Study selection and data acquisition

This nonsystematic literary review was performed in May 2024 using PubMed, EMBASE, Scopus, and Web of Science databases. The search terms utilized were “robotic prostatectomy”, “prostate cancer”, “nerve sparing”, “perinatal tissue”, “allograft”, “potency”, and “continence” alone or in combination. After removal of duplicates, all articles were reviewed and judged for scientific merit by authors RP and JM. Exclusion criteria were non-peer reviewed studies, abstract-only articles, non-English language articles, and studies that did not include either continence or potency outcomes. All studies included in this literature review adhered to ethical guidelines and received appropriate approvals regarding human subject participation.

Pre-clinical evidence of perinatal tissue-derived membrane allografts for nerve protection, repair and regeneration

Despite promising clinical findings, the potential mechanisms underpinning the therapeutic potential of perinatal tissue allografts have yet to be fully elucidated. Preclinical studies may provide initial clues as to the mechanisms by which these allografts may protect and help promote accelerated repair, regeneration and functional recovery of damaged nervous tissue.

To the best of the authors’ knowledge, the earliest and only known pre-clinical study evaluating the use of perinatal tissues to stimulate and support genitourinary nerve repair was reported by Burgers et al. [51] The authors transected a 5 mm segment of the cavernous nerves of sexually active male rats and subsequently anastomosed the gap with interpositional membranes or autologous nerve grafts. Membranes included AM allografts or polymeric membranes with or without nerve growth factor (NGF) [51]. Results demonstrated that rats receiving the AM graft displayed improved sexual behavior compared to both the nerve injury control rats and rats that received polymeric at 2-months post-op [51]. Moreover, the percentage of AM-treated rats that were able to achieve erection was statistically greater than the injury control and comparable to rats treated with polymeric grafts containing NGF [51]. The authors speculated that therapeutic benefit derived from the AM was due to either the release of neurotropic growth factors and/or the laminin-containing ECM that have been shown to support neuron growth [51]. Taken together, this study demonstrated that AM was able to stimulate and support regrowth of injured genitourinary nerves.

Although pre-clinical research focusing on the efficacy of perinatal tissue derived allografts to promote repair and regeneration of the genitourinary nerves is limited, studies evaluating their ability to promote repair of other peripheral nerves are increasing. These investigations point to several potential cellular mechanisms by which perinatal membrane derived allografts may support nerve repair and regeneration. For example, Lui et al. demonstrated that AM supports neuron growth and maturation in vitro [52]. Moreover, the authors demonstrated that wrapping AM around injured sciatic nerves prevented the formation of adhesions, reduced pro-inflammatory messenger RNA (mRNA) expression in local cells, and promoted a pro-regenerative / anti-inflammatory phenotype in local macrophages [52]. The authors also noted that the AM treated nerves had more dense and evenly distributed axons concomitant with increased presence of proliferating Schwann cells compared to injured controls [52]. Similarly, Mohammed et al. and Milgiliche et al. demonstrated the neuro-regenerative effects of perinatal tissue allografts using in vivo pre-clinical peripheral nerve injury models [53, 54]. Wolfe et al. demonstrated that wrapping repaired peripheral nerves with AM had fewer adhesions, significantly less perineural fibrosis, and improved nerve function at earlier time-points compared to injured controls and nerves wrapped with collagen [55]. Lemke et al. illustrated that the use of AM allografts as a nerve wrap decreased the occurrence of fibrosis and adhesions, while suppressing local tissue inflammation compared to untreated controls in a rat sciatic nerve perineural fibrosis model [56]. Furthermore, use of AM allografts decreased the occurrence of demyelination and hastened nerve recovery and regeneration [56]. Reduced fibrosis of peripheral nerves treated with perinatal membrane allografts have also been observed in other peripheral nerve transection models [57].

Taken together, these preclinical studies suggest that perinatal tissue allografts may possess physical and biological characteristics that can protect and support healing and regeneration of injured nerves and hasten return of nerve function and health. This may be due to both the neurotrophic growth factors and anti-inflammatory cytokines contained within them [58, 59]. Additionally, the allografts can serve as protective barriers to adhesions and thus may protect against tissue tethers which may impart traction injuries on the nerve bundles.

Clinical evidence of perinatal tissue allograft efficacy as an adjunct to RARP

Since 2015, eight clinical studies have been published demonstrating the efficacy of perinatal tissue allografts in radical prostatectomy treatments (Table 1) [60].

Table 1 Summary of eight published studies examining the use of perinatal tissue allografts in radical prostatectomy

One of the first clinical series using dehydrated human amnion-chorion membrane (dHACM) as a protective wrap around the NVB during nerve sparing RARP was reported by Patel et al. [61] In this observational, retrospective, propensity score matched analysis, two patient groups (n = 58/group) were matched for age, body mass index (BMI), hypertension, diabetes, smoking history, Sexual Health Inventory for Men (SHIM) scores, PSA levels, Gleason scores, pre-operative American Urological Association symptom (AUA) scores, and D’Amico classifications. Group 1 patients received the dHACM graft wrapped around the NVB and group 2 served as controls. Post-operative potency was defined as the ability to maintain an erection with or without the use of Phosphodiesterase-5 (PDE-5) inhibitors while continence was defined as the use of zero safety pads per day. All patients completed a minimum follow-up period of 8-weeks. Results indicated that the mean time to continence was significantly shorter for group 1 (1.21 months) compared to group 2 (1.83 months; p = 0.033) [61]. Additionally, the mean time to potency was significantly shorter in group 1 (1.34 months) compared to group 2 (3.39 months; p = 0.007). [61]

Krol et al. presented a case study of a 67-year-old male who underwent a bilateral, nerve sparing RARP with NVBs allograft wrapping prior to posterior reconstruction [62]. This case study utilized dehydrated umbilical cord tissue, the only example of use of this material type in the literature. At 1 month postoperatively, the patient reported minimal stress urinary incontinence and the ability to achieve erections with 75% rigidity. At 1.5 months after surgery, the patient reported further improvements in continence and erections with 100% rigidity. The authors highlighted that patients who received tissue allografts had a faster time to recovery of continence and potency compared to the reported historical averages of 2.66 and 7.72 months, respectively. [62]

Razdan et al. performed a retrospective matched longitudinal cohort analysis of 1400 patients who underwent bilateral nerve sparing RARP to determine the impact of wrapping the CNVs with dehydrated AM allografts on early return to sexual potency [63]. Patients in the intervention (AM; n = 700) and control (no AM; n = 700) groups were matched for age, BMI, AUA score, PSA, clinical stage, baseline sexual function, Charlson comorbidity index and nerve sparing status. Study results indicated that patients receiving AM allografts demonstrated an earlier return to potency compared to controls (60.85 ± 61.2. days vs. 95.53 ± 76.2 days). Additionally, the number of patients achieving potency every month was significantly higher in the AM group compared to controls, and by the end of the 1-year follow-up, significantly higher potency rates were observed in the AM group compared to controls (93.1% vs. 87.1%) [63]. Time to potency recovery was also significantly less in the AM group.

Ahmed et al. conducted a retrospective review of 200 patients who received bilateral, nerve sparing RARP [64]. The patients were split into two matched groups of statistically similar preoperative characteristics including BMI, age, comorbidities, smoking history, Gleason scores, and clinical stages. Out of these patients, 100 were treated with a cryopreserved UC allograft wrapped around the neurovascular bundles to assess acceleration of continence recovery rates. Post-operatively, all patients were assessed for continence based upon pad usage (0 or 1 safety pads per day) at 3, 6, 9, and 12 months postoperatively. Results indicated that the use of the allografts hastened return of continence at each time point compared to those who did not receive allografts at 1 month (65% vs. 44%; p = 0.018), 3 months (83% vs. 70%; p = 0.03), and at 12 months (97% vs. 87%; p = 0.009) [57]. When continence was defined as 0 pad usage, the percentage of patients exhibiting continence was statistically greater in the UC allograft group compared to controls at all time-points investigated (1 month: 55% vs. 30%; p = 0.003, 3 months: 68% vs. 52%; p = 0.021, 6 months: 84% vs. 64%; p = 0.001, 12 months (90% vs. 80%; p = 0.048). [64]

A controlled, matched propensity score analysis performed by Ogaya-Pinies et al. assessed expedited recoveries of potency by using dehydrated amnion/chorion membrane graft (dHACM) as a wrap around the neurovascular bundles after bilateral nerve sparing RARP procedures [65]. The study also examined the impact of using the dHACM on patients undergoing partial nerve sparing procedures. Study groups included 235 patients who received dHACM during their prostatectomy (group 1) and 705 patients controls (group 2). Overall, the mean time to potency was significantly shorter for group 1 (2.37 months) compared to group 2 (3.94 month; p < 0.001). The potency recovery rates with respect to time for group 1 versus group 2, respectively were as follows: 37% vs. 26.2% (p < 0.001) at 1 month, 65.1% vs. 57.8% (p < 0.001) at 3 months, 73.6% vs. 67.4% (p < 0.001) at 6 months, 77.9% vs. 72.9% (p < 0.001) at 9 months, and 80.4% vs. 78.7% (p < 0.001) at 12 months. In regard to potency outcomes by degree of nerve sparing, the investigators found that the time to potency was significantly shorter in patients receiving dHACM after full nerve sparing procedures (2.19 months) as compared to patients with full nerve sparing without dHACM (2.78 months; p = 0.029). Similarly, time to potency was significantly shorter in patients receiving dHACM after partial nerve sparing procedures (3.05 months) as compared to patients with partial nerve sparing without dHACM (3.92 months; p = 0.021). [65]

Elliot et al. performed a retrospective analysis evaluating the use of AM or UC tissue allografts (n = 162) placed intra-operatively over the bilateral NVBs versus controls that did not receive grafts (n = 181) [4]. Results demonstrated a statistically significant (p = 0.01) earlier return to continence in patients who received cryopreserved AM grafts (A1: 1.41 months) or cryopreserved UC grafts (A2: 1.45 months) versus controls (C: 1.64 months) [4]. The proportion of patients exhibiting continence for those receiving cryopreserved AM or UC grafts compared to controls were as follows: 1 month (A1: 81.2%, A2: 76.6%, C: 61.8%), 6 months (A1: 91.0%, A2: 84.3%, C: 79.7%), 9 months (A1: 94.6%, A2: 84.3%, C: 87.5%) and 12 months (A1: 98.2%, A2: 89.5%, C: 91.0%), respectively.

More recently, Noel et al. measured the medium-term functional outcomes in patients undergoing nerve sparing RALP treated with intra-operative dHACM allograft placement [29]. Five hundred twenty-nine patients were included in the study and underwent either partial bilateral nerve sparing (n = 138) or full bilateral nerve sparing (n = 391) RALP. Functionally, 82% of patients were sexually active following the procedure, defined by the ability to maintain erections for penetrative intercourse, and 96% regained continence, which was defined by zero pad usage. The median time to potency was 119 days, while the median time to continence was 42 days. When age was compared, patients ≤ 55 years old showed a median time to potency of 80 days vs. patients > 55 years old with 167 days (p = 0.005). Partial vs. full nerve sparing procedures were also compared, in which median time to potency for full nerve sparing patients was 92 days vs. 184 days in partial nerve sparing (p = 0.03) [29].

Finally, Barski et al. performed a proof of concept study exploring early functional outcomes in 14 patients undergoing open, nerve sparing radical prostatectomy that had both methylene blue and dHACM applied [66]. Methylene blue, a tinctorial dye and antioxidant [67, 68], was used to visualize the prostatic neuro-vascular plexus while amnion was placed around the nerves as well as at the dorsal portion of the vesico-urethral anastomosis. Results demonstrated that 40%, 70%, and 80% of patients recovered continence (defined as no pad) at 3 weeks, 3 months, and 12 months post-op, respectively. [66] The investigators also reported improved vesico-urethral anastomotic healing as indicated by no signs of scarring and the beginning of epithelialization in the urothelial mucosa as compared to controls evaluated with postoperative cystoscopy [66].

Taken together, the aforementioned clinical investigations indicate that the use of perinatal allografts as wraps around the NVB during RARP may quicken return to potency and continence in patients with localized PCa.

Discussion / Synthesis

Prostatectomy continues to be a mainstay of treatment for intermediate to high-risk prostate cancer and, despite the past several decades of advancements in surgical technique, there continues to be significant post-operative incontinence and erectile dysfunction morbidity [69]. Animal models and other pre-clinical studies have repeatedly elucidated how AM allografts support neurologic healing, diminish inflammation, and reduce fibrosis, although the exact mechanisms are not yet fully understood. The clinical studies reviewed in this article repeatedly demonstrate not only a statistically significant reduction in time-to-return for continence and potency, but also a clinically significant reduction time-to-return of several weeks to several months for both continence and potency.

As AM allografts continue to be used in more patients, the question emerges as to which pre-operative patient factors result in the most improved post-surgical outcomes. The studies reviewed here differ in their inclusion criteria. Several studies restricted the treated population to older patients, patients with pre-operative erectile and continence function close to normal, or patients with bilateral nerve sparing surgery, whereas others did not limit the treated population in such ways. In the context of this limitation, the data was mixed concerning which patient factors were associated with the most functional improvement. The studies generally concluded that using the allograft in bilateral nerve sparing offered the most improvement compared to unilateral nerve sparing. However, with regards to age, Ahmed et al. (UC allograft) found that patients > 60 had the most improvement with the allograft [64], however Razden et al. and Noel et al. (both dHACM allograft) found that younger patients benefitted the most from the graft [29, 63]. There was no consensus if patients with better pre-operative erectile and continence function who received the allograft had improved post-operative outcomes.

The studies included in this review differed in the type of allograft utilized. dHACM has been commercially available the longest and thus has been the most studied, but Ahmed et al. and Krol et al. used either cryopreserved or dehydrated UC allografts, respectively. [62, 64] However, new perinatal tissue allografts continue to become available, including a multi-layer, minimally processed graft that includes the intermediate layer in addition to the amnion and chorion, which has not yet been clinically studied [70].

The influence of AM allograft placement on biochemical recurrence (BCR) of PCa is a consequential question, especially in the time since Alvim et al. found faster relapse in prostate tumor cell models treated with AM allografts compared to control [71]. Overall, clinical studies of AM allografts have shown similar-to-lower rates of BCR in AM or UC treated groups compared to control [4, 29, 63, 72]. Thus, although there are in-vitro concerns that perinatal tissue allograft use could increase prostate cancer recurrence rates, this has not been substantiated by any in-vivo studies. However, as an emerging field, further study into the influence of perinatal tissue allograft use on BCR rates is warranted.

The studies presented in this review collectively have significant limitations. Most notably, several different allograft materials are represented in these studies, including dHACM, dehydrated UC, cryopreserved UC, and dehydrated amnion. Thus, although all of these materials are classified as perinatal tissue allografts, the significant heterogeneity in specific allograft type limits the generalizability of the outcomes. We theorize that as the perinatal allograft technology progresses, allograft material and preparation will begin to standardize across the industry. All the studies in this review are retrospective; some studies use propensity score matched analyses or retrospective matched longitudinal cohort analysis to improve study validity, but none of the studies resemble a randomized, controlled trial. Additionally, follow-up times are between 1 to 3.5 years, which is viable to study functional outcomes but much too short to make robust conclusions for oncologic outcomes. Furthermore, none of the literature examined surgeon nerve sparing RARP experience as a confounder of functional outcomes; we postulate that patients with experienced and adept surgeons would benefit less from allograft placement compared to patients of less-experienced nerve sparing surgeons, although this is merely a hypothesis. To date, no vigorous cost–benefit analysis of AM allografts has been conducted, although there is significant potential for cost-savings if allograft use can reduce post-prostatectomy treatment for erectile dysfunction and incontinence. Although the allografts discussed in this review were provided free-of-charge for investigational purposes, similar materials used commercially in wound healing cost $900-$2700 per graft. Since the emerging field of AM allograft placement in prostatectomy still lacks prospective, randomized controlled studies, this represents a noteworthy avenue for further study.