Bridging Engineering and Immunology

Society today finds itself in the midst of the greatest technological revolution in the history of mankind. Engineering has pervaded nearly every aspect of our life and transformed how we think about human progress. Over recent decades, the spheres of medicine and engineering have begun to overlap as well, resulting in several groundbreaking innovations. Technologies like magnetic resonance imaging (MRI) and next generation sequencing (NGS) have allowed modern medical professionals to pursue disease to a greater extent than ever before. An emerging discipline that has been borne from the synergy of medicine and engineering is the field of immunoengineering. Per the Journal of Biomedical Materials Research, immunoengineering is “a new discipline that creates and applies engineering tools and principles to investigate and modulate the immune system” (Green, 2020). Research in this discipline has illuminated paths to a deeper understanding of cancer, transplant medicine, and many other complex biological mechanisms.

One of the most fascinating areas of research within immunoengineering is primary lymphoid organ engineering. The key premise of this research is to regenerate tissues like bone marrow -- the main site of immune cell maintenance in the human body -- in order to create a biologically accurate model that can be studied in a lab setting. This can be achieved in two ways: through 3-D in-vitro cell cultures, or the development of a microfluidic device commonly known as an “organ on a chip.” 

To engineer bone marrow via cell culture, we must use hematopoietic stem cells, or HSCs. HSCs are multipotent stem cells, meaning that they can self-renew and differentiate into a spectrum of blood cells. They are already used in a wide variety of clinical applications, including treatments for bone marrow diseases, cancer, immune cell dysfunctions, and modulation of the immune response following whole-organ transplantations. Despite this widespread use, there are many risks associated with using HSCs, including graft-versus-host disease (a rejection of transplanted organs by the recipient’s immune system) and organ failure. Bone marrow that is engineered in a laboratory setting can be used as a model or predictive platform to study the behavior of HSCs in a variety of environments. Findings that follow from such studies can then be employed for the development of strategies to circumvent issues associated with HSC use.  

Current research surrounding engineered HSCs involves the growth of cells on a 3-D scaffold that is then subjected to specific microenvironmental regulations or changes. These microenvironmental changes can be achieved by introducing extracellular matrix proteins to the cells, modifying the mechanical properties of the scaffold material, or culturing stromal cells, the cells that constitute different types of connective tissue in our bodies,  along with the HSCs in order to more accurately model the topology of bone marrow that is found in the body. The way that HSCs respond to these various changes to their environment can be studied and measured in order to gain a greater insight into how they function in our bodies (Kim et al., 2019). 

Another avenue for engineering human bone marrow in the lab is the “organ on a chip” model, as alluded to before. According to the Wyss Institute for Biologically Inspired Engineering at Harvard University, an organ chip is a “microfluidic device lined with human cells that can be used for drug development, disease modeling, and personalized medicine” (Ingber, 2020).  They are essentially cell culture devices modeled off of computer chips, and  living, breathing cross-sections of the organs found in our bodies. Traditionally, organ chips are composed of a flexible polymer about the size of a computer memory card and contain microfluidic channels lined by organ-specific cells and endothelial vascular cells. One of the biggest benefits derived from this type of model is the ability to integrate fluids like saline or cell culture media directly into the chip. This  allows for a more accurate representation of the organ in our bodies, and gives scientists the ability to study the mass transport kinetics of drugs or introduce molecular gradients within the chip. 

“Bone marrow-on-a-chip” is one of the many iterations of this technology that have been developed, and it is an integral tool driving the cutting edge of immunology research today. Researchers at the Wyss Institute, the site where this technology was first realized, have observed that the bone marrow generates billions of blood cells every day and is therefore affected by cancer treatments like chemotherapy and radiation the same way that tissue in the human body is. Due to its incredible efficacy in representing human tissue, the bone marrow chip will be used to predict the effect of new chemotherapeutic drugs, assist in the design of clinical trials for rare genetic disorders, advance personalized medicine, and more (Behrens, 2020).

It should be noted that the benefits of the organ-on-a-chip surpass simply the scientific agency afforded to biomedical researchers. Clinical studies are time-consuming and expensive, regularly costing upwards of $2 billion. Benchtop research in the biological sciences involves a heavy cost of animal life in the form of murine, canine, and primate models. The organ-on-a-chip model is a cheaper, more time-efficient, and more ethical alternative to modeling human disease in-vitro, and thus is a hallmark revolution in the way science will be conducted moving forward. 

A perhaps more well-known application of immunoengineering is the development of cancer immunotherapies. These therapies can take a variety of forms, including immune cell hijacking, antibody-based therapies, immunomodulator delivery, and adoptive T-cell transfer therapy (CAR-T Cell Therapy for Brain Tumors). Notably, CAR-T cell therapy has been widely used for the elimination of a type of brain tumor called glioblastoma.

CAR-T cell therapy works by isolating T cells from the bloodstream and then genetically engineering them to express a receptor called a chimeric antigen receptor (CAR). Chimeric antigen receptors are proteins that give T cells the ability to recognize and target cancer cells. Per City of Hope Cancer Center, the newest form of CAR-T cell therapy, now in clinical trials, uses “memory” T cells which remain in your body after attacking the cancer (2020). The hope is that they then grow into an active reservoir of cancer-killing cells capable of stopping future outbreaks.  One of the biggest challenges in treating brain tumors is finding a way to eliminate the disease such that no cancer cells are left behind. Surgery, radiation, and chemotherapy are effective in treating the disease in general, but ineffective in achieving this specific goal. Here, CAR-T cell therapy has shown promise.

Immunoengineering is just one of countless fields that have emerged as a result of the integration of engineering and medicine. As the technological revolution we are currently living through progresses, the overlap between these fields will begin to continue to grow more prominent. From the implementation of designer babies to the alteration of our fundamental biology in order to facilitate space travel, engineering will be the driving force of progress in medicine, and thus a catalyst of the advancement of human civilization.

References

Behrens, H. (2020, February 7). Bone marrow-on-a-chip models damage and disease. https://physicsworld.com/a/bone-marrow-on-a-chip-models-damage-and-disease/

CAR-T Cell Therapy for Brain Tumors: City of Hope cancer center. (2019, October 29). https://www.cityofhope.org/research/car-t-cell-therapy/car-t-cell-therapy-for-brain-tumors

Green, J. (2020, August 04). Immunoengineering has arrived. https://onlinelibrary.wiley.com/doi/abs/10.1002/jbm.a.37041

Immunoengineering with Biomaterials for Enhanced Cancer Immunotherapy. (2018, January 31). https://www.advancedsciencenews.com/immunoengineering-biomaterials-enhanced-cancer-immunotherapy/

Ingber, D. (2020, May 22). Human Organs on Chips. https://wyss.harvard.edu/technology/human-organs-on-chips/

Kim, S., Shah, S., Graney, P., & Singh, A. (2019, April 03). Multiscale engineering of immune cells and lymphoid organs. https://www.nature.com/articles/s41578-019-0100-9