# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 1 Introduction  
End-stage organ failure affects millions of people every year in the United States alone. Heart disease is particularly burdensome to the healthcare system, having been the leading cause of death in the US for the past decade, with heart failure contributing to 1 in 8 deaths in 2017 according to the Center for Disease Control [1]. Chronic kidney disease had a prevalence of 15% in the US, or approximately 37 million people, in 2019, with over 661,000 of these individuals having progressedto end-stage renal disease (ESRD) [2; 3]. While various therapies can mitigate the progression of organ disease, autologous organ transplantation is currently the gold standard for end-stage organ failure [4]. Kidney transplants have been shown to improve patient survival when compared to dialysis, and transplants of the liver, heart, and lungs are life-saving [4]. However, while organ transplantation is an immensely beneficial technology, it is significantly limited by the shortage of transplantable organs. From 1991 to 2019, the number of individuals on the waiting list for organ transplants has rapidly increased from around 23,000 to over 112,000, while the numbers of organ donors and organ transplant operations performed have increased relatively marginally from 7000 to 19,000 and 15,000 to 39,000, respectively [5]. Figure 1 graphically represents the disparity resulting from different growth rates of individuals in need of organs and number of transplants performed. This large difference in organ supply and demand contributes to the deaths of 20 people every day who are on a transplant waitlist [5]. In addition to the disparity between number of donors and number of patients on the waitlist, the shortage of transplantable organs is exacerbated by the fact that on average, only 0.3% of individuals die in a way that makes their organs viable for transplantation, as deaths caused by old age, disease, or severe physical trauma can compromise the functionality of organs [5]. International organ transplantation data illustrates a similar trend globally. A report in 2017 by the Global Observatory on Donation and Transplantation found that data comprising 82 member states, whose data was representative of approximately 75% of the global population, showed that the 139,024 organ transplantations performed that year barely accommodated 10% of the global need [6]. Figure 1: In the US: (**a**) Most needed organs on the transplant waitlist and their respective percentages in 2020 as of March, (**b**) number of individuals on the waitlist and the number of transplantations performed from 1991 to 2019, and (**c**) number of transplants performed in 2019 organized by organ. Even if a viable organ is successfully excised, patient-donor compatibility concerns can prevent transplantation from occurring [7]. A blood type match is necessary for all organs, but other congruencies such as body size as well as geographical location of donor and patient can affect the viability of some organs, limiting the potential for transplantation [7]. Furthermore, individuals who are fortunate enough to receive a life-saving organ transplant must remain on immunosuppressivedrugs indefinitely to prevent organ rejection via an immune response [8]. Rejection occurs because transplanted organs are attacked by the patient's immune system due to the patient's immune cells' identifying the antigens present on the surface of the donated organ cells as foreign [8]. Immunosuppressant drugs decrease the likelihood of transplant rejection; however, they also put the transplant recipient at risk. Patients become more susceptible to infections at the site of surgery while the wounds have yet to heal, and for the rest of their lives, they are more susceptible to bacterial pathogens and viruses [9]. Due to a shortage of organs available, limitations of autologous organ transplants, and an increase in the population of individuals that require organ transplants, there remains an unmet clinical need for novel therapies to treat patients with end-stage organ failure.