# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 7 Major Challenges and Barriers to Market
### Regulatory Approval  
A unique challenge confronting the development of engineered tissues and organs not encountered in the use of donor organs is the administrative policies that must be satisfied. In the US, the Health Resources Service Administration regulates the National Organ Transplant Program. However, engineered whole organs fall under the category of HCT/Ps (human cells, tissue, and cellular and tissue-based products), and are regulated by the FDA via the Center for Biologics Evaluation and Research (CBER) and under Title 21 of the Code of Federal Regulations (CFR) [199]. Parts 1270 and 1271 of Title 21 specifically outline the rules and practices that must be adhered to when implanting or infusing HCT/Ps, including policies for screening and testing the tissue sources [200]. Furthermore, because of the novel and untried nature of engineered whole organs in humans, any engineered organ developed would be subject to Premarket Approval (PMA) regulations according to part 814 of Title 21 before being eligible for establishment as a medical product [199,200]. Parts 1270 and 1271 of Title 21 specifically outline the rules and practices that must be adhered to when implanting or infusing HCT/Ps, including policies for screening and testing the tissue sources [200]. An engineered whole organ would be considered a Class III device under PMA guidelines, which is the most stringently regulated device type. This is understandable as Class III devices are those that will be used to sustain human life or prevent substantial impairment of health and are devices with the highest risks associated with their use [199,201]. A PMA application must demonstrate safety and effectiveness of the proposed device via non-clinical laboratory testing in compliance with part 58 of CFR Title 21, with these non-clinical studies demonstrating enough merit for the device to safely advance to clinical investigations to show safety and effectiveness in humans, which must also be included in the PMA application. It is crucial to maintain ethical protocols and patient safety when beginning clinical studies for a Class III PMA. Though there are study protocols that can be adapted from previous clinical studies using allogenic transplants and synthetic implants, the novel and high-risk nature of implanting engineered whole organs means that new, stringent approaches for assessing the safety of engineered whole organs in preclinical and clinical studies will need to be developed. Further administrative challenges will need to be dealt with for any whole organ device that receives PMA. A novel device such as an engineered whole organ will likely be unviable in the medical device market if insurance companies do not reimburse costs for implementing it. Because of this, a new medical device will benefit from being developed to benefit not only patients but also insurance companies, i.e., be cost effective. As such, preclinical and clinical tests of an engineered whole organ should be done to demonstrate the device's safety, efficacy, and capacity to perform without costly downsides of current methods of treating end-stage organ disease. For engineered whole organs, this condition could potentially be achieved largely due to the fact that the organs will use patient-specific cells, eliminating insurance costs associated with allogenic transplants (e.g., medication for patients on a transplant waitlist, medication after transplant surgery to mitigate transplant rejection, and potential subsequent surgery if transplant rejection does occur). However, while engineered whole organs have some potential advantages over allogenic organ transplants in terms of economic costs, there is also a potential downside. Namely, the process of engineering whole organs is expensive, as specific cell culture and tissue engineering materials, methods, and training are needed in most, if not all, whole organ engineering approaches.