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Regenerative Medicine: The Future of Organ Transplantation

Organ transplants are a lifesaving force to treat diseases that once would have been fatal. Since the first kidney transplant in 1954, organ transplants have become a common treatment to replace damaged organs and save lives (Leppke et al., 2013). If your heart fails, it can be replaced. If your kidney is diseased, a friend or family member can donate one of theirs. Even skin can be taken from your own body and grafted to an area affected with severe burn damage. However, roadblocks to organ transplants include increasingly long waiting lists, lack of donors, organ rejection, infections, and risks associated with immunosuppressants has meant that not all those who need an organ transplant will receive one (Dzobo et al., 2018; Fishman, 2017). In the US, an average of 17 people die each day while waiting for an organ transplant (Organ Donation Statistics, 2023). Thankfully, advances in regenerative medicine, such as organ regeneration, offer the chance to reestablish or replace these failing parts of the body to make them functional once again.


What is Regenerative Medicine?

As defined by Mason and Dunnill (2007), “regenerative medicine replaces or regenerates human cells, tissue or organs, to restore or establish normal function.” As distinct from ‘repairing’, in regeneration, new tissue is synthesized to replace damaged tissue and restore full function. Repair is where scar tissue is produced to restore functionally, but the original structure of the organ is not restored (Yannas, 2015). Regenerative medicine aims to replace damaged tissue and organs to restore the body’s full function (Mason and Dunnill, 2007).


While human tissue regeneration is limited, certain forms of regeneration, such as bone and cell regeneration, do occur naturally. Additionally, the liver can still regenerate after 90% of its volume is removed (Khojasteh et al., 2013; Andersson, 2021). However, unlike some amphibians, human tissue has relatively low regenerative capabilities; humans cannot regrow organs and body parts on demand. Technological and biological advancements in regenerative medicine have the potential to allow human organs to be regenerated as needed. Regenerated organs may even be more successful and safer than donated organs, depending on the cells used. Cells from the patient (autologous), another human (allogeneic), or from a different species such as animals (xenogenic) can be used for regeneration (Dzobo et al., 2018). Where possible, using the patient’s own autologous tissue would have a lower chance of organ rejection and would not require the immunosuppression treatments of traditional organ transplantation (Orlando et al., 2011).

Figure 1: Allogenic (donor) and Autologous Whole Organ Decellularization (Ryan et al., 2014)


One of the most famous and controversial examples of the potential of bioengineering occurred when Cao et al. (1997) produced cartilage in the shape of a human ear on the backs of mice. The cartilage was produced from chondrocytes which were reseeded onto a biodegradable polyglycolic acid scaffold and implanted into pockets in the subcutaneous layer of the mice. This innovative technology successfully produced new cartilage and showed that bioengineering could be used to reproduce basic body parts. As the engineered cartilage ears could be implanted, this technology has potential applications in reconstructive surgery.


Organ Regeneration

Regenerative medicine has already been used to develop simple tissue structures such as skin, upper airways, and bladders that have been successfully implanted in patients. The shape of tissues and organs is essential to their ability to function, so it is imperative that materials used in regenerative medicine have the same morphology and characteristics as those tissues (Dzobo et al., 2018). Methods such as the decellularization of donor organs have been widely used as tissue-specific 3D structures that can be reseeded with the desired cultured cells (Badylak et al., 2011). In an innovative study to improve the bladder function of patients with end-stage bladder disease, Atala et al. (2006) engineered autologous bladders from patients' bladder biopsies. Using cell culture techniques, urothelial and smooth muscle cells were seeded on biodegradable collagen-polyglycolic acid matrices in a ‘bladder’ shape. The tissue-engineered bladders were then implanted and used to reconstruct the patients' diseased bladders. The surgeries were a success: bladder function improved for all patients, and side effects associated with non-autologous bladder transplants did not occur. Biopsies of the tissue-engineered autologous bladders showed they contained the three-layered structure (urothelial cell-lined lumen, submucosa, and muscle) of natural bladder tissue, showing that true bladder tissue had been engineered.

Figure 2: Methods for Whole Kidney Regeneration (Yamanaka & Yokoo, 2015)


In order for regenerative medicine to succeed, it is essential that the low natural regeneration potential of human cells is enhanced. The polystyrene dishes commonly used to culture cells in vitro for regenerative medicine do not create an optimal environment for these cells. In the body, the interaction between cells of the extracellular matrix (ECM) enhances their activity (Hinderer et al., 2016). Preserving the ECM improves cell differentiation, migration, and proliferation, all of which can drastically improve the success of the cells (Crapo et al., 2011). Therefore, to enhance cell activity and improve regeneration, biomaterials composed of ECM components have been used to make the in vitro experience more like the in vivo one and significantly improve activity in cultured cells (Tabata & Katayama, 2021).


While engineering simple tissues like bladders for human use has been successful, the development of more complex tissue structures and complex modular organs (CMO) fit for implantation has not yet been achieved (Orlando et al., 2011). Some progress has been made with Ott et al. (2008) having produced an ex-vivo heart by decellularizing a heart and reseeding cardiac and endothelial cells around the decellularized scaffold. These bioartificial hearts produced macroscopic contractions and generated pump function under the electrical stimulus. Baptista et al. (2011) used similar methods to decellularize animal livers which were then reseeded with human endothelial and fetal liver cells. The livers showed hepatic, endothelial, and biliary epithelial markers. These studies show that functional bioartificial hearts and liver-like tissue can be produced in vitro, and suggest the potential for future production of viable CMOs for transplantation (Ott et al., 2008; Baptista et al., 2011). However, methods used in the decellularization process can degrade the tissue, affecting the mechanical process of the tissue. This may remove signaling molecules and limit the ECM (Dzbo et al., 2018). 3D bioprinting can use other properties, aside from decellularization, to regenerate organs.

Figure 3: Decellularized Whole Organ Scaffolds for the Regeneration of Kidneys (Huling et al., 2016)


Bioprinting

Advances in 3D printing have paved the way for 3D bioprinting of complex living tissues, layer-by-layer, using robotic biofabrication, offering an alternative to solid scaffolds (Jain & Bansal, 2015). 3D bioprinting is used in regenerative medicine to place cells in a highly structured and controlled manner, distinct from decellularized scaffolds. 3D bioprinting is a complex and delicate process involving inputs from engineering, biomaterials science, cell biology, physics, and medicine (Murphy & Atala, 2014). There are several bioprinting methods, such as inkjet (sprays droplets of bio-ink or scaffold) and microextrusion (pours bio-ink or scaffold onto a stage), and laser-based (using ultraviolet light to cure polymers) (Dzobo et al., 2018; Kačarević et al., 2018).


Figure 4: Bioinks for 3D Bioprinting (Heid & Boccaccini, 2020)

These processes require ‘bio-inks’ (Dzobo et al., 2018). Bio-inks are biocompatible materials such as hydrogels, cell aggregates, starch, cellulose, and decellularized ECM components that can be used to form the structure of 3D-printed tissue and organs. There are many factors to be considered when selecting bio-inks, such as how well it will fuse to a specific tissue, post-bioprinting maturation, degradation, commercial availability, and if the bio-ink is compatible with the immune system (Hospodiuk et al., 2017). 3D bioprinting has been used to produce 3D tissues like cartilage, blood vessels, vascular grafts, tracheal splints, and aortic valves. These tissues had the ability to produce the ECM proteins collagen and fibronectin, demonstrating the success of these 3D bioprinted tissues (Murphy & Atala, 2014; Mao & Mooney, 2015; Xu et al., 2012). There is still a long way to go. 3D bioprinted structures have low cell viability (Dzobo et al., 2018). For bioprinted organ-like structures to be implanted into humans, their lifespan must be at least several years but is currently limited to days. Full complex modular organs have also not yet been created (Jain & Bansal, 2015).


Conclusion

There is great cause for optimism in the future of regenerative medicine. Organ regeneration and bioprinting have the potential to develop methods to not only replace a piece of the body that has failed but be seamlessly integrated into natural body tissues to preserve life. As the next phase in organ transplantation, tailor-made, autologous structures could carry less risk of infection and organ rejection than donated organs. There are still several limitations and challenges to be overcome, such as the ability of these materials to survive in vivo. Further technological advancement is required to bridge these gaps. There is viable hope that regenerative medicine may significantly alleviate the strain on organ transplantation by providing an alternative to donated organs.

Bibliographical References:

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