The hurdles of nanotoxicity in transplant nanomedicine.

Nanomedicine has matured significantly in the past 20 years and a number of nanoformulated therapies are cleared by regulatory agencies for use across the globe. Transplant medicine is one area that has significantly benefited from the advancement of nanomedicine in recent times. However, while nanoparticle-based therapies have improved toxicological profiles of some drugs, there are still a number of aspects regarding the biocompatibility and toxicity of nanotherapies that require further research. The goal of this article is to review toxicological profiles of immunosuppressant therapies and their conversion into nanomedicine formulations as well as introduce future challenges associated with current in vitro and in vivo toxicological models.

A Call to Accountability: Reporting Outcomes in Vascularized Composite Allotransplantation.

Because nearly all the vascularized composite allotransplants performed in the United States have been proposed and carried out as research, the ethical duty to report outcomes pertains. This duty is set forth in several international statements, including the World Health Organization's Statement on Public Disclosure of Clinical Trial Results, the 2013 Helsinki Declaration, and the Singapore Statement on Research Integrity. These international statements call for the reporting of negative and inconclusive outcomes as well as positive outcomes, and for the reporting of results from previously unreported past research. In 2014, the Organ Procurement and Transplant Network vascularized composite allotransplant committee proposed mandatory data collection and submission requirements for transplants, but only for those which took place in September 2015 or later. Reporting of data for the allotransplants which took place before September 2015 was regarded as optional, even though the pre-September 2015 transplants represent the majority of vascularized composite allotransplants in the United States and all the long-term outcome data. We encourage the American Society of Reconstructive Transplantation and the Organ Procurement and Transplant Network committee to embrace the international ethical standards and to hold all vascularized composite allotransplant programs in the United States accountable for reporting data on outcomes of pre-September 2015 transplants.

Is Skin the Most Allogenic Tissue in Vascularized Composite Allotransplantation and a Valid Monitor of the Deeper Tissues?

Since the 1960s, skin has been considered to be the most allogenic tissue in humans. This tenet has remained unquestioned in the reconstructive transplant arena, which has led to skin serving as the sole monitor for early rejection in vascularized composite allotransplantation. In this article, the authors question the validity of this belief. The authors' hypothesis is that skin is not always an accurate monitor of rejection in the deep tissues, thus questioning the positive and negative predictive value of the punch biopsy for suspected vascularized composite allotransplantation rejection. A search was carried out identifying vascularized composite allotransplantation publications where the allogenicity of transplanted skin was evaluated. Eighteen publications claimed skin was found to be the most allogenic tissue in humans, justifying its use as a superior monitor for rejection. Eight publications demonstrated skin to be a poor monitor of rejection deeper to the skin. Two vascularized composite allotransplantation animal studies reported skin rejecting simultaneously with the deeper tissues. Finally, three publications discussed a skin and kidney allograft, transplanted simultaneously, indicating skin allogenicity was equivalent to the that of the kidney allograft. Much of the literature in human vascularized composite allotransplantation claims skin to be an excellent monitor of the deep tissues. The conclusion from this study is that skin does not always function as a good monitor for what could be rejecting in the deep tissues. The authors believe continued research is necessary to focus on expanding novel monitoring techniques and technologies to accurately diagnose vascularized composite allotransplantation rejection without tissue destruction.

A Flow Dynamic Rationale for Accelerated Vascularized Composite Allotransplant Rejection.

BACKGROUND: From 1996 to 2000, Diefenbeck et al. carried out six knee vascularized composite allotransplants. The allotransplants were composed of bone, soft tissue, and femoral vascular pedicle (25 to 40 cm). All rejected between 14 and 56 months. Failures were attributed to chronic rejection. In 2008, the Louisville team lost their fourth patient's hand transplant at 8 months. During the rejection workup, intraoperative findings noted a thickened arterial pedicle attributed to intimal hyperplasia with significant fibrotic perivascular tissue and a near "no-flow phenomenon." No cutaneous rejection was appreciated and failure was attributed to chronic rejection. METHODS: Data were collected from two teams, one in Germany and the other in Louisville, Kentucky. The population under study consisted of the six knee and one hand transplants. The factor of interest was the long donor arterial pedicle. The outcome measurements were transplant survival time and histopathologic results. RESULTS: There are only seven published vascularized composite allotransplant cases where a donor artery longer than 25 cm was used. This cohort represents a 100 percent accelerated failure rate. The cause of these losses remains unexplained. The donor arteries suffered from T-cell-mediated rejection and ischemia-induced media/adventitial necrosis. CONCLUSIONS: We hypothesize that the donor artery rejected at an accelerated rate because of ischemia caused by disruption of the external vasa vasorum in conjunction with intimal hyperplasia induced by T-cell-mediated rejection that led to disruption of the Windkessel effect. Loss of this effect presented as intimal hyperplasia accelerated by ischemia causing an expedited transplant failure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.