# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 5 Recent Developments and Accomplishments
### Pancreas  
The pancreas is a heterogeneous organ that has both exocrine and endocrine functions. The exocrine function is performed by acinar cells, which secrete enzymes to aid in digestion. In contrast, endocrine activity is carried out by the islets of Langerhans, which produce hormones to regulate glucose levels within the blood. Pancreatic tissue transplantation is primarily used for patients with severe cases of type I diabetes (T1D), which eliminates the insulin-producing beta cells of the pancreas causing hyperglycemia. Inadequate control of blood glucose levels can lead to significant complications and may require an islet transplantation to restore beta cell function. However, there are a limited number of donor pancreata available, which currently makes this strategy unsustainable as a long-term treatment option for T1D. In addition to organ shortage, islet transplantation is associated with a significant loss of islets due to poor blood supply reducing the effectiveness of this therapy. Finally, this allogeneic cell source requires immunosuppression to avoid transplant rejection. To address these concerns, researchers are evaluating the efficacy of naturally derived acellular scaffolds to generate novel therapies for treating T1D. Bioengineering the endocrine pancreas presents several challenges. One of these challenges is to replicate the islet cell niche, which consists of a unique three-dimensional ECM structure and vasculature embedded within a cluster of endocrine cells [123]. Top-down whole pancreas engineering methods have been developed to utilize native pancreatic ECM as a scaffold to support islet cell function [124; 125; 126; 127; 128]. [PERSON] et al., used perfusion decellularization to obtain an acellular ECM scaffold from whole mouse pancreata and characterized both exocrine and endocrine function after reseeding the scaffold with acinar (AR4 ZJ) and mouse beta cells (MIN-6) [124]. Whole pancreata were harvested from Institute for Cancer Research (ICR) mice perfused through the pancreatic vasculature via the hepatic portal vein. Detergent-based solutions, 0.5% SDS and 1% Triton X-100, were used in tandem with nucleases to clear cellular components. Acellular pancreatic scaffolds were subcutaneously implanted into C57 BL/6 mice for 14 days and showed active angiogenesis within the implantation site while limiting the immune response, which is critical for islet survival. Upon recellularization with acinar and beta cells, amylase and C-peptide expression confirmed that these cells localized within their specific physiological niche. [PERSON] et al. developed a more clinically translatable approach by utilizing porcine pancreata to generate ECM scaffolds, which were seeded with human stem cells and porcine islets [125]. Porcine pancreata were perfused with 1% Triton X-100 and 0.1% ammonium hydroxide for 24 h then rinsed with phosphate buffered saline for 5 more days until tissues were decellularized. Porcine scaffolds seeded with human amniotic fluid-derived stem cells grew significantly after 7 days in culture, confirming cytocompatibility. Additionally, porcine islets that were seeded onto pancreatic ECM demonstrated an increase in metabolic activity and insulin production between 3 and 7 days. [PERSON] et al., decellularized human pancreatic tissues to move toward the development of a bioartificial endocrine pancreas (BAEP) [126]. The BAEP was generated by decellularizing human pancreata via perfusion of 1%Triton X-100 and 0.1% ammonium hydroxide for 48 h and washing with PBS for an additional 5 days. A chorioallantoic membrane (CAM) angiogenic assay showed that pancreatic ECM triggered neovascularization and did not significantly differ from VEGF, which demonstrates the angiogenic potential of the ECM. Additionally, human pancreatic ECM showed the ability to direct immune cell fate by inhibiting naive CD4+ T-cell proliferation, triggering T-cell apoptosis and pushing naive CD4+ T-cells toward T-reg cells.