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LABORATORY INVESTIGATION J Neurosurg 130:184–196, 2019 Novel experimental surgical strategy to prevent traumatic neuroma formation by combining a 3D-printed Y-tube with an autograft Anne Bolleboom, BSc,1,2 Godard C. W. de Ruiter, MD, PhD,3 J. Henk Coert, MD, PhD,4 Bastiaan Tuk,2 Jan C. Holstege, MD, PhD,1 and Johan W. van Neck, MD, PhD2 Departments of 1Neuroscience, and 2Plastic and Reconstructive Surgery, Erasmus University Medical Center, Rotterdam; 3Department of Neurosurgery, Medical Center Haaglanden, The Hague; and 4Department of Plastic and Reconstructive Surgery, Utrecht University Medical Center, Utrecht, The Netherlands OBJECTIVE Traumatic neuromas may develop after nerve injury at the proximal nerve stump, which can lead to neuropathic pain. These neuromas are often resistant to therapy, and excision of the neuroma frequently leads to recur- rence. In this study, the authors present a novel surgical strategy to prevent neuroma formation based on the principle of centro-central anastomosis (CCA), but rather than directly connecting the nerve ends to an autograft, they created a loop using a 3D-printed polyethylene Y-shaped conduit with an autograft in the distal outlets. METHODS The 3D-printed Y-tube with autograft was investigated in a model of rat sciatic nerve transection in which the Y-tube was placed on the proximal sciatic nerve stump and a peroneal graft was placed between the distal outlets of the Y-tube to form a closed loop. This model was compared with a CCA model, in which a loop was created between the proximal tibial and peroneal nerves with a peroneal autograft. Additional control groups consisted of the closed Y-tube and the extended-arm Y-tube. Results were analyzed at 12 weeks of survival using nerve morphometry for the occur- rence of neuroma formation and axonal regeneration in plastic semi-thin sections. RESULTS Among the different surgical groups, the Y-tube with interposed autograft was the only model that did not result in neuroma formation at 12 weeks of survival. In addition, a 13% reduction in the number of myelinated axons regenerating through the interposed autograft was observed in the Y-tube with autograft model. In the CCA model, the authors also observed a decrease of 17% in the number of myelinated axons, but neuroma formation was present in this model. The closed Y-tube resulted in minimal nerve regeneration inside the tube together with extensive neuroma forma- tion before the entrance of the tube. The extended-arm Y-tube model clearly showed that the majority of the regenerat- ing axons merged into the Y-tube arm, which was connected to the autograft, leaving the extended plastic arm almost empty. CONCLUSIONS This pilot study shows that our novel 3D-printed Y-tube model with interposed autograft prevents neu- roma formation, making this a promising surgical tool for the management of traumatic neuromas. https://thejns.org/doi/abs/10.3171/2017.8.JNS17276 KEY WORDS neuroma; sciatic nerve; nerve regeneration; axon; rat; 3D printing; peripheral nerve ORMATION of a traumatic neuroma after peripheral ability, which render them sensitive to ectopic stimuli,3,17,25 nerve injury is a clinical problem, often leading to ultimately leading to spontaneous neuropathic pain and long-term functional deficits. Data obtained from abnormal evoked pain.1,13,37 Despite a variety of treat- Ftrauma populations revealed that an estimated 2%–3% ments, such as simple excision of the neuroma, insertion of patients have experienced a major peripheral nerve in- of the proximal nerve stump into an adjacent anatomical jury28,33 and that approximately 3%–5% of these patients structure, or covering the nerve stump with a cap or epi- develop a painful neuroma at the site of injury.32 The axons neurium,24,35,36 there is presently no uniformly successful trapped in a neuroma show abnormal and increased excit- treatment for symptomatic neuromas.25 The resection of ABBREVIATIONS CCA = centro-central anastomosis; PO = propylene oxide; PPD = paraphenylenediamine. SUBMITTED March 8, 2017. ACCEPTED August 8, 2017. INCLUDE WHEN CITING Published online February 9, 2018; DOI: 10.3171/2017.8.JNS17276. 184 J Neurosurg Volume 130 • January 2019 ©AANS 2019, except where prohibited by US copyright law Unauthenticated | Downloaded 10/11/21 02:53 AM UTC A. Bolleboom et al. FIG. 1. Schematic presentations of the different types of customized 3D-engineered conduits: the open Y-tube (A), the closed Y-tube (B), and the extended-arm Y-tube (C). The dimensions presented are millimeters. Ø = diameter. a neuroma often leads to a transient relief of pain, but the endoneurial tubes are filled,10 and thus the axons would problems often return within a few months because of the penetrate into neighboring tissue where they can form a regenerative capacity of the peripheral nervous system.20,36 neuroma. Experimental studies have demonstrated that As a consequence, surgery often does not lead to sufficient axonal regeneration in the CCA model is not haphazard pain relief in the long term, while pharmaceutical pain but rather arranged, and that the number of regenerating treatment is notoriously ineffective. Therefore, neuromas axons in the CCA model is reduced.9 remain a clinical problem and urgently require a more ef- In the present study, we developed a novel surgical fective approach.18 model to prevent the formation of neuromas by creating a The primary aim of each therapeutic approach after 3D-printed Y-tube that can be customized to exactly fit the nerve injury is to restore the function of the nerve by con- proximal injured nerve end. In this model, the upper arms necting the proximal nerve stump to the distal nerve.12 If a of the Y-tube were connected by a peroneal autograft, nerve defect cannot be directly restored without tension to while the single arm was connected to the proximal sciatic the nerve ends, the current gold standard for repair is inter- nerve stump. With the aid of this Y-tube with autograft, position of an autologous nerve graft to bridge the defect.29 we intended to create a closed loop to induce regrowth However, the distal nerve stump is not always available for of injured axons into the Y-tube and thereafter through reconstruction, for example, after amputation or in cases the graft, which we hypothesized would reduce the pos- of small sensory nerve branches. As an alternative for sibility of an irregular arrangement of regenerating axons different covering and capping methods of the proximal and thereby prevent neuroma formation. An advantage of nerve stump, Slooff and Samii introduced a novel clinical this Y-tube with autograft is that it is applicable to single- technique in the late 1970s, the centro-central anastomo- nerve injuries, with a relatively straightforward surgical sis (CCA).30,31 In this CCA method, each pair of fascicles procedure. The CCA method was used as a control in our of the proximal nerve is reconnected to this nerve—or, experiments. Here, we show that the use of a Y-tube with in cases of multiple severed nerves, with each other—to autograft is an effective approach in preventing neuromas, prevent the occurrence of neuromas.30,31 This method was which also reduces the number of regenerating axons and later investigated experimentally.9,10 Gil-Salú et al. created is easily applicable in nerve surgery. an anastomosis between 2 proximal nerve ends with the interposition of an autograft.9 Recently, there has been a Methods renewed interest in the CCA method by Boroumand et al., who used this model in a clinical setting in patients Preparation of the 3D-Printed Nerve Conduits who underwent lower-limb amputation.4 Both experimen- In this study, 3 types of customized nerve conduits tal9,10 and clinical4,11,31 studies have suggested that the CCA were used: the open Y-tube, the closed Y-tube, and the ex- method is effective in reducing the size of terminal neuro- tended-arm Y-tube (Fig. 1). Conduits were made of poly- mas and in minimizing neuroma-related pain. ethylene-like material (Endur RGD450, Stratasys) using The mechanisms by which the CCA method reduces layer-by-layer 3D printing performed on a commercially neuroma formation are not known. One theory is that the available 3D printer (Objet 30 Pro, Stratasys). During fab- CCA method reduces neuromas by guiding regenerating rication, support material (FullCure 705, Stratasys) was axons into an autograft, protected from surrounding tis- used to prevent any changes in the dimensions of the con- sues, where they grow into the remaining empty endoneu- duits and was removed preoperatively. To fabricate con- rial tubes of the graft.10,31 If an autograft is not interposed duits with anatomically accurate dimensions, the diam- and the terminal stumps of the fascicles are sutured direct- eters of the sciatic and peroneal nerves in a 180-g Lewis ly end to end, it is suspected that the axons of each fascicle rat were measured (0.8 mm and 0.6 mm, respectively) and could not penetrate into the opposite fascicle because the used as tissue templates to design the conduits. To prevent J Neurosurg Volume 130 • January 2019 185 Unauthenticated | Downloaded 10/11/21 02:53 AM UTC A. Bolleboom et al. FIG. 2. Illustrations showing the different types of nerve repair. A: The open Y-tube, in which the proximal sciatic nerve (S) is in- serted into the single arm of the conduit and a 10-mm-long peroneal (P) nerve graft is connected to the distal arms of the Y-tube to create a closed loop. B: The CCA, which is formed by the direct coaptation of the proximal tibial (T) and peroneal nerves, placing between them a 10-mm-long peroneal nerve graft.

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