Efficacy of Combined High-Intensity Laser Therapy and Collagenase Chemonucleolysis in Lumbar Disc Herniation Management: a Prospective Randomized Controlled Trial

Abstract

Introduction

Lumbar disc herniation (LDH) is a prevalent degenerative spinal disorder. While collagenase chemonucleolysis is effective in long-term LDH management, delayed symptom relief remains a limitation. Recent studies suggest that high-intensity laser therapy (HILT) may enhance tissue repair and pain modulation, providing a rationale for exploring its synergistic effects with collagenase therapy. This study aimed to investigate whether combining HILT with collagenase chemonucleolysis could accelerate early postoperative recovery in patients with lumbar disc herniation.

Methods

This single-blind randomized controlled trial was conducted at the Department of Pain Management, The First People’s Hospital of Changzhou, between October 2023 and October 2024. This single-center, single-blind randomized controlled trial finally enrolled 60 eligible patients with lumbar disc herniation; participants were randomly assigned to the experimental (HILT + collagenase) or control (collagenase alone) group using a computer-generated randomization sequence with 1:1 allocation. Group assignments were concealed in sealed opaque envelopes until intervention initiation. All participants underwent collagenase chemonucleolysis, with the control group receiving standard postoperative care combined with sham laser therapy, while the experimental group received additional high-intensity laser irradiation alongside conventional treatment. The primary endpoints comprised visual analog scale (VAS) pain scores and clinical efficacy rates evaluated using modified MacNab criteria, while secondary outcomes included the Oswestry Disability Index (ODI), straight-leg-raising angle measurements, and 36-Item Short Form Health Survey (SF-36) quality of life assessments, with standardized evaluations conducted at five predefined intervals: preoperative baseline, 1 week, 1 month, 3 months, and 6 months postoperatively. Statistical analyses were performed using SPSS 20.0. Continuous variables were compared via independent t-tests or Mann–Whitney U tests, while categorical variables were analyzed using chi-squared tests. All tests were two-tailed, with P < 0.05 considered statistically significant.

Results

A total of 60 patients (30 per group) with a mean age of 57.15 ± 9.18 years completed the study. Baseline characteristics including age, gender, body mass index (BMI), herniation level, and symptom duration showed no significant intergroup differences (all P > 0.05). No significant baseline differences were observed between groups regarding age (58.00 ± 7.13 versus 57.06 ± 9.08 years), gender distribution (male: 53.3% versus 50.0%), or disease duration (5.17 ± 3.45 versus 5.73 ± 3.07 months) (all P > 0.05). The results showed that there was no statistically significant difference in baseline data between the two groups of patients. At 1 week and 1 month postoperatively, the experimental group demonstrated significantly better outcomes compared with the control group in terms of pain VAS scores, excellent/good rate, Oswestry Disability Index (ODI) scores, and Short Form 36 (SF-36) quality of life scores (all P < 0.05). However, at 3 and 6 months postoperatively, no significant differences were observed between the two groups. The lack of sustained intergroup differences is supported by small effect sizes (Cohen’s d = 0.15 for ODI at 3 months; 95% CI: [−2.74, 0.74]) and overlapping confidence intervals in SF-36 domains, indicating that HILT’s therapeutic impact is clinically meaningful only during the early inflammatory phase, with diminishing relevance as collagenase-mediated remodeling dominates long-term recovery.

Conclusions

Our findings demonstrate that high-intensity laser therapy augmentation of collagenase chemonucleolysis significantly improves early postoperative pain and functional outcomes in patients with lumbar disc herniation. However, the therapeutic advantage diminishes by 3 months, suggesting this combination therapy primarily accelerates early recovery rather than altering long-term prognosis.

Key Summary Points

Why carry out this study?

Collagenase chemonucleolysis demonstrates delayed clinical efficacy (3+ months) and transient postoperative pain exacerbation (30–45% incidence), necessitating adjunctive therapies to bridge early recovery gaps.

High-intensity laser therapy (HILT) offers nonpharmacological pain modulation via photobiomodulation, yet its role postchemonucleolysis remains underexplored despite mechanistic synergy with enzymatic decompression.

What was learned from the study?

Adjunctive HILT significantly reduced early postoperative pain (ΔVAS = 1.93 at 1 month; P < 0.001) and improved functional metrics (ODI and SF-36) within the first postoperative month compared with sham therapy.

Treatment benefits converged by 3 months, aligning with collagenase’s maximal enzymatic efficacy, indicating HILT’s transient adjuvant role rather than long-term disease modification.

Uncontrolled confounders (preoperative analgesia and age-related compliance disparities) and small effect sizes (Cohen’s d < 0.2 at 3 months) limit generalizability to heterogeneous lumbar disc herniation (LDH) populations.

Introduction

Lumbar disc herniation (LDH) represents a prevalent clinical disorder characterized by intervertebral disc degeneration, annulus fibrosus rupture, and subsequent nerve root compression caused by nucleus pulposus extrusion, leading to a constellation of clinical symptoms [1]. As a primary etiology of lumbosacral radiculopathy, LDH has emerged as a major contributor to lower back pain and sciatica, particularly among middle-aged and elderly populations [2].The incidence of this condition has shown a progressive upward trend, paralleling the demographic shift toward an aging society and the evolving patterns of modern lifestyles [3].

Both conservative management and surgical intervention have demonstrated efficacy in the treatment of lumbar disc herniation [4, 5]. Current management of LDH includes surgical discectomy (effective but invasive, 30% risk of postoperative scar formation [6]) and minimally invasive techniques (e.g., endoscopic spine surgery with 85% 5-year success rate [7]). While conservative approaches, including physical therapy and pharmacological management, may offer symptomatic relief in the short term, surgical decompression has been shown to provide superior long-term outcomes in terms of symptom resolution, functional recovery, and quality of life improvement for patients with persistent or severe disc herniation [8].

Surgical approaches for LDH include traditional open surgery, endoscopic surgery, and minimally invasive interventional procedures. Collagenase chemonucleolysis represents a targeted enzymatic therapy that specifically hydrolyzes type II collagen fibers, the predominant structural components of the nucleus pulposus [9]. Through this biochemical process, collagenase catalyzes the degradation of these fibers into absorbable amino acid fragments, thereby reducing the volume of herniated nucleus pulposus tissue and alleviating neural compression. This enzymatic decompression effectively relieves compression of nerve roots and the dural sac [10]. Additionally, collagenase may mitigate pain via the inhibition of phospholipase A2 activity [11]. Unlike endoscopic surgery, collagenase chemonucleolysis exhibits delayed clinical efficacy during the early postoperative phase and requires prolonged bed rest, likely due to inflammatory mediators released by degradation products and immobilization-related complications [12] LDH-induced radicular pain stems from mechanical compression of nerve roots and the release of proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). High-intensity laser therapy (HILT) modulates inflammatory responses and improves local microcirculation, while collagenase chemonucleolysis selectively degrades herniated disc tissue. The combination may synergize immediate analgesia with long-term structural repair.

HILT exerts therapeutic effects through photobiomodulation (PBM) on damaged or dysfunctional tissues, triggering mitochondria-mediated cellular responses that reduce pain and inflammation while accelerating tissue repair [13]. While PBM offers advantages of noninvasiveness and accelerated tissue repair [14], its efficacy in deep tissue penetration remains limited. By contrast, chemonucleolysis enables targeted enzymatic degradation of herniated discs [12], but delays symptom relief by 3–5 days. Our study bridges this gap by combining HILT with collagenase to leverage both immediate analgesic effects and long-term structural repair. Currently, HILT is extensively utilized in clinical settings for managing acute and chronic pain of diverse etiologies [15, 16]. Despite the established role of collagenase chemonucleolysis, no studies have explored adjuvant therapies to address its delayed therapeutic onset. However, there remains a paucity of research investigating its potential to abbreviate the postchemonucleolysis pain response period and expedite functional recovery in patients undergoing collagenase enzymatic decompression for lumbar disc herniation. Prior research has focused on isolated applications of laser therapy or enzymatic dissolution, without systematic investigation of their combined effects on both nociceptive signaling and tissue remodeling. This study aims to systematically evaluate the efficacy of HILT in mitigating both acute and chronic pain responses associated with collagenase chemonucleolysis, particularly focusing on its role in managing early postoperative discomfort and preventing long-term pain complications. We hypothesize that HILT combined with collagenase chemonucleolysis will reduce postoperative visual analog scale (VAS) scores by ≥ 2 points within 7 days compared with collagenase monotherapy. This research addresses three critical clinical needs: (1) shortening the therapeutic latency period of collagenase chemonucleolysis from 5–7 days to ≤ 3 days; (2) reducing early postoperative opioid consumption by 50–70%; and (3) establishing standardized HILT parameters (10 J/cm²energy density, 100 ms pulse width) for future protocol replication. To date, no studies have explored strategies to shorten the delayed therapeutic onset of collagenase chemonucleolysis (typically 5–7 days). This trial is the first to evaluate whether HILT can accelerate early stage efficacy.

Methods

Study Design

This single-blind randomized controlled trial was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

CONSORT-Compliant Trial Presentation

Trial design: single-blind, parallel-group randomized controlled trial (RCT) with 1:1 allocation to experimental (HILT + collagenase) or control (sham laser + collagenase) groups.

Participants: adults aged 40–70 years with lumbar disc herniation (LDH) confirmed by magnetic resonance imaging (MRI), persistent symptoms ≥ 6 months, and failure of ≥ 3 months of conservative treatment. Exclusion criteria included spinal instability, infection, or collagenase allergy.

Allocation consisted of block randomization (block size = 4) by disc herniation level (L4–L5/L5–S1) using computer-generated sequences; allocation concealment was performed via sequentially numbered, sealed opaque envelopes.

Blinding: participants and outcome assessors were blinded to group assignment. Sham laser therapy (identical device, no energy output) maintained blinding.

Interventions: both groups received standard collagenase chemonucleolysis. The experimental group added HILT (LTS-1500, 15 W, 10 J/cm², five daily sessions); the control group received sham laser.

Primary outcomes included VAS pain scores; secondary: Oswestry Disability Index (ODI), straight-leg-raising angle, Short Form-36 (SF-36). Assessments were conducted at baseline, 1 week, 1 month, 3 months, and 6 months postoperatively.

Throughout the study, outcome assessors and statisticians remained blinded to group allocation, with emergency unblinding protocols established for severe adverse events. The study was carried out at the Department of Pain Management, The First People’s Hospital of Changzhou (a tertiary medical center with ISO 15189-certified laboratory facilities) between October 2023 and October 2024. Follow-up assessments were completed by February 2025. The trial was registered prior to participant enrollment at the Medical Research Registration and Filing Information System (www.medicalresearch.org.cn) (registration number: MR-32-25-022787), adhering to World Health Organization (WHO) International Clinical Trials Registry Platform standards.

Patients diagnosed with LDH were enrolled in this clinical investigation. Figure 1 illustrates the patient selection and randomization process. All patients were fully informed about the study protocol and provided written informed consent prior to participation. Participants were randomly assigned to either the experimental or control group using a computer-generated random number Table (1:1 allocation ratio), stratified by age (40–55 years versus 56–70 years). Allocation concealment was maintained through sequentially numbered, sealed opaque envelopes prepared by an independent statistician. The envelopes were opened only after baseline assessments to prevent selection bias.

Fig. 1.

Flow diagram of the clinical trial

Throughout the study, both patients and outcome assessors remained blinded to group allocation. An independent reviewer responsible for outcome evaluation was not involved in intervention delivery or data collection. To maintain blinding, the intervention team was separate from the outcome assessment team. Unblinding occurred only in cases of medical emergencies and was documented in compliance with ethical guidelines.

Blinded outcome assessors conducted standardized evaluations at five predetermined time points: preoperative baseline, postoperative week 1, postoperative month 1, postoperative month 3, and postoperative month 6. Data collection procedures followed CONSORT guidelines and utilized validated instruments, including the visual analog scale (VAS), Oswestry Disability Index (ODI), and SF-36 Quality of Life Questionnaire, to ensure methodological rigor. This institution has obtained the rights to use the ODI and VAS scores.

The primary outcome was the pain severity measured by the visual analog scale (VAS; 0–10) [17], validated in prior LDH studies (test–retest reliability: intraclass correlation coefficients [ICC] = 0.89). Secondary outcomes included functional improvement assessed via the Oswestry Disability Index (ODI; Cronbach’s α = 0.87) [18]; Neurological recovery evaluated through the straight-leg raise test (interrater agreement: κ = 0.78). Based on senior clinicians’ expertise and relevant literature, we defined the minimal clinically important difference (MCID) thresholds as: 3 points for visual analog scale (VAS) scores and 15 points for Oswestry Disability Index (ODI).

Patient Eligibility

Diagnoses were confirmed by board-certified pain medicine physicians with ≥ 5 years of clinical experience in lumbar disc herniation (LDH) management. Diagnostic criteria incorporated both MRI findings and clinical evaluation results.

Inclusion criteria included: (1) patients meeting the diagnostic criteria for lumbar disc herniation (LDH) (International Classification of Diseases [ICD]-10: M51.1; ICD-11: FA50.0 or FA50.1). (2) Patients with a disease course exceeding 1 month and having undergone at least 2 weeks of conservative therapy. (3) Patients between the ages of 40 and 70 years with a (4) body mass index (BMI) 18.5–30 kg/m² (excluding obesity or malnutrition as confounders). (5) Patients had to have the ability to comprehend the study protocol and provide written informed consent (using a standardized international template). The diagnostic criteria for lumbar disc herniation are as follows: (1) radiating pain in the lower limb, with pain location corresponding to the affected nerve distribution area; (2) abnormal sensation in the lower limb, with reduced superficial sensation in the corresponding affected nerve distribution area of the skin; (3) positive findings in the straight leg raising test, straight leg raising reinforcement test, contralateral straight leg raising test, or sciatic nerve traction test; (4) weakened tendon reflex compared with the healthy side; (5) decreased muscle strength; and (6) presence of disc herniation and nerve compression confirmed by lumbar spine MRI or computed tomography (CT), which aligns with the symptoms and signs of the affected nerve [15]. Diagnosis of lumbar disc herniation requires meeting three out of the first five criteria, in addition to the sixth criteria (recommended level A, evidence level 1a).

Exclusion criteria included: (1) lumbar spondylolisthesis (Meyerding grade ≥ II), congenital/degenerative bony spinal stenosis (sagittal diameter < 10mm), vertebral fracture (Genant semi-quantitative grade ≥ 1), spondylolysis, or scoliosis (Cobb angle > 10°); (2) spinal infections (e.g., tuberculosis and discitis), tumors (primary/metastatic), or inflammatory diseases (ankylosing spondylitis and rheumatoid arthritis); (3) cauda equina syndrome (urinary retention, saddle anesthesia, or anal sphincter dysfunction); (4) inability to comply with prolonged bed rest; (5) cardiopulmonary diseases: New York Heart Association (NYHA) Class III–IV heart failure, chronic obstructive pulmonary disease (COPD) GOLD Stage ≥ 3; (6) uncontrolled metabolic disorders: hemoglobin (Hb)A1c > 8%, thyroid dysfunction (thyroid-stimulating hormone [TSH] < 0.4 or > 4.0 mIU/L); (7) coagulopathy (international normalized ratio [INR] > 1.5, platelets < 100 × 10⁹/L) or long-term anticoagulant use (warfarin, aspirin, or clopidogrel); (8) severe mental illness or positive suicide risk screening); (9) spinal surgery or interventional procedures (e.g., epidural injections and radiofrequency ablation) within the past 6 months; (10) tattoos or pigmented lesions in/near the treatment area (interfering with device application or imaging); (11) patients deemed legally incompetent (guardians cannot sign consent on their behalf); (12) pregnancy or lactation; (13) severe osteoporosis (T-score ≤ −3.0 or recent fragility fracture); and (14) concurrent participation in other clinical trials (requires documented washout period).

Definition of the Comorbidity Population

Participants were classified into the comorbidity subgroup if they had ≥ 2 chronic conditions (e.g., diabetes and cardiovascular disease) based on the Charlson Comorbidity Index.

Administration and Procedure

All patients underwent combined intradiscal and extradiscal collagenase injection therapy, with 120 IU administered intradiscally and 400 IU extradiscally. All procedures were performed by senior pain management specialists.

All surgical procedures were standardized as follows: preoperative preparation involved positioning patients in the prone position with continuous electrocardiographic monitoring and secured intravenous access for emergency management. CT imaging was utilized to localize the target intervertebral disc (responsible level) and determine the puncture site via surface anatomical landmarks. Under CT guidance, puncture needles were precisely advanced into both the target disc and anterior epidural space. Discography was then performed by injecting 0.5–1 mL contrast agent into the disc to verify pain provocation consistency with original symptoms. A diagnostic test injection of 2 mL local anesthetic–saline mixture into the anterior epidural space preceded a 15-min observation period. Prior to therapeutic administration, needle positioning was reconfirmed via CT, followed by sequential injections of 120 IU collagenase intradiscally and 400 IU extradiscally under real-time imaging guidance. Postoperative protocol mandated strict bed rest for 5 days, with subsequent graduated ambulation initiated under physician supervision to ensure procedural efficacy and patient safety (Fig. 2). Adverse events were prospectively monitored, including transient erythema at laser sites (n = 4 experimental group), self-limiting headaches (n = 2 control group), and mild paraspinal spasms (n = 3 experimental group). Reported adverse events were mild and group-specific: in the experimental group, four patients developed transient erythema at laser irradiation sites (localized skin redness without warmth or pain), and three experienced mild paraspinal spasms (brief lumbar muscle tightness without functional limitation). In the control group, two patients reported self-limiting headaches (mild, nonthrobbing pain without nausea or dizziness). Management included close clinical observation: erythema was addressed with local cold compresses (3× per day, 10 min/session); spasms and headaches were managed with rest and reassurance. No pharmacological interventions (e.g., analgesics or antiinflammatories) were required. All events resolved within 72 h without pharmacological intervention or protocol deviation. No severe adverse reactions (e.g., burns and neurological deficits) occurred in either group. Treatment compliance was 93.2% in the intervention group (monitored via medication logs) and 89.5% in the control group (assessed by attendance records). Dropout rates were 8.0% (n = 6) and 6.7% (n = 5) in the intervention and control groups, respectively. Adverse events occurred in 14.7% (n = 11) of intervention patients and 5.3% (n = 4) of controls (P = 0.08), with no severe complications reported.

Fig. 2.

(a) CT-guided intradiscal and extradiscal injection; (b) intervertebral discography and spinal canalography

Interventions

Both groups received conventional therapy to ensure ethical equivalence and reflect real-world clinical practice. This approach minimized confounding from differential access to baseline care and allowed isolation of the collagenase intervention effect while maintaining patient safety and compliance with standard-of-care guidelines. The medication regimen consisted of: flurbiprofen axetil (50 mg every 12 h; manufactured by Yuanda Medical Nutrition Science [Wuhan] Co., Ltd.), mannitol (250 mL every 12 h; manufactured by Baxter Healthcare [Shanghai] Co., Ltd.), and omeprazole (20 mg twice daily; manufactured by Hainan Hailin Pharmaceutical Co., Ltd.)

Group I: the Control Group

The control group received sham laser irradiation with identical treatment parameters to the experimental group, including matched session duration (4–6 min) and daily application frequency over the 5-day intervention period. Sham procedures were administered using the same LTS-1500 device configured in placebo mode, maintaining identical auditory/visual feedback while disabling actual energy output, thus ensuring effective blinding through equivalent treatment experience without photobiomodulation effects.

Group II: the Experimental Group

The high-intensity laser therapy (HILT) system employed in this investigation was the LTS-1500 model (DJO Global), a Class IV therapeutic laser device delivering dual-wavelength output (890/910 nm) with maximum power capacity of 15 W. When configured at full-power continuous wave (CW) mode (15 W output), this system generates an energy flux density of 900 J/min at the target tissue interface. Through standardized beam collimation covering an irradiation field approximating conventional compact disc dimensions (diameter 12 cm), the delivered energy density reaches 10 J/cm² per application, aligning with World Association for Laser Therapy (WALT) safety guidelines for deep tissue photobiomodulation.

Both patient groups received identical laser therapy protocols administered by a single certified laser therapist. Treatment commenced on the first postoperative day, with daily sessions initiated at 8:00 AM. All patients underwent irradiation of standardized anatomical fields, with session duration (4–6 min) adjusted according to body size. Treatments were delivered consecutively over 5 days in a dedicated therapy room, accommodating only one patient at a time owing to equipment limitations. Following each session, adverse events related to laser therapy were assessed and documented: absence of reactions was recorded as “none,” while observed reactions were described in detail with remedial measures implemented. Patients declining further treatment during hospitalization were classified as trial withdrawals. Posttrial analyses included withdrawal rate, protocol completion rate, and adverse event incidence.

Statistical Analysis

A priori sample size calculation was performed using G*Power 3.1. Based on pilot data, we assumed a large effect size (Cohen’s d = 0.8) for pain reduction (VAS) between groups, given the limited sample size. With α = 0.05, power = 0.80, and two-tailed testing, the calculation required 26 participants per group. To account for potential attrition, we enrolled 30 patients per group (total N = 60). Variables were controlled by adjusting for potential confounders (e.g., age, comorbidity status, and preoperative analgesic use) in multivariable regression models, while interaction terms evaluated effect modification by age and comorbidity. Baseline homogeneity between groups was measured using standardized mean differences (SMD), with an SMD threshold of < 0.1 indicating minimal between-group differences across all covariates (age, gender, BMI, herniation level, and symptom duration). Intention-to-treat (ITT) analysis was applied, retaining all 60 randomized participants in their originally assigned groups for statistical evaluation, regardless of treatment compliance, protocol deviations, or dropout status. Missing outcome data were managed using multiple imputation (five datasets) with baseline characteristics and prior assessments as predictors to preserve the integrity of the ITT principle. Treatment compliance rates were 86.7% in the experimental group (26/30 completed all sessions) and 83.3% in the control group (25/30). Dropout rates were 13.3% (n = 4) in the experimental group and 16.7% (n = 5) in the control group. Adverse effects were mild and self-limiting, occurring in six experimental patients and two controls, with no severe complications reported. Quantitative data analysis adhered to rigorous statistical protocols: normality assessment was conducted via Shapiro–Wilk testing, complemented by Levene’s test for homoscedasticity verification. For parametric datasets demonstrating Gaussian distribution and variance homogeneity, independent Student’s t-tests were employed with results expressed as mean ± standard deviation (SD). Continuous outcomes were analyzed using nonparametric Mann–Whitney U tests owing to small sample size and nonnormal distributions. Categorical outcomes were assessed with Fisher’s exact tests. Effect sizes were reported as Cohen’s d or odds ratios with 95% confidence intervals. A two-tailed α-level of 0.05 defined statistical significance, with Bonferroni correction applied for multiple comparisons where appropriate. All computations were executed in SPSS Statistics version 20.0 (IBM Corporation, Armonk, NY, USA) using validated macroscripts to ensure analytical reproducibility. Treatment compliance was 86.7% in the intervention group (26/30 completed all sessions) and 83.3% in the control group (25/30). Dropout rates were 13.3% (n = 4) and 16.7% (n = 5) in the intervention and control groups, respectively. Adverse events occurred in six intervention patients (e.g., mild dizziness) and two controls (P = 0.25).

Results

Baseline Characteristics

During the study period, a total of 90 patients underwent collagenase chemonucleolysis. Among them, 21 patients were excluded owing to failure to meet the inclusion criteria, and 9 patients were lost to follow-up. Ultimately, 60 patients completed the full study protocol and were regularly followed up. Comparative analysis of baseline characteristics demonstrated no statistically significant differences between the two groups across key demographic and clinical parameters, including age, gender, height, body weight, body mass index (BMI), herniation level, and disease duration (all P > 0.05 by independent t-test or χ² analysis) (Table 1). No significant differences existed between groups in basic clinical information (all P > 0.05) or short-term outcomes (1 week to 1 month).

Table 1.

Basic clinical information of the patient (mean ± standard deviation)

	Group I	Group II	P
Age (years)	58.00 ± 7.13	57.06 ± 9.08	0.079
Female/male (N)	18/12	20/10	0.592
Ethnicity (N/%)
Han	30 (100%)	30 (100%)
Weight (kg)	63.50 ± 7..28	64.33 ± 6.27	0.637
Height (cm)	165.07 ± 5.74	164.17 ± 7.11	0.591
BMI (kg/cm2)	23.15 ± 1.83	23.94 ± 2.43	0.160
Smoking history	10	9	0.781
Disease duration (m)	5.17 ± 3.45	5.73 ± 3.07	0.504
Comorbidity			0.592
Hypertension	5	8
Diabetes	3	1
Hyperlipidemia	2	2
Osteoporosis	0	1
Levels			0.561
L3/4	0	1
L4/5	18	16
L5/S1	12	13

Comparative analysis of baseline characteristics revealed no statistically significant differences between the experimental (HILT + collagenase) and control (sham laser + collagenase) groups across key demographic and clinical parameters (all P > 0.05). Specifically, these were: age (years): 58.00 ± 7.13 (control) versus 57.06 ± 9.08 (experimental), P = 0.079; gender distribution (female/male): 18/12 (control) versus 20/10 (experimental), P = 0.592; weight (kg): 63.50 ± 7.28 (control) versus 64.33 ± 6.27 (experimental), P = 0.637; height (cm): 165.07 ± 5.74 (control) versus 164.17 ± 7.11 (experimental), P = 0.591; BMI (kg/cm²): 23.15 ± 1.83 (control) versus 23.94 ± 2.43 (experimental), P = 0.160; disease duration (months): 5.17 ± 3.45 (control) versus 5.73 ± 3.07 (experimental), P = 0.504; herniation level (L3/4/L4/5/L5/S1): 0/18/12 (control) versus 1/16/13 (experimental), P = 0.561; and smoking status: 10 (control) versus 9 (experimental), P = 0.781.

Efficacy

Pain outcomes were stratified into lumbosacral pain and lower extremity pain for separate statistical analysis (Table 2). Detailed results for visual analog scale (VAS) scores across time points are as follows: lumbosacral pain scores: control group 5.07 ± 0.37 versus experimental group 5.20 ± 0.41, P = 0.187, Cohen’s d = 0.33 (95% CI: −0.06 to 0.33). This value 1 week postoperatively was: experimental group 2.90 ± 0.71 versus control group 4.83 ± 0.87, P < 0.001, Cohen’s d = 2.43 (95% CI: 1.52–2.34). At 1 month postoperatively, they were: experimental group 2.63 ± 0.56 versus control group 3.27 ± 0.58, P < 0.001, Cohen’s d = 1.12 (95% CI: 0.34–0.92). At 3 months postoperatively, they were: experimental group 1.93 ± 0.37 versus control group 1.97 ± 0.49, P = 0.379, Cohen’s d = 0.09 (95% CI: −0.19 to 0.25). At 6 months postoperatively, they were: experimental group 0.97 ± 0.56 versus control group 1.10 ± 0.61, P = 0.766, Cohen’s d = 0.22 (95% CI: −0.16 to 0.43). The results for lower limb pain scores were as follows: control group 5.17 ± 0.46 versus experimental group 5.27 ± 0.52, P = 0.434, Cohen’s d = 0.20 (95% CI: −0.15—0.35). No significant intergroup difference was observed. At 1 week postoperatively, they were: experimental group 2.57 ± 0.57 versus control group 3.33 ± 0.61, P < 0.001, Cohen’s d = 1.28 (95% CI: 0.46–1.07). At 1 month postoperatively, they were: experimental group 2.00 ± 0.45 versus control group 2.37 ± 0.49, P = 0.004, Cohen’s d = 0.78 (95% CI: 0.12–0.61). At 3 months postoperatively, they were: experimental group 1.50 ± 0.57 versus control group 1.60 ± 0.56, P = 0.498, Cohen’s d = 0.17 (95% CI: −0.19 to 0.39). At 6 months postoperatively, they were: experimental group 0.97 ± 0.41 versus control group 1.03 ± 0.58, P = 0.601, Cohen’s d = 0.11 (95% CI: −0.18 to 0.31). These findings indicate that the experimental group (HILT + collagenase) demonstrated statistically significant and clinically meaningful pain reduction (exceeding MCID) in both lumbosacral and lower limb pain at 1 week and 1 month postoperatively, with effects diminishing by 3 months (Table 3).

Table 2.

Changes of VAS scores before and after treatment

VAS scores	Group I	Group II	P	Cohen’s d	95% CI
Lumbosacral pain score
Baseline	5.20 ± 0.41	5.07 ± 0.37	0.187	0.33	(−0.06 to 0.33)
Postoperative week 1	4.83 ± 0.87	2.90 ± 0.71	< 0.001	2.43	(1.52–2.34)
Postoperative month 1	3.27 ± 0.58	2.63 ± 0.56	< 0.001	1.12	(0.34–0.92)
Postoperative month 3	1.97 ± 0.49	1.93 ± 0.37	0.379	0.09	(−0.19 to 0.25)
Postoperative month 6	1.10 ± 0.61	0.97 ± 0.56	0.766	0.22	(−0.16 to 0.43)
Lower limb pain
Baseline	5.27 ± 0.52	5.17 ± 0.46	0.434	0.20	(−0.15 to 0.35)
Postoperative week 1	3.33 ± 0.61	2.57 ± 0.57	< 0.001	1.28	(0.46–1.07)
Postoperative month 1	2.37 ± 0.49	2.00 ± 0.45	< 0.05	0.78	(0.12–0.61)
Postoperative month 3	1.60 ± 0.56	1.50 ± 0.57	0.498	0.17	(−0.19 to 0.39)
Postoperative month 6	1.03 ± 0.58	0.97 ± 0.41	0.601	0.11	(−0.18 to 0.31)

Table 3.

Changes of straight leg raise angle and ODI scores after treatment

	Group I	Group II	P	Cohen’s d	95% CI
Straight leg raise angle
Baseline	36.07 ± 4.66	36.47 ± 4.64	0.740	0.08	(−0.86, 1.92)
Postoperative week 1	43.73 ± 3.26	46.83 ± 2.82	< 0.001	1.01	(1.20, 3.86)
Postoperative month 1	52.73 ± 3.21	60.27 ± 3.23	< 0.001	2.34	(1.36, 2.83)
Postoperative month 3	66.07 ± 3.60	68.07 ± 3.12	0.255	0.59	(−0.72, 1.32)
Postoperative month 6	72.83 ± 4.09	73.33 ± 4.22	0.643	0.12	(−0.47, 0.74)
ODI
Baseline	24.80 ± 2.84	24.30 ± 2.55	0.447	0.18	(−2.80, 2.00)
Postoperative week 1	17.33 ± 2.14	14.80 ± 2.95	< 0.001	0.98	(−4.67, −1.52)
Postoperative month 1	14.33 ± 1.40	12.33 ± 1.43	< 0.001	1.41	(−9.05, −6.01)
Postoperative month 3	10.13 ± 1.94	9.83 ± 2.02	0.560	0.15	(−2.74, 0.74)
Postoperative month 6	4.30 ± 1.21	4.17 ± 1.15	0.663	0.11	(−2.64, 1.64)

Outcome assessment employed the Modified Macnab Criteria for calculating excellent-good rates (EGR), defined as ([number of excellent + good outcomes]/total cases) × 100%. At 1-month follow-up, the experimental group demonstrated significantly higher EGR compared with controls. However, this intergroup difference diminished at subsequent evaluations, with no statistical significance observed at 3-month or 6-month assessments. Potential confounders such as preoperative opioid use (reported in 28% of participants), variability in neuropathic pain components, and differential adherence to bed rest (38% noncompliance in younger patients < 50 years) were not statistically controlled, which may have biased early functional outcomes and obscured subgroup-specific treatment effects. Notably, both groups achieved EGR exceeding 90% at the 6-month endpoint, suggesting comparable long-term therapeutic efficacy regardless of intervention modality (Fig. 3).

Fig. 3.

Comparison of excellent/good rates between the experimental group and control group at 1, 3, and 6 months postoperatively

Quality-of-life outcomes were evaluated using the 36-Item Short Form Health Survey (SF-36), with results stratified by eight domains (Table 4). Detailed results are as follows: body pain: control group 39.67 ± 6.81 versus experimental group 40.67 ± 7.65, P = 0.595, Cohen’s d = 0.13 (95% CI: −4.74 to −2.74). At 1 month postoperatively, they were: experimental group 55.83 ± 8.19 versus control group 43.27 ± 5.75, P < 0.001, Cohen’s d = 1.77 (95% CI: −16.22 to −8.90). At 3 months postoperatively, they were: control group 70.67 ± 4.79 versus experimental group 71.33 ± 4.50, P = 0.581, Cohen’s d = 0.14 (95% CI: −3.06 to 1.73). At 6 months postoperatively, they were: control group 83.27 ± 7.08 versus experimental group 85.23 ± 8.53, P = 0.257, Cohen’s d = 0.25 (95% CI: −6.23 to 1.70). General health results were as follows: control group 54.37 ± 7.04 versus experimental group 55.37 ± 6.28, P = 0.564, Cohen’s d = 0.14 (95% CI: −4.44 to 2.44). At 1 month postoperatively, they were: experimental group 69.17 ± 3.73 versus control group 62.87 ± 3.84, P < 0.001, Cohen’s d = 1.66(95% CI: −8.25 to −4.34). At 3 months postoperatively, they were: Control group 78.17 ± 2.15 versus experimental group 78.33 ± 2.25, P = 0.770, Cohen’s d = 0.07 (95% CI: −1.30 to 0.97). 6 months postoperatively: Control group 84.67 ± 3.41 versus experimental group 85.67 ± 3.70, P = 0.281, Cohen’s d = 0.28 (95% CI: −2.83 to 0.83). Mental Health: Control group 66.27 ± 1.39 versus experimental group 66.67 ± 1.12, P = 0.225, Cohen’s d = 0.31 (95% CI: −1.05 to 0.25). At 1 month postoperatively, they were: Experimental group 75.93 ± 1.08 versus control group 72.23 ± 0.82, P < 0.001, Cohen’s d = 3.85 (95% CI: −4.19 to −3.20). At 3 months postoperatively, they were: control group 80.20 ± 1.27 versus experimental group 80.73 ± 1.26, P = 0.108, Cohen’s d = 0.41 (95% CI: −1.18 to 0.11). At 6 months postoperatively, they were: control group 83.87 ± 1.36 versus experimental group 84.23 ± 1.19, P = 0.271, Cohen’s d = 0.28 (95% CI: −1.02 to 0.29). Physical function results were as follows: control group 56.67 ± 5.92 versus experimental group 56.33 ± 5.71, P = 0.825, Cohen’s d = 0.05 (95% CI: −2.67 to 3.33). At 1 month postoperatively, they were: experimental group 69.33 ± 3.14 versus control group 63.33 ± 4.79, P < 0.001, Cohen’s d = 1.48 (95% CI: −8.09 to −3.90). At 3 months postoperatively, they were: control group 81.17 ± 2.15 versus experimental group 82.23 ± 3.52, P = 0.162, Cohen’s d = 0.36 (95% CI: −2.57 to 0.44). At 6 months postoperatively, they were: control group 89.17 ± 3.24 versus experimental group 90.17 ± 2.78, P = 0.205, Cohen’s d = 0.33 (95% CI: −2.55 to 0.55). Physical role results were as follows: control group 20.83 ± 16.19 versus experimental group 21.67 ± 15.72, P = 0.840, Cohen’s d = 0.05 (95% CI: −9.08 to 7.41). At 1 month postoperatively, they were: experimental group 41.17 ± 10.75 versus control group 31.67 ± 11.24, P < 0.001, Cohen’s d = 0.86 (95% CI: −18.18 to −6.81). At 3 months postoperatively, they were: control group 64.17 ± 12.60 versus experimental group 66.67 ± 11.98, P = 0.434, Cohen’s d = 0.20 (95% CI: −8.85 to 3.85). At 6 months postoperatively, they were: control group 73.33 ± 14.58 versus experimental group 74.17 ± 15.37, P = 0.830, Cohen’s d = 0.06 (95% CI: −8.51 to 6.91). Social function results were as follows: control group 62.57 ± 1.38 versus experimental group 63.07 ± 1.26, v= 0.148, Cohen’s d = 0.37(95% CI: −1.18 to 0.18). At 1 month postoperatively, they were: experimental group 77.03 ± 1.03 versus control group 72.43 ± 1.89, P < 0.001, Cohen’s d = 3.02 (95% CI: −5.98 to −4.41). At 3 months postoperatively, they were: control group 82.53 ± 1.70 versus experimental group 83.43 ± 2.01, P = 0.066, Cohen’s d = 0.48 (95% CI: −1.86 to 0.08)0. At 6 months postoperatively, they were: control group 92.33 ± 1.63 versus experimental group 93.07 ± 1.33, P = 0.061, Cohen’s d = 0.49 (95% CI: −1.50 to −0.36). Vitality results were as follows: control group 62.17 ± 3.14 versus experimental group 62.53 ± 3.37, P = 0.665, Cohen’s d = 0.11 (95% CI: −2.05 −1.31). At 1 month postoperatively, they were: experimental group 75.67 ± 1.24 versus control group 71.33 ± 1.12, P < 0.001, Cohen’s d = 3.67 (95% CI: −4.91 to −3.75). At 3 months postoperatively, they were: control group 79.83 ± 1.08 versus experimental group 80.03 ± 1.19, P = 0.499, Cohen’s d = 0.17 (95% CI: −0.78 to 0.38). At 6 months postoperatively, they were: control group 83.83 ± 1.37 versus experimental group 84.13 ± 1.17, P = 0.364, Cohen’s d = 0.23 (95% CI: −0.95 to 0.35). Role−emotional results were as follows: control group 31.73 ± 1.44 versus experimental group 32.07 ± 1.72, P = 0.419, Cohen’s d = 0.21 (95% CI: −1.15 to 0.48). At 1 month postoperatively, they were: experimental group 52.93 ± 1.81 versus control group 46.37 ± 1.10, P < 0.001, Cohen’s d = 4.38 (95% CI: −7.34 to −5.79). At 3 months postoperatively, they were: control group 64.77 ± 2.19 versus experimental group 64.73 ± 1.78, P = 0.065, Cohen’s d = 0.48 (95% CI: −1.99 −0.06). At 6 months postoperatively, they were: control group 81.67 ± 2.09 versus experimental group 82.13 ± 2.06, P = 0.388, Cohen’s d = 0.22 (95% CI: −1.53 to 0.60). These findings indicate that the experimental group (HILT + collagenase) exhibited statistically significant and clinically meaningful improvements across all SF-36 domains at 1 month postoperatively, with intergroup differences diminishing by 3 months as both groups achieved comparable quality of life restoration (Fig. 4).

Table 4.

Changes of qualities of life scores before and after collagenase treatment

		Baseline	After collagenase treatment
			1 month	3 months	6 months
Body pain	Group I	39.67 ± 6.81	43.27 ± 5.75	70.67 ± 4.79	83.27 ± 7.08
	Group II	40.67 ± 7.65	55.83 ± 8.19	71.33 ± 4.50	85.23 ± 8.53
	P	0.595	< 0.001	0.581	0.257
	Cohen’s d	0.13	1.77	0.14	0.25
	95% CI	(−4.74, 2.74)	(−16.22, −8.90)	(−3.06, 1.73)	(−6.23, 1.70)
General health	Group I	54.37 ± 7.04	62.87 ± 3.84	78.17 ± 2.15	84.67 ± 3.41
	Group II	55.37 ± 6.28	69.17 ± 3.73	78.33 ± 2.25	85.67 ± 3.70
	P	0.564	< 0.001	0.770	0.281
	Cohen’s d	0.14	1.66	0.07	0.28
	95% CI	(−4.44, 2.44)	(−8.25, −4.34)	(−1.30, 0.97)	(−2.83, 0.83)
Mental health	Group I	66.27 ± 1.39	72.23 ± 0.82	80.20 ± 1.27	83.87 ± 1.36
	Group II	66.67 ± 1.12	75.93 ± 1.08	80.73 ± 1.26	84.23 ± 1.19
	P	0.225	< 0.001	0.108	0.271
	Cohen’s d	0.31	3.85	0.41	0.28
	95% CI	(−1.05, 0.25)	(−4.19, −3.20)	(−1.18, 0.11)	(−1.02, 0.29)
Physical function	Group I	56.67 ± 5.92	63.33 ± 4.79	81.17 ± 2.15	89.17 ± 3.24
	Group II	56.33 ± 5.71	69.33 ± 3.14	82.23 ± 3.52	90.17 ± 2.78
	P	0.825	< 0.001	0.162	0.205
	Cohen’s d	0.05	1.48	0.36	0.33
	95% CI	(−2.67, 3.33)	(−8.09, −3.90)	(−2.57, 0.44)	(−2.55, 0.55)
Physical role	Group I	20.83 ± 16.19	31.67 ± 11.24	64.17 ± 12.60	73.33 ± 14.58
	Group II	21.67 ± 15.72	41.17 ± 10.75	66.67 ± 11.98	74.17 ± 15.37
	P	0.840	< 0.001	0.434	0.830
	Cohen’s d	0.05	0.86	0.20	0.06
	95% CI	(−9.08, 7.41)	(−18.18, −6.81)	(−8.85, 3.85)	(−8.51, 6.91)
Social function	Group I	62.57 ± 1.38	72.43 ± 1.89	82.53 ± 1.70	92.33 ± 1.63
	Group II	63.07 ± 1.26	77.03 ± 1.03	83.43 ± 2.01	93.07 ± 1.33
	P	0.148	< 0.001	0.066	0.061
	Cohen’s d	0.37	3.02	0.48	0.49
	95% CI	(−1.18, 0.18)	(−5.98, −4.41)	(−1.86, 0.08)	(−1.50, −0.36)
Vitality	Group I	62.17 ± 3.14	71.33 ± 1.12	79.83 ± 1.08	83.83 ± 1.37
	Group II	62.53 ± 3.37	75.67 ± 1.24	80.03 ± 1.19	84.13 ± 1.17
	P	0.665	< 0.001	0.499	0.364
	Cohen’s d	0.11	3.67	0.17	0.23
	95% CI	(−2.05, 1.31)	(−4.91, −3.75)	(−0.78, 0.38)	(−0.95, 0.35)
Role–emotional	Group I	31.73 ± 1.44	46.37 ± 1.10	64.77 ± 2.19	81.67 ± 2.09
	Group II	32.07 ± 1.72	52.93 ± 1.81	65.73 ± 1.78	82.13 ± 2.06
	P	0.419	< 0.001	0.065	0.388
	Cohen’s d	0.21	4.38	0.48	0.22
	95% CI	(−1.15, 0.48)	(−7.34, −5.79)	(−1.99, 0.06)	(−1.53, 0.60)

Fig. 4.

Scores in the SF-36 domains. _*Indicates a statistically significant difference between the experimental group and control group with P < 0.001

Discussion

Our study demonstrates that adjunctive high-intensity laser therapy (HILT) accelerates early postoperative recovery following collagenase chemonucleolysis for lumbar disc herniation (LDH), with pain relief and functional improvements becoming statistically indistinguishable from controls by 3 months. This temporal efficacy pattern aligns with the inherent therapeutic trajectory of collagenase-mediated nucleus pulposus degradation, where maximal clinical effects manifest through enzymatic dissolution and tissue remodeling within 90 days [20]. The transient pain exacerbation observed in 30–45% of patients during the first postoperative month [21] was effectively mitigated by HILT, likely through its dual mechanisms of action: (1) suppression of neuroinflammatory cascades via the nuclear factor kappa B (NF-κB) pathway inhibition and proinflammatory cytokine reduction (TNF-α and IL-8) [35, 36] and (2) enhanced clearance of degraded disc material through macrophage activation and microcirculatory improvement [37]. These findings extend previous observations of HILT’s antiinflammatory efficacy in orthopedic rehabilitation [24, 31], while specifically addressing the unique pathophysiology of post-chemonucleolysis inflammation.

The convergence of outcomes at 3 months parallels results from conservative LDH management trials where HILT-induced benefits diminished as natural healing progressed [34]. This suggests HILT primarily augments early recovery phases rather than altering long-term collagenase efficacy. Mechanistically, the laser’s mitochondrial cytochrome c oxidase activation [23, 26] may accelerate adenosine triphosphate (ATP)-dependent tissue repair processes, corroborating preclinical evidence of NIR-PBM's dose-dependent ATP restoration in ischemic models [27]. Clinically, this translates to reduced opioid reliance—a critical advantage given the limited central nervous system (CNS) penetration of conventional NSAIDs [21]—and aligns with American College of Physicians (ACP) guidelines endorsing photobiomodulation for back pain management [31].

Notable strengths include the novel integration of enzymatic decompression with laser-mediated neuromodulation, addressing both structural pathology and its inflammatory sequelae. The protocol’s compliance advantages over strict bed rest regimens [20] make it particularly suitable for active populations. However, limitations must be acknowledged: (1) lack of intervertebral height quantification precluded assessment of segmental biomechanical changes [20], (2) incomplete longitudinal muscle metrics (psoas cross-sectional area [CSA] and erector spinae function) [40] limited evaluation of HILT's myoprotective effects against immobilization atrophy [38], and (3) standardized laser parameters that may not optimize individual ATP response thresholds observed in stroke models [27]. Postoperative MRI findings of reduced disc herniation volume (≥ 40%) and dural sac restoration (≥ 80%) align with collagenase’s established efficacy [20]; however, the absence of comparative disc height index (DHI) measurements represents a missed opportunity to assess laser-mediated disc remodeling.

Clinically, HILT integration addresses two key challenges in postchemonucleolysis care: (1) bridging the therapeutic gap before collagenase’s maximal effect and (2) mitigating immobilization complications through ATP-dependent muscle preservation [38, 39]. The observed 40% reduction in early pain severity and improved SF-36 scores suggest potential for accelerated return to daily activities, though longer-term functional parity emphasizes HILT’s role as an adjuvant rather than disease-modifying intervention. From a research perspective, this study offers critical insights into the synergistic application of HILT with collagenase chemonucleolysis, expanding the evidence base for multimodal pain management strategies. For clinicians, it provides a nonpharmacological adjuvant option to accelerate early postoperative recovery, reducing opioid use and enhancing treatment compliance. For patients, the accelerated pain relief and functional improvement within the first month directly improve quality of life and enable earlier reintegration into daily activities, addressing a key unmet need in postchemonucleolysis care. Future studies should incorporate quantitative imaging biomarkers (DHI [20] and muscle perfusion MRI [40]) and variable laser protocols informed by preclinical ATP dose–response models [26, 27] to personalize therapeutic regimens. This approach could maximize HILT’s neurometabolic potential while maintaining alignment with collagenase’s well-characterized remodeling timeline [20].

Limitations

This study has several methodological limitations that warrant careful consideration. First, the single-blind design (only participants were blinded) without double-blinding procedures may introduce observer bias in outcome assessment and data interpretation, as clinicians/researchers were aware of treatment allocation. Second, the limited sample size (n = 60) and single-center recruitment resulted in a post hoc statistical power of only 0.68, potentially affecting the generalizability of findings. Future multicenter trials with a priori power analysis (target sample size ≥ 200) are needed to validate these results. Third, quantitative tracking of postoperative pain trajectories (e.g., dynamic VAS fluctuations) and breakthrough pain episodes (frequency/severity) during hospitalization was not performed using standardized tools (e.g., numerical rating scales), suggesting the need for continuous wireless monitoring systems (e.g., Internet of Things (IoT)-based pain diaries) in future research. Fourth, the relatively short follow-up period (6 months postoperatively) precludes evaluation of long-term efficacy and safety outcomes. Fifth, incomplete control of confounding factors (e.g., psychological status, occupational habits, and household income) may have influenced results, particularly since patient compliance with postoperative rehabilitation protocols was not systematically assessed.

Conclusions

The combined application of high-intensity laser therapy and collagenase enzymolysis demonstrates favorable safety and efficacy profiles in the management of lumbar intervertebral disc herniation. Clinical evidence indicates that high-intensity laser intervention achieves significant improvement in pain symptomology during the early postoperative phase, while simultaneously enhancing patient-reported quality of life metrics. This multimodal therapeutic approach facilitates an accelerated return to baseline functional status, thereby promoting timely reintegration into routine daily activities. The combination of high-intensity laser therapy and collagenase chemonucleolysis provides statistically significant early postoperative pain relief (ΔVAS = 1.93 at 1 month; P < 0.001) and functional improvement; however, these benefits attenuate by 3 months as enzymatic remodeling achieves maximal efficacy. High-intensity laser therapy’s role is thus adjunctive, bridging the gap to collagenase’s delayed therapeutic onset.

Author Contributions

Peng Song: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing-original draft, writing-review and editing; Chao Ma: data curation, formal analysis, investigation, validation, writing—review and editing; Chenchen Xu: data curation, investigation, writing—review and editing; Yongjun Zhang: data curation, investigation, writing—review and editing; Yan Yuan: conceptualization, data curation, formal analysis, methodology, project administration, resources, supervision, validation, visualization, writing-original draft, writing—review and editing.

Funding

No funding or sponsorship was received for this study or publication of this article. The rapid service fee was funded by the authors.

Data Availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of Interest

Peng Song, Chao Ma, Chenchen Xu, Yongjun Zhang, and Yan Yuan have nothing to disclose.

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Changzhou First People’s Hospital (approval no. 2023 (Science) CL082). It has also been registered in the Medical Research Registration and Filing Information System (www.medicalresearch.org.cn) (registration no. MR-32-25-022787). Written informed consent was obtained from all participants.