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Vascularized composite allotransplantation: a field is maturing

Brandacher, Gerald

Current Opinion in Organ Transplantation: October 2018 - Volume 23 - Issue 5 - p 559–560
doi: 10.1097/MOT.0000000000000574
COMPOSITE TISSUE TRANSPLANTATION: Edited by Gerald Brandacher

Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Correspondence to Gerald Brandacher, MD, FAST, Associate Professor of Surgery, Scientific Director, Reconstructive Transplantation Program, Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Ross Research Building/Suite 749D, 720 Rutland Avenue, Baltimore, MD 21205, USA. Tel: +1 443 287 6679; e-mail: brandacher@jhmi.edu

Vascularized composite allotransplantation (VCA) has become a valid therapeutic and restorative option for patients with severe tissue defects not amendable to conventional reconstruction [1,2]. Significant advances in both basic science and translational research over the last decade paired with highly encouraging functional and immunological clinical outcomes in the majority of patients have lead VCA to transition from an experimental and sometimes controversial procedure to an accepted and rapidly expanding field with great promise [3].

In this special issue of Current Opinion in Organ Transplantation, leaders in the field of VCA provide a comprehensive overview of some of those latest developments as well as some of the emerging challenges of this innovative field.

The current gold standard of static cold tissue preservation is insufficient to preserve vascularized composite allografts for more than a few hours, which creates a technological bottleneck for broader application of VCA. Uygun and colleagues (pp. 561–567) discuss how the latest advances in machine perfusion, organ preservation, and cryobiology could allow us to overcome this hurdle and provide an outlook on the potential clinical impact of those technologies on the field of VCA. The authors lay out a vision of how advancements in organ preservation can alleviate the current constraints of implementing improved matching and allocation practices, desensitization protocols, and potential tolerance induction regimens in the cadaveric donor setting that is mandated for VCA.

The requirement of life-long multidrug immunosuppression in order to enable allograft survival and to treat and reverse acute rejection episodes remains another pace-limiting obstacle toward more widespread application of VCA. Rieben et al. (pp. 568–576) from the University of Bern review how targeted immunosuppression using innovative drug delivery systems may allow an increase in therapeutic efficacy while reducing systemic toxicity of maintenance immunosuppression. Due to its accessibility, VCA offers unique opportunities for site-specific delivery of immunosuppressive medications directly to the graft and thus is a promising new approach for improving patient compliance and graft survival while reducing the intensity and frequency of acute rejection episodes and risk of chronic rejection.

The overall success of VCA is dictated, however, not only by controlling the alloimmune response but also specifically by the pace and quality of nerve regeneration. Following transplantation, the recipient's peripheral nerve axons must regenerate into the graft to innervate the transplanted muscle and skin. This process ultimately allows the recipient to establish motor control over and receive sensory input from the graft. However, success of proximal arm and leg transplants, in particular, has been hampered by the limitations of nerve regrowth across long distances, resulting in poor regeneration and functional recovery. Thus, strategies to enhance nerve regeneration and optimize functional recovery will have significant impact to further broaden clinical application of these innovative reconstructive procedures. Tung and Mackinnon (pp. 577–581) from Washington University review the underlying pathophysiologic mechanisms of nerve regeneration after VCA and relevant research in stem cell-based therapies to overcome these issues.

As the field of VCA is maturing and more long-term follow-up data become available, features suggestive of chronic rejection have been recently documented in patients after both hand and upper extremity transplantation as well as face transplantation [4]. Kanitakis and the team from Lyon, France (pp. 582–591) discuss important questions related to chronic rejection such as how to properly define chronic rejection for vascularized composite allografts, what the specific diagnostic criteria are, what represents triggering factors, what the pathogenetic mechanisms involved are, and, most importantly, if there are any adequate treatment options for chronic rejection in VCA.

Given the highly encouraging immunological and functional outcomes seen after upper extremity and face transplantation over the past two decades, indications for novel types of VCA, specifically urogenital VCA including penile and uterus transplantation, have been rapidly expanding [5,6]. Bränström from Gothenburg, Sweden (pp. 592–597) reviews the current status and future direction of uterus transplantation (UTx) – with a particular emphasis on a discussion of live donor UTx versus deceased donor UTx – and provides recommendations for scientific development and further expansion of the UTx field.

Along the same line of expanding indications for VCA, Pomahac and colleagues (pp. 598–604) discuss in a thought-provoking opinion piece if pediatric face transplantation is a viable option. Given that reported outcomes document that face transplantation is a life-enhancing, feasible, and ethically justified procedure for appropriate patients and that pediatric hand transplantation has been successfully performed with equally good outcomes, the time is ripe to seriously consider how to properly expand the field of face transplantation into pediatric patients. Specific topics that are reviewed by the authors include indications, pediatric patient and donor selection criteria, immunosuppressive strategies, informed consent, and procedural and ethical considerations. As efforts towards pediatric face transplantation are progressing, appropriate collaboration between adult and pediatric colleagues will be essential to mitigate risks associated with expanding surgical innovation between respective patient demographics.

Finally, McDiarmid from UCLA (pp. 605–614) discusses lessons learned over several decades of solid organ transplantation in children and their relevance to the emerging field of pediatric VCA. Particular attention is thereby placed on the risk–benefit ratio of immunosuppression as it applies to children receiving a life-enhancing transplant as compared with a life-saving transplant. The author draws from the vast experience of managing immunosuppression and monitoring outcomes in more than 1000 pediatric liver transplants at UCLA. This provides a most valuable perspective, as many of the current practices in VCA are still extrapolated from research, standards, and clinical protocols in solid organ transplantation. Thus, this accumulated experience over several decades of solid organ transplantation for children is most relevant to develop the new field of VCA for children.

We would like to thank all the authors for contributing their expertise and time and the Editor-in-Chief for making this special issue on VCA possible. We hope that you will enjoy reading this series of articles on some of the hottest and most controversial topics in the field of VCA.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES

1. Shores JT, Malek V, Lee WPA, Brandacher G. Outcomes after hand and upper extremity transplantation. J Mater Sci Mater Med 2017; 28:72.
2. Khalifian S, Brazio PS, Mohan R, et al. Facial transplantation: the first 9 years. Lancet 2014; 384:2153–2163.
3. Brandacher G. The science of reconstructive transplantation. New York, USA: Humana Press; 2015.
4. Kanitakis J, Petruzzo P, Badet L, et al. Chronic rejection in human vascularized composite allotransplantation (hand and face recipients): an update. Transplantation 2016; 100:2053–2061.
5. Tuffaha SH, Cooney DS, Sopko NA, et al. Penile transplantation: an emerging option for genitourinary reconstruction. Transpl Int 2017; 30:441–450.
6. Brännström M, Johannesson L, Bokström H, et al. Livebirth after uterus transplantation. Lancet 2015; 385:607–616.
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