Below find linked an open access paper that looks at what has to be done to reach the goal of engineered patient-matched organs, built as needed for transplantation, and the resulting end to shortages and waiting lists. It is interesting for putting some figures on the table for time and cost for the various lines of development required. From my perspective, over the longer term of the next twenty to fifty years, the interesting race in tissue engineering and regenerative medicine is between as-needed production of patient-matched tissues and organs for transplant on the one hand and in-situ restoration of all damage in existing tissues and organs on the other. If organs can be comprehensively repaired in place through regenerative medicine, a process that would have to incorporate the SENS portfolio of damage repair therapies for the old, and thus be much more than just an evolution of the stem cell approaches in their infancy today, then there would be little need for transplantation. At present the production of tissues for transplant is much more advanced, however, on the verge of producing useful, functioning sections of internal organs for medicine rather than research.
Thus, over the next couple of decades the immediate race is between the varied established approaches to engineering organs to order, between the range of possible ways to improve transplantation procedures, and between the research groups specializing in different organs or methodologies. These methodologies include decellularization of existing donor organs, xenotransplantation of transgenic pig organs, the bioprinting of tissue scaffolds and cells, and force-growing tissues from stem cells, with the latter still having a long way to go yet. Researchers have demonstrated tiny sections of functional tissue for the kidney, liver, intestines, thymus, and various other organs, but at present these are intended to speed up research. They are only a stepping stone. Scaling up beyond a sliver of tissue is a real challenge, as it involves building complex vascular networks to supply the cells, something that has been a roadblock for more than a decade now, and this despite a great deal of funding, ingenuity, and effort. This is why decellularization and xenotransplantation (or both together) have gathered support and funding: they represent a shorter path to expanding the supply of viable organs.
There are other challenges to the near future of organ engineering beyond those involved in building blood vessel networks of tiny capillaries. All will require time and effort to overcome, and while the scientific community devoted to this work has better funding and support than those involved in aging or rejuvenation research, there is never enough funding or support as would be justified given the end results. No society in history has devoted as much to research as would make sense from a purely logical point of view, sad to day. It is human nature to be consumed by what is, and not with what might be. Progress is an afterthought, which is why even in fields with a sizable output of papers and trials, it is still the case that we need the advocacy of groups like the Methuselah Foundation and the New Organ prize series. Research prizes and contests such as the NASA Vascular Tissue Challenge spur progress, and faster progress towards engineered organs is a good thing indeed.
Bioengineering Priorities on a Path to Ending Organ Shortage
There are four main pathways that we will consider at a high level on a path to end organ shortage through bioengineering: (1) bioprinting organs and tissues, (2) recellularization strategies, (3) cellular repair or regeneration, and (4) xenotransplantation.
Bioprinting
3D printing, or layer-by-layer building of organs and tissues, is a process in which cells and intercellular materials are laid out (also referred to as 3D bioprinting, biofabrication, or additive manufacturing) to create a functioning tissue or organ. This living construct would then be implanted into the patient to replace lost organ functionality.
Recellularization Strategies
Through the use of existing tissue scaffolds from other organs or biologic material, new functionality can be provided to patients. These scaffolds must first be cleared of all endogenous cells, and then repopulated with new cells to form a functional bioengineered organ, at which time the newly formed organ would be implanted into the patient. Cells can also be seeded onto/within biodegradable scaffolds that slowly breakdown after implant, leaving only the desired cells and the extracellular matrix they have deposited. One example of promising work in this area is tissue-engineered autologous urethras for patients.
Cellular Repair or Regeneration
In vivo repair/regeneration of damaged organs can be accomplished by delivering small molecules, growth factors, or genetically modified cells into existing organs in a patient. It is expected that the new cells integrating into existing tissues may increase tissue functionality through a paracrine effect, as well as by directly supplementing functional cells. Additionally, growth factors or genome-editing techniques could boost organ functionality or stimulate regeneration. Genome-editing techniques, such as the clustered, regularly interspaced, short palindromic repeat (CRISPR) technology, are showing promise in this area. It is expected that advances in CRISPR and other genetic modification systems could repair tissues that harbor genetic damage as a result of cancer, disease, or trauma, and thereby remove the need for replacement tissues in some patients.
Xenotransplantation
The use of genome-editing of animals to alter immune recognition and prevent organ rejection is another promising area that could help reduce the increasing shortage of donor organs. In principle, suitably modified animal organs could then be transplanted into human patients (xenotransplantation). Much uncertainty remains regarding the appropriate functional and genetic modifications and the necessary safety precautions that would be required for successful xenotransplantation, but some encouraging progress is being made.
Technical Feasibility and Cost to Arrive at Successful Solutions to Bioengineering Challenges and Limitations
We reached out to 35 leaders in the field to delve into each of these challenges and limitations to provide perspectives on the technical feasibility of addressing each of these bioengineering challenges, as well as the estimated cost to arrive at successful solutions for the proposed bioengineering challenges. The majority of those polled (67%) indicated that we have, for the most part, identified the major bioengineering challenges. These cover a wide range of areas, including manufacturing, storage and distribution challenges, regulatory and standards challenges, and technological challenges.
Mapping: 5-10 years, costing $1M-50M
It is important to improve our understanding of the detailed structures and organization of cells within each organ to accurately bioengineer tissues to replace lost functionality. Maps of cell placement, phenotype, function, organization, and interaction have not been created in sufficient detail to reliably provide a blue print to repair or replace the functions of existing organs. The generation of a comprehensive "cellular atlas" for each organ would provide great benefit to reconstruction and repair of organ functionality. This cellular atlas would consist of both genetic and development mapping. In many solution pathways, bioengineered organs will likely not be perfect mimics of native organs, but nonetheless will deliver the functions needed. For example, pancreatic islet transplants delivered into the liver can function, but do not replicate the microenvironmental pancreas map.
Vascularization: 5-15 years, costing $50M-100M
Engineering thick tissues in vivo or ex vivo requires the ability to create an internal vascular system that provides the required nutrients to all cells. This has not yet been achieved for tissues thicker than a few millimeters. In order to engineer thick-tissue organs such as the heart, liver, lung, or kidney, this challenge must be overcome. Some progress has been made toward this goal. For example, co-transplantation of hematopoietic and mesenchymal stem/progenitor cells has been shown to improve vascularization in a bioengineered tissue graft model. Developing strategies such as this to improve vascularization in bioengineered tissues and organs, through the addition of cells, small molecules, biomaterials, or other methods, will aid regenerative mechanisms as well as ensure sufficient diffusion of nutrients and oxygen and removal of waste.
Integration: 5-15 years, costing $100M-1B
The nervous and lymphatic systems are not intentionally reestablished at the time of organ transplant, so it remains unclear if bioengineered tissues and organs will behave in the same manner as their native counterparts, or if they will require additional connections to successfully integrate with the patient's body. A need for innervation and lymphatic drainage may be a complex challenge that varies from one organ to the next. Solutions may also vary with the pathways being pursued. Connecting thick tissues to an existing host's vasculature will require different techniques than integrating new vascularized tissues, or other thin-walled structures. Interesting work has shown nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation. Expanding work such as this to larger tissues, and eventually to bioengineered organs, will be critical to ensure proper organ function.
Immunosuppression: 5-10 years, costing $1M-50M
Immunosuppression has been critical for allowing for graft survival and limiting rejection after organ transplantation. However, the long-term use of immunosuppression carries with it several side-effects, such as progressive renal impairment. When cells or tissues are implanted into new patients, immunosuppression requirements can greatly reduce the quality of life, damage the transplanted organ if left unchecked, and increase the risk of infection, cancer, cardiovascular disease, diabetes mellitus, and others. Immunosuppressive drugs are also expensive. Eliminating the need for immunosuppression would be ideal. This may be addressed by using autologous cell sources, the genetic modification of cells and tissues, and possibly by methods we have not yet conceived to induce tolerance in organ transplantation.
Cell manufacturing and sourcing: 5-10 years, costing $50M-100M
There is great need to create more reliable sources of different types of cells that are required to produce each desired organ function. We do not yet have enough reliable, replicable sources of key cell types that can be provided at economical costs and scale. The purity and quality of existing cell sources must also be improved to better prepare bioengineered tissues and organs. Autologous cell sourcing techniques are preferred to banking of allogeneic sources, as the use of autologous cells would mitigate rejection and minimize the need for immunosuppression requirements; however, allogeneic sources are far more cost-effective.
Envisioned Impact Eliminating Organ Shortage Would Have on Disease and Global Economies
An extensive report on improving organ donation and transplantation was prepared by the RAND Corporation in 2008. This report is comprehensive and interested readers are encouraged to review. The authors provided projections on organ donation and transplantation rates, quality-adjusted life years and life years saved, health risks to patients, living organ donation, cross-border exchange, and health inequalities. Their most favorable scenario projected health benefits including transplanting up to 21,000 more organs annually in the EU, which would save 230,000 life years or gain 219,000 quality-adjusted life years (QALYs). For social impacts, it was predicted that increasing organ transplantation will have a positive effect on quality of life for organ recipients, and will lead to increased participation in both social and working life activities. RAND Europe projects the economic benefits of implementing policies to improve organ donation and transplantation of up to €1.2 billion in potential savings in treatment costs, and productivity gains of up to €5 billion. These calculations are based solely on increasing transplants by 21,000 more organs annually. Imagine the projected savings globally for completely eliminating organ shortage!
View the full article at FightAging
