Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain

RPNIs have demonstrated their potential to serve as a treatment for postamputation pain as well as prevent the development of painful neuromas. The fundamental distinction between the RPNI procedure and alternative approaches to managing neuromas, such as nerve capping, applying proximal pressure, or employing thermal procedures on the distal nerve, lies in the primary goal of the severed nerve reinnervating a physiologically appropriate end organ. Additionally, an important contrast between RPNI and techniques like neuroma transposition and muscle implantation and burying, where the nerve's end target is also appropriate, is the use of denervated muscle targets. In cases where the muscle target is already innervated, each muscle fiber is already in physiological contact and occupied by a nerve fiber. This means that the freshly cut nerve cannot reinnervate the muscle and will thereby more likely redevelop a painful neuroma. Furthermore, in comparison to TMR surgery, where the freshly cut nerve end is coapted to a nearby expendable motor nerve and its accompanying motor end units of a target muscle, both techniques utilize a denervated target muscle. However, a distinction lies in the fact that RPNI employs a non-vascularized muscle graft, whereas in TMR, the nerve reinnervates a vascularized muscle. Furthermore, there are two other important differences with TMR related to the sizable caliber mismatch between donor and recipient nerves and the need to sacrifice otherwise healthy innervations. The size mismatch between donor and recipient nerves can potentially result in a neuroma-in-continuity, and the sacrificed nerves might develop painful neuromas. Moreover, the TMR procedure could be considered more complex than RPNI, as it incorporates techniques such as nerve transfers and coaptation. Whereas RPNI requires a longitudinal dissection to separate the never fascicles, the rest of the steps can be performed by a broader range of surgeons, including orthopedic surgeons, general surgeons, and others involved in amputations, rather than exclusively requiring the expertise of nerve surgeons, microsurgeons, or hand surgeons. Furthermore, there have been several combinations of both RPNI and TMR using key concepts of each technique. For example, nerve-to-nerve coaptation, including free muscle graft wrapping over the coaptation²⁹ or splitting the nerve in two and performing coaptation with one part and RPNI constructs with the other³⁰.

The procedure involves critical steps that must be carefully considered to ensure successful outcomes. Firstly, the muscle graft harvesting process should align with the muscle fiber axis to prevent disruption of individual muscle fibers, and the muscle graft should be trimmed off all connective tissue to optimize regeneration. The choice of the harvest site may vary depending on availability. In primary amputations, we recommend using the amputated part when possible. For transradial amputations, the brachioradialis muscle is a suitable donor site, while for transhumeral amputations, the triceps muscles can be utilized. In the case of lower extremity amputations, such as transradial and transfemoral, the ipsilateral proximal thigh, typically the vastus lateralis, serves as a suitable harvesting site. Furthermore, for transfemoral amputations, the sartorius and gracilis muscles are also viable donor options¹⁸. However, these mentioned harvest sites for each amputation level should be seen as recommendations. In RPNI surgery for pain relief, when the amputated part is not available, the harvest site could be from any of the aforementioned sites independently of the amputation level.

Moreover, it's vital to consider the ratio between the nerve stump and the muscle graft. Grafts that are excessively thick are susceptible to central necrosis, and grafts that are too thin or insufficiently denervated muscle fibers will result in neuroma formation within the RPNI construct. In this protocol, we recommend that the nerve stump is a maximum of 4-6 mm thick in diameter for a muscle graft with dimensions of 3 cm long, 1.5 cm wide, and 0.5 cm thick. The dimensions can be adjusted based on the nerve's thickness; for nerves with a diameter up 10 mm, the width of the nerve graft can be up to approximately 2 cm, but it should still facilitate complete wrapping of the nerve, extending at least 1 cm proximal to its end¹⁸. The nerve's circumference should be covered without causing any tension while also maintaining sufficient thinness to enable revascularization. In cases of thick nerves, such as the sciatic nerve, we recommend fascicular dissection, creating several RPNIs instead of creating one large RPNI (see Table 1).

The RPNI surgery is an easy, safe, straightforward, and reliable treatment; however, the technique has its drawbacks when compared to the conventional treatment. As previously documented in the literature by Dellon et al., this method involves additional surgical steps, necessitating the use of more Current Procedural Terminology (CPT) codes, such as incorporating a muscle graft. This, in turn, results in increased time needed in the surgical theater and thereby increased surgical expenses³¹. The additional surgical time of performing RPNI or TMR is highly dependent on the amputation level and the number of constructs. However, despite the associated increase in expenses, several vital long-term considerations come into play. Individuals experiencing chronic pain following amputation require continuous pain management, encompassing medication, rehabilitation, and specialized interventions. Additionally, postamputation pain often leads to heightened healthcare utilization, involving frequent visits to healthcare providers, emergency room trips, and hospital admissions. Surgical interventions like RPNI or TMR, designed to treat postamputation pain, have the potential to significantly extend the lifespan, promote mobility, gainful employment, and enhance the overall quality of life for individuals with postamputation pain. By alleviating suffering, facilitating improved functional outcomes, and fostering psychological well-being, these interventions offer invaluable benefits that extend far beyond mere financial considerations.

In addition to their role in neuroma management, RPNIs have also been employed in patients with limb loss to enhance motor and sensory prosthetic function^30,32,33,34. By providing a stable and responsive interface between the residual nerve and prosthetic technology, RPNIs enable individuals with limb loss to achieve more natural and precise control over their prosthetic limbs. This advancement has the potential to greatly enhance their mobility, dexterity, and quality of life³⁰. As a result, RPNIs represent a multifaceted approach that not only manages neuroma-related issues but also offers promising solutions for the broader needs of individuals with amputation, further underscoring their significance in the field of amputation rehabilitation.