# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 3 History of Whole Organ Engineering  
### Origin and Foundational Technologies  
The concept of tissue engineering as a field came into being in the late 1980s, both largely established and popularized as a distinct field of research by [PERSON] and [PERSON] from the former's research article describing the use of polymer networks as cellular scaffolds and their combined review article outlining the scientific basis and future directions of the novel field [10; 11]. Tissue engineering was primarily established to develop technology to overcome the limits of organ transplantation, with whole organ engineering being a recent development in the field that has shown the potential to do so [12]. The fundamental concept of tissue engineering is to utilize a biocompatible material to form a scaffold onto which cells can adhere to and grow on in order to form tissue. The term \"biomaterial\" encompasses a vast array of materials from glass to hydrogels, with the best biomaterial for engineering a tissue being whichever best mimics the tissue type. For example, porous tantalum metallic scaffolds are suitable for engineering bone tissue due to their mechanical strength [13]. In comparison, polymeric biomaterials have been used to develop soft-tissue organs, which are particularly relevant for patients with end-stage organ failure. These biomaterials have been used in a range of tissue engineering applications due to their material chemistry allowing for versatility in fabrication methods [13; 14]. Synthetic polymers, such as poly(glycolic acid) (PGA), poly(lactic acid), and poly(lactic acid-co-glycolic acid) (PLGA), are the most well-studied and commonly used synthetic biomaterials in tissue engineering due to their in vivo degradability by hydrolysis and their biocompatibility [15]. However, while synthetic polymers can be formed into desirable scaffold structures, they are inadequate for engineering functional tissue because their lack of cell adhesion sites reduces their ability to direct cell activity [16; 17; 18]. Natural polymers are another category of polymeric biomaterials that are often used for engineering soft tissue. Alginate is a natural polymer widely used in tissue engineering due to its abundance, gelation characteristics, hydrophilicity, and physical similarities to native ECM [19; 20; 21]. However, alginate does not have cell-binding side groups, making it difficult for cells to adhere to it, and has been found to limit cell migration and proliferation [22]. As the goal of whole organ engineering is to direct cellular activity to form tissue and organ constructs, the native biomaterial scaffolding of the ECM seems best suited for tissue and organ engineering purposes. Some of the most significant early research showing the feasibility of tissue engineering was performed by [PERSON] in 1988, where he showed the ability of biocompatible synthetic polymers to act as scaffold material for cells to be seeded onto [12]. [PERSON] also demonstrated the value of ECM proteins by coating the polymers with collagen and fibronectin to increase cell adhesion [12]. Additionally, [PERSON] identified limitations of tissue engineering research that would need to be addressed to engineer larger scale tissue, such as tissue size being restricted by the distance gas and nutrients can diffuse. [PERSON] and [PERSON] helped to further establish tissue engineering as a distinct field with their review article in 1993 by presenting research that used biomaterial scaffolds as cell adhesion substrates for various cell types of each germ layer, such as nerve bridges composed of polymers laden with Schwann cells [10]. In 1997, [PERSON] et al. utilized embryonic chick cardiomyocytes and a collagen gel to generate one of the first contractile engineered cardiac tissues, demonstrating the viability of tissue engineering to be applied to cardiac regenerative medicine [23].