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[69]
for infection-related concerns . As the cumulative experience with OI expands and the natural history
of the skin penetration site becomes better delineated, the technique for implant placement and soft tissue
manipulation is sure to evolve.

Future directions
Current research efforts aim to improve the safety of OI, while also leveraging the percutaneous abutment
as a conduit for prosthetic feedback and control. While OI has been successfully used in the extremity,
in the absence of a seal between the implant and surrounding soft tissue, soft tissue integration would
dramatically decrease the risk for infection and ameliorate the chronic inflammation currently experienced
at the implant interface [Figure 6]. Efforts are currently underway to use bioprinting and tissue engineering
to generate a dynamic dermal seal. From the standpoint of neuromuscular integration, the osseintegrated
implant and percutaneous abutment serve as a convenient channel through which to directly connect
implantable sensors with the prosthetic. Direct connectivity dramatically increases the clinical potential
offered by feedback and control strategies that are currently hampered by the need for surface detection,
such as regenerative peripheral nerve or agonist–antagonist myoneural interfaces. The enhanced OPRA
(e-OPRA), which utilizes a modified abutment screw to allow passage of transcortical wires between
[70]
implantable electrodes and the terminal device, is already in clinical use in Europe .

EXTREMITY VASCULARIZED COMPOSITE ALLOTRANSPLANTATION
Background
Joseph Murray, an American plastic surgeon, performed the first kidney transplant in the world in 1954 at
[71]
the Peter Bent Brigham Hospital in Boston, Massachusetts . A decade later, the first hand transplantation
[72]
was performed in Ecuador . However, the patient suffered from irreversible rejection and the graft was
explanted three weeks later . The second hand transplantation was performed in Lyon, France in 1998
[72]
[73]
but eventually failed due to noncompliance with immunosuppression regimen . Although unsuccessful,
this case demonstrated the feasibility of the procedure and the importance of compliance/postoperative
care. This was followed in January 1999 by the first hand transplantation in the United States, in Louisville,
Kentucky [73,74] .

The field of extremity VCA quickly gained popularity as replantation data suggested better functional
[75]
outcomes when compared with revision amputation and prosthetic fitting . By 2009, 53 successful hand
transplants had been performed worldwide . Now, roughly 150 upper limb transplantations in 100 patients
[76]
have been performed to date at 45 centers worldwide, including those in United States, France, China,
Austria, Italy, Spain, Belgium, Poland, Mexico, and Australia [76-85] . In 2015, the world’s first pediatric bilateral
hand-forearm transplantation and, in 2016, the first transatlantic hand transplantation were performed at
the University of Pennsylvania under the direction of the senior author (Levin LS) [78,86] .

Although it has been advocated as a reasonable pursuit, successful VCA for lower limb amputees have not
[87]
been reported to date . This is mainly due to the fact that, when compared to prosthetic options, the risks,
including those associated with surgery and lifelong immunosuppression, outweigh potential benefits. For
this reason, the presented discussion on VCA is limited to upper extremity.

Hand and upper-limb transplantation represents the most commonly performed surgery in the growing
field of VCA [88,89] . The hand transplantation process consists of patient selection, preoperative evaluation/
preparation including cadaveric practice runs, the procurement and transplantation procedure,
immunosuppression maintenance, and postoperative rehabilitation and follow-up [88,90] . Significant progress
has been made in the past several decades in extremity VCA, including 3D printing, novel implants,
improved imaging techniques [e.g., functional magnetic resonance imaging (MRI)], immunosuppressive
[88]
regimens, and efficiency of surgical technique .