As a component of the European Society for Organ Transplantation (ESOT) call for action in 2022, Transplant International launched a special issue entitled "Diversity, Equity, and Inclusion in Transplantation" (1). The call for papers focused on sex, gender, ethnic and racial disparities in transplant access, management and outcomes. Emphasis was put on the changes of policies/interventions required to address the existing inequities and the needs to build a true global access and foster a culture of diversity and inclusion in transplantation research.With regards to sex and gender inequity, studies from USA and Nepal demonstrated barriers in the liver and kidney transplant processes, limiting the access to women from entering and completing waitlist evaluation (2,3), highlighting how they face barriers to be considered for surgery. Notably, this also reflects the disparity in the living donation process (4): in a context where countries in Southeast Asia were reported to have the lowest rates of deceased donors, the majority of kidney living donors are women, although the highest proportion of recipients are men. To further explore the disparities in this area, a review compared the top organ donor countries, to elucidate possible interventions and establish a fair transplant process in Southeast Asia (5). This article provides a brilliant approach by analyzing the differences in healthcare systems and how resources and organization can impact the effectiveness of transplant programs in addition to education and cultural attitude. Within the variety of economic and developmental backgrounds, the authors identified Malaysia as one of the potential countries able to build an effective deceased donor program, recognizing the general principle that there is no "one size fits all" for organ donation systems, but that government support through financial inputs in healthcare, and therefore access to publicly funded healthcare, is fundamental for successful donation and transplantation activity.Another interesting report dealing with a sustainable model to overcome the gender and social disparity in renal replacement therapy in Low and Middle Income Countries (6) showed that establishing satellite centers reduces patient time and travel costs, with a model of community-government partnership, where dialysis and transplantation are integrated and offered "free of cost" to all in need.Adequate women representation is a known unmet need in clinical science, with a documented discrepancy between the epidemiological prevalence of a disease and the rate of women enrolled in related clinical trials. Vinson et al. found that in the field of kidney transplantation, women's representation is more adequate when compared to other medical disciplines. However, they remain significantly underrepresented in research trials testing immunosuppressive drugs and surgical interventions. This finding is particularly striking in the context of the known increased risk of rejection for women, raising the hypothesis that this might also be partially related to the disparity in accessing interventional research (7).Inequity in transplant access and management was described for rural and remote populations, as well as specific ethnic and caste groups, where cultural beliefs could be inherent causes of bias (8). Particular emphasis was given therefore to the proposal of eliminating race from eGFR calculations (9) in accessing national waitlist, a decision approved a few years ago by the OPTN Board (10), which settled in this way the tone towards a more equitable assessment of prospective transplant and donor candidates. This remarkable change could have consequences for living kidney transplantation; a UK study (11) investigated how to improve decision making from the healthcare professional's perspective for people from diverse ethnic groups, as this precious resource remains underutilized. An education strategy seems realistic to implement the diversity of the organ donor registry, aiming to gain the support of key influencers (such as religious and community leaders, media editors, local figures) and tackle barriers negatively influencing support for organ donation in minority ethnic groups (12,13). To this purpose, it is relevant to stress how difficult it remains to determine the impact of patient ethnicity, race or immigration background, especially in consideration of the inconsistency of how migrant and ethnic minority populations are defined in European studies (14). This is why when analyzing such complex systems, it is recommended to consider an intersectionality approach (15) i.e., non-medical aspects of an individual's life, as where they live, are raised, engage in recreational activities, and their vocation, to better represent the full environmental context leading to disparity in organ transplantation access, management and outcomes.Luckily, the prevention and elimination of inequities related to patient characteristics is increasingly being recognized in transplant research. It has been reported that the demand for organs can largely be reduced if there is a sustained commitment to public health interventions and culturally competent approaches are implemented in the management of long-term conditions, taking also into consideration the demand from underrepresented minority populations, such as migrants (16). In this regard, the current state of the art in Italy was reviewed (17) and described that minority ethnic background individuals and immigrants present significantly higher rates of cardiovascular disease and endocrinological disorders, potentially leading to organ failure. Unfortunately, despite the presence of a public health system with universal healthcare coverage, non-European born residents are less likely to receive living kidney donation transplantation and more likely to have inferior long-term outcomes compared with European born individuals. These findings are not novel in general and reproduce what was already reported in other health national system realities, such as the UK (18) and USA (19).To complete the insights into organ donation and transplantation in the immigrant population in Italy, a mention to the comparison of refusal rates showed that these were higher, especially in some non-native Italian populations countries, supporting the need for communication approaches tailored for cultural diversities, when discussing donation with families with a potential language barrier and a non-western cultural background. (20).It is worth remembering that the standard approaches to patient education and management are less likely to be effective with subjects from immigrant and/or ethnic minority groups, and instead tailored interventions to meet the needs of these populations remain a challenge. For instance, a report found that in abdominal transplant recipients language preference other than English was independently associated with delay to vaccination in the USA (21). It would be therefore worth exploring alternative ways, for example by the use of digital technology, as the reconstruction of education after the COVID-19 pandemic (22) revealed an unforeseen potential.Could then modern technology help in pushing the boundaries of the XXI century transplant outcomes? Medical digitalization is nowadays being increasingly utilized in clinical practice, and it was suggested that blockchain technology (23), defined as a peer-to-peer distributed database without centralized authority, could soon become of pivotal importance in overcoming some limitations of transplant programs. In particular, it was suggested that distribution ledger technology could affect the organ donor traffic in the black market, by providing a real integration between different national health systems with real-time auditability.What could be the role of scientific societies, institutions and stakeholders? According to a survey by the Equity, Diversity, and Inclusion Committee of ESOT, reported as a qualitative research approach, the main areas of intervention included initiatives aiming to foster a culture of transparency in selection procedures, always considering diversity when evaluating candidates and anonymizing applications to eliminate inherent bias, using different languages in meetings and diverse panels in conferences, limiting the tenure of Council members, and promoting a bottom-up instead of a top-down organization (24). The recruitment of professionals from a variety of countries, backgrounds, and ethnicities or the facilitation of combining career and family life could be supported by initiatives such as access to digital learning solutions, i.e, webinars and online courses. In fact, the disparities described above could significantly hinder career development, which limits creativity and innovation by professionals from minority groups. Individuals from all backgrounds should instead have equal opportunities to enter and excel in their field and this will also promote scientific advancement and better care for the patients (25).Our modern Society increasingly embraces the general concept of equity for all individuals, and organ donation and transplantation must follow this ethical principle and have a transparent system to assure no discrimination is carried out (26). To achieve health equity, the same treatment options must be available to any individual affected by end-stage organ failure, regardless of sex, gender, race, ethnicity, socioeconomic backgrounds and their interplay. As the transplantation journey is a multistep process, the disparity affecting one or more phases, from clinician's referral for evaluation to the actual moment when transplant occurs, should be explored for possible interventions to reduce the existing evidence in disparity when receiving an organ transplant. The aim of this special issue is to build on the promotion of health care and social equity worldwide, by highlighting possible areas of interventions, following what professional groups in the transplant community have identified as strategic initiatives or explicit goals in their mandates.As a component of the European Society for Organ Transplantation (ESOT) call for action in 2022, Transplant International launched a special issue entitled "Diversity, Equity, and Inclusion in Transplantation" (1). The call for papers focused on sex, gender, ethnic and racial disparities in transplant access, management and outcomes. Emphasis was put on the changes of policies/interventions required to address the existing inequities and the needs to build a true global access and foster a culture of diversity and inclusion in transplantation research.With regards to sex and gender inequity, barriers in the liver transplant process, preventing female patients from entering and completing transplant evaluation were demonstrated in studies both from the USA and Nepal (2,3), highlighting how women, encounter barriers to enter the waitlist. Notably, this also reflects the disparity in the living donation process (4), as countries in Southeast Asia were reported to have the lowest rates of deceased donors. To further empasize this concept, a review compared the top 10 organ donor countries with in Southeast Asia, to elucidate possible interventions and establish a fair transplant process (5): despite the variety of economic and developmental backgrounds making the comparison difficult, the authors identified Malaysia as one of the potential countries able to build an effective deceased donor program, similar to those of the Western world, recognizing the general principle that there is no "one size fits all" for organ donation systems, but that government support through financial inputs in healthcare is fundamental for a successful shortening of the waiting list time.Another interesting report dealing with a sustainable model to overcome the gender and social disparity in renal replacement therapy in Low and Middle Income Countries (6) showed that establishing satellite centers reduces patient time and travel costs, with a model of community-government partnership, where dialysis and transplantation are integrated and offered "free of cost" to all in need.Interestingly, despite the better representation of women in clinical trails in the field of kidney transplantation compared to other medical disciplines, one study highlighted how females remain underrepresented in research trials examining post-transplant immunological related aspects and long-term outcomes (7).Inequity in transplant access and management was described for rural and remote populations, as well as specific ethnic and caste groups, where cultural beliefs could be inherent causes of bias (8). Particular emphasis was given therefore to the proposal of eliminating race from eGFR calculations (9) in accessing national waitlist, a decision approved a few years ago by the OPTN Board (10), which settled in this way the tone towards a more equitable assessment of prospective transplant and donor candidates. This remarkable change could have consequences for living kidney transplantation; a UK study (11) investigated how to improve decision making from the healthcare professional's perspective for people from diverse ethnic groups, as this precious resource remains underutilized. An education strategy seems realistic to implement the diversity of the organ donor registry, aiming to gain the support of key influencers (such as religious and community leaders, media editors, local figures) and tackle barriers negatively influencing support for organ donation in minority ethnic groups (12,13). To this purpose, it is relevant to stress how difficult it remains to determine the impact of patient ethnicity, race or immigration background, especially in consideration of the inconsistency of how migrant and ethnic minority populations are defined in European studies (14). This is why when analyzing such complex systems, it is recommended to consider an intersectionality approach (15) i.e., non-medical aspects of an individual's life, as where they live, are raised, engage in recreational activities, and their vocation, to better represent the full environmental context leading to disparity in organ transplantation access, management and outcomes.Luckily, the prevention and elimination of inequities related to patient characteristics is increasingly being recognised in transplant research. It has been reported that the demand for organs can largely be reduced if there is a sustained commitment to public health interventions and culturally competent approaches are implemented in the management of long-term conditions, taking also into consideration the demand from underrepresented minority populations, such as migrants (16). In this regard, the current state of the art in Italy was reviewed (17) and described that minority ethnic background individuals and immigrants present significantly higher rates of cardiovascular disease and endocrinological disorders, potentially leading to organ failure. Unfortunately, despite the presence of a public health system with universal healthcare coverage, non-European born residents are less likely to receive living kidney donation transplantation and more likely to have inferior long-term outcomes compared with European born individuals. These findings are not novel in general and reproduce what was already reported in other health national system realities, such as the UK (18) and USA (19).To complete the insights into organ donation and transplantation in the immigrant population in Italy, a mention to the comparison of refusal rates showed that these were higher, especially in non-native Italian populations from non Western countries, with the exception of individuals from Sri Lanka (20).It is worth to remember that the common approaches to patient education and management are less likely to be effective with subjects from immigrant and/or ethnic minority groups and instead that tailored interventions to meet the needs of these populations remain a challenge, in fact because of language barriers. For instance, a report found that in abdominal transplant recipients language preference other than English was independently associated with delay to vaccination in the USA (21). It would be therefore worth exploring alternative ways, for example by the use of digital technology, as the reconstruction of education after the COVID-19 pandemic ( 22) revealed an unforeseen potential.Could then modern technology help in pushing the boundaries of the XXI st century transplant outcomes? Medical digitalization is nowadays being increasingly utilized in clinical practice, and it was suggested that blockchain technology (23), defined as a peer-to-peer distributed database without centralized authority, could soon become of pivotal importance in overcoming some limitations of transplant programs. In particular, it was suggested that distribution ledger technology could affect the organ donor traffic in the black market, by providing a real integration between different national health systems with real-time auditability.What could be the role of scientific societies, institutions and stakeholders? According to a survey by the Equity, Diversity, and Inclusion Committee of ESOT, a substantial contribution was identified in initiatives aiming to foster a culture of transparency in selection procedures, always considering diversity when evaluating candidates and anonymizing applications to eliminate inherent bias, using different languages in meetings and diverse panels in conferences, limiting the tenure of Council members, and promoting a bottom-up instead of a top-down organization (24). The recruitment of professionals from a variety of countries, backgrounds, and ethnicities or the facilitation of combining career and family life could be supported by initiatives such as access to digital learning solutions, i.e, webinars and online courses. In fact, the disparities described above could significantly hinder career development, which limits creativity and innovation by professionals from minority groups. Individuals from all backgrounds should instead have equal opportunities to enter and excel in their field and this will also promote scientific advancement and better care for the patients (25).Our modern Society inc reasingly embraces the general concept of equity for all individuals, and organ donation and transplantation must follow this ethical principle and have a transparent system to assure no discrimination is carried out (26). To achieve health equity, the same treatment options must be available to any individual affected by end-stage organ failure, regardless of sex, gender, race, ethnicity, socioeconomic backgrounds and their interplay. As the transplantation journey is a multistep process, the disparity affecting one or more phases, from clinician's referral for evaluation to the actual moment when transplant occurs, should be explored for possible interventions to reduce the existing evidence in disparity when receiving an organ transplant. The aim of this special issue was to build on the promotion of health care and social equity worldwide, by highlighting possible areas of interventions, following what professional groups in the transplant community have identified as strategic initiatives or explicit goals in their mandates.
Introduction and Structural Organization of Transplantation in Argentina Argentina is the eighth largest country in the world (surface area of 2,780,400 km2), and the third most populated country in South America (its estimated population is 44,494,502). It is divided into 24 autonomously governed provinces (1). The health care system in Argentina, which covers >22 million people, is decentralized, with multiple state-dependent funders consisting of social security, public, and private subsectors. There are 4.5 hospital beds per 1000 inhabitants and 3.49 physicians per 1000 inhabitants (overall there are 166,187 physicians in the country) (2,3). There is one nephrologist for every 40 patients, ranking third in Latin Ame rica in terms of the number of nephrologists per million inhabitants (4,5). The first kidney transplantation in Argentina was performed in Buenos Aires in 1957 by Lanari et al. (6). Over the next several decades, a series of laws were sequentially passed, aiming to streamline the national transplantation processes. These ultimately led to the creation of a single national, decentralized organization called the National Central Institute for the Coordination of Ablation and Implantation (INCUCAI), an entity under the National Ministry of Health. INCUCAI's mission is to promote, regulate, and coordinate activities related to the procurement and transplantation of organs, tissues, and cells at a national level, guaranteeing transparency, equity, and quality (7). In 2003, the INCUCAI created a database system called The National Procurement and Transplantation Information System of the Argentine Republic to track, assess, regulate, and manage all transplant activities in Argentina. It provides free online access to all essential information related to organ transplantation and the registry of patients on dialysis. This system is also used to help guide health policies and clinical research (8). The country is divided into five procurement regions, encompassing 157 transplantation centers. Of these centers, 61 perform kidney transplants, 35 liver, 16 kidney-pancreas, 28 heart, eight lung, five heart and lung, and four intestinal transplants. Historically, the vast majority of transplant surgeries were performed by a combination of vascular surgeons and urologists, but recently general surgeons specifically trained in multiorgan transplantation services have joined the services and established laparoscopic living donor nephrectomy techniques. Pre- and post-kidney transplant care is managed by transplant nephrologists as a fundamental part of a multidisciplinary team that also includes psychologists, social workers, specialized nurses, etc. The Argentine Society of Transplantation, which brings together all transplant professionals, was established in 1982 (3,4). Argentina supports the Declaration of Istanbul and participates actively through its scientific societies in the summit of the Pontifical Academy of Sciences to combat organ trafficking and transplant tourism (3,7). Kidney Transplantation in Argentina The characteristics of the kidney transplant population in Argentina are shown in Table 1. There have been 15,774 kidney transplants performed in Argentina since 1998 (1). Of these, 89% were performed in adult patients and 11% in pediatric ones. The majority of transplants originate from deceased donors with the predominant cause of death being stroke (52%) and traumatic brain injury (39%) (1,8). In 2005, a major initiative was made to increase organ donation by the passing of the Law of Presumed Consent. However, although this law established that all persons should be considered potential donors, donation still required confirmation from a family member. This law was updated in 2018 that established that all people are potential donors, unless they had previously declared themselves as nondonors to INCUCAI. Although family refusal to donate was already decreasing (from 45% in 2016 to 33% in 2018), the new law further reduced the rate of refusal to 13% in 2019. These changes have increased the donation rate from 11.8 per million population (PMP) in 2016, to 15.8 PMP in 2018, and 19.9 PMP in 2019. Indeed, barriers to donation are now more logistical in nature (e.g., limitations in the universal harvesting and transportation of organs throughout the country), rather than due to social or cultural grounds. Table 1. - Characteristics of kidney transplant recipients in Argentinaa General Characteristics of the Health Care in ESKD and Kidney Transplant in Argentine Population 44,938,712 Population on dialysis (HD+PD) 30,607 Population of ESKD on the waiting list 5221 (17%) Population with a functioning kidney transplant 11,486 Adult LDKTs (2019) 3998 (92%) Pediatric LDKTs (2019) 367 (8%) Number of KT centers 61 Cost of peritransplant module (20 days post-transplantation) US$4840 b Monthly cost of the post-transplantation module (average) US$212 b Comparison DDKT DDKT LDKT Total KT from 1998 to the present 15,740 5069 KT per year (2019) 1232 359 Source: DDKT versus LDKT, % 69 31 Age of the recipient, yr, mean±SD 45.5 (45.2–45.8) 36.3 (35.9–36.7) Male, % 57% 57% Cold ischemia time, mean±SD 19.37 (19.2–19.5) 1.5 (1.35–1.62) Time on dialysis until kidney transplantation, mean±SD 6.1 (5.97–6.22) 1.96 (1.89–2.05) Years on the waiting list, mean±SD 2.32 (2.35–2.40) 0 Causes of death post-transplant, % DDKT LDKT Infection 43 36 Cardio-cerebrovascular 24 19 Other 15 13 Neoplasm 7 19 Causes of graft loss, % DDKT LDKT Chronic allograft dysfunction 38 48 Others 30 32 Acute rejection 17 15 Primary nonfunction 7 1 Vascular complications 3 2 Urological complications 1 1 Infection 2 0 Noncompliance 1 0 Recurrent disease 1 1 HD, hemodialysis; PD, peritoneal dialysis; KT, kidney transplant; LDKT, living donor kidney transplant; DDKT, deceased donor kid ney transplant.aOfficial data from National Central Institute for the Coordination of Ablation and Implantation between January 1, 1998 and December 31, 2019.bUsing the unofficial exchange rate as of August 2021 (approximately 186 Argentine pesos per dollar). Despite these advances in donation, overall transplantation rates are insufficient to meet demand. The overall ESKD dialysis population in Argentina is 30,607 patients, of whom 5221 (17%) are on the waiting list (2). The average waiting time on the transplant list is >6 years. In 2019, there were 1674 kidney transplants, 69 simultaneous kidney-pancreas, 19 kidney-liver, and five kidney-heart transplants. Of the 1674 kidney transplants, 1325 (79%) were deceased donor kidney transplants (DDKT) and 349 (21%) were living donor kidney transplants (LKTD). This percentage of LKDT has hovered between 20% and 30% over the last 10 years. In total, 97% of LKDTs came from related donors, and 14% were performed preemptively. Although paired donation is allowed in the national exchange program, they are quite rare. The cost of renal transplantation is predominantly covered by governmental agencies including the National Institute of Social Security for Retirement and Pensions (47%), public insurance (35%), and provincial social security (12%); commercial insurance accounts for the remaining <10%. These insurances cover almost all transplant-related costs. In general, patients do not incur any out-of-pocket costs for any post-transplant care, other than for a few prophylactic medications. In 2021, the estimated cost for the kidney transplantation module (including kidney transplant surgery and all immunosuppression and general medication during first 20 days) was close to US$4840 (considering the unofficial exchange rate of approximately 186 Argentine pesos per dollar; however, there is an alternative market with values that differ greatly from the official ones because the Argentine government imposes very high taxes and strict restrictions for the purchase of foreign currency). It was US$212 per consult for the monthly post-transplantation module (monthly outpatient clinic visit) (4). Outcomes and most Common Complications of Kidney Transplantation in Argentina As expected, adults that receive an LDKT have better patient and graft survival rates than adults receiving DDKT (5,8). Patient survival rates for LDKT versus DDKT were 98% versus 90%, 95% versus 80%, and 90% versus 68%, at 1, 5, and 10 years, respectively. However, graft survival rates were 97% versus 83%, 87% versus 66%, and 71% versus 46%, for these same time points (Figure 1, A and B) (5,8). The main causes of graft loss in DDKT were chronic allograft dysfunction (38%) followed by acute rejection (17%), primary nonfunction (7%), infections (2%), vascular complication (3%), urological complication (1%), noncompliance (1%), recurrent disease (1%), and others (30%) (5,8). Of note, in Argentina, infection constitutes a main cause of death in patients with functioning grafts close to 43% for DDKT, similar to that reported by the Latin America Dialysis and Transplant Registry (9).Figure 1.: Patient and graft survival in deceased donor kidney transplant versus living donor kidney transplant in Argentina from 1998 to 2019. LDKT, living donor kidney transplant; DDKT, deceased donor kidney transplant.Effect of Delayed Graft Function A major challenge for optimizing transplant outcomes in Argentina, as in most of Latin America, is the high incidence of delayed graft function (DGF) after DDKT (approximately 60%). The causes of DGF in Argentina are multifactorial, but predominantly related to suboptimal organ maintenance due to prolonged cold ischemia time and limited access to extracorporeal perfusion machines (9,10). Because DGF results increased length of stay, need for dialysis, infection rates, acute rejection (with the associated decrease in graft and patient survival), and costs, it has had an increasingly detrimental effect on the advancement of kidney transplantation in Argentina. Other barriers negatively affecting organ donation in the country include: (1) sociocultural problems related to fear and myths about donation, (2) lack of educational campaigns in schools, (3) lack of early identification of potential donors in the health care facilities, and (4) suboptimal education regarding transplantation to health care personnel (3,9). Future Perspectives and New Challenges The kidney transplant program in Argentina has made much progress since its inception. Some of the major advances include (1) a legal framework and structured governmental organizations that oversee organ donation and transplantation, these have improved access to transplants; (2) the development of a network of highly skilled personnel, which has improved outcomes due to better transplant and post-transplant care; and (3) an online registry system for traceability of donation-transplantation process (5). However, there are still several challenges to overcome. First, we must further educate our health care administrators and funders so they recognize that kidney transplantation is the most cost-effective treatment for advanced CKD, because it not only restores the patient's quality of life, but also significantly improves survival (compared with patients that remain on dialysis), and lowers public health costs. That is, it needs to be recognized as the treatment of choice. Second, we must increase the donor pool by increasing the use of expanded criteria deceased donors and strongly encourage the growth of LDKT programs. Finally, we must improve organ preservation by incorporating the routine use extracorporeal perfusion machines, reduce cold-ischemia times, and develop donor procurement protocols for organ harvesting post-circulatory death. We believe these measures would further improve the national transplant program. Disclosures R.A. Maldonado reports receiving speaker honoraria from AstraZeneca, Novartis, and Sandoz; reports being a scientific advisor or member as the Coordinator of Transplant Work Group of the Argentine Society of Nephrology, and Member of Kidney Transplant Committee of Argentine Society of Transplantation; and reports other interests/relationships as President of the Córdoba Society of Nephrology. The remaining author has nothing to disclose. Funding None.
As we reflect on 75 years of experimental publications in Plastic and Reconstructive Surgery, a few thoughts come to mind. The first is how far we have come as a field. Investigations have progressed from simple observations of the natural history of transferred tissue to mechanistic descriptions of intracellular alterations and the integration of emerging technologies in reconstructive procedures. The second is the astonishing breadth of the field. Essentially, plastic surgery has laid claim to all of human anatomy and its associated functions, yet we are constrained to none. The third is the pervasive sense of exhilaration in exploration. Perhaps the reason for the latter is that plastic surgery has always been a specialty defined by autonomy of thought in pursuit of solutions, unified only by the central objective of structural and functional restoration. Thus, the inherent nature of the specialty is one that is built on fundamental research and continually evolves through innovation and discovery. On the seventy-fifth anniversary of Plastic and Reconstructive Surgery, we will discuss some of the major advances in plastic surgery research, highlight some landmark discoveries over the years, and, of course, mention some of our personal favorites. Tissue Transfer and Transplantation In the first issue of Plastic and Reconstructive Surgery in 1946, Lyndon Peer published his innovative and unconventional experiments to better understand the growth of pediatric cartilage grafts.1 To do this, he implanted autogenous cartilage grafts, from various anatomical locations, into infants and children and explanted them a few years later. From these experiments, he concluded that the cartilage grafts grew: maybe. As unusual as it may have been to perform these experiments, particularly in infants and children, he was pursuing one of the primary areas of interest in plastic surgery investigation: the quest to understand the impact of tissue transfer and remodeling. In the 1940s to 1950s, the ideas of moving autologous or homologous tissues were simultaneously developing. Early studies in vascularized autologous tissue transfer were focused on methods to improve flap vascularity and techniques to monitor flap perfusion. From a historical perspective, one of our favorite advances during this period was the repurposing of Millikan’s ear oximeter, originally designed for pilots during World War II and credited as the origin of modern pulse oximetry, for perfusion monitoring of pedicled flaps following transfer.2 Regarding autologous tissue transfer, perhaps the most consequential advance occurred in 1957, when Harry J. Buncke developed techniques for transferring blocks of tissue on 1-mm vessels. He subsequently demonstrated successful replantation of digits and ears in animal models (Fig. 1).3 Shortly after the first report by Buncke, Goldwyn observed that viability of large, pedicled island flaps was improved with microvascular anastomoses, predicting the possibility of free tissue transfer.4 These pioneers of microsurgery sparked a decade of microsurgical advances starting with the proof-of-principle demonstration by Krizek et al. of the first abdominal musculocutaneous free flaps in a canine model,5 followed by the introduction of functional free flaps with neurotization by Tamai et al.,6 and the addition of bone by Ostrup and Fredrickson,7 culminating in clinical translation in 1973.8Fig. 1.: The birth of microsurgery. Before the work by Buncke and Schulz in 1965, salvage of amputated fingers was attempted by means of grafting of either composite tissues or osseous components under a pedicled flap. During the late 1950s and 1960s, the increase in understanding of transferring tissues on microanastomoses suggested that replantation of an entire digit may be possible. Thus, Buncke and Schulz designed a set of animal experiments using a rhesus monkey model to best imitate human finger replantation. In their series of nine experimental replantations, only one survived (experiment 6, animal 5). However, the success of this one experiment was the proof-of-principle result that opened the field of microsurgery. Vessel clamped and measured at 0.8 mm in diameter (above, left); microanastomosis (below, left). Experiment 6 at 2 weeks after surgery (center) and animal 5 with replanted finger at 3 months after surgery (right). (Reprinted with permission from Buncke HJ, Schulz WP. Experimental digital amputation and reimplantation. Plast Reconstr Surg. 1965;36:62–70.)Simultaneously, consideration of allogeneic sources for tissue transfer was expanding in the postwar era, with an emphasis on methods of banking skin allografts9 and reducing allograft rejection with varying techniques such as radiation therapy and steroid administration.10,11 After the reports from Murray et al. regarding renal allotransplantation,12,13 attention shifted to vascularized composite tissues, converging with the gains in microsurgical techniques. One of the first attempts at understanding vascularized composite allotransplantation was performed by Goldwyn et al. in 1966 using canine limbs (Fig. 2).14 Although all of the allotransplants in this study ultimately failed, they demonstrated that rudimentary immunosuppression delayed rejection. Remarkably, they also observed that different tissue types exhibited variable rejection rates, astutely foreshadowing the work by Lee et al. in 1991 demonstrating differences in antigenicity of tissue types.15 Over the course of the 1970s to 1990s, progressive developments in the understanding of free flap perfusion16–20 and transplant immunology21–26 gradually reduced the morbidity in autologous transfer, increased the functionality of autologous transfer, and culminated in clinical translation of vascularized composite allotransplants.Fig. 2.: Early vascularized composite allotransplantation. Unlike replantation, few attempts at understanding extremity allotransplantation were occurring until the 1960s. Inspired by a clinical report of a failed extremity allotransplant, Goldwyn and colleagues sought to understand the effects of immunosuppression in their seminal study of canine limb allotransplantation. Although all of the transplants were ultimately rejected, the authors demonstrated that immunosuppression delayed rejection reliably and that tissue types varied in their rates of rejection. Shown is a femoral arteriogram of an azathioprine-treated canine limb allotransplant at postoperative day 18 with patent distal arteries. (Reprinted with permission from Goldwyn RM, Beach PM, Feldman D, Wilson RE. Canine limb homotransplantation. Plast Reconstr Surg. 1966;37:184–195.)Synthesizing Tissue and Creating Function The second exciting area of plastic surgery investigation was focused on the idea of synthesizing tissue and creating function. The major differences between the two areas of investigation are that the latter has a rebellious streak, breaking all the rules of nature by creating function in an area devoid of function; plastic surgery is still in its infancy in this area. Although the idea of synthesizing tissue is age-old, the ability to do so has been very challenging. The first attempt to synthesize tissue was presented in Plastic and Reconstructive Surgery in 1952 by Kathryn Lyle Stephenson, who implanted cartilage extracts into rodent muscles and supplemented them with hormones to create ectopic cartilage.27 Unfortunately, these experiments were unsuccessful, but they stimulated a series of novel experiments that would ultimately become the field of regenerative medicine. The ensuing two decades saw few investigations in regenerative medicine until the exceptional work of Snyder et al. in 1973, where they described successful mandibular distraction osteogenesis in a canine model (Fig. 3).28 These experiments were ultimately translated into the clinical arena by McCarthy et al. 20 years later.29 The study by Snyder et al., in concept, is one of our favorites in that distraction was and continues to be one of the only examples of completely endogenous, clinically useful, surgically practical tissue synthesis.Fig. 3.: Regenerating bone. Although gains in clinical knowledge have occurred for both autologous and homologous tissue transfer, tissue synthesis has yet to enter the clinical arena in a substantial manner, with the exception of distraction osteogenesis. Inspired by the ideas of lengthening bones, Snyder et al. hypothesized that the same concepts could be applied to the facial skeleton. In a canine model, Snyder and colleagues surgically created a shortened mandible such that a severe crossbite was present. After 6 weeks of healing, the authors osteotomized the mandible and placed an external fixator (left) that was lengthened at a rate of 1 mm/day for 14 days and consolidated for 6 weeks. At the end of the consolidation period, a radiograph was taken (right) demonstrating bony healing. This pilot experiment by Snyder and colleagues in 1973 eventually led to the clinical translation of mandibular distraction by McCarthy et al. and is one of the only examples of tissue synthesis that has reached the clinical realm. (Reprinted with permission from Snyder CC, Levine GA, Swanson HM, Browne EZ Jr. Mandibular lengthening by gradual distraction: Preliminary report. Plast Reconstr Surg. 1973;51:506–508.)During the 1980s, the idea that biological tissue could be synthesized by artificial materials started to crystallize. One of the most significant additions to the literature during that period was the description and eventual conceptual clinical translation of an artificial biomaterial guiding peripheral nerve regeneration in a rat sciatic nerve model by Seckel et al. (Fig. 4)30 and in a nonhuman primate model by Dellon and Mackinnon.30,31 This concept was shortly followed by investigations on creating other tissues, such as cartilage,32 using the same strategy of synthetic, biodegradable polymers with incorporated cellular material. Vacanti and colleagues demonstrated the most dramatic example with the culturing and in vivo implantation of chondrocytes on a polymeric scaffold in the shape of an ear.33–35 However, despite the incredible enthusiasm generated by seeing human ears on the backs of nude mice, long-term stability in immunocompetent settings remains elusive.Fig. 4.: Guiding regeneration with materials. The 1980s were marked by an increasing interest in guiding regeneration with scaffolding materials. Two groups, Seckel et al. and Dellon and Mackinnon, demonstrated in two different animal models that peripheral nerve gaps could be successfully regenerated with the interposition of a resorbable polymeric nerve guide to span the gap. These studies ushered in a vast number of investigations using resorbable materials as an inert scaffold for delivery of trophic factors or cells for a variety of tissue types. Shown is the experimental design using rat sciatic nerve gaps as described by Seckel and colleagues. (Reprinted with permission from Seckel BR, Chiu TH, Nyilas E, Sidman R. Nerve regeneration through synthetic biodegradable nerve guides: Regulation by the target organ. Plast Reconstr Surg. 1984;74:173–181.)The concept of guiding tissue regeneration gained in popularity and became an area of intense investigation in the 1990s to 2000s. In particular, there was an explosion of interest in growth factors and growth factor delivery, especially bone morphogenetic proteins in the realm of bone regeneration.36–39 However, around 2009, it started to become clear that supraphysiologic dosages of growth factors were unlikely to be reasonable clinical solutions for regeneration. Although tissue could be regenerated, the complete lack of control over that regeneration, with no reliable approaches to stop that growth, created regulatory barriers to clinical translation.40 Particularly with the concurrent revelations on the complexity of calvarial suture biology by Roth et al.,41–44 the conclusion emerged that bone regeneration was unlikely to be accomplished by any one single factor but rather was the summation of multiple cues from a defined microenvironment. Over the past decade, technological advances at both the micro and macro levels have allowed us to truthfully ask the question of whether recapitulation of nature is absolutely necessary for functional restoration. At the micro level, efforts have shifted in the direction of fabricating microenvironments that may not be identical to the mature tissue itself, but the milieu necessary to generate the mature tissue over time. That is, single-tissue regeneration has evolved toward integrating sophisticated and tunable biomaterials tailored to globally organize multicellular responses with the goal of eliminating delivery of exogenous growth factors or ex vivo–expanded progenitor cells. The challenge now lies in detailed characterization of cell-material interactions. At the macro level, technological advances in engineering and robotics beg the question about whether functional replacement requires biological tissues. In the realm of limb loss, advances in prosthetics are arguably outpacing the possibilities of safe immunosuppression. In other words, design and implementation of the interfaces between biology and machinery may replace the need for transfer of composite biological tissues for optimal function.45–48 The evolution of the two major lines of plastic surgery investigation is truly a reflection of the spirit of plastic surgery, interrelated yet boundless in the incorporation of new ideas and fields of study. Ultimately, plastic surgery has always been the home for the creative people in medicine; the idealists who believe that there is a solution to everything; the eternal optimists who see zero limits, only challenges to be accepted; and the extraordinary people who rejected the mundane and instead chose the adventure (Fig. 5). We enthusiastically look forward to the evolution of the next 75 years, which are sure to be just as thrilling as the first.Fig. 5.: Over the past 75 years of experimental publications in Plastic and Reconstructive Surgery, investigations have progressed from simple observations of the natural history of transferred tissue to mechanistic descriptions of intracellular alterations and the integration of emerging technologies in reconstructive procedures. Plastic surgery has always been a specialty defined by autonomy of thought in pursuit of solutions, unified only by the central objective of structural and functional restoration. The inherent nature of the specialty is one that is built on fundamental research and continually evolves through innovation and discovery.
Organ and Tissue Transplantation Research
Reconstructive Surgery and Microvascular Techniques