Medicine (ASRM) conference to solicit human clinical trial partners
THE EXIT: After achieving encouraging results in animal model trials where the SmartFlo embryo culture system demonstrated improved mouse embryo development, we began exploring partnerships with IVF clinics across the country for human clinical trials. Clinics in California, Texas, Florida, and South Carolina installed SmartFlo systems and began recruiting patients for clinical trials. We began receiving hundreds of patient inquiries as news of our alternative method for embryo culture began circulating in clinics and online forums.
We promoted the system at large conferences including the American Society for Reproductive Medicine (ASRM) to generate awareness and solicit partnerships. During this time, the company received an acquisition bid from one of the largest Artificial Reproductive Technology (ART) companies in the world to absorb our intellectual property, and decided to proceed with the acquisition deal.
