By approaching biology through an engineering lens, cell and tissue manufacturing have the potential to revolutionize medicine, but the nascent fields have challenges to overcome before they can realize true commercial viability.
One emerging facet of manufacturing of products from living organisms can be defined as either cell or tissue manufacturing. Cell manufacturing describes the process of developing and producing cell-based reagents or therapeutics. For example, Chimeric Antigen Receptor (CAR)-T-cells used in immunotherapy cancer treatments are grown in bioreactors after being harvested from the individual and weaponized to target and destroy cancer cells, according to Thomas Tubon, Ph.D., executive director of the NSF ATE Coordination Network: Advanced Manufacturing for Cell & Tissue-based Products at the School of Applied Science, Engineering and Technology at Madison Area Technical College in Wisconsin.
Tissue manufacturing, on the other hand, can involve 3D deposition printing of specific types of cells combined with biomaterials to create bio-ink used in printing. These printed living structures can then undergo maturation under the appropriate culturing conditions.
The road to successful cell-based manufacturing is riddled with speed bumps. Engineers must overcome problems related to scale before it can be commercially viable. “You can grow cells in a one-liter bioreactor but to make an effective and reproducible therapeutic, you are going to want to scale up manufacturing process to produce thousands of liters.” Tubon says.
This is not easy as simply switching to a larger size because the process also involves differences in media formulation and culture characteristics that will ensure the right environment for cell growth. “We have to think about metrics like dissolved oxygen, temperature, pH and a host of other parameters,” Tubon says.
Bioprinting tissues will have to address its own set of challenges. “The bottleneck toward the fabrication of sustainable, clinically relevant tissues is effective vascularization. You need to print the blood vessels inside the tissue so they will feed the cells,” says Dr. Ibrahim Tarik Ozbolat, Hartz Family Associate Professor at Penn State University. Localization of cells and depositing the right cells to develop the physiologically- and histologically-relevant tissues is another concern.
Growing tissue by bioprinting runs into serious speed bumps when thickness increases, according to Dr. Ken Church, CEO at nScrypt, which has created bioprinting devices for tissues. Getting angiogenesis to tissue that is even one centimeter thick has been a challenge. “When you start getting tissue to a certain thickness, there is a fail point,” he says. “Waste needs to come out, oxygen needs to be fed in and this cannot be done very effectively, so you get dead zones.”
Bioprinting tissue is riding the peak of the Gartner hype curve, according to Church, which means misconceptions abound. “The theory is you take a syringe, you get yourself a little x-y control, put them together and you got yourself a bioprinter,” he says. “When is a pancake a pancake? If you put all the ingredients together and do not cook it, you still have only batter. That is where many are with bioprinting. Just tossing ingredients together does not yield that pancake. You need to go through the bio-incubator process [and] you need a lot more integrated control. Cellular matrices, collagen, hyaluronic acid—all of these need their own special handling environments.”
Engineers in bioprinting
It takes biologists, T-cell and B-cell experts and engineers to successfully assemble bioprinting and tissue engineering projects, according to Church. Mechanical engineers address the many challenges associated with dispensing cells. Reducing shear forces on living cells during the printing process is one example. “Computational fluid modeling plays very well with what is going on in biology,” Church says. “Mechanical engineers and CFD [computational fluid dynamics] can also tell me about blood flow mechanisms and how I can address them in bioprinting tissue.”
Design engineers need to factor in temperatures at which materials are bioprinted as well. “If collagen is run through at room temperature, it will start gelling and get deposited as amorphous chunks, not a monolithic solid piece,” Church says.
Engineers need to address viscosity and temperature issues related to biomaterials as well as how to ensure porosity of biopolymers so tissues can grow effectively. “We are also going to have to create plumbing in this tissue, micro-channels through which oxygen and nutrients can get in and waste pushed out,” Church says. “This is the roadmap for engineers.”
Manufacturing considerations such as supply chain management and automated processing also need to be applied in the cell and tissue manufacturing context, according to Tubon. “There is also a need for a cross-disciplinary approach between engineers and biologists to ensure the success of this field,” he adds.
The future of cell and tissue manufacturing
What should design engineers keep an eye on to get ahead? “Clinical translation of connective or epithelial tissues like bone, cartilage [and] skin will be earlier compared to solid organs like the heart, pancreas or lung as they are much more complicated in physiology,” Ozbolat says. “These will take more time to be well vascularized.”
According to Church, “as we go through the Gartner hype curve, we are starting to see some successes now in growing such things as corneas, cartilage, some skin. Do not look for a heart next month, though. Look for that in maybe 10 years.”