Introduction
The prevalence of spine surgery has seen a notable increase globally. A multicenter study in Japan, involving nine hospitals, reported a 2.4-fold increase in spinal surgeries from 2003 to 2017, with a 2.6-fold increase in surgeries for degenerative conditions [1]. Similarly, a study in South Africa indicated a 26% increase in spine surgeries over the past decade [2]. Despite these advancements, chronic pain post-surgery or failed back surgery syndrome remains a significant issue, affecting nearly 40% of patients. This persistent pain is often attributed to structural and non-structural factors, including postoperative changes in the local microenvironment, maladaptive sensory nervous system changes, glial cell activation, and inflammation. Surgical handling of the nerve roots or dorsal root ganglia can induce fibrosis, leading to late-onset pain [3,4].
Localized and targeted delivery of anti-inflammatory agents can mitigate postoperative pain without the risks associated with systemic administration of anti-inflammatory analgesics or opioids. Although various methods, including epidural injections, irrigation, or intravenous administration of anti-inflammatory drugs have been explored, the use of gelatin sponges as a delivery vehicle for anti-inflammatory agents in spine surgery remains understudied and warrants further research [5,6]. Gelatin sponges, widely used in spinal surgeries for their hemostatic properties, also help prevent adhesions between neural elements and soft tissues [7]. Recent studies have investigated the use of gelatin sponges impregnated with anti-inflammatory analgesics to deliver localized anti-inflammatory effects directly at the surgical site, yielding varied results.
Therefore, this systematic review and meta-analysis aimed to evaluate the safety and efficacy of anti-inflammatory-impregnated gelatin sponges in spine surgery. Our findings may help address a significant gap in spinal surgery literature by synthesizing the available evidence of their potential benefits in controlling postoperative pain and reducing inflammation.
Methods
This systematic review and meta-analysis were conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8]. The review protocol is registered in the PROSPERO International Prospective Register of Systematic Reviews (registration no., CRD42024556146).
Data sources and search strategy
We conducted a comprehensive literature search using the following biomedical databases: PubMed, Europe PMC, ScienceDirect, and Google Scholar. The search strategy included keywords such as “anti-inflammatory gelatin sponge,” “gelfoam,” “postoperative pain,” “outcomes,” and “spine surgery.” These terms were combined using Boolean operators “AND” and “OR.” Table 1 provides a detailed list of the search terms used.
Eligibility criteria
The selection of articles was based on the PICO framework: (1) Population: patients undergoing spine surgeries; (2) Intervention: use of anti-inflammatory (corticosteroids, non-steroidal anti-inflammatory drugs [NSAIDs])-impregnated gelatin sponges during spine surgery; (3) Control: patients not receiving anti-inflammatory gelatin sponges or placebo sponges (e.g., receiving normal saline); and (4) Outcomes: pain scores (back pain and leg pain), disability index, neurological function, and length of hospital stay.
Studies with irrelevant outcomes, review articles, case reports, case series, animal studies, cadaveric studies, and studies not available in full-text format were excluded.
Study selection and data extraction
Two authors (A.P., Y.Y.) independently conducted the literature search and data extraction. Any discrepancies were resolved through discussion with two additional authors (J.T., Y.S.). Data were tabulated using Google Sheets (Google LLC, Mountain View, CA, USA) and Microsoft Excel 2019 (Microsoft Corp., Redmond, WA, USA). Extracted data included study characteristics (sample sizes, surgical types, mean or median age, drug mixtures used in gelatin sponges, and length of hospital stay), and outcomes such as Visual Analog Scale (VAS) scores for leg pain and back pain at various postoperative intervals (preoperative, 1 day, 2 days, 1 week, 1 month, and 3 months), disability indices such as the Oswestry Disability Index (ODI) and Neck Disability Index (NDI), Japanese Orthopedic Association (JOA) scores, and intervention-related complications.
Outcomes
The primary outcome was postoperative pain measured by VAS scores for both back pain and leg pain. Secondary outcomes included disability indices (ODI and NDI), JOA scores, and adverse events associated with the use of anti-inflammatory gelatin sponges. Additional evaluations of each outcome reported were performed using the Grading’s of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment [11].
Statistical analysis
Meta-analyses were performed using Cochrane Review Manager (RevMan) Web (Cochrane). Heterogeneity among the included studies was assessed using the chi-square test (p≤0.05 considered significant) and the I2 statistic. In case of substantial heterogeneity (I2 ≥50%), the random-effects model was used for pooled analysis. For continuous variables, mean differences (MDs) and 95% confidence intervals (CIs) were calculated using the inverse variance method. All p≤0.05 was considered indicative of statistical significance.
Results
Literature search results
The schematic illustration of the study selection process is depicted in the PRISMA diagram (Fig. 1). A total of 472 records were retrieved through database searches. After removing 90 duplicates, 382 articles underwent title and abstract screening, resulting in the exclusion of 360 articles. The full texts of 22 articles were assessed, following which eight articles were excluded due to duplicates (n=6), irrelevant outcome measures (n=1), and abstract-only publication (n=1). Finally, 13 articles were included in the analysis [12–24].
Characteristics of the included studies
The characteristics of the 13 included studies are summarized in Table 2. These studies comprised six RCTs, two retrospective cohorts, four prospective cohorts, and one case-control study, with a combined study population of 1,323 patients. All studies involved the intraoperative use of anti-inflammatory-soaked gelatin sponges (gelfoam) during various spine surgeries. The publication dates ranged from 2006–2008 and 2017–2024. The surgical procedures in the included studies varied, with five of the 13 studies focusing on minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). The anti-inflammatory agents used included corticosteroids like triamcinolone acetonide, dexamethasone, and methylprednisolone. Notably, Du et al. [12–15] reported using a cocktail of dexamethasone, ropivacaine, and vitamin B12 in the gelatin sponge, while Kumari et al. [19] in 2018 used a mixture of levobupivacaine and dexamethasone. Most studies compared the anti-inflammatory gelatin sponges with placebos such as normal saline-soaked sponges.
Risk of bias and GRADE assessment
All the included observational studies had an NOS score of 7–8, indicating a low risk of bias (Table 3). The risk of bias in RCTs was evaluated using the Cochrane Collaboration’s RoB 2.0 tool (Fig. 2). Among the six RCTs, five showed a low risk of bias, while one presented some concerns due to issues related to randomization and missing outcome data. The summary of the GRADE assessment is shown in Table 4. Based on the GRADE assessment, three outcomes (VAS for back pain, leg pain, and length of stay) showed moderate quality in results, as there were no serious publication biases but had serious inconsistency. However, two outcomes (disability index and JOA scoring) had low quality, because of serious publication biases and inconsistency in results.
Meta-analysis results
Visual Analog Scale score for back pain
The pooled analysis of VAS scores for back pain (Fig. 3) revealed that the use of anti-inflammatory gelatin sponges significantly decreased postoperative VAS scores for back pain (MD, −0.62; 95% CI, −0.78 to −0.46; p<0.00001), with significant heterogeneity among the studies (χ2=278.61, degrees of freedom [df]=40, p<0.00001, I2=86%). Subgroup analyses indicated significantly lower VAS scores in the treatment group at 1 day (MD, −0.84; 95% CI, −1.16 to −0.52; p<0.00001), 2 days (MD, −1.03; 95% CI, −1.54 to −0.51; p<0.0001), 1 week (MD, −1.16; 95% CI, −1.53 to −0.78; p<0.00001), 1 month (MD, −0.35; 95% CI, −0.68 to −0.01; p=0.04), and 3 months postoperatively (MD, −0.47; 95% CI, −0.57 to −0.38; p<0.00001), with no significant differences preoperatively (MD, −0.24; 95% CI, −0.55 to 0.08; p=0.14).
Visual Analog Scale score for leg pain
The pooled analysis for VAS scores for leg pain also showed significant reductions (MD, −0.60; 95% CI, −0.87 to −0.34; p<0.00001), with a significant heterogeneity among the studies (χ2=152.93, df=24, p<0.00001, I2=84%) (Fig. 4). The treatment group showed significantly lower VAS scores at 1 day (MD, −0.66; 95% CI, −1.11 to −0.21; p=0.004), 2 days (MD, −1.13; 95% CI, −2.16 to −0.10; p=0.03), and 1 week postoperatively (MD, −0.93; 95% CI, −1.09 to −0.76; p<0.00001). No significant differences were found preoperatively (MD, −0.07; 95% CI, −0.30 to 0.16; p=0.55), at 1 month (MD, −0.23; 95% CI, −0.58 to −0.12; p=0.2), or 3 months (MD, −0.23; 95% CI, −0.58 to −0.12; p=0.2).
Disability index
The pooled analysis of disability index scores showed no significant differences between the treatment and control groups (MD, −0.59; 95% CI, −1.88 to 0.70; p=0.37) (Fig. 5). Subgroup analyses also indicated no significant differences preoperatively (MD, 0.35; 95% CI, −2.23 to 2.94; p=0.79), at 1 month (MD, −0.67; 95% CI, −2.68 to 1.34; p=0.51), or 3 months postoperatively (MD, −0.17; 95% CI, −3.64 to 3.31; p=0.93).
Japanese Orthopedic Association score
The pooled analysis of JOA scores indicated a significant improvement in the treatment group (MD, 0.98; 95% CI, 0.00 to 1.96; p=0.05), with a significant heterogeneity among the studies (χ2=57.59, df=5, p<0.00001, I2=91%) (Fig. 6). Subgroup analyses showed significantly higher JOA scores in the treatment group at 3 days (MD, 0.68; 95% CI, 0.14 to 1.23; p=0.01) and 6 days postoperatively (MD, 2.50; 95% CI, 1.87 to 3.12; p<0.00001). No significant differences were observed in the preoperative JOA level (MD, −0.21; 95% CI, −0.56 to 0.14; p=0.24).
Length of hospital stay
The pooled analysis of hospital length of stay demonstrated a significantly shorter hospital stay in the treatment group (MD, −0.99; 95% CI, −1.68 to −0.31; p=0.004), with significant heterogeneity among the studies (χ2=71.23, df=4, p<0.00001, I2=94%) (Fig. 7).
Complications and adverse events
Table 5 summarizes the complications and adverse events reported in the included studies. Common adverse events included postoperative nausea and vomiting (PONV), headache, surgical site infection, and urinary retention. One study reported bilateral limb weakness that resolved within 24 hours and hypotension. Another study reported deep vein thrombosis in one patient which resolved within 6 months. Two studies reported reoperations and revision surgeries.
Discussion
This meta-analysis demonstrates that the use of anti-inflammatory-impregnated gelatin sponge can significantly reduce postoperative back and leg pain in patients undergoing spine surgeries. Additionally, corticosteroid-impregnated gelatin sponges were found to improve JOA scores and reduce the length of hospital stay compared to the control group. However, there were no significant differences between the intervention and control groups with respect to disability indices (ODI and NDI). Our synthesis of data did reveal some complications and adverse events, including PONV, surgical site infection, urinary retention, hypotension, bilateral limb weakness, and deep vein thrombosis.
Our results are consistent with a previous meta-analysis conducted by Ranguis et al. [25] in 2010, which examined the effectiveness of epidural steroids in lumbar spine surgeries across 12 RCTs. Their study found that perioperative epidural steroids significantly reduced postoperative back pain for 12–24 hours and radicular pain for up to 1 week, as well as shortened hospital stays. Ranguis et al. [25] also reported a significantly lower risk of not returning to full-time work in the steroid group, an outcome that was not assessed in our study.
Additional research, such as the study by Geisler et al. [26] in 2022, has demonstrated the effectiveness of postoperative multimodal pain management, including NSAIDs, epidural steroids, and other analgesic agents, in significantly reducing pain scores and decreasing the need for opioid rescue analgesics. However, their study did not specifically investigate the use of anti-inflammatory agents impregnated within absorbable gelatin sponges, which is the focus of our meta-analysis [26].
Wilson-Smith et al. [27] in 2018 conducted a meta-analysis of 17 RCTs to evaluate the effectiveness of epidural steroids post-microdiscectomy and laminectomy. Their analysis revealed that epidural steroids significantly reduced postoperative VAS scores at 1 and 3 months postoperatively but did not significantly impact VAS scores within the first 24 hours. They also compared different types of epidural steroids, noting that dexamethasone and methylprednisolone were more effective than triamcinolone acetonide. Our study yielded comparable findings regarding shorter length of hospital stay. However, their study also measured postoperative analgesia use, which was not assessed in our meta-analysis [27].
Our meta-analysis found no significant differences in disability indices (ODI and NDI) between the intervention and control groups. The lack of significant changes may be attributable to the included studies’ findings showing no significant relationship between the disability indices in pooled analyses. However, our pooled analysis did indicate improvements in JOA scores in patients treated with anti-inflammatory gelatin sponges compared to controls, suggesting enhanced postoperative neurological function [28].
Our meta-analysis revealed that anti-inflammatory-impregnated gelatin sponges can significantly reduce postoperative back and leg pain in patients undergoing spine surgeries, including MIS-TLIF. The inclusion of several studies focusing on MIS-TLIF, a surgical approach gaining popularity due to its minimally invasive nature, highlights the potential benefits of this intervention in this surgical context.
MIS-TLIF was the most commonly performed procedure in the studies included in our meta-analysis. Many studies on MIS-TLIF have investigated multimodal analgesia approaches for reducing postoperative pain and improving functional outcomes. The use of corticosteroid-impregnated gelatin sponges in these surgeries has shown promising results, particularly in reducing postoperative pain and improving early functional recovery. This is consistent with the findings of our meta-analysis, which showed that corticosteroid-impregnated gelatin sponges significantly reduced postoperative back and leg pain and improved JOA scores, reflecting enhanced neurological function in MIS-TLIF surgery [12–15,22].
Among the 13 studies included in our meta-analysis, several focused specifically on MIS-TLIF. These studies consistently reported significant reductions in pain scores and shorter hospital stays with use of anti-inflammatory gelatin sponges. For instance, Du et al. [12] in 2018 and Du et al. [13] in 2021 demonstrated a notable decrease in VAS scores for both back and leg pain, as well as an improved length of stay in patients undergoing MIS-TLIF. Similarly, Haws et al. [22] in 2019 reported consistent pain reduction with the use of methylprednisolone-impregnated sponges during MIS-TLIF procedures.
Anti-inflammatory agents, particularly corticosteroids, are known to reduce postoperative pain by inhibiting inflammatory responses and preventing the secretion of neuropeptides that stimulate nerve fibers. Corticosteroids, either administered locally or systemically, have been effective in managing postoperative pain, recognized as a persistent issue termed “failed back syndrome [29–31].”
In some cases, corticosteroids have been used in combination with local anesthetic drugs (e.g., ropivacaine, bupivacaine, levobupivacaine), dexmedetomidine, and vitamin B12. These combinations can enhance the safety and effectiveness of pain management strategies [12–14,20,21]. Gelatin sponges offer an effective delivery system for targeted drug administration, allowing for sustained release and increased local concentrations of therapeutic agents. This enhances the efficacy and duration of drug action, particularly in the surrounding sinuvertebral nerves, which are known to contribute to low back pain and lower extremity neuralgia. In the context of spine surgeries, gelatin sponges can be conveniently placed directly over the nerve root, leveraging the easy access to epidural space [12,20,32,33]. The consistency of findings across MIS-TLIF studies in this meta-analysis suggests that anti-inflammatory gelatin sponges may be particularly well-suited for this patient population. The unique technical challenges and postoperative concerns associated with MIS-TLIF, such as minimizing tissue disruption and managing inflammation in a confined surgical area, make the localized delivery of anti-inflammatory agents via gelatin sponges an attractive solution that can enhance patient outcomes [12–14,22].
However, there are certain pitfalls associated with the use of anti-inflammatory gelatin sponges, including risks associated with local anesthetic penetration into the dura mater, such as hypotension and vomiting. Therefore, the use of gelatin sponge is strictly prohibited if dural rupture is suspected during the operation [12,13,20,21]. To mitigate this risk, some spine surgeons employ a technique involving the placement of artificial dura mater attached to the surface of the dura mater, followed by the application of gelatin sponge impregnated with anti-inflammatory drugs around the target nerve roots. This approach prevents nerve root adhesion and slows the effect of the spread of the drug to the dural space [12,13]. Additionally, gelatin sponge-induced mass effect can cause postoperative paresis, emphasizing the need for careful surgical preparation and technique [7].
The strengths of our meta-analysis include the inclusion of recent studies (2017–2024) and a focus on the use of anti-inflammatory gelatin sponges in spine surgery, an area not extensively covered in previous meta-analyses. We also included additional outcome measures, such as JOA scores and disability indices.
Limitations of our study include heterogeneity among the included studies, variations in drug mixtures used in gelatin sponges, small sample sizes, and inconsistent reporting of outcome measures. Future research should aim to standardize these variables to improve the robustness and applicability of findings.
Conclusions
This systematic review and meta-analysis indicate that anti-inflammatory-impregnated gelatin sponges are an effective adjunct in spine surgeries, reducing postoperative pain, shortening hospital stays, and improving neurological function. Gelatin sponges offer a distinct advantage for delivering anti-inflammatory and analgesic drugs in spine surgeries due to their ability to absorb multiple drugs, prevent drug dilution, and prolong the duration of action and therapeutic effects. However, spine surgeons must be aware of potential adverse effects, such as dural compression caused by swollen sponges, although this is rare. While this meta-analysis supports the broader application of anti-inflammatory gelatin sponges in various spine surgeries, the promising results from MIS-TLIF-specific studies indicate the need for further research on this subgroup. Future studies should investigate the optimal dosage and composition of drugs used in gelatin sponges for MIS-TLIF patients or compare outcomes between MIS-TLIF and other surgical techniques to identify the most beneficial contexts for this intervention. We recommend further large-scale, prospective trials to evaluate the efficacy and safety of gelatin sponges as a delivery method for corticosteroids and NSAIDs in spine surgeries.
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