https://orcid.org/0000-0002-6460-7974
Abstract
Organ transplantation is predicted to increase as life expectancy and the incidence of chronic diseases rises. Regenerative medicine-inspired technologies challenge the efficacy of the current allograft transplantation model.
A literature review was conducted using the PubMed interface of MEDLINE from the National Library of Medicine. Results were examined for relevance to innovations of organ bioengineering to inform analysis of advances in regenerative medicine affecting organ transplantation. Data reports from the Scientific Registry of Transplant Recipient and Organ Procurement Transplantation Network from 2008 to 2019 of kidney, pancreas, liver, heart, lung and intestine transplants performed, and patients currently on waiting lists for respective organs, were reviewed to demonstrate the shortage and need for transplantable organs.
Regenerative medicine technologies aim to repair and regenerate poorly functioning organs. One goal is to achieve an immunosuppression-free state to improve quality of life, reduce complications and toxicities, and eliminate the cost of lifelong antirejection therapy. Innovative strategies include decellularization to fabricate acellular scaffolds that will be used as a template for organ manufacturing, three-dimensional printing and interspecies blastocyst complementation. Induced pluripotent stem cells are an innovation in stem cell technology which mitigate both the ethical concerns associated with embryonic stem cells and the limitation of other progenitor cells, which lack pluripotency. Regenerative medicine technologies hold promise in a wide array of fields and applications, such as promoting regeneration of native cell lines, growth of new tissue or organs, modelling of disease states, and augmenting the viability of existing ex vivo transplanted organs.
The future of organ bioengineering relies on furthering understanding of organogenesis, in vivo regeneration, regenerative immunology and long-term monitoring of implanted bioengineered organs.
Tomorrow's world today
The challenges of organ transplantation have been the overwhelming demand and the ideal of immunosuppression-free strategies1. Allocation of donor organs may exhibit racial, sex, age and geographical disparity, and this may worsen as the gap between supply and demand widens1–5. Based on the Organ Procurement and Transplant Network database, by the end of 2009, there were 105 567 patients waiting for solid organ transplantation (kidney, pancreas, liver, heart, lung and intestine) and 28 458 transplants performed, whereas by the end of 2019, there were 112 568 patients waiting and 39 718 solid organ transplants performed6. Regenerative medicine (RM) is dedicated to replacing and/or repairing tissues and organs for functional restoration, which may represent a solution to these critical challenges.
The history of organ transplantation can be split into three phases, or eras (Fig. 1)7. The first phase spans from the early days of surgical science (surgery era). Technical feasibility was proven, but outcomes were limited by the lack of effective antirejection therapies until ciclosporin projected the field into the immunology era. On the one hand, immunosuppression allowed transplantation to become the standard of care for many diseases but, on the other, it does so at the cost of side-effects. For this reason, research has focused on strategies to achieve immune tolerance in an immunosuppression-free status (IFS) whereby the recipient accepts an allograft without immunosuppressants. In more recent years, the field has been transitioning into the regenerative era in tandem with other developments, such as big data, exchanged pair donation chains, and transplants across blood groups or among incompatible donors8–11. Recent achievements in organ bioengineering and regeneration technologies to manufacture organs from the patient's own cells may offer the genesis of organ-on-demand and IFS.
Phases in the history of organ transplantation
CRISPR, clustered regularly interspaced short palindromic repeats. Reproduced from reference 7 with permission.
The long-term management of transplant recipients is focused on reduction in morbidity and mortality and improving quality of life, while balancing side-effects of immunosuppressive drugs with risk of graft failure. Chronic disease management may be termed a halfway technology because the focus is not on cure12. Organ transplantation should be considered a halfway technology for two reasons: it does not directly target the underlying disease, and long-term immunosuppression may induce life-changing side-effects. RM may render organ transplantation a full-way technology if medication can be avoided. The feasibility of this approach has been proven with implantation of sections of the urinary tract or upper airways, but it is only a matter of time before complex organs are bioengineered13–19.
Decellularization is a process in which an acellular extracellular matrix (aECM) scaffold can be obtained by using chemical or physical means to remove cellular components of living tissue20. The product of decellularization is a three-dimensional (3D) ultrastructure of ECM that may be used as a natural scaffold for application in tissue engineering and RM21. Ideally, the aECM scaffold retains both structural integrity and existing biochemical properties of the native tissue nanostructure. Studies have shown that aECMs exhibit bio-inductive properties comparable to those of native tissue for cellular chemotaxis, including attachment, migration, proliferation and function22. These constructs have the advantage of maintaining tissue-specific cell functions and phenotypes to induce host tissue remodelling. Previous studies23–38 have had success in obtaining aECM scaffolds from virtually all mammalian organs. They preserve the native vasculature for adequate perfusion of constructs able to withstand physiological blood pressures, something that has been a challenge to RM methods relying on progenitor cell embryogenesis39,40. Other obstacles include damage to innate ECM during tissue processing or inadequate recellularization of structurally complex organs.
Advantages of 3D printing, as an alternative strategy for organ manufacturing, include automation of construct fabrication, reliable reproducibility, increased resolution and the potential for mass production. Applications of 3D-printed acellular constructs are prolific in orthopaedics and maxillofacial surgery. They are used in preoperative planning, personalized drug delivery, and fabrication of models for use in dentistry, cardiovascular disease, facial plastic and reconstructive surgery, and limb prostheses19,41–44. Possibly the most anticipated and exponential applications of 3D printing are those in tissue engineering, which may collectively be referred to as bioprinting. Biomaterials used for bioprinting constructs compatible with human physiology include both naturally derived polymers (such as alginate, gelatin, collagen, fibrin and hyaluronic acid) and synthetic polymers (for example, polyethylene glycol)7. A combination of synthetic and naturally derived polymers produces a functionally superior material that retains both the structural integrity and innate physiological interactions. Current resolution limits of bioprinter technology are 2 μm for acellular constructs, and 50 μm for those that include encapsulated cells45. Successful preclinical studies46–48 have implemented 3D bioprinted cartilage and bone tissues in animal models. It has been difficult to produce vascular, neurological and lymphatic networks in biologically printed constructs, or to maintain viable tissues that exceed 1 cm in thickness49. Slow printing speeds and printer resolution restrictions have limited the size of 3D bioprinted constructs so far. It is theorized that current bioprinting techniques lack geometrical complexity owing to insufficient use of multipolymer constructs and multiple cell lines, which consequently extends to inadequate replication of organ vasculature leading to inadequate tissue perfusion.
Use of embryonic stem cells (ESCs) remains one of the earliest forms of RM technologies. ESCs, which are found within the inner cell mass of blastocyst-stage embryos, retain their ability to differentiate into all adult cell types. ESC-based modalities, however, remain limited because of the potential tumorigenic risk, risk of immune rejection, and ethical dilemmas surrounding use of human embryos7. Another well described method is the harvesting of mesenchymal stem cells (MSCs) from the patient's bone marrow, periosteum, periodontal ligament or adipose tissue50. Initial animal studies47 suggested that MSC-derived chondrocytes do not retain regeneration abilities and fail to engraft, which limits their practical application in RM therapies. Instead, MSC-based therapies are useful for both direct and indirect stimulation of endogenous repair, relying on paracrine factors to mediate this process7. The concept of induced pluripotent stem cells (iPSCs) navigates these challenges by reprogramming somatic stem cells to have the same potential plasticity as ESCs51.
β-Cell replacement offers a formidable platform for the application of stem cell-based technologies to transplant medicine. A new, potentially inexhaustible source of transplantable insulin-producing cells, β-cells and islets for type 1 diabetes may be available soon52–54. Among the RM technologies of interest to transplant medicine, stem cell technology is the one that has the greatest potential for clinical translation (Table 1).
State-of-the-art regenerative medicine technologies
| State of the art | Perspective and hurdles to overcome | Potential for translation within the next decade | |
|---|---|---|---|
| Decellularization | Virtually all organs from all clinically relevant mammalian species including humans can be decellularized to obtain acellular ECM scaffolds Acellular ECM scaffolds preserve most, yet not all, molecular and physical characteristics of the innate ECM, as the decellularization process damages the ECM to an extent that depends on the method and organ Partial regeneration of endothelial and parenchymal compartments has been reported, yet results are inconsistent and difficult to reproduce The maturation phase reported in the literature for different organs was always far inferior to the time needed in utero to develop the organs in question Implantation in vivo of a viable and functioning bioengineered organ has never been reported | In-depth understanding of mechanisms underlying organ development, regeneration and homeostasis In-depth understanding of the mechanisms of ECM scaffold–cell interactions Cell selection for recellularization Harmonious harnessing of lymphatic, nervous and vascular components Improving the design of ad hoc bioreactors to support maturation Strategies to achieve adequate recellularization | Low, not in the foreseeable future for solid organs like kidneys, hearts, etc. |
| 3D printing | Successful isolation and expansion of many functional and supportive cell types Replication of mechanical and biophysical properties of simple tissues at the macro level Bioprinting of cells with natural and synthetic biomaterials with high resolution Implantation and in vivo maturation of small avascular tissues | Production of an adequate number of regeneration-competent cells that do not elicit an immune response following transplantation ECM-based materials that provide much stronger mechanical strength while maintaining cell-supportive environment Improvements in speed, resolution, material flexibility and scalability of bioprinters Bioprinting of multiscale vascular networks within instructive bioink that promotes angiogenic sprouting and neovascularization | Low, likely not in the foreseeable future |
| Stem cells | Generation of various types of complex organoids in vitro (e.g. renal, liver, heart, pancreas) from different strains of human progenitors including iPSCs Generation of human pancreatic tissue in vivo following transplantation of multipotent progenitor-derived organoids in mice Multipotent progenitors can be generated from individual patients, circumventing the need for immunosuppressants after transplantation | Organoids derived from multipotent progenitors typically resemble fetal tissues/organs and are unlikely to mature into functioning adult organs Organoids derived from multipotent progenitors that are generated in vitro do not have the blood vessels, lymphatics and neuronal innervation required to function in vivo | High, likely within the next decade |
| IBC | Development of functional rat pancreas following IBC of Pdx1–/– mouse blastocysts Generation of a biallelic knockout in pigs using nuclease-based genome editing shows it could be possible to generate pig embryos for IBC that lack specific organs Development of mouse–human and pig–human chimeric embryos using ‘primed’ human iPSCs | Low yield and efficiency: chimerism is extremely low (< 1%) To improve the efficiency of generating human–pig chimeric embryos, greater understanding is needed of how the status of human iPSCs (whether they are naive, primed or intermediate) affects their ability to integrate into postimplantation pig embryos The contribution of human iPSCs to developing pig embryos is limited and it has not yet been possible to generate human organs using IBC Even if the above challenges were addressed, a further problem is that human organs developed using IBC would have pig blood vessels, lymphatics and neuronal innervation, which would lead to immune rejection | Low, likely not in the foreseeable future |
| RM for ischaemia–reperfusion | Multiple candidate cell populations showing efficacy beyond previous small molecule alternatives Emerging evidence of favourable biodistribution avoiding off-site effects Natural organ architecture available in transplant context Complementary benefits with normothermic ex vivo perfusion | Obtaining adequate numbers of point-of-care-derived autologous cells Obtaining adequate numbers of efficacious, non-immunogenic GLP-manufactured allogeneic cells Reassurance regarding potential vascular/microvascular complications | High, likely within the next decade |
| State of the art | Perspective and hurdles to overcome | Potential for translation within the next decade | |
|---|---|---|---|
| Decellularization | Virtually all organs from all clinically relevant mammalian species including humans can be decellularized to obtain acellular ECM scaffolds Acellular ECM scaffolds preserve most, yet not all, molecular and physical characteristics of the innate ECM, as the decellularization process damages the ECM to an extent that depends on the method and organ Partial regeneration of endothelial and parenchymal compartments has been reported, yet results are inconsistent and difficult to reproduce The maturation phase reported in the literature for different organs was always far inferior to the time needed in utero to develop the organs in question Implantation in vivo of a viable and functioning bioengineered organ has never been reported | In-depth understanding of mechanisms underlying organ development, regeneration and homeostasis In-depth understanding of the mechanisms of ECM scaffold–cell interactions Cell selection for recellularization Harmonious harnessing of lymphatic, nervous and vascular components Improving the design of ad hoc bioreactors to support maturation Strategies to achieve adequate recellularization | Low, not in the foreseeable future for solid organs like kidneys, hearts, etc. |
| 3D printing | Successful isolation and expansion of many functional and supportive cell types Replication of mechanical and biophysical properties of simple tissues at the macro level Bioprinting of cells with natural and synthetic biomaterials with high resolution Implantation and in vivo maturation of small avascular tissues | Production of an adequate number of regeneration-competent cells that do not elicit an immune response following transplantation ECM-based materials that provide much stronger mechanical strength while maintaining cell-supportive environment Improvements in speed, resolution, material flexibility and scalability of bioprinters Bioprinting of multiscale vascular networks within instructive bioink that promotes angiogenic sprouting and neovascularization | Low, likely not in the foreseeable future |
| Stem cells | Generation of various types of complex organoids in vitro (e.g. renal, liver, heart, pancreas) from different strains of human progenitors including iPSCs Generation of human pancreatic tissue in vivo following transplantation of multipotent progenitor-derived organoids in mice Multipotent progenitors can be generated from individual patients, circumventing the need for immunosuppressants after transplantation | Organoids derived from multipotent progenitors typically resemble fetal tissues/organs and are unlikely to mature into functioning adult organs Organoids derived from multipotent progenitors that are generated in vitro do not have the blood vessels, lymphatics and neuronal innervation required to function in vivo | High, likely within the next decade |
| IBC | Development of functional rat pancreas following IBC of Pdx1–/– mouse blastocysts Generation of a biallelic knockout in pigs using nuclease-based genome editing shows it could be possible to generate pig embryos for IBC that lack specific organs Development of mouse–human and pig–human chimeric embryos using ‘primed’ human iPSCs | Low yield and efficiency: chimerism is extremely low (< 1%) To improve the efficiency of generating human–pig chimeric embryos, greater understanding is needed of how the status of human iPSCs (whether they are naive, primed or intermediate) affects their ability to integrate into postimplantation pig embryos The contribution of human iPSCs to developing pig embryos is limited and it has not yet been possible to generate human organs using IBC Even if the above challenges were addressed, a further problem is that human organs developed using IBC would have pig blood vessels, lymphatics and neuronal innervation, which would lead to immune rejection | Low, likely not in the foreseeable future |
| RM for ischaemia–reperfusion | Multiple candidate cell populations showing efficacy beyond previous small molecule alternatives Emerging evidence of favourable biodistribution avoiding off-site effects Natural organ architecture available in transplant context Complementary benefits with normothermic ex vivo perfusion | Obtaining adequate numbers of point-of-care-derived autologous cells Obtaining adequate numbers of efficacious, non-immunogenic GLP-manufactured allogeneic cells Reassurance regarding potential vascular/microvascular complications | High, likely within the next decade |
ECM, extracellular matrix; 3D, three-dimensional; iPSC, induced pluripotent stem cell; IBC, interspecies blastocyst complementation; RM, regenerative medicine; GLP, good laboratory practice.
State-of-the-art regenerative medicine technologies
| State of the art | Perspective and hurdles to overcome | Potential for translation within the next decade | |
|---|---|---|---|
| Decellularization | Virtually all organs from all clinically relevant mammalian species including humans can be decellularized to obtain acellular ECM scaffolds Acellular ECM scaffolds preserve most, yet not all, molecular and physical characteristics of the innate ECM, as the decellularization process damages the ECM to an extent that depends on the method and organ Partial regeneration of endothelial and parenchymal compartments has been reported, yet results are inconsistent and difficult to reproduce The maturation phase reported in the literature for different organs was always far inferior to the time needed in utero to develop the organs in question Implantation in vivo of a viable and functioning bioengineered organ has never been reported | In-depth understanding of mechanisms underlying organ development, regeneration and homeostasis In-depth understanding of the mechanisms of ECM scaffold–cell interactions Cell selection for recellularization Harmonious harnessing of lymphatic, nervous and vascular components Improving the design of ad hoc bioreactors to support maturation Strategies to achieve adequate recellularization | Low, not in the foreseeable future for solid organs like kidneys, hearts, etc. |
| 3D printing | Successful isolation and expansion of many functional and supportive cell types Replication of mechanical and biophysical properties of simple tissues at the macro level Bioprinting of cells with natural and synthetic biomaterials with high resolution Implantation and in vivo maturation of small avascular tissues | Production of an adequate number of regeneration-competent cells that do not elicit an immune response following transplantation ECM-based materials that provide much stronger mechanical strength while maintaining cell-supportive environment Improvements in speed, resolution, material flexibility and scalability of bioprinters Bioprinting of multiscale vascular networks within instructive bioink that promotes angiogenic sprouting and neovascularization | Low, likely not in the foreseeable future |
| Stem cells | Generation of various types of complex organoids in vitro (e.g. renal, liver, heart, pancreas) from different strains of human progenitors including iPSCs Generation of human pancreatic tissue in vivo following transplantation of multipotent progenitor-derived organoids in mice Multipotent progenitors can be generated from individual patients, circumventing the need for immunosuppressants after transplantation | Organoids derived from multipotent progenitors typically resemble fetal tissues/organs and are unlikely to mature into functioning adult organs Organoids derived from multipotent progenitors that are generated in vitro do not have the blood vessels, lymphatics and neuronal innervation required to function in vivo | High, likely within the next decade |
| IBC | Development of functional rat pancreas following IBC of Pdx1–/– mouse blastocysts Generation of a biallelic knockout in pigs using nuclease-based genome editing shows it could be possible to generate pig embryos for IBC that lack specific organs Development of mouse–human and pig–human chimeric embryos using ‘primed’ human iPSCs | Low yield and efficiency: chimerism is extremely low (< 1%) To improve the efficiency of generating human–pig chimeric embryos, greater understanding is needed of how the status of human iPSCs (whether they are naive, primed or intermediate) affects their ability to integrate into postimplantation pig embryos The contribution of human iPSCs to developing pig embryos is limited and it has not yet been possible to generate human organs using IBC Even if the above challenges were addressed, a further problem is that human organs developed using IBC would have pig blood vessels, lymphatics and neuronal innervation, which would lead to immune rejection | Low, likely not in the foreseeable future |
| RM for ischaemia–reperfusion | Multiple candidate cell populations showing efficacy beyond previous small molecule alternatives Emerging evidence of favourable biodistribution avoiding off-site effects Natural organ architecture available in transplant context Complementary benefits with normothermic ex vivo perfusion | Obtaining adequate numbers of point-of-care-derived autologous cells Obtaining adequate numbers of efficacious, non-immunogenic GLP-manufactured allogeneic cells Reassurance regarding potential vascular/microvascular complications | High, likely within the next decade |
| State of the art | Perspective and hurdles to overcome | Potential for translation within the next decade | |
|---|---|---|---|
| Decellularization | Virtually all organs from all clinically relevant mammalian species including humans can be decellularized to obtain acellular ECM scaffolds Acellular ECM scaffolds preserve most, yet not all, molecular and physical characteristics of the innate ECM, as the decellularization process damages the ECM to an extent that depends on the method and organ Partial regeneration of endothelial and parenchymal compartments has been reported, yet results are inconsistent and difficult to reproduce The maturation phase reported in the literature for different organs was always far inferior to the time needed in utero to develop the organs in question Implantation in vivo of a viable and functioning bioengineered organ has never been reported | In-depth understanding of mechanisms underlying organ development, regeneration and homeostasis In-depth understanding of the mechanisms of ECM scaffold–cell interactions Cell selection for recellularization Harmonious harnessing of lymphatic, nervous and vascular components Improving the design of ad hoc bioreactors to support maturation Strategies to achieve adequate recellularization | Low, not in the foreseeable future for solid organs like kidneys, hearts, etc. |
| 3D printing | Successful isolation and expansion of many functional and supportive cell types Replication of mechanical and biophysical properties of simple tissues at the macro level Bioprinting of cells with natural and synthetic biomaterials with high resolution Implantation and in vivo maturation of small avascular tissues | Production of an adequate number of regeneration-competent cells that do not elicit an immune response following transplantation ECM-based materials that provide much stronger mechanical strength while maintaining cell-supportive environment Improvements in speed, resolution, material flexibility and scalability of bioprinters Bioprinting of multiscale vascular networks within instructive bioink that promotes angiogenic sprouting and neovascularization | Low, likely not in the foreseeable future |
| Stem cells | Generation of various types of complex organoids in vitro (e.g. renal, liver, heart, pancreas) from different strains of human progenitors including iPSCs Generation of human pancreatic tissue in vivo following transplantation of multipotent progenitor-derived organoids in mice Multipotent progenitors can be generated from individual patients, circumventing the need for immunosuppressants after transplantation | Organoids derived from multipotent progenitors typically resemble fetal tissues/organs and are unlikely to mature into functioning adult organs Organoids derived from multipotent progenitors that are generated in vitro do not have the blood vessels, lymphatics and neuronal innervation required to function in vivo | High, likely within the next decade |
| IBC | Development of functional rat pancreas following IBC of Pdx1–/– mouse blastocysts Generation of a biallelic knockout in pigs using nuclease-based genome editing shows it could be possible to generate pig embryos for IBC that lack specific organs Development of mouse–human and pig–human chimeric embryos using ‘primed’ human iPSCs | Low yield and efficiency: chimerism is extremely low (< 1%) To improve the efficiency of generating human–pig chimeric embryos, greater understanding is needed of how the status of human iPSCs (whether they are naive, primed or intermediate) affects their ability to integrate into postimplantation pig embryos The contribution of human iPSCs to developing pig embryos is limited and it has not yet been possible to generate human organs using IBC Even if the above challenges were addressed, a further problem is that human organs developed using IBC would have pig blood vessels, lymphatics and neuronal innervation, which would lead to immune rejection | Low, likely not in the foreseeable future |
| RM for ischaemia–reperfusion | Multiple candidate cell populations showing efficacy beyond previous small molecule alternatives Emerging evidence of favourable biodistribution avoiding off-site effects Natural organ architecture available in transplant context Complementary benefits with normothermic ex vivo perfusion | Obtaining adequate numbers of point-of-care-derived autologous cells Obtaining adequate numbers of efficacious, non-immunogenic GLP-manufactured allogeneic cells Reassurance regarding potential vascular/microvascular complications | High, likely within the next decade |
ECM, extracellular matrix; 3D, three-dimensional; iPSC, induced pluripotent stem cell; IBC, interspecies blastocyst complementation; RM, regenerative medicine; GLP, good laboratory practice.
Interspecies blastocyst complementation (IBC) is another promising application of iPSCs for the generation of autologous tissue. Targeted removal of cells destined for development of a specific organ allows manipulation of a host blastocyst. This permits insertion of donor iPSCs into the host blastocyst to produce an autologous organ in allogeneic and interspecies circumstances55,56. It is possible to use a compatible host (such as pig) to create organs for patients that will retain size, function and adequate vascularization comparable to that of host organs. The IBC method holds potential because of its ease of application and increased viability of engineered tissue in host animals, but has yet to produce complex organs57,58. Potential problems include zoonoses, host contamination causing organ rejection, and reverse contamination by the donor iPSCs leading to health problems in the animals.
The toxicity of immunosuppressive drugs not only poses a danger to the patient but is also a significant alloantigen-independent factor in chronic allograft nephropathy. As such, 50 per cent of nephropathic kidney transplants are lost within 10 years secondary to chronic allograft nephropathy59. The cost and encumbrance of drugs is very difficult for patients60–62. A transplanted organ must be from a genetically identical donor or immunological tolerance must be achieved to get IFS. Complete tolerance has been seen in a small proportion of patients weaned off immunosuppressive drugs54,63,64, such that IFS is not immediate or necessarily durable18,63,64. Bioengineered organs hold promise in achieving IFS; however, the immune reaction to these organs remains largely uncharacterized. Regardless of the fabrication method, bioengineered constructs are composed of two structures: the cellular compartment and the ECM. During implantation of acellular allogeneic and xenogeneic scaffolds, the host immunological response results in an acute cellular infiltrate that includes both neutrophilic and giant cell infiltrations67. The cellular component of a bioengineered graft may also trigger an acute rejection response because it is well known that both allogeneic pluripotent stem cells and autologous adult cells may still elicit an inflammatory response after manipulation in culture, even when harvested directly from the host. It has also been suggested that the ECM component of scaffolds retains the ability to induce T cell apoptosis and CD4-positive T cell conversion through innate properties of transforming growth factor β68–70. The transition of proinflammatory macrophage phenotype M1 to an M2 phenotype occurring 1–2 weeks after implantation may improve remodelling outcomes by using host tissue remodelling and repair mechanisms7. Thus, for successful implantation of bioengineered constructs in host organisms, a balance must be achieved between subduing an immune response to the introduction of a foreign body while retaining an immunological response to augment host regenerative processes.
Ante litteram, transplant medicine has applied RM concepts since the dawn of the modern era. All attempts to minimize organ damage – from procurement, storage/transportation to implantation – are strategies to enhance tissue repair and function. Ex vivo lung perfusion allowed a quadrupling of transplantable lungs by encouraging ‘marginal’ organs to achieve better functional reserve in a modern world. In order for the organ to be repaired, numerous therapies are being investigated, among which are the in situ delivery of interleukin (IL) 10 or the infusion of MSCs71. RM therapies may augment existing organ transplantation by reducing need for donor tissue and increasing the viability of tissue ex vivo. Selected RM technologies are currently in phase I and Ib clinical trial studies, including the first RM therapeutic drug (MSI-1436) for myocardial tissue repair72. A preclinical large animal study73 has investigated the use of in situ delivery of IL-10 to repair injured donor lungs ex vivo for transplantation, and combat ischaemia–reperfusion injury.
RM may be the new frontier for transplant medicine74. Transplant conferences are now incorporating sessions on RM and tissue engineering (Fig. 2). Transplant societies are funding tissue engineering-driven research and launching RM committees. The Cell Transplant Society, a sister society to The Transplant Society, was founded in 1992 and has been quite active ever since. As RM progressed, the name of the society was recently changed to its current Cell Transplant and Regenerative Medicine Society75. The American Society of Transplantation established the Transplant Regenerative Medicine Community of Practice76 at the World Transplant Conference held in San Francisco in 2014, and the European Society for Organ Transplantation inaugurated the European Cell Therapy and Organ Regeneration Section77 in 2019, at its biannual congress held in Copenhagen, Denmark.
Strategies to bring the two fields of regenerative and transplant medicine together
Disclosure
The authors declare no conflict of interest.
