Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes.

Pre-clinical studies are an obligatory tool to develop and translate novel therapeutic strategies into clinical practice. Acute and chronic rejection mediated by the recipient’s immune system remains an important limiting factor for the (long-term) survival of vascularized composite allografts (VCA). Furthermore, high intensity immunosuppressive (IS) protocols are needed to mitigate the immediate and long-term effects of rejection. These IS regiments can have significant side-effects such as predisposing transplant recipients to infections, organ dysfunction and malignancies. To overcome these problems, tolerance induction has been proposed as one strategy to reduce the intensity of IS protocols and to thereby mitigate long-term effects of allograft rejection. In this review article, we provide an overview about animal models and strategies that have been used to induce tolerance. The induction of donor-specific tolerance was achieved in preclinical animal models and clinical translation may help improve short and long-term outcomes in VCAs in the future.

Free tissue transfer is widely used for the reconstruction of complex tissue defects. The survival of free flaps depends on the patency and integrity of the microvascular anastomosis. Accordingly, the early detection of vascular comprise and prompt intervention are indispensable to increase flap survival rates. Such monitoring strategies are commonly integrated into the perioperative algorithm, with clinical examination still being considered the gold standard for routine free flap monitoring. Despite its widespread acceptance as state of the art, the clinical examination also has its pitfalls, such as the limited applicability in buried flaps and the risk of poor interrater agreement due to inconsistent flap (failure) appearances. To compensate for these shortcomings, a plethora of alternative monitoring tools have been proposed in recent years, each of them with inherent strengths and limitations. Given the ongoing demographic change, the number of older patients requiring free flap reconstruction, e.g., after cancer resection, is rising. Yet, age-related morphologic changes may complicate the free flap evaluation in elderly patients and delay the prompt detection of clinical signs of flap compromise. In this review, we provide an overview of currently available and employed methods for free flap monitoring, with a special focus on elderly patients and how senescence may impact standard free flap monitoring strategies.

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