Key psychosocial challenges in vascularized composite allotransplantation

Psychosocial factors are important elements in the assessment and follow-up care for vascularized composite allotransplantation(VCA) and require multidisciplinary evaluation protocols. This review will highlight differences between VCA with solid organ transplantation(SOT), provide information on the psychosocial selection of VCA candidates, ethical issues, psychological outcomes, and on the need for multicenter research. VCA is primarily a life-enhancing procedure to improve recipients' quality of life and psychological well-being and it represents a potential option to provide reproduction in case of penile or uterine transplantation. The risk benefit ratio is distinctly different than SOT with candidates desiring life enhancing outcomes including improved body image, return to occupations, restored touch, and for uterine transplant, pregnancy. The Chauvet Workgroup has been convened with membership from a number of transplant centers to address these issues and to call for multicenter research. A multicenter research network would share similar evaluation approaches so that meaningful research on psychosocial variables could inform the transplant community and patients about factors that increase risk of non-adherence and other adverse psychosocial and medical outcomes.

Nerve regeneration in vascularized composite allotransplantation:current strategies and future directions

Vascularized composite allotransplantation(VCA)has emerged as a viable treatment option for limb and face reconstruction of severe tissue defects.Functional recovery after VCA requires not only effective immunosuppression,but also consideration of peripheral nerve regeneration to facilitate motor and sensory reinnervation of donor tissue.At the time of transplantation,the donor and recipient nerves are typically coapted in an end-to-end fashion.Following transplantation,there are no therapies available to enhance nerve regeneration and graft reinnervation,and functional outcomes are dependent on the recipients’innate regenerative capacities.Functional outcomes to date have been promising,but there is still much room for improvement,studies have demonstrated reliable return of protective sensation(pain,thermal,gross tactile),while discriminative sensation and motor function show more inconsistent results.In order to maximize the benefit afforded to the by VCA,we must develop consistent and reliable procedures and therapies to ensure effective nerve regeneration and functional outcomes.New technologies,such as nerve guidance conduits and fibrin glues,and the use of stem cells to facilitate nerve regeneration remain untested in VCA but are proving worthwhile in the context of peripheral nerve repair.VCA presents a unique set of challenges with regards to surgical techniques,postoperative regimen,and health of donor tissue.In this review,we discuss current challenges underlying achievement of nerve regeneration in VCA and discuss novel technologies and approaches to translate nerve regeneration into functional restoration.

Expanding the top rungs of the extremity reconstructive ladder:targeted muscle reinnervation,osseointegration,and vascularized composite allotransplantation

Osseointegration(OI),targeted muscle reinnervation(TMR),and vascularized composite allotransplantation(VCA)are just a few ways by which our reconstructive ladder is evolving.It is important to recognize that amputation does not necessarily denote failure,but surgeons should strive to find ways to provide these patients with means for obtaining better satisfaction and quality of life postoperatively.TMR and OI have added options for mutilating lower extremity injuries that necessitate amputation.More recently,the senior author(Levin LS)described the"penthouse"floor of the reconstructive ladder being VCA.Despite the advances in VCA over the last 20 years,there are many challenges that face this discipline including indications for patient selection,minimizing immunosuppressive regimens,standardizing outcome measures,establishing reliable protocols for monitoring,and diagnosing and managing rejection.Herein,the authors review TMR,OI,and VCA as additional higher rungs of the reconstructive ladder.

Ethical challenges in vascularized composite allotransplantation of the lower extremity:lessons learned from hand transplantation and implications for the future

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.

Complex upper extremity injuries:targeted muscle reinnervation,free functional muscle transfer,and vascularized composite allotransplantation

Restoration of upper extremity function poses a unique surgical challenge.With considerations ranging from ensuring appropriate skeletal support and musculotendinous and ligamentous anatomy,restoring adequate vascularity and innervation,and providing sufficient soft tissue coverage,upper extremity injuries present a diverse range of reconstructive problems.Recent history has been marked by an expansion of novel techniques for addressing these complex issues.Sophisticated modalities,such as targeted muscle reinnervation,free functional muscle transfer,and vascularized composite allotransplantation,have become some of the most powerful tools in the armamentarium of the reconstructive surgeon.This review article aims to define the distinguishing features of each of these modalities and reviews some of their unique advantages and limitations.

The intragraft vascularized bone marrow component plays a critical role in tolerance induction after reconstructive transplantation

The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood.In this study,vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation(CBMT)or vascularized bone marrow(VBM)transplantation from Balb/c(H2d)to C57BL/6(H2b)mice were compared.Either high-or low-dose CBMT(1.5×10^(8)or 3×10^(7)bone marrow cells,respectively)was applied.In addition,recipients were treated with costimulation blockade(1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2,respectively)and short-term rapamycin(3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks).Similar to high-dose conventional bone marrow transplantation,5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival(>120 days).In contrast,significantly shorter median survival was noted in the low-dose CBMT group(~64 days).Consistently high chimerism levels were observed in the VBM transplantation group.Notably,low levels of circulating CD4^(+)and CD8^(+)T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients(>30 days)but not in low-dose VBM transplant recipients.Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro.Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.