Nasal Mucosa Regeneration After Reboot Surgery: Electron Microscopy and Histology Insights in CRSwNP

ABSTRACT

Background

Chronic rhinosinusitis with nasal polyps (CRSwNP) often requires multiple treatments. When topical steroids prove insufficient, endoscopic sinus surgery (ESS) is the primary intervention. Among surgical options, reboot surgery is an innovative approach that offers the potential for prolonged disease control in rapidly recurring cases, delaying the need for monoclonal antibody (mAb) therapy. Our study investigates the histological and ultrastructural aspects of mucosal regeneration post‐reboot surgery, providing evidence beyond clinical observations.

Methods

Five adult patients with recurrent CRSwNP, having undergone previous ESS, were enrolled in our study along with one control patient. All underwent partial reboot surgery, and biopsies were taken at pretreatment, 3‐, 12‐, and 24‐months post‐op. Analysis included clinical history, demographics, nasal polyps score, CT scans, and ACCESS score. All biopsies were analyzed using light (LM) and electron microscopy (both in transmission and scanning mode [TEM and SEM], respectively). Clinical response was assessed with Sinonasal Outcome Test‐22 (SNOT‐22) and Visual Analog Scale (VAS).

Results

Difference of means of SNOT‐22 and VAS scores, pre versus at 24 months, were statistically significant (69.8 vs. 18.6, p = 0.043; 9.2 vs. 1.2, p = 0.038, respectively). The histological and ultrastructural analysis revealed significant changes in mucosal morphology, collagen composition, vascularity, and cell adhesion, with gradual restoration of normal epithelium and ciliary structure over time.

Conclusion

Evidence of mucosal regeneration was provided at LM and electron microscopy. Reboot surgery is an innovative procedure that may be considered a valid alternative to mAbs, especially in younger patients, considering costs of medication and long‐term safety.

Level of Evidence

Level 4.

CRSwNP often requires multiple treatments, with monoclonal antibodies (mAbs) and endoscopic sinus surgeries used to manage resistant cases. This study focused on five patients undergoing reboot surgery, analyzing mucosal regeneration through biopsies and clinical outcomes over 24 months. It revealed complete non‐scarred regeneration of the nasal mucosa, alongside improvements in symptom scores. The findings suggest that reboot surgery may offer a cost‐effective, long‐term alternative to mAbs, particularly for younger patients.

1. Introduction

Chronic rhinosinusitis (CRS) is a disorder of the nose and paranasal sinuses that affects approximately 5%–15% of the general population and has a high burden on society and patients' quality of life (QoL) [1, 2]. The conventional CRS classification into CRSwNP (with nasal polyps) and CRSsNP (without nasal polyps) is now seen as too simple and insufficient for patient categorization. CRSwNP, primarily associated with type‐2 inflammation pathways [3], is often encumbered by recurrent and difficult‐to‐treat symptoms [4] that require multiple‐modality treatment [5]. Achieving lasting results is challenging. In unregulated situations, individuals and healthcare professionals may resort to improper self‐administered treatments, leading to repeated oral corticosteroid (OCS) use and significant long‐term side effects.

The advent of monoclonal antibodies (mAbs) targeting type‐2 inflammation pathways certainly changed the paradigm of treatment and prognosis of CRSwNP and its associated comorbidities [6, 7, 8, 9, 10]. The upper and lower airways are intricately connected both anatomically and immunologically, forming a unified system (“united airways”) where inflammation in one segment influences the other [11]. The advancement of systemic treatments (mAbs) targeting specific immune pathways highlights the importance of understanding the connection between the upper and lower airways. However, it is crucial to recognize that mAbs are not universally applicable. Cases showing drug resistance or clinical contraindications require thoughtful consideration of alternative strategies. Additionally, the economic aspect of mAb therapies, given the potential for excessive prescribing and significant financial consequences, should not be disregarded.

Patients experiencing persistent and recurrent diseases often undergo frequent endoscopic sinus surgeries (ESS). In such cases, more extensive surgical procedures are recommended for prolonged disease control [7]. The reboot technique was presented by Alsharif et al. [7] in 2019 and consists of the removal of the entire inflamed mucosa of the paranasal sinuses up to the periosteum, to favor postoperative reconstitution of new mucosa [12]. Two reboot surgery variants were described, involving either Draf III or Draf IIb procedures based on frontal sinus involvement. Reboot presents similarities with the nasalization technique originally described by Jankowski in 1995 [13], which involved a large opening of the maxillary, sphenoidal, and frontal ostia, middle turbinates resection, and maximal removal of the ethmoidal mucosa. This later modified into preservation of the mucosa of the sinuses' ostia. The focus of nasalization is the lateral masses of the ethmoid with their overlying mucosa.

Reboot surgery in patients with resistant CRSwNP aims to “restart” the nasal mucosa by eliminating the infiltrating inflammatory component. Studies have investigated clinical and endoscopic outcomes [14, 15], but a gap persists in the microscopic understanding of mucosal changes post‐reboot surgery, including mucociliary activity and its native barrier functions. While concerns about scar tissue formation exist, our research suggests an alternative path for mucosal regeneration.

Our study explores the reboot approach, not only observing the clinical evolution of symptoms after surgery but also undertaking a comprehensive histological and ultrastructural analysis, seeking to uncover the nuances of postoperative mucosal regeneration.

2. Materials and Methods

This prospective interventional study was conducted at Humanitas Research Hospital (Milano, Italy) between April 2019 and March 2023. It followed ethical standards outlined in the Declaration of Helsinki and was approved by the Hospital's Ethical Committee (ref/ICH/3402). All included patients gave their informed consent for the study.

Among the 58 patients with recalcitrant CRSwNP referred to our rhinology unit and waitlisted for reboot surgery, the first five consecutive patients who agreed to sample collection for research purposes were included in the study. All of them had already undergone at least one ESS before reboot, and they all had eosinophilic CRwNP. Clinical history and demographic characteristics were collected for all patients (Figure 1): age, gender, comorbidities, number of previous ESS, time to relapse after previous surgeries, courses of OCS. nasal polyps score (NPS) [16] was assigned at endoscopic examination. A CT scan was indicated prior to surgery, and the ACCESS score [17] was assessed. The ACCESS score assigns a value to each sinus based on the degree of surgical dissection achieved in previous operations (0 indicates complete dissection, 1 is for partial or incomplete dissection, and 2 implies that no surgery was performed). An additional patient was included as a control; this patient was randomly selected as the first eligible candidate to present at the clinic meeting the criteria for control enrollment. They had previously undergone a maxillary antrostomy and anterior ethmoidectomy for a retention cyst of the maxillary sinus. Since they required surgery for recurrent inferior turbinates hypertrophy, they also provided consent to undergo a biopsy at the same site as the CRSwNP patients.

FIGURE 1.

Preoperative patients' characteristics. Pre‐op and post‐op nasal endoscopies. Patients' general characteristics are reported in the upper part of the figure. (A–E) Pre‐reboot nasal endoscopic views of patients included in the study. Recurred polyps filled entirely the nasal cavities. (A) Left nasal cavity, Grade 4 polyps (i.e., completely obstructing the nasal cavity) with thick discharge sitting on it. (B) Left nasal cavity, multiple Grade 3 polyps (i.e., extending beyond the middle meatus yet without completely obstructing the nasal cavity). (C) Right nasal cavity, multiple Grade 4 polyps. (D) Left nasal cavity, one large Grade 3 polyp in the front and a Grade 4 polyp in the back, with thick discharge sitting on top of it. (E) Right nasal cavity, Grade 3 polyps. (F–J) Post‐reboot endoscopic views of patients' nasal cavities, at the 24‐month mark time. Mucosa appeared healthy, without signs of recurrence. All paranasal sinuses could be identified; there were no signs of inflammation or infection. (Upper right corner) Area (segmented line) of the ethmoid that was the site for the post‐reboot biopsies, due to its accessibility in awake patients under local anesthesia. e = ethmoidal roof; f = frontal sinus; it = inferior turbinate; m = maxillary sinus; mt = middle turbinate; p = polyp; s = septum; sph = sphenoid sinus.

All participants underwent partial reboot as revision surgery after at least one failed ESS [7]. Biopsies were collected at four different time points along the study: pretreatment, and at 3, 12, and 24 months. Topical steroids were suspended 2 weeks prior to surgery and biopsies. The specimens were 5 × 5 mm‐wide biopsies that were obtained from different spots within the same area in each patient, that is, the lateral aspect of the ethmoid, where it is close to the posteromedial wall of the maxillary sinus (Figure 1). Biopsies were taken under local anesthesia in an outpatient setting. Biopsy specimens were analyzed with light (LM) and electron microscopy, both in transmission and scanning mode (TEM and SEM, respectively).

Postoperative care included daily saline rinses, and nasal irrigations with 1‐mg budesonide twice a day for the entire length of the study. At each timepoint, the subjects were administered the SNOT‐22 [18, 19] and Visual Analog Scale (VAS) to answer the question “How bad are your nasal symptoms overall?” The minimal clinically important difference (MCID) was calculated between baseline and 24 months.

2.1. Surgical Technique

The technique consists in the removal of the mucosa from the paranasal sinuses down to the periosteum, after removal of bony structures as in ESS procedures [7, 14, 15]. The periosteum is left intact as much as possible, especially at the level of sinus ostia, not to expose the underlying bone that may determine a higher risk of aberrant scarring. Thus, drilling is avoided unless bony excess is of impediment for a clearer surgical field and effective surgery, such as in cases where a Draf III procedure is necessary. Following the complete removal of ethmoidal cells, it is essential to entirely clear the mucosal lining from the ethmoidal roof and the lamina papyracea. Similarly, if the middle turbinate is still intact and can be preserved, thorough removal of mucosa from its lateral aspect should be conducted. Completeness of removal might be impaired in some areas, such as the alveolar recess of the maxillary sinus; the use of a 70° endoscope and curved instruments is mandatory to perform the most extended demucosization possible. Likewise, to access the frontal sinus, it is necessary to perform either Draf IIb or Draf III procedures, depending on the ease of reaching the sinus walls and the extension of the pathology. Generally, the removal of mucosa from the most lateral aspects of the frontal sinus depends on its depth and can be subtotal. As in Alsharif et al. [7], Draf IIb is done in “partial” reboot, while Draf III in “full” reboot.

2.2. Histochemistry, Immunohistochemistry, Transmission Electron Microscopy (TEM), and Scanning Electron Microscopy (SEM)

Techniques used for specimens' analyses are described in Supporting Information.

2.3. Statistics

Descriptive statistics were conducted with SPSS (Version 28 for Macintosh, IBM). Correlations and statistical significance were determined with nonparametric tests (due to the small study population), that is, the Wilcoxon (Mann–Whitney) matched‐pair signed‐rank test (Z) for comparing means. All statistical tests were two‐sided, and alpha and beta errors were set at 0.05 and 0.20. The MCID was calculated using both the anchor‐based and the distribution‐based approaches.

3. Results

The study examined five patients (three females and two males) with a mean age of 48 ± 12 years, all of whom had asthma and two with aspirin hypersensitivity. None were smokers. On average, patients underwent 2.7 ± 2.3 previous FESS (range 2–6), with a mean follow‐up of 17 months (range 12–24). The pre‐reboot ACCESS score was 1.2 (range 0–3), indicating the prior FESSs were performed effectively, with complete dissection of all sinuses.

No patients had complications from reboot or required additional surgeries post‐reboot; three of them needed crust debridement twice a week for about 3 weeks.

Preoperative evaluations showed an average NPS of 7.1 ± 0.9, which consistently dropped to zero after surgery and remained stable for the entire length of the study. Additionally, SNOT‐22 [19] and VAS scores were assessed at all postoperative timepoints, revealing statistically significant improvements at 3 and 24 months, while results were not significantly different at 12 months (Figure 2). The scores at baseline and the final follow‐up differed significantly. The preoperative SNOT‐22 score was 69.8 and significantly improved to 18.6 at 24 months (p = 0.043). Similarly, the VAS global score decreased from 9.2 preoperatively to 1.2 at 24 months (p = 0.038) (Figure 2). For the SNOT‐22 and VAS global, the anchor‐based MCIDs were 51.2 and 8.0, while the distribution‐based MCIDs were 12.9 and 0.42, respectively.

FIGURE 2.

SNOT‐22 and VAS global score at the different timepoints. The Wilcoxon matched‐pair Z test (Z) was used to test the significance of the difference of means between the timepoints (*p < 0.05, ns = nonsignificant).

A subset of SNOT‐22 items, specifically those related to rhinologic symptoms (Items #1–5, #7–8, and #12), also showed a significant reduction over the four timepoints (p = 0.043). The SNOT‐22 item assessing olfactory and taste dysfunction had an initial average score of 4.6 (range: 0–5) across the five patients. Patients reported a subjective improvement, with the average score decreasing to 1.5 (range 1.4–1.6) at 3 months post‐op and remaining stable at subsequent timepoints. However, the difference in the mean scores was not statistically significant for any of the timepoints (p = 0.066).

Microscopic analysis showed significant post‐reboot changes. Pre‐reboot mucosa was unstructured (Figure 3), but by 24 months, it formed a pseudostratified columnar epithelium with ciliated, secretory, and basal cells. Re‐epithelialization progressed from a sparse layer at 3 months to fully differentiated mucosa at 24 months. Eosinophilic infiltration dropped from 11.6 ± 18.54 eos/HPF pre‐reboot to 0.2 ± 0.23 at 3 months, rising to 4.4 ± 4.88 at 24 months, still lower than presurgery. PAS staining confirmed mucin‐filled goblet cells at 24 months (Table 1). Sirius red staining showed collagen remodeling, and CD34 staining indicated improved vascularity. E‐cadherin remained downregulated, while Ki67+ cells showed no distinct patterns (Figure 4).

FIGURE 3.

Visualization of mucosal regeneration as observed through light microscopy. (A, B) Normal mucosa. (A, B) Normal ciliated pseudostratified epithelium (pse), goblet cells, and underlying lamina propria (LP). Cilia of cells are facing the luminal side, that is the nasal cavity. (C–F) Pathological mucosa with CRSwNP. (C–F) Display a disrupted mucosa with damaged epithelium (de) or residuals of epithelial cells (arrows). Some areas of the mucosa are devoid of a superficial epithelial layer. (G–L) Modifications of the mucosa along the regeneration process. (G, H) Mucosa at the 3‐month mark post‐reboot; epithelial cells are still not differentiated and appear in a single layer of cylindrical cells. (I, J) Pluristratification (ple) of epithelial cells at the 12‐month mark post‐reboot; cell differentiation toward the ciliated type is still not found in the specimens. (K, L) 24‐month mark time post‐reboot, when the mucosa comprises a ciliated pseudostratified epithelium (pse), goblet cells, and an underlying lamina propria (LP), that altogether resemble the aspect of normal mucosa (A).

TABLE 1.

Morphological features of the samples at each timepoint. Eosinophils are expressed as mean ± standard deviation, range in brackets. Extracellular matrix (ECM) is described only in the features regarding collagen types. Vascularity is wholly described according to the shape, irregularity, and number of blood vessels in the mucosa. Periodic acid–Schiff (PAS) stain detects polysaccharides, such as mucins, that are present and produced by goblet cells in the nasal mucosa. E‐cadherin is a surface protein involved in cell‐to‐cell adhesions. Ki‐67 is a marker that describes cellular proliferation and mitotic activity.

	Eosinophils	ECM	Vascularity	PAS (mucins)	E‐cadherin	Ki‐67
Pre‐reboot	11.6 ± 18.54 (0.4–56.2)	Collagen type III > type I	Large and irregularly shaped vessels with dispersed pattern distribution	Absent	Absent	Absent
Post 3 months	0.2 ± 0.23 (0–0.4)	Heterogeneous (mixture of collagenic protein types)		Scarce presence	Absent	Absent
Post 12 months	0.3 ± 0.42 (0–0.6)		Very small and regular in shape vessels with uniform pattern distribution	Scarce presence	Absent	Absent
Post 24 months	4.4 ± 4.88 (1–10)	Collagen type I—dense		Scarce presence	Absent	Absent

FIGURE 4.

Histological features observed throughout the light microscopy and polarized light. (A) Pre‐reboot, hematoxylin–eosin stain. Prior to surgery, the samples displayed a mucosa (m) lacking structure, with no distinct respiratory cells or organized cellular layers. (B) 24 months post‐surgery. A significant change occurred. The mucosa (m) adopted a pseudostratified columnar appearance (square bracket) resembling natural nasal epithelium. (C) 24 months post‐surgery. Alcian blue staining indicated the presence of acidic mucins (arrowheads) after surgery. (D) 24 months post‐surgery. Sirius red staining and polarized light microscopy revealed a shift from collagen type III fibrils to a prevalence of collagen type I fibrils (f‐I, orange‐to‐red fibrils), suggesting dynamic extracellular matrix remodeling during re‐epithelialization. Fiber alignment remained unchanged between pre‐ and post‐surgery samples. (E) Pre‐reboot. Examination with CD34 antibodies showed noticeable changes in vascularity. Prior to surgery, vessels exhibited irregular shapes, uneven distribution, and relatively large lumens (arrowheads). Post‐surgery (F), vessels (arrowheads) displayed a more uniform pattern with smaller lumens, possibly suggesting a stabilization in the regeneration process back to a normal state.

Ultrastructural analysis (TEM/SEM) confirmed epithelial restoration. Control SEM showed a densely ciliated surface (Figure 5A,B), while TEM highlighted the “9 + 2” cilia structure (Figure 5D) and goblet cells (Figure 5E). Intercellular junctions (tight, adherens, desmosomes) were intact (Figure 5F). Pre‐reboot samples showed disrupted mucosa with irregular cell shapes and detaching desmosomal connections (Figure 6A,B). Post‐reboot, regeneration progressed from multilayered epithelia at 3–12 months to fully restored mucosa at 24 months (Figure 7A–O). Desmosomes decreased intercellular space by 12 months (Figure 7G–O), and by 24 months, TEM confirmed a complete epithelial layer with ciliated, goblet, and basal cells (Figure 7L). Cilia retained their “9 + 2” structure (Figure 7K), and SEM showed full epithelial coverage (Figure 7P).

FIGURE 5.

Control mucosa of the sinus. (A, B) SEM images. (B) An enlargement of the white square in (A); it highlights the normal appearance of cilia (white arrowheads). They are grouped into blocks, each belonging to a single ciliated cell. (C–F) TEM images. (D, E) Enlargements of the black and white squares in (C), respectively. (C) A cross‐section of two ciliated cells (CC₁ and CC₂) and a goblet cell (GC) with mucin vesicles (m). (D) Longitudinal (arrows) and cross sections (arrowheads) of the cilia display their expected microtubular structure (nine outer microtubules doublets + two inner doublets). (F) The normal intercellular junctions: Tight junction (blue arrow); adherens junction (yellow arrow); and desmosome (green arrow).

FIGURE 6.

Electron microscopy images of the mucosa in chronic rhinosinusitis with nasal polyps. (A, B) Pre‐reboot unhealthy mucosa with disrupted appearance. (A) SEM image of the mucosa with abnormal superficial cells that are residues of epithelial cells (rEP), large intercellular space (*), finger‐like projections (yellow arrowheads) of cells losing intercellular junctions, and areas of mucosa devoid of an epithelial layer (m). (B) TEM image focuses on the finger‐like projections (flp) and the impaired junctions (arrow = desmosome; arrowhead = residual of desmosome) that are part of the damaged cells spreading apart (* = large intercellular space).

FIGURE 7.

Respiratory epithelium regeneration process after reboot surgery. The image illustrates the restoration pathway of the respiratory epithelium over time. Histological sections and electron microscopy are reported to show the morphological and functional changes that accompany clinical improvement. (A–C, M) Presurgery: The epithelium is partially or completely absent, with residual epithelial cells lacking cilia. (D–I, N, O) 3–12 months post‐reboot: Migration of basal cells, cell proliferation, junction formation, and reorganization toward a pseudostratified epithelium are observed. (J–L, P) 24 months post‐reboot: Complete regeneration of the ciliated, pseudostratified respiratory epithelium with formed intercellular junctions (blue arrow = tight junction; yellow arrow = adherens junction; green arrow = desmosome). The results of the SNOT‐22 and VAS are reported in the panel at the bottom of the figure.

4. Discussion

The nasal and paranasal sinus lining has the fundamental roles of filtering foreign particles, regulating air temperature and moisture, and defending against infections [20]. Disruptions of the mucosal lining can affect the entire respiratory system [1, 21, 22, 23, 24]. CRSwNP, often driven by type‐2 inflammation, causes mucosal remodeling, ciliated cell loss, and inflammation, leading to symptoms of congestion, rhinorrhea, headache, and infections that may persist despite long‐term topical and surgical therapy. With FESS, the drainage pathways and ventilation of the sinuses are restored. However, mucosal disease and the accompanying symptoms can persist or rapidly recur in severe cases [14, 25, 26, 27], due to cytokines and inflammatory cells that perpetuate the inflammatory process, impeding a complete return to optimal health and functionality [3, 22, 28, 29].

This study assessed reboot surgery for its potential to restore the mucosa to a healthier state [7, 14, 15, 30]. Presurgery samples of CRSwNP patients showed severe mucosal damage: decayed epithelial remnants, exposed lamina propria, and abundant inflammatory cell infiltration despite previous surgery and local steroidal therapy. During reboot, the sinuses were demucosalized, but gradual re‐epithelization was observed in the months that followed the procedure. By 3 months, sparse non‐ciliated cells were present, progressing to multilayered, still mostly non‐ciliated cells at 12 months. By 24 months, the mucosa resembled its normal state with pseudostratified epithelium, ciliated cells, and goblet cells. The significant reduction in eosinophils (11.6 ± 18.54 eos/HPF pre‐op vs. 4.4 ± 4.88 eos/HPF at 24 months) may lower the risk of recurrence. We hypothesize that nasal steroids helped suppress eosinophil infiltration through their anti‐inflammatory effects. This reduction could explain the observed symptom control, consistent with the role of eosinophils in the Th2 response. However, long‐term effects and count fluctuations remain uncertain, and further research is needed to assess the persistence of these improvements.

Reconstitution of the nasal mucosa after injuries was also studied by other groups. Ohashi et al. [31] investigated mucosal regeneration in rabbits after septal injuries. Complete regeneration took 6 weeks, with ciliated cells appearing after 3 weeks. Shaw et al. [32] explored reciliation in sheep nasal tissue, finding slower than expected healing; for full‐thickness injuries, regeneration was delayed due to the absence of a basement membrane. Reciliation was ongoing at 12 weeks, but longer‐term outcomes were not reported. Our study followed mucosal regeneration after full‐thickness removal of all sinuses' mucosa. Surprisingly, the time required for complete remucosalization was longer than expected based on available literature, but it showed consistent relief of symptoms Sustained control of symptoms persisted till 24 months; at this time point, a fully organized neo‐epithelium was found on microscopy (Figure 6). We hypothesize that variations in re‐epithelization timing may be influenced by factors like the extent of mucosal removal and topical budesonide use. While steroids promote healing by reducing inflammation, they may suppress epithelial proliferation and fibroblast activity, potentially delaying tissue repair. We also contemplate that periosteum preservation may impact mucosal reconstitution, though this was not explored in our study. These points suggest areas for future research.

From a clinical standpoint, postsurgical recurrence remains a challenge that impacts long‐term results of ESS. DeConde and Smith reported endoscopic polyp detection in 40% of patients 18 months after surgery [33], and in Hopkins and Lund [34] study up to 20% of patients underwent revision surgery within 5 years. Surely, the disease endotype can significantly impact. Eosinophilic histology is a risk factor, but surgical procedure type and extent also affect outcomes [27]. Innovative strategies are needed for this persistent challenge. In 2019, Alsharif et al. [7] detailed the reboot procedure, aiming for complete demucosalization of sinuses to achieve infiltrate‐free mucosa, potentially reducing recurrence and extending symptom‐free intervals. A 2020 case report demonstrated re‐epithelialization post‐reboot surgery in a CRSwNP patient [30]. Another study [15] with 30 severe CRSwNP patients showed significant improvement in recurrence rate, clinical remission length, symptoms, QoL, and OCS intake clearance of reboot compared to standard ESS. Gomes et al. study [14] on smell kinetics favored reboot over ESS, maintaining olfactory improvement and having lower polyp recurrence at 24 months. Patients with a history of prior surgery exhibit a notably higher rate of subsequent surgeries; with symptomatic recurrence occurring within 3 years of the initial procedure, the risk of treatment failure surpasses 33% [34]. Also, the extent of ESS seems inversely proportional to the risk of subsequent revision, highlighting the necessity for alternative strategies for pluri‐operated and rapidly recurring patients, such as mAbs, or potentially, reboot surgery. Certainly, monoclonal antibodies in CRSwNP offer a novel approach, targeting pathways to reduce inflammation and prevent polyps [35]. Choosing between surgery and mAbs depends on factors like efficacy, cost‐effectiveness, disease severity, patient preferences, side effects, and long‐term outcomes. Surgical options, such as reboot, effectively manage CRSwNP, providing lasting relief and reducing polyp recurrence. However, disadvantages should be considered in both treatment scenarios. Surgery entails risks such as bleeding, infection, or smell changes, varying among patients. mAbs, while effective, have ongoing costs and individual responses may vary, potentially making them more expensive in the long run, especially in younger patients, and ongoing research is essential for establishing their side effects and long‐term outcomes [6, 36, 37].

In our cohort, the mean improvement in SNOT‐22 scores was 51.2 points, exceeding both the anchor‐based MCID (51.2) and distribution‐based MCID (12.9). The anchor‐based MCID for SNOT‐22 and VAS global were 51.2 and 8.0, respectively, indicating significant symptom reduction. In contrast, the distribution‐based MCID values were smaller: 12.9 for SNOT‐22 and 0.42 for VAS global. While the distribution‐based MCID offers a statistical threshold, the anchor‐based MCID better reflects clinically meaningful patient‐perceived improvement, so these results suggest that reboot provided significant clinical benefit from the patients' perspective.

The demonstration of nasal mucosa restoration at 24 months post‐reboot is crucial for correlating regeneration with sustained symptom improvement. For researchers and clinicians that are evaluating the applicability of reboot surgery in their surgical practice, micro‐ and ultrastructural analyses offer evidence of effective mucosal regeneration over scar tissue formation. This could guide treatment decisions, especially on rapidly relapsing CRSwNP patients whose QoL is significantly reduced due to the natural course of their disease. Furthermore, studying mucosal ultrastructure contributes to scientific knowledge on tissue repair, applicable beyond nasal mucosa.

Our study had limitations that may affect the generalizability of our findings. The small sample size limits statistical reliability and may not fully reflect the broader population. Another limitation is the biopsy site, as a single subsite may not fully represent mucosal regeneration across all sinuses. Analyzing specimens from multiple subsites would provide a better understanding of mucosal changes after reboot. As a result of these limitations, our findings should be interpreted as preliminary and primarily hypothesis‐generating, requiring validation in larger, more diverse cohorts to ensure reliability and generalizability.

However, to the best of our knowledge, no previous research has ever thoroughly examined the histological, immunohistological, and ultrastructural changes in nasal mucosa post‐reboot surgery. Despite limited data, patients displayed progressive remucosalization and nearly normal reepithelization of sinus walls. Further inferences from microscopic data should be developed with a larger specimen group, strengthening evidence of mucosal regeneration after reboot surgery.

5. Conclusion

In conclusion, the study provides compelling evidence of progressive post‐reboot remucosization over time, confirmed by both microscopic and ultrastructural analyses. Restoration at both cellular and tissue levels mirrors the significant clinical improvement experienced by patients. These findings suggest that reboot surgery may offer substantial long‐term benefits in rapidly recurring and plurioperated CRSwNP patients.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1. This supplement provides additional details on the techniques used for specimens’ analysis. The protocols for histochemistry and immunohistochemistry are described, including staining methods for morphological analysis, collagen fiber characterization, mucin detection, and mast cell identification. The methodologies for Transmission Electron Microscopy (TEM) and scanning electron microscopy (SEM) are also outlined.

Pirola F., Vezzoli E., Falqui A., et al., “Nasal Mucosa Regeneration After Reboot Surgery: Electron Microscopy and Histology Insights in CRSwNP ,” The Laryngoscope 135, no. 9 (2025): 3082–3092, 10.1002/lary.32166.