Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future
0Abstract
Vascularized composite allotransplantation (VCA) is a novel surgical practice that involves the transplantation of multiple tissue types as a functional unit without the primary purpose of extending life. While VCA of the upper extremity is becoming increasingly accepted and performed, VCA of the lower extremity remains largely unexplored despite its acknowledged potential value. There are inherent ethical concerns surrounding VCA that are dominated by a conflict between the principles of beneficence and maleficence. The primary question is whether the quality-of-life benefits to the patient outweigh the risks associated with long-term immunosuppression for a non-lifesaving procedure. In addition, the ethical conversation involves concerns regarding informed consent, donor autonomy, patient privacy and public disclosure, patient selection, and unique considerations in the pediatric patient. Lower extremity VCA has additional ethical issues compared to upper extremity VCA, as current lower limb prostheses provide excellent, near baseline function that upper limb constructs have not yet been able to achieve. In this review, we discuss the ethical challenges of lower extremity VCA using available evidence for the upper extremity. We also compare ethical considerations of VCA of the extremity with other surgical alternatives to limb loss - namely, limb salvage and replantation - and address how the conversation may be altered with further advancements in immunosuppression and prosthetic technology.
Keywords
INTRODUCTION
Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a functional unit, usually without the primary purpose of extending life. This practice is in contrast with solid organ transplantation, which is often lifesaving in nature. Among the most widely practiced and publicized forms of VCA is transplantation of the upper extremity, including the forearm and hand. VCA of the lower extremity, conversely, is a frontier that has been only minimally explored but has potential value. The number of individuals with loss of at least one lower limb in the United States was estimated at 1,027,000 in 2005 and projected to more than double by 2050[1]. This pool may be up to three times larger than that of upper extremity amputees[1]. Amongst these individuals, 43% would be interested in VCA of the lower extremity[2]. However, compared with upper extremity VCA, VCA of the lower extremity has a higher ethical burden, as lower extremity prosthetics offer excellent function for amputees with substantial potential for enhancing the quality of life of qualified patients[3,4].
Here, we discuss the ethical considerations surrounding VCA of the lower extremity - informed largely by evidence for upper extremity transplantation - in its current state of practice as well as how new advancements in immunosuppression and technology may change the conversation. We also compare VCA with limb salvage and replantation in this context.
HISTORY OF VCA OF THE LOWER EXTREMITY
The first lower extremity transplantation occurred in 2006 between three-month-old ischiopagus twins, a unique autologous situation for which the recipient did not necessitate immunosuppression[5-7]. In 2011, the first attempt at bilateral transfemoral transplantation in an adult patient was performed after the 20-year-old recipient sustained traumatic above-knee amputations from a motor vehicle accident[8]. Unfortunately, the recipient developed brain lymphoma 15 months post-transplant and immunosuppression was ceased, resulting in rejection and the removal of both limbs[9,10]. The third and fourth attempts occurred in 2012 as part of the world’s first efforts at triple and quadruple extremity allotransplantation, respectively[11,12]. Both recipients experienced rejection in the immediate postoperative period that required reamputation of the allografts. The third recipient died within 5 months and the fourth recipient within 1 week of the procedure due to complications[11,12]. Most recently, in 2018, a 32-year-old male underwent unilateral transfemoral transplantation after an above-knee amputation one year prior. Only a six-month follow-up has been published, at which point the recipient was partially weight-bearing with evidence of sensory and motor function recovery[13]. These five reports are the only known cases of VCA of the lower extremity, with none taking place in the United States.
While the evidence for lower extremity transplantation is sparse, roughly 150 patients have received hand transplantations since the first successful attempts in 1998 and 1999[14,15]. Following successful early outcomes, in 2002, the International Registry on Hand and Composite Tissue Transplantation (IRHCTT) was established as a means of collecting and synthesizing outcomes data in a centralized manner. Over the past decade, experimental immunosuppressive protocols have been adopted by medical centers nationwide and internationally. In 2014, the U.S. Department of Health and Human Services’ Organ Procurement and Transplantation Network (OPTN) Final Rule was modified to include limbs (both upper and lower extremity), faces, and other VCAs under the definition of “organs” in order to supervise the processes for identifying potential donors, requesting authorization, and safely and effectively allocating VCAs[16]. At the time of publication, 20 unique transplant programs for any type of VCA (e.g., limb, abdominal wall, face, genitourinary organ) have been approved by OPTN[17]. These include 11 centers for upper extremity and three for lower extremity transplantation: Brigham and Women’s Hospital, Medstar Georgetown Transplant Institute, and University of Chicago Medical Center[17].
RISK-BENEFIT PROFILE OF VCA
The primary ethical conflict surrounding VCAs is whether the quality-of-life benefits to the patient outweigh the long-term risks associated with an extensive non-lifesaving procedure. In ethical terms, this is considered a conflict between beneficence and nonmaleficence. Beneficence holds that patient’s best interests are paramount, while nonmaleficence refers to an obligation to avoid preventable harm. The OPTN Final Rule provides a distribution framework for organ transplantation focused on the just allocation of scarce resources, as there is more demand for traditional, lifesaving transplants (e.g., kidney, liver, heart) than available organs[18]. In contrast, the primary ethical issue in VCA is focused on whether the procedure itself is ethical, rather than fair allocation. A standardized protocol for measuring and reporting outcomes does not currently exist, but the benefits and risks of upper extremity VCA are well-documented in the literature and can be largely extrapolated to the conversation on lower extremity VCA - although key differences do exist.
Benefits
The main goal of VCA of the extremity is to improve quality of life via restoration of sensation and motor function after limb loss. All viable transplanted hands have demonstrated normal skin color and texture as well as normal hair and nail growth, arterial blood supply, and venous outflow[19]. Reports released by the IRHCTT have shown that all documented upper extremity allograft recipients have recovered protective sensibility (i.e., ability to detect pain, thermal stimuli), with 91% of patients redeveloping tactile sensibility and 82% regaining partial discriminative sensibility[20]. There is no reason to expect that VCA of the lower extremity cannot also demonstrate such successful restoration of sensory function. Importantly, the first lower extremity allograft recipient has recovered diminished but present sensation to light touch[7]. The most recent recipient demonstrated early signs of sensory recovery as well, although long-term data is not available[13]. Recovery of protective sensibility and proprioception, which contribute to effective ambulation, alone would represent a substantial benefit over available prostheses - the most common alternative to VCA of the extremity[21].
Currently, the level of functional recovery required for restoration of lower extremity gait, balance, and postural control is unknown, although these motor functions are far less intricate than those of the hand and are arguably easier to achieve. The distal intrinsic muscle reinnervation critical to restoring near baseline function for the hand is speculated to be less crucial to attaining meaningful lower extremity function[22]. This is rooted in the fact that the knee plays a greater role in ambulation than the foot and ankle, giving greater importance to proximal versus distal innervation[23]. To date, many hand transplant recipients have exhibited motor function sufficient to perform gripping and pinching actions and recovery of a number of manual skills. Patients with bilateral transplantations have also been able to achieve symmetric use of their hands[19]. In the short term, the two initial attempts at lower extremity VCA have shown a return to ambulation with assistance and a nearly normal passive range of motion with good strength throughout, although the active range of motion was markedly decreased compared to baseline[7,8]. The most recent attempt has also shown some active range of motion and partial weight-bearing at six-months postop[13]. The greater distance that must be traversed with nerve regeneration in the lower versus upper extremity must be another consideration, however, as nerves regenerate at a peak rate of 1 mm/day-3 mm/day while motor endplates remain responsive only on the scale of years after denervation, after which functional recovery is unlikely[24,25]. Accordingly, denervation muscle atrophy can present a greater challenge for motor and sensory outcomes of lower extremity VCA, and patient outcomes post-transplant may be more akin to individuals with peripheral nerve injuries (i.e., foot drop in the setting of peroneal nerve damage)[26].
Overall, the less intricate nature of lower extremity motor function may mean that allotransplantation has greater potential for restoring normal levels of function than has been shown with VCA of the hand. Yet, the more straightforward function of the lower extremity is also why lower extremity prosthetics are more effective than upper extremity prosthetics at re-approximating the functional demands of the native limb. Further, it is unclear how weight-bearing factors come into this discussion, as the upper limb is not subject to the same loads that burden the lower limb. Whether lower extremity allografts are capable of meeting the long-term demands that prosthetics are designed for has also yet to be explored. At the very least, VCA of the lower extremity may offer the possibility of converting from an above-knee to below-knee amputation, which has benefits in energy expenditure, cardiovascular strain, and independence[27].
The beneficence argument for VCA of the extremity is further strengthened when the psychosocial components of quality of life are also considered. Improvement in motor skills allows recipients to resume their previous jobs, perform activities of daily living, and have a normal social life[28,29]. VCA also offers the benefit of aesthetic restoration of body image that exceeds what can be achieved with prosthetics, salvage procedures, and replantation. An important and increasingly recognized consequence of severe disfigurements, such as limb loss, is that of “social death” - a construct constituting social isolation, loneliness, ostracism, loss of personhood, altered role and identity, and personal harm - which has been associated with physical pain and increased risk of mortality[30-33]. VCA carries the potential for the treatment of social death - admittedly more applicable to upper versus lower extremity amputees, as the former is more visible - that cannot be attained through alternatives. In fact, both functional and psychosocial outcomes following hand transplantation have been shown to be superior to those associated with the use of alternatives after limb amputation[34-37]. At up to 18 years post-transplantation, patients have shown decreasing disability with excellent and improving outcomes per appearance, sensibility, mobility, psychological and social acceptance, daily activities and work status, and patient satisfaction and general well-being[38]. Similar observations can likely be anticipated for patients after lower extremity transplantation. By centering perspective around the whole person, VCA has been proposed as “lifesaving” in recent literature[30,33]. This thereby negates the argument against the procedure as only life-enhancing and demonstrates how VCA of the extremity can promote the best interests of the patient on multiple dimensions.
Risks
While the potential benefits of VCA of the extremity are evident, there are substantial risks. First, postoperative complications are an inherent risk for any extensive surgical procedure. Reported complications for hand transplantation have included postoperative vessel thromboses, skin necrosis, ischemic reperfusion injury, surgical site infections, pneumonia, sepsis, and acute limb loss[38-40]. Similar complications would be expected for procedures involving the lower extremity, but the larger operative area carries a greater risk for considerable blood loss - especially for proximal or bilateral transplants - than for upper extremity VCA.
The primary concern surrounding VCA is recipients’ susceptibility to allograft rejection and a requirement for long-term immunosuppression. Almost all hand transplant recipients experience at least one episode of acute rejection within the first posttransplant year, and additional episodes beyond this point are not rare[29,38,41]. Chronic rejection is an emerging threat that has been reported in nine cases to date, with graft loss occurring in four. Despite the high documented rejection rate, graft survival rates hold at approximately 70% in patients with > 10 years of follow-up[38]. A complex immunosuppressive regimen is necessary for VCA that follows protocols well-established for solid organ transplantation. They typically involve induction with mono- or poly-clonal antibody therapy followed by lifelong maintenance with triple-drug combinations[19,42]. Such extensive immunosuppression can cause complications, including but not limited to metabolic disturbances, opportunistic infections, malignancies, and thromboses - thereby carrying risks for shortening life and creating harm for the recipients[38]. These risks are exemplified by two of the four cases of true lower extremity allotransplantation, which were complicated by the development of a primary central nervous system lymphoma and disseminated aspergillosis with multi-organ failure and early death[26]. Interestingly, however, immunosuppressive medications have been shown to accelerate the rate of nerve regeneration - although the implications for functional recovery are unclear[43,44]. Centers have also reported using similar dosage and serum level requirements as those widely accepted for solid organ transplantation[45]. Other than medical consequences, the necessity for immunosuppression, along with physiotherapy specific for limb transplantation, further generate substantial time and financial costs that may create a burden on the patient’s behalf.
Additionally, the psychosocial burden for recipients and families must be considered. Experts note that candidates often underestimate the difficulties experienced in the posttransplant period, especially since the quality of life tends to decrease in the first three months after the procedure before improvement is seen, not reaching baseline reported quality of life until approximately one year after hand transplantation[46-48]. Recipients frequently develop mood changes and anxiety in this perioperative period and during episodes of acute rejection[46]. Moreover, a psychosocial challenge of extremity transplantation involves assimilation of the new limb into the recipient’s body image. The visible nature of VCA of the extremity can result in body image distortion and a disrupted sense of bodily integrity, leading to negative self-evaluation and a reduced sense of well-being[49,50]. Inability to psychologically integrate the allograft may then lead to nonadherence with medications and subsequent rejection. This process can exacerbate recipients’ emotional and physical distress, as they would be faced with not only reexperiencing loss of a limb but also potential lesser function than before the transplant from further amputation of the preexisting stump. Visibility of the transplant may also lead to psychological regression, negative responses from family and friends, and acute distress[33]. Furthermore, caregivers of recipients must endure substantial burdens from balancing employment and other responsibilities with the demands of long-term care, which are only amplified for family members who are untrained and unprepared to perform the skilled medical tasks required of them[51].
The novelty of VCA means candidates must assume an inherent risk of uncertainty regarding outcomes and complications of the procedure. Long-term data, while expanding for VCA of the hand, does not yet exist for VCA of the lower extremity. Therefore, limb transplantation can cause harm to the patient that may or may not be superseded by the benefits discussed earlier.
Finally, as previously discussed, there are differences in the functionality of upper and lower limb prostheses and hence, distinctions in the ethical considerations for VCA. While upper extremity prosthetics provide acceptable function, they have not yet been able to provide the dexterity needed to attain function similar to baseline[52]. Meanwhile, lower extremity constructs have shown an excellent return to the limb’s less complex range of motion, with many patients able to achieve independent ambulation[3,4]. Accordingly, the risk for potential harm is higher for lower extremity VCA, as a meaningful alternative exists without the risks of immunosuppression.
INFORMED CONSENT
Given the complexity and high-risk profile of VCA, issues surrounding patient autonomy are central to the ethical conversation. Candidates must understand the implications of their decision and receive sufficient education to provide informed consent. The discussion should thoroughly address the burdens, commitments, and demands of VCA - including but not limited to adherence with and complications of long-term immunosuppression, potential initial decreases in quality of life, and psychosocial challenges. Benefits are likely easily imaginable for candidates, whereas the extent of risks assumed is less transparent. This discrepancy in knowledge is further worsened by the publicity surrounding extremity transplantation. Media coverage unsurprisingly tends to focus on the positives of the procedure and on patients with the best outcomes, thereby creating misunderstanding regarding the true risk-benefit profile amongst potential candidates and compromising informed consent[53].
It is pertinent to note that VCA candidates, especially bilateral amputees, may be particularly vulnerable to accepting the substantial risk involved with the experimental nature of limb transplantation[54,55]. This may further contribute to the agreement without appropriate consideration of the risks involved. Thus, while patient autonomy must be prioritized and recipients have a right to choose, the decision for VCA must also be approached with a caution that requires scrutiny from providers.
DONOR AUTONOMY
In contrast with solid organs, VCAs are not currently a routine part of first-person or family authorization for organ donation[56]. The Uniform Anatomical Gift Act creates the option to register as an organ donor when applying for a driver’s license and is thereby the most appropriate means for ensuring donor consent. However, the existing law does not currently cover VCAs[57]. In 2018, Pennsylvania became the first state to modify its adaptation of the law to include VCAs[58]. As such, the question of autonomy largely remains unaddressed for donors in the extremity transplantation process. VCA donation currently requires separate and explicit authorization by the donor prior to death or, more commonly, by family as surrogate decision-makers after death. Surrogate consent, while better than no consent, is not equivalent to first-person consent. The current practice of asking for VCA separately also carries the concern about negatively influencing the willingness to donate solid organs, which can further decrease an already insufficient supply[59].
Furthermore, limb transplantation is tied to a social significance that can make donation especially difficult for donor families. The potential for post-transplantation rejection and discarding of the allograft(s) may be difficult for donor families to accept but a realistic consequence about which they must be informed[60]. If explantation were to occur, they may learn of the event through the media. An additional psychological deterrent would be knowing another person has the attributes of a loved one, especially if there are markings that are unique or recognizable on the allograft. In these cases, limbs may not be eligible for donation. If the allograft is deemed to be an otherwise excellent match, the recipient must also agree to accept the potential identifiability of the markings. Therefore, discussion of the potential consequences and possibility of failure should be considered when obtaining informed consent from donor families.
PATIENT PRIVACY & PUBLIC DISCLOSURE
Loss of patient privacy is a risk that should be assumed with modern-day VCA, as the procedure is commonly reported on through print, social, and visual media[61]. The novelty of VCA creates a conflict between physician and institution excitement for publicity and recipient/donor right to privacy and confidentiality. Outside of medicine, the success of VCA is largely judged by the general public on aesthetic outcomes and media depictions of transformation. Such perceptions can influence willingness to donate allografts, funding, and general support for or against future procedures[33]. To date, media reports have largely focused on the benefits of VCA for the recipient, which may increase the availability of allografts but lack an accurate portrayal of the difficult course to recovery[61]. Transplant centers have an ethical obligation to develop public trust by reporting on both positive and negative outcomes, and data-sharing is essential for continued improvement in the field[62]. However, these duties come at the cost of donors and recipients who may be subjected to unwanted media scrutiny. In order to achieve sufficient informed consent, both recipients and donor families should be cautioned that their identities will likely be revealed[63]. With the rise in social media, patient privacy and confidentiality are at increased risk of compromise, and institutions should continue to aid potential candidates in understanding these possibilities.
PATIENT SELECTION
The fairness of candidate selection for extremity transplantation has been questioned due to its strict criteria. Maximum clinical success requires selection based on anatomic, medical, and psychosocial factors. Contraindications have been outlined and include age > 65 years, serious coexisting medical or psychological conditions (i.e., coronary artery disease, diabetes, alcoholism), history of malignancy within five years of remission, human immunodeficiency virus infection, positive crossmatch with the donor, and positive pregnancy test in female candidates - although these are becoming less stringent with evolution of the field[64]. Surgical indications remain undefined, and standardized criteria for inclusion and exclusion of recipients are lacking[65].
Given the experimental nature of the procedure, institutions and providers may choose the “easier” patient to avoid negative outcomes and bypass those with the greatest need. Patients with better social support and less significant psychological complications are considered more suitable, as adaptive coping styles, supportive family and friends, stable finances, and logistical factors have been shown to be predictors of successful outcomes[66]. However, substantial differences exist in the already subjective mental health evaluation of candidates[49], thereby leaving room for biases to act. In optimizing outcomes, decisions may be indirectly colored by discrimination based on disability, criminal history, suicidal behavior, or socioeconomic status. Issues regarding access to and disparities in VCA are further complicated by some institutions considering certain causes of limb loss as contraindications to VCA, as a history of risky behavior can reflect a non-psychologically ideal candidate[67,68]. As a result, less psychosocially ideal patients are often passed over as candidates. While these selection methods are not equitable, their restrictions may be non-negotiable given the necessity of long-term medical appointments, a complex immunosuppressive regimen, and physical rehabilitation for successful outcomes. It must be noted that currently, the field of VCA remains experimental and most reported patients are enrolled in review board-approved clinical trials with institution-dependent inclusion criteria. Therefore, the concept of “need” is still under study. Equitable allocation of care and fair patient selection will become more central to the ethical conversation if extremity transplantation utilization increases.
ETHICAL CHALLENGES OF PEDIATRIC VCA
As discussed previously, the first case of lower extremity transplantation occurred between three-month-old ischiopagus twins. In 2000, a 28-day-old infant with congenital absence of the hand was the first pediatric recipient of an upper extremity allograft from her monozygotic twin[69]. The first attempt at pediatric extremity VCA with a non-biologically identical donor was performed in 2010 outside the United States. The recipient was a 17-year-old female with bilateral proximal-third arm amputations who underwent bilateral transplantation and expired in the immediate postoperative period[70]. The first successful bilateral hand transplantation in a pediatric patient was performed in 2015 at the University of Pennsylvania[71]. The 8-year-old recipient was already immunosuppressed because he had previously received a kidney transplant at age 4. To date, these remain the only examples of pediatric VCA of the extremity, but most are not reflective of true allotransplantation or its associated risks. Expansion of VCA access to the pediatric population - where lifelong immunosuppression is required and patients cannot provide autonomous consent - raises even more ethical issues.
There are unique concerns of VCA in a growing child[72,73]. The young age at initiation of immunosuppression means greater life years at risk and near-certain development of serious adverse effects, including malignancy, shortened life expectancy, and eventual loss of the graft to rejection[74,75]. A key risk demonstrated for pediatric solid organ transplantation is the higher susceptibility for end-stage renal disease and subsequent need for a kidney transplant as well[76]. Such adverse events are enhanced by the association of young age, especially adolescence, with decreases in adherence to immunosuppression[77]. In fact, the incidence of poor adherence in pediatric transplantation ranges from 30% to 76%, with contributing factors across multiple dimensions related to adjustment difficulties during these transitional years[78,79]. Further, the use of corticosteroids and early transplantation has been shown to negatively impact skeletal growth and neurocognitive function, resulting in delay and more psychiatric difficulties[73]. All the above can have deleterious effects on quality-of-life measures across the lifespan. Interestingly, despite avid concern that grafts may not grow at appropriate rates, follow-up from the first pediatric hand transplant recipients demonstrated allograft growth rates comparable to established nontransplant norms[69,71]. However, this encouraging finding also brings attention to another area of concern for pediatric VCA. Limited long-term data exists for all pediatric transplantation - not only VCA. This is mainly due to a lack of randomized clinical trials in the pediatric population plus the small number of cases each year[74,80]. Thus, the uncertainty surrounding pediatric extremity transplantation is substantial.
Moreover, the decision for pediatric VCA calls into question whether parental consent is adequate for complex, elective procedures with lasting implications for the child. Pediatric care typically requires informed consent from the recipient’s parent/guardian with assent of the child playing a larger role as they age[81]. This model focuses on the idea of the “best interests of the child” rather than autonomy[82]. However, it is unclear if VCA meets those best interests. Consent in VCA must be held to a higher standard because the procedure is non-lifesaving, and patient cooperation is necessary. Nevertheless, even when discussed in depth, the long-term, active participation in therapy and immunosuppression required of recipients is unlikely to be understood by younger individuals. Rather, the option to wait and involve the child in the decision when they are older may be preferred, given the current state of the science.
VCA VERSUS LIMB SALVAGE AND REPLANTATION
Other than amputation and use of prostheses, traditional surgical treatment modalities for limb loss include limb salvage and replantation of the detached extremity. While replantation - like VCA - is more conventionally seen for the upper extremity, an increasing number of cases involving the lower extremity have been reported in recent years[83-91]. For VCA to be ethically pursued, it must at least be in a state of clinical equipoise; that is, not clearly worse than these available treatment options.
At present, decision-making in limb-threatening lower extremity trauma has been grounded in the results of two clinical trials: the Lower Extremity Assessment Project (LEAP) and the Major Extremity Trauma Research Consortium (METRC). Evidence from LEAP revealed similar functional outcomes for limb salvage versus amputation, with a substantial proportion of patients in both groups experiencing significant disability and being limited in or unable to work[92-97]. Outcomes were also more affected by a patient’s economic, social, and personal resources than the treatment option pursued or the level of injury[92,93,96]. METRC produced similar findings, reporting that patients who underwent limb salvage would have had small differences in most outcomes had they undergone amputation[98,99]. Importantly, mobility scores would have been significantly improved for amputation[98,99]. No strong evidence currently exists for replantation or VCA of the lower extremity.
Inherent differences in the circumstances surrounding limb salvage and replantation versus allotransplantation may favor the latter in terms of patient benefit. Limb salvage and replantation make use of the injured extremity in acute, urgent operations that must occur shortly after trauma. Consequently, they involve little predictability, minimal preoperative planning, and greater ischemia time. In VCA, the allograft tissues are less damaged, the procedure is better controlled given its more elective nature, and the recipient is more clinically stable at the time of surgery and able to begin rehabilitation earlier[37]. Importantly, VCA of the lower extremity is not mutually exclusive from limb salvage, replantation or amputation, as VCA could still be performed in the future if another option is initially pursued.
As discussed above, the argument for VCA involves its recovery of sensory and motor function, decreased disability, and psychosocial benefits - although existing data is from upper extremity, not lower extremity VCA. Both limb salvage and replantation procedures also offer the key benefit of restoration of sensation, but hand transplantation has demonstrated higher rates of recovery for tactile and discriminative sensibility (80%-90% vs. 30%-60% for replantation)[20,100]. Transplanted hands also exhibit finer two-point discrimination than replanted hands, although this measure is not an essential goal for the lower extremity[28,101,102]. Otherwise, replants have shown superior strength, perhaps due to greater muscle atrophy in transplant recipients secondary to extended time between limb loss and VCA, but lesser recovery of intrinsic muscle use[28,103]. Further, salvage and replantation are associated with a higher degree of scarring and a greater risk of unequal lower extremity lengths due to bone-shortening from the inciting trauma[104,105]. VCA has the benefit of having excess tissues available for procurement to maximize cosmetic results. Per overall quality of life, limb salvage has demonstrated psychological results near equivalent to amputation, with substantial postoperative rates of depression, anxiety, substance abuse, and suicidal ideation[96]. In contrast, replantation and allotransplantation have reduced concerns related to body image, independence, and social reintegration[106,107]. Patients undergoing both procedures have been able to resume suitable work, with transplant recipients reporting higher satisfaction[108,109]. It must also be mentioned that while physical rehabilitation is required for all three options, VCA was initially thought to require the additional burden of cognitive therapy to gain control of the allograft. Yet, evidence suggests that this may not be necessary, as immediate cortical integration has been demonstrated in upper extremity VCA recipients long after amputation, and a substantial concern has been removed from the argument against allotransplantation[110].
With the use of autologous tissues for salvage and replantation, the harms related to allogeneic tissue are no longer relevant. There is no requirement for long-term immunosuppression and thus no assumption of its associated risks. However, limb salvage does require extensive debridement, fasciotomies, revascularization, and fixation and is known to be associated with a high rate of complications, including infection, thrombosis, necrosis, impaired bone healing, and the need for secondary procedures[111,112]. It must be noted that lower extremity replantation has been associated with a high rate of complications as well, with up to 86% of patients requiring secondary surgeries and a low rate of autograft survival at 45%, albeit available data is sparse[85]. Using an individual’s own tissues also precludes the development of psychosocial issues with limb assimilation and body integrity that can cause critical consequences for VCA of the extremity. Finally, at present, the acceptance and continued practice of limb salvage and replantation means less uncertainty and more access to long-term data relative to allotransplantation.
Ultimately, the ethical considerations surrounding limb salvage, replantation, and VCA of the lower extremity are profoundly nuanced. It must be reinforced that the data discussed above are from available evidence on the upper extremity. Lower extremity alternatives to amputation carry more substantial burdens relative to upper extremity equivalents, given the higher and excellent level of function that available prosthetics provide for the lower extremity. With increasingly effective prosthetics, this ethical discussion must be revisited based on the latest science.
HOW MEDICAL INNOVATION CHANGES THE CONVERSATION
Prosthetic alternatives
Specific to VCA of the extremity, the function and benefits provided by the allograft must be weighed against those of prosthetics. A recent survey found that for hand transplantation, recipients experience increased satisfaction driven by social and aesthetic values and a greater sense of independence with the allograft compared with available prosthetic options. Caregivers similarly report less unease with leaving transplanted patients alone due to the superior functionality provided[113]. Again, contrary to options for the upper extremity, lower extremity prosthetic devices are more effective constructs that have demonstrated excellent outcomes with a high rate of return to independent ambulation[3,4]. Yet, patients still often reject them due to discomfort, weight, or limited usefulness - especially for above-knee amputees[114-116]. Rejection rates are as high as 1 in 3 for lower limb prostheses, compared with over 1 in 2 for upper limb constructs[117,118].
Ongoing research has been focused on enhancing the functionality and applicability of prosthetic devices. In addition to technological innovations that address socket, interface, and alignment concerns, advanced options include targeted sensory and muscle innervation, bionics, and bone-anchored prostheses[119]. The use of microprocessor-controlled components has enabled greater functional achievements in above-knee amputees, allowing real-time dynamic gait and ambulation management that permits adjustments with advancing progress during postoperative rehabilitation. Potential merits include reduced effort during ambulation, improved symmetry and natural gait, and a lower risk of falls[120,121]. Targeted sensory innervation transfers peripheral sensory nerves to denervated proximal skin and allows restoration of tactile feedback, pain, temperature, and proprioception, thus addressing a key pitfall of traditional prosthetic constructs[52,122,123]. Similarly, targeted muscle innervation, which involves the transfer of functioning nerves that have lost their operational target to intact proximal muscles, can confer additional degrees of active motion to myoelectric prostheses and has gained considerable momentum in recent years[124]. This technique also has the added benefit of reduced phantom limb pain[125], considerable morbidity in patients with lower extremity amputations. Moreover, actively powered prosthetic joints (i.e., bionics) have become more sophisticated, with new technology allowing a wider range of movements and easier transition between ambulation modes[126-128]. Osseointegration, which involves the attachment of titanium implants to the residual bone as an anchor for prostheses, has further been explored as a solution to complications regarding socket fit and comfort with encouraging early results[129,130]. More than functional benefits, recipients have reported that osseointegrated prostheses have strengthened their sense of body integrity[131]. However, despite these improvements, cosmetic values have not been a major focus of current research initiatives, especially for the lower extremity. Despite being less visible than upper extremity prostheses, studies have shown that having a lower limb device with an appearance in line with one’s body perception induces prosthesis embodiment and satisfaction[132,133]. Advanced constructs are also costly, and patients’ accessibility to these newer technologies is questionable[134]. As prosthetics become more advanced and able to meet the goal of a replacement with near-identical function and appearance as the missing limb, indications for VCA may shift out of favor due to its higher risk profile.
Immunosuppression
The main argument against VCA is its requirement for lifelong immunosuppression that places recipients at risk of adverse events, graft loss, and a shortened lifespan. Traditionally, extremity transplants have been maintained with a triple-drug immunosuppressive regimen after antibody-based lymphocyte depleting induction therapy - most commonly involving the use of polyclonal or monoclonal antibodies, tacrolimus, mycophenolate mofetil and steroids, all of which have significant long-term side effects[19,42].
Recent initiatives have sought to determine regimens that cause less morbidity with equal or greater effectiveness in reducing the risk of rejection, to reduce or eliminate the need for lifelong immunosuppression. At the forefront is an effort to induce donor-specific transplantation tolerance and achieve chimerism, which refers to the coexistence of donor and recipient immune cells. Multiple strategies have been proposed, including hematopoietic stem cell transplantation, costimulation blockade and cell-based therapies[135]. Topical immunosuppression may also help prevent rejection without the substantial risks implicated with systemic immunosuppression. While tolerance has been induced in various protocols for small animal models, large animal studies have largely been unsuccessful[136]. Without consistent evidence supporting immunomodulation in non-human models, the transition from bench to bedside remains limited. Nevertheless, some centers have attempted the adoption of minimal immunosuppression protocols. Of note, a joint team at the Johns Hopkins University School of Medicine and University of Pittsburgh has achieved lower rates of morbidity with the use of hematopoietic stem cell transplantation with low-dose tacrolimus monotherapy - although chimerism was not realized with this regimen[137,138]. At two years follow-up, their five-patient cohort had no signs of chronic rejection, infrequent acute rejection episodes, and an acceptable side effect profile. Elsewhere, the application of a minimal immunosuppression protocol resulted in acute rejection necessitating explantation within one year of initial hand transplantation[136]. Therefore, the advent of more effective, less toxic immunosuppressive therapies has the potential to reduce some of the ethical controversy surrounding VCA and create a more favorable risk-benefit profile.
General advancements
Another key ethical consideration of VCA of the extremity is that it is a novel procedure, which limits the data currently supporting decision-making. As time passes, a greater number of procedures will be performed, transplant facilities will have more experience with allotransplantation, and more long-term data will be available. Eventually, there will likely also be greater supervision and management of the allocation process as well as fading media scrutiny. Correspondingly, compared with the current state of VCA, future candidates may assume a lower risk of uncertainty regarding outcomes and complications of the procedure. The concerns discussed previously surrounding patient selection, understanding, and privacy may also be lessened with further development of the field.
CONCLUSION
VCA of the lower extremity is an emerging field with considerable ethical challenges, given it is being a life-enhancing rather than lifesaving procedure. The primary ethical tension is between the principles of beneficence and nonmaleficence, though there are also relevant concerns about informed consent. Experts have been increasingly in favor of the ethicality of hand transplantation[139,140], a shift in opinion which may be partially influenced by advancements in immunosuppression that alter the risk-benefit profile[19,138]. However, lower extremity transplantation is likely to remain controversial given the high function and technological innovations of lower limb prosthetics - where a shortcoming for upper extremity alternatives exists. Both are not currently and will unlikely become the best option for the majority of amputees, but VCA is a good alternative for patients who fail other reconstructive treatments. Overall, the ethical considerations surrounding VCA will continue to evolve with the data, particularly if advancements in immunosuppression decrease associated morbidities.
DECLARATIONS
Authors’ contributionsMade substantial contributions to conception and design of the study and performed data analysis and interpretation: Xu AL, Humbyrd CJ
Performed data acquisition, as well as provided administrative, technical, and material support: Xu AL, Humbyrd CJ
Availability of data and materialsNot applicable.
Financial support and sponsorshipNone.
Conflicts of interestBoth authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2022.
REFERENCES
1. Ziegler-Graham K, MacKenzie EJ, Ephraim PL, Travison TG, Brookmeyer R. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch Phys Med Rehabil 2008;89:422-9.
2. Carty MJ, Duclos A, Talbot SG, Tullius SG, Pribaz JJ, Pomahac B. Attitudes regarding lower extremity allotransplantation among lower extremity amputees. Plast Reconstr Surg 2014;134:1334-42.
3. Berke GM, Fergason J, Milani JR, et al. Comparison of satisfaction with current prosthetic care in veterans and servicemembers from Vietnam and OIF/OEF conflicts with major traumatic limb loss. J Rehabil Res Dev 2010;47:361-71.
4. Aaron RK, Herr HM, Ciombor DM, et al. Horizons in prosthesis development for the restoration of limb function. J Am Acad Orthop Surg 2006;14:S198-204.
5. Zuker R. Lower-extremity hindquarter transplantation in conjoined twins. Hand Transplantation. Springer: Milano. 2007. p. 435-41.
6. Zuker RM, Redett R, Alman B, Coles JG, Timoney N, Ein SH. First successful lower-extremity transplantation: technique and functional result. J Reconstr Microsurg 2006;22:239-44.
7. Fattah A, Cypel T, Donner EJ, Wang F, Alman BA, Zuker RM. The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity. Am J Transplant 2011;11:2762-7.
8. Cavadas PC, Thione A, Carballeira A, Blanes M. Bilateral transfemoral lower extremity transplantation: result at 1 year. Am J Transplant 2013;13:1343-9.
9. BBC. First double leg-transplant patient has legs amputated. Available from: https://www.bbc.com/news/health-22855670 [Last accessed on 24 Apr 2022].
10. Cavadas PC, Thione A, Blanes M, Mayordomo-Aranda E. Primary central nervous system posttransplant lymphoproliferative disease in a bilateral transfemoral lower extremity transplantation recipient. Am J Transplant 2015;15:2758-61.
11. Nasir S, Kilic YA, Karaaltin MV, Erdem Y. Lessons learned from the first quadruple extremity transplantation in the world. Ann Plast Surg 2014;73:336-40.
12. CBS News. World’s first quadruple limb transplant fails at Turkish hospital. Available from: https://www.cbsnews.com/news/worlds-first-quadruple-limb-transplant-fails-at-turkish-hospital/ [Last accessed on 24 Apr 2022].
13. Arudchelvam J, Ratnayake A, Wijesinghe N, Kariyawasam L, Rajakrishna P, Anver S. Trans-femoral lower limb transplantation in a Sri Lankan patient: a case report and surgical technique. Ceylon Med J 2018;63:35-6.
14. Dubernard J, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. The Lancet 1999;353:1315-20.
15. Jones JW, Gruber SA, Barker JH, Breidenbach WC. Successful hand transplantation. One-year follow-up. Louisville hand transplant team. N Engl J Med 2000;343:468-73.
16. Vascularized Composite Allograft Transplantation Committee. Implement the optn’s oversight of vascularized composite allografts (VCAs). Available from: https://optn.transplant.hrsa.gov/media/1118/05_vca_implementation.pdf [Last accessed on 24 Apr 2022].
17. U.S. Department of Health and Human Services. Member Directory. Organ Procurement and Transplantation Network. Available from: https://optn.transplant.hrsa.gov/members/member-directory/ [Last accessed on 24 Apr 2022].
18. Prentice M, OPTN/UNOS Ad Hoc Geography Committee. Frameworks for organ distribution. Available from: https://optn.transplant.hrsa.gov/media/2565/geography_publiccomment_201808.pdf [Last accessed on 24 Apr 2022].
19. Park SH, Eun SC, Kwon ST. Hand transplantation: current status and immunologic obstacles. Exp Clin Transplant 2019;17:97-104.
20. Petruzzo P, Lanzetta M, Dubernard JM, et al. The international registry on hand and composite tissue transplantation. Transplantation 2010;90:1590-4.
21. Huchon L, Badet L, Roy AC, et al. Grasping objects by former amputees: the visuo-motor control of allografted hands. Restor Neurol Neurosci 2016;34:615-33.
22. Carty MJ, Zuker R, Cavadas P, Pribaz JJ, Talbot SG, Pomahac B. The case for lower extremity allotransplantation. Plast Reconstr Surg 2013;131:1272-7.
23. Veenstra KM, Sprangers MA, van der Eyken J, Taminiau AH. Quality of life in survivors with a Van Ness-Borggreve rotationplasty after bone tumour resection. J Surg Oncol 2000;73:192-7.
24. SUNDERLAND S. Rate of regeneration in human peripheral nerves; analysis of the interval between injury and onset of recovery. Arch Neurol Psychiatry 1947;58:251-95.
25. Gupta R, Chan JP, Uong J, et al. Human motor endplate remodeling after traumatic nerve injury. J Neurosurg 2020:1-8.
26. Gorantla VS, Zor F, Nasir S, Breidenbach WC, Davis MR. Lower extremity transplantation: concepts, challenges, and controversies. Springer: New York. 2017. p. 195-212.
27. Kegel B, Carpenter ML, Burgess EM. Functional capabilities of lower extremity amputees. Arch Phys Med Rehabil 1978;59:109-120.
28. Jablecki J, Kaczmarzyk L, Patrzalek D, Domanasiewicz A, Chełmoński A. A detailed comparison of the functional outcome after midforearm replantations versus midforearm transplantation. Transplant Proc 2009;41:513-6.
29. Petruzzo P, Gazarian A, Kanitakis J, et al. Outcomes after bilateral hand allotransplantation: a risk/benefit ratio analysis. Ann Surg 2015;261:213-20.
30. Bramstedt KA. A lifesaving view of vascularized composite allotransplantation: patient experience of social death before and after face, hand, and larynx transplant. J Patient Exp 2018;5:92-100.
31. Williams KD. Ostracism: The kiss of social death: ostracism: the kiss of social death. Social and Personality Psychology Compass 2007;1:236-47.
32. Holt-Lunstad J, Smith TB, Baker M, Harris T, Stephenson D. Loneliness and social isolation as risk factors for mortality: a meta-analytic review. Perspect Psychol Sci 2015;10:227-37.
33. Caplan AL, Parent B, Kahn J, et al. Emerging ethical challenges raised by the evolution of vascularized composite allotransplantation. Transplantation 2019;103:1240-6.
34. Salminger S, Roche AD, Sturma A, Mayer JA, Aszmann OC. Hand transplantation versus hand prosthetics: pros and cons. Curr Surg Rep 2016;4:8.
35. Salminger S, Sturma A, Roche AD, et al. Functional and psychosocial outcomes of hand transplantation compared with prosthetic fitting in below-elbow amputees: a multicenter cohort study. PLoS One 2016;11:e0162507.
36. Kubiak CA, Etra JW, Brandacher G, et al. Prosthetic rehabilitation and vascularized composite allotransplantation following upper limb loss. Plast Reconstr Surg 2019;143:1688-701.
37. Heineman J, Bueno EM, Kiwanuka H, et al. All hands on deck: hand replantation versus transplantation. SAGE Open Med 2020;8:2050312120926351.
38. Petruzzo P, Sardu C, Lanzetta M, Dubernard JM. Report (2017) of the international registry on hand and composite tissue allotransplantation (IRHCTT). Curr Transplant Rep 2017;4:294-303.
39. Shores JT, Imbriglia JE, Lee WP. The current state of hand transplantation. J Hand Surg Am 2011;36:1862-7.
40. Jabłecki J, Kaczmarzyk L, Domanasiewicz A, Chełmoński A, Kaczmarzyk J. Unsuccessful attempt of forearm transplantation-case report. Ann Transplant 2010;15:53-56.
41. Thaunat O, Badet L, Dubois V, Kanitakis J, Petruzzo P, Morelon E. Immunopathology of rejection: do the rules of solid organ apply to vascularized composite allotransplantation? Curr Opin Organ Transplant 2015;20:596-601.
42. Elliott RM, Tintle SM, Levin LS. Upper extremity transplantation: current concepts and challenges in an emerging field. Curr Rev Musculoskelet Med 2014;7:83-8.
43. Chabas JF, Alluin O, Rao G, et al. FK506 induces changes in muscle properties and promotes metabosensitive nerve fiber regeneration. J Neurotrauma 2009;26:97-108.
44. Rustemeyer J, van de Wal R, Keipert C, Dicke U. Administration of low-dose FK 506 accelerates histomorphometric regeneration and functional outcomes after allograft nerve repair in a rat model. J Craniomaxillofac Surg 2010;38:134-40.
45. Rifkin WJ, Manjunath AK, Kantar RS, et al. A Comparison of immunosuppression regimens in hand, face, and kidney transplantation. J Surg Res 2021;258:17-22.
46. Jowsey-Gregoire SG, Kumnig M, Morelon E, Moreno E, Petruzzo P, Seulin C. The Chauvet 2014 meeting report: psychiatric and psychosocial evaluation and outcomes of upper extremity grafted patients. Transplantation 2016;100:1453-9.
47. Sifferlin A. I can do absolutely nothing. The first American with a double hand transplant wants them removed. Available from: https://time.com/4419959/double-hand-transplant-surgery/ [Last accessed on 24 Apr 2022].
48. Dobbs D. The devastating allure of medical miracles. Available from: https://www.wired.com/story/devastating-allure-of-medical-miracles/ [Last accessed on 24 Apr 2022].
49. Kumnig M, Jowsey-Gregoire SG. Key psychosocial challenges in vascularized composite allotransplantation. World J Transplant 2016;6:91-102.
50. Smith PJ, Cendales LC. Psychosocial dimensions of hand transplantation: lessons learned from solid organ transplantation. Curr Opin Organ Transplant 2019;24:705-13.
51. Dorante MI, Devine E, Talbot SG. Should a Caregiver’s QoL be considered in decisions about whether a patient has an experimental double-hand transplant? AMA J Ethics 2019;21:E943-952.
52. Pierrie SN, Gaston RG, Loeffler BJ. Current concepts in upper-extremity amputation. J Hand Surg Am 2018;43:657-67.
53. Teven CM, Grant SB. Plastic surgery’s contributions to surgical ethics. AMA J Ethics 2018;20:349-56.
54. Lange MM, Rogers W, Dodds S. Vulnerability in research ethics: a way forward. Bioethics 2013;27:333-40.
55. Majzoub RK, Cunningham M, Grossi F, Maldonado C, Banis JC, Barker JH. Investigation of risk acceptance in hand transplantation. J Hand Surg Am 2006;31:295-302.
56. Guidance to Organ Procurement Programs (OPOs) for VCA Deceased Donor Authorization. Available from: https://optn.transplant.hrsa.gov/media/1137/vca_donor_guidance.pdf [Last accessed on 24 Apr 2022].
57. National Conference of Commissioners on Uniform State Laws. Revise uniform anatomical gift act. Available from: https://www.donornetworkwest.org/wp-content/uploads/uaga_final_aug09.pdf [Last accessed on 24 Apr 2022].
58. Pennsylvania General Assembly. Chapter 86: anatomical gifts. Available from: https://www.legis.state.pa.us/WU01/LI/LI/CT/HTM/20/00.086..HTM [Last accessed on 24 Apr 2022].
59. Rahmel A. Vascularized composite allografts: procurement, allocation, and implementation. Curr Transplant Rep 2014;1:173-82.
61. Rodrigue JR, Tomich D, Fleishman A, Glazier AK. Vascularized composite allograft donation and transplantation: a survey of public attitudes in the United States. Am J Transplant 2017;17:2687-95.
62. Magill G, Benedict J, Plock JA, Krones T, Gorantla VS. Brocher Working Group on VCA. Existing and evolving bioethical dilemmas, challenges, and controversies in vascularized composite allotransplantation: an international perspective from the brocher bioethics working group. Transplantation 2019;103:1746-51.
63. Henderson ML, Clayville KA, Fisher JS, et al. Social media and organ donation: Ethically navigating the next frontier. Am J Transplant 2017;17:2803-9.
65. Gorantla VS, Plock JA, Davis MR. Reconstructive transplantation: evolution, experience, ethics, and emerging concepts. Springer: New York. 2017. p.539-52.
66. Shores JT. Recipient screening and selection: who is the right candidate for hand transplantation. Hand Clin 2011;27:539-43, x.
67. Siemionow MZ, Gordon CR. Institutional review board-based recommendations for medical institutions pursuing protocol approval for facial transplantation. Plast Reconstr Surg 2010;126:1232-9.
68. McQuinn MW, Kimberly LL, Parent B, et al. Self-inflicted gunshot wound as a consideration in the patient selection process for facial transplantation. Camb Q Healthc Ethics 2019;28:450-62.
69. McDiarmid SV. Vascularized composite allotransplantation in children: what we can learn from solid organ transplantation. Curr Opin Organ Transplant 2018;23:605-14.
70. Amaral S, Kessler SK, Levy TJ, et al. 18-month outcomes of heterologous bilateral hand transplantation in a child: a case report. The Lancet Child & Adolescent Health 2017;1:35-44.
71. Azoury SC, Milbar N, Kimia R, et al. Four-year follow-up of the world’s first pediatric bilateral hand-forearm transplants: do they grow as expected? Plast Reconstr Surg 2020;146:1325-9.
72. Shaul R, Borschel G, Flynn J, Hanson M, Wright L, Zuker R. Ethical issues in pediatric vascularized composite allotransplantation. Ethical Issues in Pediatric Organ Transplantation 2016;66:169-91.
73. Doumit G, Gharb BB, Rampazzo A, Papay F, Siemionow MZ, Zins JE. Pediatric vascularized composite allotransplantation. Ann Plast Surg 2014;73:445-50.
74. Malik S, Kassaï B, Cochat P. Overview of pediatric organ transplantation: current opinion and future perspectives on immunosuppression. Curr Opin Organ Transplant 2015;20:527-35.
75. Amaral S, Levin LS. Pediatric and congenital hand transplantation. Curr Opin Organ Transplant 2017;22:477-83.
76. Ruebner RL, Reese PP, Denburg MR, Abt PL, Furth SL. End-stage kidney disease after pediatric nonrenal solid organ transplantation. Pediatrics 2013;132:e1319-26.
78. Shemesh E, Annunziato RA, Arnon R, Miloh T, Kerkar N. Adherence to medical recommendations and transition to adult services in pediatric transplant recipients. Curr Opin Organ Transplant 2010;15:288-92.
79. Fredericks EM, Zelikovsky N, Aujoulat I, Hames A, Wray J. Post-transplant adjustment--the later years. Pediatr Transplant 2014;18:675-88.
80. Azeka E, Saavedra L, Fregni F. Clinical research in pediatric organ transplantation. Clinics 2014;69:73-5.
81. COMMITTEE ON BIOETHICS. Informed consent in decision-making in pediatric practice. Pediatrics 2016;138:e20161484.
82. Barfield RC, Church C. Informed consent in pediatric clinical trials. Curr Opin Pediatr 2005;17:20-4.
83. Zubairi AJ, Hashmi PM. Long term follow-up of a successful lower limb replantation in a 3-year-old child. Case Rep Orthop 2015;2015:425376.
84. Li XL, Wang W, Liu F, Hu W, Liang DS. Successful lower limb replantation of knee-level amputation in a child: a case report. J Foot Ankle Surg 2020;59:427-30.
85. Fufa DT, Lin CH, Lin YT, Hsu CC, Lin CH. Survival and secondary surgery following lower extremity replantation. J Reconstr Microsurg 2014;30:419-26.
86. Fang J, Li H, Dou H, et al. Crossover replantation after bilateral traumatic lower limb amputations: a case report. J Med Case Rep 2012;6:218.
87. Bosma NH, Teunis T, Eberlin KR, Jupiter JB. Lower limb replantation after guillotine amputation: a 29-year follow-up. J Reconstr Microsurg 2015;31:681-3.
88. Yu G, Lei HY, Guo S, Yu H, Huang JH, Liang SH. Successful replantation of both lower legs in a 41-year-old man. Chin J Traumatol 2011;14:250-252.
89. Tudosie A, Popescu S, Cinteza D, et al. Rehabilitation in a patient with replantation of amputated distal leg. Maedica (Bucur) 2011;6:36-44.
90. Cavadas PC, Landín L, Ibáñez J, Roger I, Nthumba P. Infrapopliteal lower extremity replantation. Plast Reconstr Surg 2009;124:532-9.
91. Ricketts S, De Steiger R, Breidahl A. Eleven-year follow-up of cross-leg replantation for traumatic bilateral amputation. J Reconstr Microsurg 2009;25:111-5.
92. Bosse MJ, MacKenzie EJ, Kellam JF, et al. An analysis of outcomes of reconstruction or amputation after leg-threatening injuries. N Engl J Med 2002;347:1924-31.
93. MacKenzie EJ, Bosse MJ. Factors influencing outcome following limb-threatening lower limb trauma: lessons learned from the Lower Extremity Assessment Project (LEAP). J Am Acad Orthop Surg 2006;14:S205-10.
94. MacKenzie EJ, Bosse MJ, Castillo RC, et al. Functional outcomes following trauma-related lower-extremity amputation. J Bone Joint Surg Am 2004;86:1636-45.
95. MacKenzie EJ, Bosse MJ, Pollak AN, et al. Long-term persistence of disability following severe lower-limb trauma. Results of a seven-year follow-up. J Bone Joint Surg Am 2005;87:1801-9.
96. McCarthy ML, MacKenzie EJ, Edwin D, Bosse MJ, Castillo RC, Starr A. LEAP study group. Psychological distress associated with severe lower-limb injury. J Bone Joint Surg Am 2003;85:1689-97.
97. Smith JJ, Agel J, Swiontkowski MF, Castillo R, Mackenzie E, Kellam JF. LEAP Study Group. Functional outcome of bilateral limb threatening: lower extremity injuries at two years postinjury. J Orthop Trauma 2005;19:249-53.
98. MacKenzie EJ, Bosse MJ, Pollak AN, Stinner DJ. The major extremity trauma research consortium: an overview. J Orthop Trauma 2017;31 Suppl 1:S1.
99. Extremity Trauma Research Consortium (METRC). Outcomes following severe distal tibial, ankle, and/or mid/hindfoot trauma: comparison of limb salvage and transtibial amputation (OUTLET). J Bone Joint Surg Am 2021;103:1588-97.
100. Sugun TS, Ozaksar K, Ada S, et al. Long-term results of major upper extremity replantations. Acta Orthop Traumatol Turc 2009;43:206-13.
101. Pei G, Xiang D, Gu L, et al. A report of 15 hand allotransplantations in 12 patients and their outcomes in China. Transplantation 2012;94:1052-9.
102. Tark KC, Kim YW, Lee YH, Lew JD. Replantation and revascularization of hands: Clinical analysis and functional results of 261 cases. The Journal of Hand Surgery 1989;14:17-27.
103. Landin L, Bonastre J, Casado-Sanchez C, et al. Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review. Transpl Int 2012;25:424-32.
105. Jensen SE, Butt Z, Bill A, et al. Quality of life considerations in upper limb transplantation: review and future directions. J Hand Surg Am 2012;37:2126-35.
106. Bachmann D. Quality of life in hand transplant patients. In: Hand Transplantation.Available from: http://eknygos.lsmuni.lt/springer/673/Part%209/363-366.pdf [Last accessed on 24 Apr 2022]
107. O’Toole RV, Castillo RC, Pollak AN, MacKenzie EJ, Bosse MJ. Determinants of patient satisfaction after severe lower-extremity injuries. J Bone Joint Surg Am 2008;90:1206-11.
108. Scott FA, Howar JW, Boswick JA Jr. Recovery of function following replantation and revascularization of amputated hand parts. J Trauma 1981;21:204-14.
109. Petruzzo P, Dubernard JM. The international registry on hand and composite tissue allotransplantation. Clin Transpl 2011:247-253.
110. Frey SH, Bogdanov S, Smith JC, Watrous S, Breidenbach WC. Chronically deafferented sensory cortex recovers a grossly typical organization after allogenic hand transplantation. Curr Biol 2008;18:1530-4.
111. Pribaz JJ, Morris DJ, Barrall D, Eriksson E. Double fillet of foot free flaps for emergency leg and hand coverage with ultimate great toe to thumb transfer. Plast Reconstr Surg 1993;91:1151-3.
112. Battiston B, Tos P, Pontini I, Ferrero S. Lower limb replantations: indications and a new scoring system. Microsurgery 2002;22:187-92.
113. Kinsley SE, Lenhard NK, Lape EC, et al. Perceived success in upper-extremity vascularized composite allotransplantation: a qualitative study. J Hand Surg Am 2021;46:711.e1-711.e35.
114. Wright TW, Hagen AD, Wood MB. Prosthetic usage in major upper extremity amputations. The Journal of Hand Surgery 1995;20:619-22.
115. Pezzin LE, Dillingham TR, Mackenzie EJ, Ephraim P, Rossbach P. Use and satisfaction with prosthetic limb devices and related services. Arch Phys Med Rehabil 2004;85:723-9.
116. Legro MW, Reiber G, del Aguila M, et al. Issues of importance reported by persons with lower limb amputations and prostheses. J Rehabil Res Dev 1999;36:155-163.
117. Biddiss EA, Chau TT. Upper limb prosthesis use and abandonment: a survey of the last 25 years. Prosthet Orthot Int 2007;31:236-57.
118. Baars EC, Schrier E, Dijkstra PU, Geertzen JHB. Prosthesis satisfaction in lower limb amputees: A systematic review of associated factors and questionnaires. Medicine (Baltimore) 2018;97:e12296.
119. Hobusch GM, Döring K, Brånemark R, Windhager R. Advanced techniques in amputation surgery and prosthetic technology in the lower extremity. EFORT Open Rev 2020;5:724-41.
120. El-Sayed AM, Hamzaid NA, Abu Osman NA. Technology efficacy in active prosthetic knees for transfemoral amputees: a quantitative evaluation. ScientificWorldJournal 2014;2014:297431.
121. Laferrier JZ, Gailey R. Advances in lower-limb prosthetic technology. Phys Med Rehabil Clin N Am 2010;21:87-110.
122. Kuiken TA, Marasco PD, Lock BA, Harden RN, Dewald JP. Redirection of cutaneous sensation from the hand to the chest skin of human amputees with targeted reinnervation. Proc Natl Acad Sci U S A 2007;104:20061-6.
123. Sensinger JW, Schultz AE, Kuiken TA. Examination of force discrimination in human upper limb amputees with reinnervated limb sensation following peripheral nerve transfer. IEEE Trans Neural Syst Rehabil Eng 2009;17:438-44.
124. Gart MS, Souza JM, Dumanian GA. Targeted muscle reinnervation in the upper extremity amputee: a technical roadmap. J Hand Surg Am 2015;40:1877-88.
125. Chang BL, Mondshine J, Attinger CE, Kleiber GM. Targeted muscle reinnervation improves pain and ambulation outcomes in highly comorbid amputees. Plast Reconstr Surg 2021;148:376-86.
126. Hargrove LJ, Young AJ, Simon AM, et al. Intuitive control of a powered prosthetic leg during ambulation: a randomized clinical trial. JAMA 2015;313:2244-52.
127. Park K, Ahn HJ, Lee KH, Lee CH. Development and performance verification of a motorized prosthetic leg for stair walking. Appl Bionics Biomech 2020;2020:8872362.
128. Young AJ, Kuiken TA, Hargrove LJ. Analysis of using EMG and mechanical sensors to enhance intent recognition in powered lower limb prostheses. J Neural Eng 2014;11:056021.
129. Hebert JS, Rehani M, Stiegelmar R. Osseointegration for lower-limb amputation: a systematic review of clinical outcomes. JBJS Rev 2017;5:e10.
130. Muderis M, Khemka A, Lord SJ, Van de Meent H, Frölke JP. Safety of osseointegrated implants for transfemoral amputees: a two-center prospective cohort study. J Bone Joint Surg Am 2016;98:900-9.
131. Lundberg M, Hagberg K, Bullington J. My prosthesis as a part of me: a qualitative analysis of living with an osseointegrated prosthetic limb. Prosthet Orthot Int 2011;35:207-14.
132. Tsakiris M, Carpenter L, James D, Fotopoulou A. Hands only illusion: multisensory integration elicits sense of ownership for body parts but not for non-corporeal objects. Exp Brain Res 2010;204:343-52.
133. Bekrater-Bodmann R. Factors associated with prosthesis embodiment and its importance for prosthetic satisfaction in lower limb amputees. Front Neurorobot 2020;14:604376.
134. Healy A, Farmer S, Eddison N, et al. A scoping literature review of studies assessing effectiveness and cost-effectiveness of prosthetic and orthotic interventions. Disabil Rehabil Assist Technol 2020;15:60-6.
135. Fryer M, Grahammer J, Khalifian S, et al. Exploring cell-based tolerance strategies for hand and face transplantation. Expert Rev Clin Immunol 2015;11:1189-204.
136. Leonard DA, Cetrulo CL Jr, McGrouther DA, Sachs DH. Induction of tolerance of vascularized composite allografts. Transplantation 2013;95:403-9.
137. Scott LR, Vijay S G, Stephen E, et al. Anesthetic management in upper extremity transplantation. Anesthesia & Analgesia 2012;115:678-88.
138. Brandacher G, Lee WP, Schneeberger S. Minimizing immunosuppression in hand transplantation. Expert Rev Clin Immunol 2012;8:673-83; quiz 684.
139. Bertrand AA, Sen S, Otake LR, Lee GK. Changing attitudes toward hand allotransplantation among North American hand surgeons. Ann Plast Surg 2014;72 Suppl 1:S56-60.
Cite This Article
Export citation file: BibTeX | RIS
OAE Style
Xu AL, Humbyrd CJ. Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future. Plast Aesthet Res 2022;9:33. http://dx.doi.org/10.20517/2347-9264.2021.116
AMA Style
Xu AL, Humbyrd CJ. Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future. Plastic and Aesthetic Research. 2022; 9(5): 33. http://dx.doi.org/10.20517/2347-9264.2021.116
Chicago/Turabian Style
Xu, Amy L., Casey Jo Humbyrd. 2022. "Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future" Plastic and Aesthetic Research. 9, no.5: 33. http://dx.doi.org/10.20517/2347-9264.2021.116
ACS Style
Xu, AL.; Humbyrd CJ. Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future. Plast. Aesthet. Res. 2022, 9, 33. http://dx.doi.org/10.20517/2347-9264.2021.116
About This Article
Special Issue
Copyright
Data & Comments
Data
0
Cite This Article 10 clicks
Like This Article 1
likes
Comments
Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.