To investigate the safety and feasibility of spider silk interposition for erectile nerve reconstruction in patients undergoing robotic radical prostatectomy (RARP).
The major-ampullate-dragline from Nephila edulis was used for spider silk nerve reconstruction (SSNR). After removal of the prostate with either uni- or bilateral nerve-sparing, the spider silk was laid out on the site of the neurovascular bundles. Data analysis included inflammatory markers and patient reported outcomes.
Six patients underwent RARP with SSNR. In 50% of the cases, only a unilateral nerve-sparing was performed, bilateral nerve-sparing could be performed in three patients. Placement of the spider silk conduit was uneventful, contact of the spider silk with the surrounding tissue was mostly sufficient for a stable connection with the proximal and distal ends of the dissected bundles. Inflammatory markers peaked until postoperative day 1 but stabilized until discharge without any need for antibiotic treatment throughout the hospital stay. One patient was readmitted due to a urinary tract infection. Three patients reported about erections sufficient for penetration after three months with a continuous improvement of erectile function both after bi- and unilateral nerve-sparing with SSNR up to the last follow-up after 18 months.
In this analysis of the first RARP with SSNR, a simple intraoperative handling without major complications was demonstrated. While the series provides evidence that SSNR is safe and feasible, a prospective randomized trial with long-term follow-up is needed to identify further improvement in postoperative erectile function due to the spider silk-directed nerve regeneration.
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Maintenance of continence and potency are major goals in radical prostatectomy . However, despite improvements in surgical techniques and postoperative treatments, a substantial proportion of prostate cancer patients undergoing radical surgery will face a permanently impaired postoperative erectile function. Bilateral nerve-sparing dissection seems to be beneficial, but (a) this cannot be offered in unfavorable tumor constellations and risk of extraprostatic extension  and (b) traction and the use of cautery on the preserved neurovascular bundles still can provoke nerve injury and neuropraxia . To improve this impending reduction in postoperative quality of life due to a limited or absent erectile recovery, a multitude of techniques to protect or replace the neurovascular bundles were described [4, 5]. Inspired by somatic nerve transplantation, sural nerve grafts were used for reconstruction of the sacrificed autonomic cavernosal nerves in the beginning of the 2000s. However, especially in patients with unilateral nerve-sparing or wide excision of the periprostatic tissue, studies showed diverging outcomes [6, 7].
Over the last years, spider silk has emerged as a new promising biomaterial that supports neuroregeneration as a guiding structure for axonal outgrowth and migration of Schwann cells . Spider silk is characterized by a high toughness and elasticity and—in contrast to other bioengineering materials for nerve regeneration like surgical suturing materials (e.g., polydiaxanone monofilaments, PDS) or silkworm silk—spider silk degrades in a physiological pH diminishing a potentially impaired neuroregeneration in an acid environment . Spider silk interposition has already provided promising results in peripheral nerve reconstruction in vitro and in vivo with axonal regeneration comparable to autologous nerve transplantation—both Radtke et al. and Kornfeld et al. demonstrated equal electrophysical results in sheep models after spider silk implantation compared to the gold standard of a full-thickness nerve graft [10, 11]. However, the impact on autonomic neuroregeneration in humans is unknown. This feasibility analysis aims to investigate the safety profile and early functional results after spider silk erectile nerve reconstruction in robot-assisted radical prostatectomy.
Patients and methods
Between October 2020 and May 2021, six patients underwent robot-assisted radical prostatectomy with spider silk nerve reconstruction after informed consent. All procedures in this analysis involving human participants were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The data were analyzed retrospectively after IRB approval (10061_BO_K_2021, Hannover Medical School).
Spider silk nerve reconstruction was proposed to selected patients scheduled for robotic radical prostatectomy for intermediate or high-risk prostate cancer with a wish for a nerve-sparing procedure. Patient selection was based on a good preoperative erectile function and the eligibility for the subsequent PDE5-inhibitor treatment as well as the availability of sterilized spider silk and surgical capacities during the COVID-19 situation. Uni- or bilateral nerve-sparing was offered in cases with a low risk of extraprostatic extension based on preoperative PSA and multiparametric MRI, numbers of positive biopsy cores and Gleason-Score in the preoperative histopathology.
Preparation of the spider silk
Spider silk was harvested from Nephila edulis that is kept and bred for scientific purposes at the Kerstin Reimers Laboratory (KLR), Department of Plastic, Esthetic, Hand, and Reconstructive Surgery at Hannover Medical School (Fig. 1a) . While different types of silk are produced by the female spider, the major-ampullate-dragline functions as the safety line that attaches the spider with the connected surrounding and is therefore characterized by a high level of stability and elasticity . Up to 500 m of dragline silk can be harvested in one process without harm to the animal using a computerized reeling machine with subsequent sterilization on the collector (Fig. 1b) [10, 11].
Intra- and postoperative course
After informed consent, robot-assisted radical prostatectomy was performed by one experienced urologist with more than 500 prior robot-assisted radical prostatectomies (NNH) via a transperitoneal approach using a daVinci Xi robotic system after administration of one single-shot cephalosporine. The neurovascular structures were spared either inter- or intrafascially whenever feasible and oncologically reasonable . The spider silk nerve reconstruction was performed bilaterally independent of the grade of nerve-sparing.
Due to the fragility of the spider fibers with a tendency to clot immediately after contact with tissue or blood, a venous graft was used to stabilize the spider silk bundle for a simplified placement. For the construction of two conduits approximately 5–8 cm of the vena saphena magna was used after dissection from the patient’s left lower leg by the plastic surgeon (PMV); this procedure was performed during the robotic radical prostatectomy. After preparation of the vein, the sterilized spider silk was pulled through the venous conduits and cut to the suitable length with protruding silk fibers on both ends (Fig. 1c, d). The spider silk conduit was inserted through a 12 mm assistant trocar and placed on the site of the neurovascular bundles after a non-nerve-sparing procedure. The overhanging silk was laid out in a fan-shaped pattern basally on the former proximal prostate bed and apically in the periurethral area to cover the majority of the divided fibers of the pelvic plexus (Fig. 2). Contact of the silk with the surrounding tissue was mostly sufficient for a stable connection, in patients with an enlarged prostate and the need for a long conduit the vein was fixed with a PDS 4–0 suture to prevent dislocation. In nerve-sparing RARP, spider silk conduits were additionally placed on the proximal and distal ends of the spared neurovascular bundles with the idea to stabilize and support the regeneration of potentially disrupted nervous structures.
White blood cell count (WBC) and C-reactive protein (CRP) were analyzed preoperatively, on postoperative day 0 and 1 as well as before discharge to evaluate potential inflammatory side effects. Complications were classified according to the Clavien–Dindo classification system .
After detailed instructions on erectile function recovery before discharge, patients received Tadalafil 5 mg once daily for at least four weeks followed by Tadalafil 20 mg on demand. Follow-up was based on questionnaires including quality of life (QLQ-30), IPSS and IIEF-5.
SPSS 27 was used for statistical analyses. Continuous data are given as median and range, categorial data are shown as numbers and percentage.
Six patients with intermediate or high-risk prostate cancer and a wish for a nerve-sparing procedure with the eligibility for the subsequent PDE5-inhibitor treatment were scheduled for robotic radical prostatectomy with spider silk nerve reconstruction (Table 1). None of the patients received neoadjuvant treatment prior to surgery. Except for one patient with cardiovascular disease and one with depression, the cohort was healthy with a median Charlson Comorbidity Index of 0. The patients were preoperative potent with a median IIEF-5 score of 22.5 ranging from 20 to 25.
While median prostate volume was 38 ml, one patient with a large prostate (130 ml) needed intraoperative ureteral stent placement and bladder neck reconstruction. Removal of multiple bladder stones was necessary in a case with a prostate volume of 90 ml. In three cases, only a unilateral interfascial nerve-sparing was feasible while in two patients a bilateral nerve-sparing with an interfascial on one and an intrafascial resection the other side could be performed; in one patient, a bilateral intrafascial full nerve-sparing was accomplished (Fig. 3). No intraoperative complications occurred, however, one patient needed to be readmitted on postoperative day 12 for intravenous antibiotic therapy because of a urinary tract infection (grade 2 complication according to the Clavien–Dindo classification); in one patient a prolonged catheterization time was necessary (grade 1 complication). Over the postoperative course, there was no morbidity observed related to the harvesting of the venous graft.
White blood cell count and C-reactive protein levels as a surrogate marker for potential inflammation peaked on postoperative day 1 but stabilized until discharge without further antibiotic treatments. There were no positive surgical margins and up until today no patient underwent adjuvant or salvage radiotherapy (Table 1).
Potency recovery was evaluated after a median of 12 weeks: the median IIEF score dropped by 13 points (0 to − 20 points). Three patients reported about erections sufficient for penetration. Over the course of time, erectile function improved in five out of six patients. Last follow-up was available after a median of 82 weeks: the IIEF-5 score improved to a median of 18.5 with a median change of − 1.5 points compared to the individual baseline (Fig. 3).
This first-in-men analysis summarizes the results of the spider silk nerve reconstruction in robot-assisted radical prostatectomy and demonstrates an uneventful intra- and postoperative course without signs of conduit rejection or other major complications. In previous in vitro and animal models there was no indication for an inflammatory response after the use of spider silk. Accordingly, white blood cell count and C-reactive protein as potential surrogate markers for inflammation remained on low levels postoperatively [15, 16]. The increase of CRP on day one is in line with the results of Martinschek et al. on post-aggression metabolism after robotic radical prostatectomy .
Publications on postoperative erectile function after radical prostatectomy provide a wide range of success rates . However, pre-, intra- and postoperative aspects have to be taken into account for an accurate prediction of postoperative sexual function. As the vast majority of these publications are in a retrospective single surgeon/single center study design they might lead to outcomes that are difficult to reproduce in a prospective, randomized multicenter setting. This assumption is underlined by two prospective randomized trials on PDE-5-inhibitors with preoperative potent patients that underwent a bilateral nerve-sparing procedure: less than 30% of the patients presented with an IIEF > 21 after 6 and 13 months . In the multicenter trial by Montorsi et al. less than half of the cohort (preoperative IIEF-5 > 21, bilateral nerve-sparing surgery and postoperative penile rehabilitation) achieved erections hard enough for penetration after 9 months . While the first potency results of our feasibility analysis are promising in this limited number of patients, a potential bias through unilateral nerve-sparing has to be addressed. The further long-term improvement due to the spider silk-directed nerve regeneration and axonal elongation has to be awaited especially in patients after a unilateral wide-excision prostatectomy as the axonal regeneration rate is 1–2 mm/day .
In the last years, a multitude of study groups investigated differing materials for nerve regeneration. With the aim to reduce perioperative neuropraxia, an inflammatory response due to surgical trauma, several membranes emitting growth factors and anti-inflammatory substances were used during nerve-sparing radical prostatectomy. Both the chitosan and the human amnion/chorion membrane allograft showed promising results [3, 21,22,23]. However, these substances can primarily be employed in patients with a successful nerve-sparing procedure to support the regeneration of remaining nerves excluding the group of patients undergoing a non-nerve-sparing prostatectomy. To improve the sexual function in the latter cohort, sural nerve graft interposition for cavernous nerve reconstruction was intensely scrutinized in the first decade of 2000, leading to heterogeneous results. Eventually, a randomized trial by Davis et al. could not confirm a significant improvement of potency two years after retropubic radical prostatectomy with unilateral sural nerve grafting . Anatomical studies of the periprostatic nerves demonstrated a highly complex structure of the neurovascular bundles; therefore, the identification of individual nerves for isolated suturing and interposition of one full-thickness nerve graft seems challenging . These difficulties might be overcome by the use of spider silk conduits: instead of a one-to-one connection of the nerves, the spider silk fibers are loosely attached to the ends of the dissected bundles and can serve as a guidance for Schwann cells  and consequently initiate a directed restoration of the broadly distributed periprostatic erectile nerves . In a sheep model Kornfeld et al. could demonstrate the time course of the structural changes in spider silk implants with detection of many small nerve bundles after 90 days in a six-centimeter defect . In comparison to the autologous nerve graft, this study demonstrated similar results for spider silk for axonal regeneration after a peripheral nerve injury.
This analysis is in line with the IDEAL recommendations for surgical innovations—in stage 1 (Innovation/idea), the purpose is defined as a proof of concept with a single digit patient number and very low number of surgeons. Further steps will follow the IDEAL process with its different stages (Development, Exploration, Assessment and Long-term study . Therefore, some limitations have to be addressed that are in line with stage 1: this feasibility and safety analysis included only a small sample size and an intermediate-term follow-up period. Additionally, the patients had differing grades of resection techniques ranging from unilateral interfascial to bilateral intrafascial nerve-sparing confounding the impact of the grade of nerve preservation and the effects of the spider silk nerve reconstruction . A randomized prospective trial is indispensable to eliminate these uncertainties.
This first-in-men analysis demonstrated a safe use of spider silk nerve reconstruction in robot-assisted radical prostatectomy without intra- or postoperative major complications. A following prospective randomized trial is needed to further reveal a long-term clinical benefit.
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Conflict of interest
The authors have no competing interest to declare that are relevant to the content of this article. Patent filed by Hannover Medical School (Peter M. Vogt and others): DE102005042455A/US8409227B2 “Neural Implant”. Spider silk implant for the treatment of nerve defects. Patent pending (20205219.7–1109, European patent office) by Hannover Medical School (Peter M. Vogt, Sarah Strauß and others): Spider silk–fibrin implant for treatment of traumatic spinal cord injuries.
Data were analyzed retrospectively after internal review board approval (10061_BO_K_2021, Hannover Medical School). Informed consent was obtained from all individuals included in this analysis.
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Harke, N.N., Strauss, S., Peters, I. et al. Spider silk erectile nerve reconstruction in robot-assisted radical prostatectomy: a first-in-men feasibility analysis. World J Urol 41, 1481–1487 (2023). https://doi.org/10.1007/s00345-023-04427-7