Sensory reinnervation of reconstructed breasts—a narrative review of deep inferior epigastric perforator flap and nipple-areola complex neurotization

Introduction

Background

In 2020, breast cancer became the most diagnosed cancer in the world, with the incidence of breast cancer in the United States expected to reach 364,000 by the year 2040 (1). The rate of breast reconstruction after mastectomy has been increasing over the years, and in 2016, more than 40% of people who underwent mastectomy in the United States opted for reconstruction (2). Reconstructive options following mastectomy include autologous or implant-based (3). Mastectomies typically involve transection of the sensory nerves that innervate the native breast tissue, leading to decreased breast sensation after reconstruction (4). This can be an unexpected outcome to patients and is often undesirable (5).

Rationale and knowledge gap

Due to the variability in spontaneous sensory recovery, reconstructed breasts can be prone to thermal and other injuries (6,7). This variability in spontaneous regeneration and has led to research on ways to restore innervation to the breast through neurotization of autologous flaps since the 1990s, with inconsistent results (8). Autologous breast reconstruction provides great long-term results with a more natural feel and appearance (9,10). Abdominal flaps, such as the deep inferior epigastric perforator (DIEP) flap, are generally preferred in autologous reconstruction because they provide excellent long-lasting aesthetic results and are well-tolerated (9,11). DIEP flaps have become the focus of surgical reinnervation techniques in autologous breast reconstruction. In addition to the reinnervation of the DIEP flap at the time of reconstruction, reinnervation of the nipple-areolar complex (NAC) has also recently gained attention. The nipple is a sensate unit in erectile function, and nipple sensation is important for women’s psychological and sexual health (12). Although several reviews have been published exploring the efficacy of DIEP neurotization and targeted nipple reinnervation (TNR) (13-15), to our knowledge, there have been no reviews that specifically synthesize the results of clinical studies that include noninnervated control groups to-date. There is a great heterogeneity in the reporting of outcomes following breast neurotization (14,15); therefore, there remains a need to focus on specific, more objective outcome measures. Therefore, we chose to focus on studies that utilized Semmes-Weinstein filaments and pressure-specified sensory devices (PSSDs) to better understand the impact of breast neurotization. Because donor intercostal nerves (ICNs) are transected to provide regenerating axons into the DIEP flap or NAC, the additional of regeneration enhancing adjuncts would be feasible to improve axon regeneration and potentially further improve sensory outcomes in patients. These options have also not been detailed in previously published articles.

Objectives

The purpose of this review is to provide an overview reinnervation of reconstructed breasts, specifically reinnervation of the DIEP flap in autologous reconstruction and TNR in the context of both autologous and implant-based reconstruction with a focus on how reinnervated breasts compare to noninnervated breasts. This review also delves into patient-reported outcomes, acknowledges the strength of spontaneous regeneration, and discusses the future potential usage of electrical stimulation to further enhance outcomes of neurotization procedures.

Relevant anatomy and background

The breast is innervated by the anterior and lateral cutaneous nerves of the 2^nd through 6^th ICNs and supraclavicular nerves (16-18). ICNs run along the inferior borders of the ribs and give off lateral branches that supply the lateral trunk and anterior branches that supply the medial chest. The NAC is mainly innervated by the anterior and lateral cutaneous branches of the 4^th ICN with varying contributions from the 3^rd and 5^th cutaneous ICNs (18).

The abdominal wall is innervated by nerve roots T10-L1, which travel between the transversus abdominis and internal oblique muscles before entering the rectus sheath and forming a plexus with the deep inferior epigastric artery (DIEA). Sensory nerve branches travel alongside the DIEA perforators (19-21).

Neurotization of the DIEP flap

Neurotization of an autologous abdominal flap after mastectomy was initially described by Slezak et al. in 1992 (22). This was performed by isolating a 4–6 cm segment of the transverse rectus abdominus muscle (TRAM) flap abdominal ICN bundle prior to direct coaptation to the anterior ramus of the lateral cutaneous branch of the 4^th ICN.

In 2009 and 2013, Spiegel et al. described the use of the anterior branch of the 3^rd ICN near the sternum rather than the lateral cutaneous branch of the 4^th ICN to innervate the DIEP flap (23-25) (Figure 1). This modification involves dissecting through the pectoralis major muscle to isolate the 3^rd ICN, which is neurotized to the T11 thoracoabdominal nerve associated with the DIEP flap. Using the 3^rd anterior cutaneous ICN improves surgical efficiency and flap mobility due to easier accessibility of this nerve. Additionally, this facilitates flap inset when using internal mammary vessels, limits traction, and minimizes the possible nerve gap. Although the ideal scenario is the direct coaptation of the ICN donor nerve to the thoracoabdominal nerve associated with the DIEP flap, nerve conduits and nerve allografts have also been reported to relieve tension on the coaptation site (23,26-28).

Figure 1 Deep inferior epigastric perforator flap neurotization to the 3^rd anterior intercostal nerve. Figure adapted from Spiegel et al., 2013 and Ducic et al., 2018 (23,26). DIEP, deep inferior epigastric perforator.

TNR

In nipple-sparing mastectomies (NSMs), TNR can be performed to improve the recovery of NAC sensation. The direct coaptation approach involves dissecting and preserving the nerves of the 3^rd through 5^th ICNs, and if these branches are long enough, then these sensory branches are then directly sutured to the dermatosensory components of the NAC with no tension (29,30).

Due to the distance between the NAC and the lateral ICN after breast reconstruction, the use of nerve allografts and autografts has also been described to decrease tension to the NAC (29,31-33). The autografts are typically harvested from the 3^rd, 4^th and 5^th lateral ICNs (32). With autologous tissue breast reconstruction, the nerve graft can be tunneled through the flap to reach the base of the NAC (Figure 2) (34). With implant-based reconstruction, the nerve graft courses along the surface of the implant to the base of the NAC (Figure 3) (35).

Figure 2 Targeted nipple reinnervation with autologous breast reconstruction. Figure adapted from Tevlin et al., 2021 (34).

Figure 3 Targeted nipple reinnervation with implant-based reconstruction. Figure adapted from Gfrerer et al., 2022 (35).

When 2–3 lateral ICN branches are similar in length but too short to reach to the NAC, to maximize possible reinnervation, all branches can be combined distally to coapt to the graft in an end-to-end fashion (29). If the branches cannot be combined, the proximal end of the graft can be split into fascicles to coapt to each nerve end-to-end. Should the length discrepancy be more significant, the shorter nerve can be connected to the longer nerve in an end-to-side fashion. These are all methods to increase the probability of successful sensory reinnervation. Although a distal neural target has been described on the underside of the NAC (31), sometimes this cannot be visualized (29,35). Transected nerve ends have been demonstrated to innervate the dermis without coaptation to a distal nerve stump in animal models (36), and the distal end of the nerve graft can be split into its fascicles to suture to the underside of the NAC to increase the reinnervation zone (29,35).

Methods

Due to the large heterogeneity in the outcomes and follow-up times of the studies reporting on breast reinnervation, a narrative review was chosen to encompass the wide range of data on this topic while offering the opportunity to incorporate discussions on patient-reported outcomes and spontaneous regeneration. In June, July, and November of 2024, the search queries <intercostal reinnervation “DIEP flap” breast reconstruction> and <“targeted nipple” reinnervation> were used to identify articles available on Google Scholar on DIEP reinnervation and TNR. This narrative review encompasses articles published in English up until November 2024. Published review articles were also evaluated to assess current perspectives on this topic. Only studies that used Semmes-Weinstein filaments, PSSDs, and the BREAST-Q were included in this review. Studies without a control group were excluded except for those that reported on PSSD values post-TNR. Because the focus of this review is on breast reconstruction, articles that evaluated the efficacy of TNR in the context of gender-affirming mastectomy without breast reconstruction were excluded. To provide a counterpoint for neurotization, articles that specifically investigated the return of spontaneous sensation after breast reconstruction were also reviewed. The literature methods are outlined in Table 1.

To create a compiled heatmap detailing the overall sensation of reinnervated breasts in the articles that reported Semmes-Weinstein filament data after DIEP reinnervation, all the reported final filament average values were first converted to a scale of 0–100 because one study reported their data as grades 1–6 while others reported the filament thickness. Once these values between 0–100 were derived, a weighted average was found for each of the 9 breast zones based on the number of control (noninnervated) and innervated breasts in each study. Heatmaps of the average noninnervated breast and average reinnervated breast were then generated based on these weighted averages. We present this article in accordance with the Narrative Review reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-25-10/rc).

Outcomes

Reinnervation of the DIEP flap

Several comparative cohort studies have been conducted to assess the efficacy of flap neurotization, specifically the DIEP flap, in breast reconstruction (23,37,38). Although outcome measures varied, Semmes-Weinstein filaments and PSSDs were two common ways to assay the return of sensation (Table 2).

Sensation of the DIEP flap evaluated by Semmes-Weinstein filaments

Blondeel et al. described one of the first comparative studies on the neurotization of abdominal perforator flaps in 1999 and found that the sensory recovery of the DIEP flap was better when it was neurotized to the 4^th ICN (39). In addition to resulting in lower pressure thresholds when measured with Semmes-Weinstein filaments, neurotization restored at minimum protective sensation over the entire surface of the breast in the majority of the flaps (75%, compared to 31% of noninnervated DIEP flaps) with “remarkably high” return of erogenous sensation. Furthermore, innervated DIEP flaps exhibited significantly lower pressure thresholds compared to noninnervated TRAM flaps in all tested zones.

In 2019, Beugels et al. (38) conducted a prospective study utilizing a novel surgical approach first described by Spiegel et al.: coaptation of the DIEP flap to the anterior cutaneous branch of the 3^rd ICN rather than the lateral cutaneous branch of the 4^th ICN (23,24,38). This study compared innervated and noninnervated flaps and used sensory testing with Semmes-Weinstein filaments of the native breast skin, the flap skin, and the nipple area (or where the nipple should have been after reconstruction) by a blinded examiner (38). They found that the rate of sensory recovery was greater in the innervated group compared to the noninnervated group. Although neither group recovered to normal thresholds, the sensory recovery of innervated flaps was superior to that of noninnervated flaps, achieving sensation within the range of “diminished protective sensation” to “diminished light touch” (42). On the other hand, sensory recovery of noninnervated flaps remained in the range of “loss of protective sensation” (39,42). Intriguingly, the native skin also exhibited a lower sensation threshold when the DIEP flap was reinnervated, a finding that the authors attributed to sprouting. Overall, regardless of the timing of the reconstruction, the sensation of both native and flap skin recovered significantly better with innervation (38).

Beugels et al. followed up this study in 2021 with a second prospective cohort study using the same surgical technique and testing with Semmes-Weinstein filaments to further evaluate factors associated with sensory recovery (37). This study found that increased age, neoadjuvant or adjuvant chemotherapy, and higher flap weight were associated with worsened sensory recovery. Similarly to the previous study, most patients did not recover to normal sensation thresholds within the follow-up period of the study. Despite the evidence of spontaneous sensory reinnervation in the noninnervated group, nerve coaptation still resulted in superior sensory recovery in all areas when immediate breast reconstruction was performed and in only the flap skin when delayed breast reconstruction was performed.

In 2020, Bijkerk et al. evaluated sensory recovery in 15 patients who underwent bilateral autologous breast reconstruction with the DIEP flap but only unilateral neurotization. Although the intention was to perform bilateral sensory nerve coaptation, flap orientation, amongst other surgical factors, was a limiting component (40). Sensation in the innervated breasts at the maximum follow-up time had reached near normal levels in both native skin and flap skin with monofilament values lower in the innervated breasts in all areas compared to noninnervated breasts. The length of follow-up in months was also significantly associated with lower monofilament values for both groups, indicating the presence of spontaneous sensory recovery; however, innervated flaps exhibited a greater improvement in sensation per month compared to noninnervated flaps.

Bubberman et al. published the preliminary results of a double-blind randomized controlled trial in 2024 (41). This study included immediate and delayed mastectomies. Sensation was evaluated with Semmes-Weinstein filaments, the PSSD, and the PATHWAY Model (to determine thermal thresholds, which showed no clear pattern between the groups). In terms of sensation evaluated by the Semmes-Weinstein filaments, thresholds were lower in most areas of innervated breasts at 24 months compared to non-innervated breasts, exhibiting significant differences in central zones of the flap. The overall sensation was also better in innervated flaps with the difference increasing over time.

Sensation of the DIEP flap evaluated by pressure devices

In 2013, Spiegel et al. used the PSSD to test sensory recovery of innervated and noninnervated DIEP flaps (23). DIEP flaps that were neurotized were either coapted directly to the 3^rd anterior ICN or with a nerve conduit. In this study, neurotization via a nerve conduit resulted in better sensory recovery of the reconstructed breast compared to direct coaptation. In fact, there was no difference observed in the sensation of the flap nor the surrounding native skin between the direct coaptation group and the non-innervated group.

The 2024 preliminary results from Bubberman et al.’s randomized controlled trial also included the PSSD to test sensory recovery (41). Similarly to their findings with the Semmes-Weinstein filaments, sensation was better in innervated flaps, with the greatest difference between innervated and noninnervated flaps being exhibited in the center of the flaps. This result was recapitulated with static and dynamic touch thresholds at 24-months after reconstruction, with more noninnervated flaps being unable to feel static touch and dynamic touch compared to innervated flaps.

Limitations

Although the studies included in this review all include a noninnervated control group, there are still several limitations and considerations for the interpretation of their results. Blondeel et al. had translated their Semmes-Weinstein filament values to a 6-point grading scale, which makes their results more difficult to compare to studies that reported raw filament values (39). Both studies conducted by Beugels et al. included nonconsecutive patients, which could be a source of selection bias (37,38). The selection of control and experimental groups in Bijkerk et al.’s study was based on unsuccessful bilateral nerve coaptations, though the use of internal controls in this case may actually be a strength of their study. Spiegel et al.’s study included inconsistent surgical methods and utilized testing zones that differ from those published in more recent papers, making their results more difficult to interpret and compare with other studies. Overall, most of the currently published studies that include a control noninnervated group for DIEP neurotization come from the same research group (4 out of 6), and there is considerable variation in the maximum follow-up times across studies. These limitations are summarized in Table 2.

Reinnervation of the NAC

Similar to sensation testing of the DIEP flap, sensation of the NAC has also been tested with Semmes-Weinstein filaments and with the PSSD in clinical studies that included a non-innervated control group (Table 3) (30,32,33,43). Notably, TNR often requires the use of a nerve allograft or autograft to bridge the gap between the NAC and the lateral 4^th ICN with the graft length ranging from 3.5–7 cm although direct neurotization to the posterior tissue of the NAC has also been reported (30,32,33,43). The maximum allograft length through which nerve regeneration is reliable is 7 cm (44-46), which also limits the size of the implant, should implant-based reconstruction be performed. The total nerve length needed for an implant-based reconstruction can be estimated based on the projection and diameter of the desired implant (44).

Sensation of the NAC evaluated by Semmes-Weinstein filaments

In 2021, Deptula and Nguyen found there to be superior sensation of the nipple and areola with TNR after immediate autologous reconstruction compared to control in a retrospectively identified cohort tested more than 8 months postoperatively with Semmes-Weinstein filaments (43). TNR did not affect the sensation of the peripheral skin compared to the noninnervated controls. One to two nerves from the 3^rd–5^th lateral ICNs were coapted to an appropriately-sized nerve autograft or allograft to reach the NAC nerve stump, if identified, or dermal surface.

In a 2024 randomized controlled trial, Juan et al. found superior sensation of the NAC and peripheral breast skin via filament testing at 3 months and 6 months post-subpectoral prosthetic breast reconstruction when TNR was performed at the time of surgical reconstruction (30). At 10 days post-reconstruction, superior sensation was already observed at the nipple in the TNR group compared to the control group. An appropriately-sized ICN was selected from the 2^nd–4^th lateral ICNs to anastomose directly to the NAC, or, if the length was deemed insufficient, a side branch was used as an autograft to bridge the gap to the NAC.

Sensation of the NAC evaluated by pressure devices

With pressure device testing, there are currently no clinical studies that include a robust control group. Djohan et al. conducted a prospective cohort study in 2020 utilizing TNR during implant-based reconstruction (33). The anterior branch of the lateral 4^th ICN was used to perform the TNR with a 7 cm allograft. Only 2 patients underwent unilateral neurotization and bilateral reconstruction, and superior sensation was found in most areas of the breast when TNR was performed except for the medial and lower quadrants.

In 2023, Peled et al. also conducted a prospective cohort study in the context of implant-based reconstruction with no control group and found that at 6 months postoperatively, 80% of the patients had good to excellent 1-point moving and 1-point static sensibility scores (32). Direct coaptation, allograft, or intercostal autograft was utilized to connect the transected 3^rd, 4^th, or 5^th lateral ICN to the posterior NAC tissue. At their most recent follow-up visit, no patients in this study experienced chronic post-mastectomy pain (32), which has a typical reported incidence of 20-60% (47-49).

Limitations

In general, the studies included in this review that focus on TNR have a relatively short follow-up period, especially compared to the evaluations of DIEP neurotization. Deptula et al. do not report a mean follow-up period, opting to report that sensation was evaluated more than 8 months postoperatively (43), and the other studies reveal a mean follow-up period that ranges from 6 to 9.2 months. With PSSD evaluation, there are currently no studies with a robust control group, which limits the interpretation of the results (32,33). The method of neurotization also varies between the studies, with some TNR being performed with direct coaptation or with varying lengths of the nerve graft. Autografts and allografts would likely result in different sensory recovery. The incision pattern for the NSM is not consistently reported in these studies, with only Juan et al. reporting that they used a radial incision (30). The incision patterns could also result in bias when comparing different studies and may also affect sensory recovery.

Patient-reported outcomes following breast reconstruction and neurotization

Although sensory assays have shown promising results in the context of neurotization after breast reconstruction, how patients view their outcomes following the procedure plays a significant role in deciding if neurotization should become a more common clinical practice.

When surveyed using the BREAST-Q in a prospective cohort study, patients who underwent neurotization of the DIEP flap scored higher in the physical well-being of the chest domain, with the differences between the innervated and noninnervated groups increasing over time (50). This effect was more apparent in patients who received delayed breast reconstruction after mastectomy and was considered to be clinically-relevant (51); however, the differences in the BREAST-Q scores never reached statistical significance (P<0.05).

In addition to the BREAST-Q, sensation-related questions were also administered. A higher percentage of patients with sensate breast reconstruction reported that the sensation of their reconstructed breast felt similar to a normal breast (16.9% vs. 3.6%, P=0.019) and perceived as part of their body (70.8% vs. 52.7%, P=0.067), improved with time (67.7% vs. 41.8%, P=0.002), and was pleasant (29.2% vs. 14.5%, P=0.065) (50). This study effectively demonstrated the positive relationship between sensory recovery and quality of life, which can be facilitated by sensory nerve coaptation of the DIEP flap. The effects reported in this study were greatest in patients who underwent delayed breast reconstruction and were not as pronounced in patients who underwent immediate breast reconstruction.

A retrospective cohort study utilizing the BREAST-Q similarly found that patients who underwent innervation of the autologous reconstructed breast reported higher scores in the physical well-being of the chest domain (52). This study also found a significant correlation between sensation and physical well-being of the chest domain of the BREAST-Q, also demonstrating the link between breast sensation and quality of life. Furthermore, five patients underwent unilateral neurotization and bilateral reconstruction, and these patients reported that the innervated breast felt “less numb” and “more like their own” compared to the noninnervated breast.

These studies outlining patient-reported outcomes demonstrate that neurotization of the DIEP flap at the time of breast reconstruction not only improves sensory recovery, but also improves the quality of life of patients.

Limitations

The clinical usefulness and interpretation of the BREAST-Q is dependent on reference values and estimated minimal important differences (53). Additionally, the appropriate administration of the BREAST-Q can affect results as Gallo et al. reported 19.5% of studies included errors in BREAST-Q administration, and 34.1% of studies had insufficient reporting of the mode of BREAST-Q administration (54). More studies are needed to establish values that constitute a relevant clinical difference for patients and to establish healthy control scores (55). Because of these limitations and inconsistencies in the administration of the BREAST-Q, the results from BREAST-Q studies should be handled critically with special consideration of whether the conclusions represent clinically-relevant differences in patient outcomes.

Spontaneous sensory regeneration

After injury, peripheral nerves do spontaneously regenerate (56-59), and sensation does spontaneously return to DIEP flaps used in breast reconstruction (60); however, this return of sensation is usually unpredictable and mostly partial (39). One study found that the inferior lateral quadrant of the breast exhibited the most sensory recovery while the superior medial quadrant exhibited the least, whereas another study found improved sensory recovery in the superior zone of the breast but found no recovery in other zones (23,60).

Shaw et al. reported that the majority of patients regained touch, pressure, pain, heat, cold, and high- and low-frequency vibration sensations approximately 2 years postoperatively with spontaneous regeneration alone (61). Furthermore, almost all patients in this study considered their chest to be comfortable to touch following reconstruction and rated their reconstructions an average of 9.3 on a scale of 1 to 10. Therefore, Shaw et al. concluded that spontaneous return of sensation following autologous tissue breast reconstruction is sufficient for patient satisfaction. These conclusions were supported by Santanelli et al. in 2011, who found that there was acceptable spontaneous sensory recovery 6 and 12 months postoperatively that improved over time; therefore, they concluded that nerve coaptation is not necessary in immediate reconstruction. They further postulated that nerve coaptation may only be indicated in cases of delayed breast reconstruction due to less robust natural regenerative processes (60).

Several studies that neurotized the DIEP also found evidence of spontaneous sensory regeneration, but neurotization resulted in superior sensory outcomes (23,37,40). Spiegel et al., notably, did not find a difference between non-innervated flaps and flaps that received direct coaptation; however, the use of a nerve conduit improved breast sensation (23). When non-innervated breasts are directly compared to innervated breasts, the sensory outcomes achieved by spontaneous regeneration (control noninnervated group), in most studies, were inferior when compared to those achieved by flap neurotization.

Future directions: enhancing regeneration of donor nerves

The use of the ICNs to provide sensory innervation to the DIEP and the NAC after reconstruction involves a planned, intentional injury to these nerves. The innate regeneration of peripheral nerves is often slow and inadequate, although placing the regenerating nerves closer to their targets through nerve transfer, as these reinnervation procedures describe, facilitates improved clinical outcomes (62,63). However, further interventions can be applied to enhance peripheral nerve regeneration.

A conditioning lesion is a well-established experimental paradigm that involves injuring a nerve (conditioning lesion) prior to another injury (test lesion) to enhance nerve regeneration (64-70). Because the conditioning lesion is rarely applicable in the clinical setting due to the need for an intentional nerve injury, conditioning electrical stimulation (CES) has emerged as a viable non-injurious option for enhancing the regeneration of peripheral nerves (71-75). One-hour of 20 Hz electrical stimulation at the time of surgical repair, known as postoperative or perioperative electrical stimulation (PES), was first established in the rat sciatic nerve injury model and has been shown to induce comparable pro-regenerative pathways as the conditioning lesion without the need for a prior nerve injury (76-80). PES has also been shown to be effective in clinical nerve injury conditions, such as carpal tunnel syndrome and cubital tunnel syndrome (81,82).

CES involves the use of the established 1-hour 20 Hz electrical stimulation paradigm prior to a planned nerve injury, effectively conditioning the nerve in a non-injurious manner, to enhance regeneration (75). CES has been shown to effectively enhance the regeneration of motor and sensory axons in rats. Furthermore, in these studies, CES was more effective than PES alone as well as CES and PES combined (73).

On the other hand, CES fails to enhance the regeneration of postganglionic sympathetic axons, which are unmyelinated C-fibers, even showing some inhibition at an acute timepoint (83). This concern may not be relevant in this setting, due to sensation being the primary clinical outcome. However, nipple erogenous sensation is thought to be governed by unmyelinated low threshold C-type mechanoreceptors (C-LTMRs) (84,85), which signal the presence of pleasant light touch and erotic stimuli (86,87). Additionally, C-LTMRs express tyrosine hydroxylase (88,89), the rate-limiting enzyme in the synthesis of norepinephrine (90,91), which is the main neurotransmitter of postganglionic sympathetic neurons. Therefore, C-LTMRs and postganglionic sympathetic axons are not only morphologically similar, but also histologically similar. The effects of electrical stimulation on C-LTMRs have not been investigated, so how CES affects erogenous sensation is currently unknown.

Based on the results of previous studies showing the efficacy of CES at enhancing motor and sensory regeneration (71-75), the use of percutaneous CES in the outpatient setting prior to the planned transection of the ICNs for breast reinnervation may further improve clinical and psychosocial outcomes. PES may also be implemented to enhance nerve regeneration. After coaptation of the donor and recipient nerves, an electrode can be placed proximal to the nerve anastomosis followed by standard skin closure and dressing procedures. A signal generator, such as PeriPulse™ manufactured by Epineuron Technologies Inc., can be connected to the electrode lead, and 1 hour of PES can be delivered in the recovery area, titrated to patient comfort (92). The electrode lead can then be removed after the conclusion of 1-hour PES.

Discussion

Distribution of sensory return after DIEP reinnervation

Overall, sensory recovery post-breast reconstruction is improved by neurotization of the DIEP flap and NAC. When all the Semmes-Weinstein filament results for the DIEP neurotization were compiled, taking the weighted averages of the monofilament values, the medial upper quadrant, which represents native skin, was the most sensitive in both noninnervated and innervated reconstructions (Figure 4). The upper quadrants of the breast also receive innervation from the supraclavicular nerve (16-18), which is not typically injured during mastectomy and therefore may contribute to the greater preservation of sensation in these areas (41). This superior sensation in the upper quadrants is likely mediated through the process of the intact nerve fibers sprouting into the denervated areas (93), as postulated by Beugels et al. (38). The lower quadrants exhibiting worse sensation could be due to the greater distances from the intact nerves in noninnervated reconstructions and from the nerve coaptation site in innervated reconstructions (41). The nipple area in DIEP reconstructions had worse sensation than the surrounding breast tissue, which further supports the need for more specific nipple reinnervation through TNR.

Figure 4 Weighted heatmap of reconstructed zones tested with Semmes-Weinstein filaments. Figure adapted from Beugels et al., 2019 (38).

The use of a nerve conduit for DIEP neurotization

In Spiegel et al.’s study of DIEP neurotization, they found that a 4 cm nerve conduit resulted in superior sensory recovery compared to direct coaptation (23). The sensitivity scores between no innervation and direct coaptation were similar in all areas of the flap while the conduit yielded better sensation of the flap superiorly, laterally, and in the nipple center compared to no innervation. Furthermore, the conduit resulted in improved sensation laterally and the nipple center compared to direct coaptation. Typically, a direct nerve repair yields the best results in terms of regeneration. Nerve autografts can lead to comparable results when a direct repair results in tension on the nerve. Conduits have only a limited role in gaps less than 3 cm, as reported by Mackinnon (94), “small-diameter, noncritical sensory nerves”, such as digital nerves (95-98). Therefore, the nerve conduit resulting in superior outcomes compared to direct coaptation in Spiegel et al.’s study provides a potential area for further investigation.

The use of a nerve graft for TNR

TNR in the context of breast reconstruction after mastectomy often requires the use of a nerve graft to achieve the length needed to reach the NAC. Deptula and Nguyen’s study included patients who underwent NSM with autologous reconstruction and patients who underwent gender-affirming bilateral mastectomies, and they noted that nerve grafts were not needed for gender-affirming mastectomies while those who underwent reconstruction all required a graft, with an average nerve graft length of 5.85 cm (43). Upon comparing the return of sensation between these two groups, sensation was superior in the gender-affirmation group in both areola sensation and peripheral breast skin, but not the nipple itself (average sensation was superior in gender-affirmation group although not significant). Interestingly, the sensation in the gender-affirmation group also exhibited lower standard deviations in all tested areas compared to the autologous reconstruction group, demonstrating that the introduction of a graft resulted in more variability in the return of sensation. However, the reduced sensation and higher variability in the NSM with autologous reconstruction group can also be attributed to the gender-affirmation group being of younger age (17.5 vs. 49 years).

In Juan et al.’s randomized controlled study on the use of TNR in immediate implant-based breast reconstruction, they observed an improvement in sensation in the TNR group compared to the control in nipple sensation as early as 10 days after reconstruction (30), although the average nipple sensation value in the TNR group was still in the “loss of protective sensation” range (99). This is a remarkable finding considering that the nerve grafts used for TNR have been reported to range from 3.5–7 cm in the context of breast reconstruction (30,32,33,43,44). This would imply, given that axons regenerate at approximately 1 mm/day (100), reinnervation to the NAC by the donor nerve should take at least 35 days. However, in Juan et al.’s study, 5–7 cm of the donor ICN was isolated prior to the insertion of the implant and subsequent NAC neurotization (30). The authors thereby performed either direct coaptation of the donor nerve to the NAC or used the side branches of their donor nerve as a nerve autograft, which is still the gold standard for nerve gap reconstruction (101-103), with some arguing that the use of nerve allografts should still be limited to small, noncritical nerves (104). Although they did not discuss the length of their autografts, it can be presumed that if they isolated long donor nerves, then their TNR procedures were more akin to nerve transfers, placing the donor nerve as close as possible to their targets (62,105-107). Early return of sensation may be possible due to direct coaptation to the NAC, but this sensation is also likely to be due to compensatory sprouting of sensory nerves preserved during the mastectomy (108).

One study that followed patients’ sensory outcomes after TNR reported no incidence of postmastectomy pain (32), and a separate study observed no incidence of neuroma or hypersensitivity (43). Therefore, another potential argument for the use of breast reinnervation techniques, in addition to improved sensory recovery, is to avoid chronic postmastectomy pain (35). Extensive research in addressing pain associated with cut nerves in the upper extremities have demonstrated the importance of reconnecting transected nerves to muscles (109-113), other nerves (114-117), or long allografts to reduce neuroma formation and phantom limb pain (118,119). The principles underlying the alleviation or prevention of pain in the aforementioned methods should also apply to breast reinnervation as a way to prevent postmastectomy pain (35), though this is currently speculative due to the paucity of data.

Considerations for delayed reconstruction

A few studies have suggested that neurotization after breast reconstruction should be a consideration primarily for patients who undergo delayed reconstruction due to more marginal effects seen in the immediate reconstruction groups, although the timeframe of delayed reconstruction was not specified (39,50,60). This marginal effect in the immediate reconstruction group, however, is inconsistent across different studies, with several cohort studies finding that immediate reconstruction with neurotization also resulted in greater sensory recovery compared to noninnervated reconstructions (23,37-39). An important consideration in planning for neurotization of the autologous DIEP flap or the NAC in a delayed reconstruction is ensuring that the 3^rd anterior and 4^th lateral ICN are preserved in the initial mastectomy, where many ICNs can be injured (108). If these nerves are injured during the mastectomy, DIEP flap reinnervation by these injured nerves would likely be less successful since earlier repair of injured nerves results in better functional outcomes (46,95). Furthermore, if the initial mastectomy transected the donor ICNs too proximally, the use of a nerve graft or conduit may further reduce sensory outcomes (95). Therefore, due to the increased likelihood of neurotization positively impacting the quality of life of patients who undergo delayed reconstruction, preservation of the chest ICNs at the time of mastectomy by the breast surgeon would be crucial for future successful neurotization of an autologous flap or NAC by the plastic surgeon (108). This would require significant interdisciplinary coordination to ensure optimal patient outcomes.

Learning curve and intraoperative time considerations

Neurotization of the DIEP flap and NAC after breast reconstruction now have considerable evidence to support that these interventions improve breast sensation and patient quality of life, but these procedures can involve a significant learning curve (40,120), as evidenced by one study experiencing a 15% failure rate at achieving bilateral neurotization (40). Although the resulting unilateral neurotization yielded an interesting internal control group for that study, the authors further showed that the success rate of neurotization ranged from 65% to 95% across 5 surgeons, with one surgeon performing 45% of all coaptation attempts and also having the highest success rate. The time it takes to perform the DIEP neurotization unilaterally has been reported to range between 8-38 minutes, although Escandón et al. noted that this may not include the time needed to dissect out the target nerves (13). In comparison, manual microvascular anastomosis of rat femoral vessels averages around 21 minutes and 18 seconds (13:21 for the vein and 7:57 for the artery) (121). DIEP microvascular anastomosis likely takes even less time due to the usage of venous couplers and larger vessels. Increasing operative time to isolate target nerves and to perform the nerve coaptation is an important factor to consider because it is an independent predictor of increased morbidity, unplanned reoperations, and length of hospitalization (122).

TNR neurotization has been reported to take 10–20 minutes unilaterally (33,35), also not accounting for the dissection of the ICNs nor the subsequent targeted muscle reinnervation or regenerative peripheral nerve interface reconstruction (to decrease the risk of chronic pain) if ICN branches are deemed too fine or short for neurotization or if ICNs are transected in error (35,123). Zhang et al. reported that an intramuscular dissection of the ICN to achieve a greater donor nerve length can add approximately 10 minutes to the case (44).

Patient costs and accessibility

Furthermore, the use of nerve allografts, conduits, and autografts for neurotization of the DIEP or the NAC comes at a significant cost. A 2024 cost comparison of digital nerve repair techniques in Florida, New York, and Wisconsin from 2016–2020 found that the median charges associated with allografts, conduits, and autografts were $29,528, $17,612, and $17,602, respectively (124). The median cost for primary repair was $12,163. The median cost of supplies for each procedure was $5,677, $3,819, and $209 for allograft, conduit, and autograft, respectively. Therefore, the use of a nerve conduit, as suggested by one study for DIEP neurotization (23), and the use of allografts and autografts for TNR pose an additional financial burden to patients. With the additional cost of neurotization and the availability of breast reinnervation procedures primarily being concentrated in academic institutions poses the additional consideration that socioeconomic status and accessibility could play a role in the superior outcomes seen in these studies. Lower socioeconomic status is associated with worse patient-reported outcomes (125), higher likelihood of becoming lost to follow-up (126), and higher usage of emergency services after surgery (127).

Conclusions

Results of clinical studies with control groups are promising and showcase the ability of the ICNs to improve sensory recovery after breast reconstruction to both the DIEP flap as well as the NAC through TNR. With sensory nerve coaptation, patients subjectively reported greater sensation with a clinically relevant improvement in their quality of life compared to patients who did not receive any reinnervation procedure. Because reinnervating the reconstructed breast involves the planned transection of several nerves, regeneration may be further improved with the use of CES, although how CES affects nipple erogenous sensation is unknown. Therefore, investing the operating time to increase the chances of higher quality sensory recovery would be worthwhile, although the learning curves involved with both of these operations are to be considered. Further investigations into ways to better enhance peripheral nerve regeneration would inform how sensory outcomes post-mastectomy can continue to be improved.

Acknowledgments

The appropriate permissions have been obtained for the publishing of the figures within this article.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-25-10/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-25-10/coif). A.L. reports receiving consulting fees from Bimini LLC and Novus health for serving on the advisory board. The other authors have no conflicts of interest to declare.

Ethical statement:The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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