Efficacy of Recombinant Human Epidermal Growth Factor in Pressure Injury Healing: Evidence from Chinese Randomized Controlled Trials

Pressure injuries (PIs) are localized damage involving the skin, mucous membranes, and/or subcutaneous tissue.¹ Age, body mass index, smoking, and anemia are all risk factors for developing PIs.^2,3 The overall prevalence of PIs in palliative care patients, a high-risk population for pressure injuries, was reported to be 12.4% (range 9.9% to 54.7%). In addition to causing significant pain and distress for patients,⁴ PIs are also a serious economic burden for patients and their families.⁵ The annual hospitalization cost in 2016 for PIs was reported to be $2,122, and the treatment cost of each patient has been estimated to range from $30 to $50 per day.⁵ The high overall cost of care also can be a huge burden for caregivers,^5,6 thereby highlighting the importance of healing PIs in a timely manner.

Current therapeutic approaches to managing PIs involve debridement, dressings, topical agents, support surfaces, and antibiotics. Other products and technologies that also being evaluated as adjuvant therapies include electrical stimulation, growth factors, skin grafts, nutrition therapy, laser technology, light therapy, electromagnetic therapy,⁷ ultrasound therapy, negative pressure wound therapy, and zinc therapy.^8,9

However, the methods currently used in clinical practice do have shortcomings; for example, gauze dressings need to be changed frequently, honey dressings have poor efficacy, and hydrogel dressings do not stay affixed to the injury.¹⁰ Additionally, standard hospital foam mattresses—widely used in clinical practice—may have negative effects on the population at high risk for PIs, so hospitals should have higher-specification foam mattresses available.¹¹ Also, some adjuvant therapies that have been investigated were demonstrated to be effective in patients with PIs but have some limitations. Therefore, better methods and techniques need to be developed and used.

Recombinant human epidermal growth factor (rhEGF) has been demonstrated to be a potential therapeutic method for wound healing. Epidermal growth factor is a single-chain polysaccharide composed of 53 amino acids; it features a variety of biological activities and a low molecular weight. EGF in the form of a solution or gel interacts with the EGF receptor in epidermal cells, promoting epithelial cell growth on wounds, stimulating fibroblasts to synthesize and secrete structural proteins such as collagen (thereby promoting tissue repair and healing), regulating the contraction and relaxation function of smooth muscle cells, and participating in the normal function of organs.¹² A study by Merner et al¹³ summarized the mechanism of EGF’s role in the treatment of PIs as follows: 1) chemotaxis—EGF can promote the migration of large numbers of cells such as epithelial cells, neutrophils and fibroblasts to the damaged area; 2) proliferation—EGF then accelerates the initiation of wound tissue regeneration, repair, and the formation of extracellular matrix and promotes granulation tissue growth and cell re-epithelialization; 3) activation and proliferation of myofibroblasts stimulate wound constriction—using EGF, wound scarring improved, notable through its effects on scar pigmentation, height, pliability, and vascularity.¹⁴

Studies have demonstrated that rhEGF can promote wound healing and reduce healing time in the treatment of diabetic foot ulcers (DFUs).¹⁵ A comprehensive systematic review and meta-analysis¹⁶ suggested that rhEGF can shorten wound healing time, reduce the scar hyperplasia rate and adverse reaction rate, and improve the wound healing rate in treating deep second-degree burns.

There were also several studies that discussed the efficacy of rhEGF in healing PIs.^17,18 However, the quality and sample size of those studies on rhEGF were poor, and there was no meta-analysis on the efficacy of rhEGF in healing PIs. Therefore, the efficacy of rhEGF for PIs is not completely clear.

The objective of this study was to perform a meta-analysis of rhEGF on the healing of PIs by synthesizing the data from all available randomized controlled trials (RCTs) using 3 outcome indicators: total efficacy rate, the proportion of complete healing, and the time to complete healing.

Literature search. The authors conducted a search of PubMed, Web of Science, the Cochrane Library, and the China National Knowledge Infrastructure (CNKI) for studies published from the inception of the databases through November 20, 2023, involving RCTs that documented use of rhEGF in healing PIs. The following keywords were used: pressure injury, bedsore, pressure ulcer, decubitus ulcer, human epidermal growth factor, and randomized controlled trial, with Boolean operators such as AND and OR used to combine search terms.

Specifically, in PubMed, the search terms were ((Pressure ulcer [MeSH Terms]) AND (epidermal growth factor [Title/Abstract])) AND (randomized control trial [Title/Abstract]). In Web of Science Databases advanced search, the search terms were: TS=(Pressure Ulcer OR Bedsore OR Bedsores OR Ulcer, Pressure OR Pressure Sore OR Ulcers, Decubitus OR Pressure Sores OR Sores, Pressure OR Bed Sores OR Bed Sore OR Ulcers, Pressure OR Sore, Bed OR Sores, Bed OR Decubitus Ulcer OR Decubitus Ulcers OR Pressure Sores OR Ulcer, Decubitus) AND TS=(recombinant human epidermal growth factor) AND TS=(randomized controlled trials OR random OR RCT). In the Cochrane Library Database, the search terms were: pressure injury in Keyword AND epidermal growth factor in Keyword AND randomized control trial in Abstract. Papers published solely in English or Chinese were retrieved in this study. The searches were adjusted to the layout and search methods of each search engine.

Inclusion criteria. The population, intervention, comparison, outcomes, study design (PICOS) strategy was used to include eligible trials.

Population (P). Patients clinically diagnosed with PIs, whether acquired outside the hospital or hospital-acquired, were included. The stage of PIs, classified according to National Pressure Injury Advisory Panel (updated from NPUAP to NPIAP),¹ was considered regardless of the age of patients and PI locations.

Intervention (I). rhEGF was studied whether administered alone or in combination for the treatment of PIs. Intervention methods included topical spraying or topical dressing.

Comparison (C). The only difference between the intervention group and the control group in the considered studies was whether rhEGF was used. Both groups had the same routine treatment, as well as the same application frequency and intervention methods, whether in combination or alone.

Outcomes (O). The primary outcome was the total efficacy rate, which was calculated as Total efficacy rate = (complete healing cases + obviously effective cases + effective cases) / total included cases × 100%. Secondary outcomes were the proportion of complete healing and the time to complete healing. Complete healing was defined as the scabbing or sloughing off of the wound. Obviously effective use of the product was defined as more than 80% reduction in wound size after drug treatment, significant growth of granulation tissue, and no exudate. Effective use of the product was defined as wound reduction of more than 30%, proliferation of granulation tissue, and a small amount of exudate. The time to healing was defined as the time from the initiation of treatment to the complete epithelial coverage of the wound.

Study design (S). Only RCTs involving use of rhEGF in the healing of PIs were included.

Exclusion criteria. Duplicate publications, conference abstracts without available full text, incomplete or implausible outcome data, nonhuman trials, reviews, and protocols were excluded.

Literature selection and data extraction. All articles were exported to EndNote X9 for de-duplication, after which the titles and abstracts were screened. Irrelevant records were excluded according to exclusion criteria. The authors determined the final included studies by screening the full texts. The literature was screened and the data were extracted by 2 reviewers. If the reviewers disagreed on an article’s inclusion, the difference was resolved by discussing with each other. If no consensus could be reached, it was referred to the third author for adjudication.

For each included trial, the following data were extracted: basic data, including first author, published year, country, and study design; patient data, including sample size, age, gender, and information on PI such as stage and location; the intervention used, including methods and application frequency; and outcomes, including total efficacy rate, proportion of complete healing, and time to complete healing.

Assessment of risk of bias. The following areas of the Cochrane risk-of-bias tool for RCTs were used to evaluate the risks of bias of included studies¹⁹: random sequence generation, allocation concealment, participant and personnel blinding, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The risk of bias for each trial was evaluated using Review Manager (RevMan version 5.4).

Statistical analyses. Data analysis was performed using Stata11.0 software. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were considered as the effect size for continuous variables, and odds rations (ORs) with the corresponding 95% CIs were for binary variables. The Cochrane I-squared (I²) test was used to assess the heterogeneity among trials; I² of more than 75% was regarded as a high level of heterogeneity, I² of more than 50% was considered medium heterogeneity, and I² less than 25% was considered low. A random effects model was applied when the I² was high.²⁰ The funnel plot is used to assess publication bias. Each point in the funnel plot represents a study, and the confidence interval represents the estimated range of the true effective size.

Three sets of meta-analysis were performed using Stata11.0 for the 3 outcome indicators. The results were presented by forest plots and summary tables. ORs for binary data and SMDs for continuous data were estimated.

Overall, 325 publications were identified; of these, after removing duplicates, 139 papers remained. After browsing the titles and abstracts, papers with no complete data (45), non-randomized controlled trials (49), animal experiments (8), and review articles (10) were all excluded. Finally, 16 trials^21-36 with sample sizes of 22 to 153, comprising 1,206 participants, were included in the current meta-analysis to estimate the efficacy of rhEGF in healing PIs (Table 1). Figure 1 shows the literature selection process.

Five studies^{23,27,29,34,36} included Stage 2 and Stage 3 PIs; 3 studies^21,24,30 included Stage 3 and Stage 4 PIs; 2 studies^26,33 included Stage 2 through Stage 4 PIs; 1 trial²² included Stage 1 through Stage 3 PIs, and 1 study³⁵ included Stage 2 PIs. Four trials^12,15,25,36 did not describe the PI stage. PI locations consisted mostly of sacrum, hip, and heel in 11 trials^{21-23,26-29,31,33,34,36}; four studies^24,30,32,35 did not describe PI locations. The type of administration of rhEGF was described only for topical applications, and application frequency and intervention methods are shown in Table 1. The duration of treatment and the evaluation time were different among trials. None of the RCTs mentioned any follow-up period. Most trials reported the age and PI size of the patients.

The 3 outcome measures (total efficacy rate, proportion of complete healing, and the time to complete healing) are shown in Table 2.

Qualitative assessment. The authors calculated a quality summary of the risk of bias based on the risk assessment for each included trial (Figure 2). Only 3 of the included RCTs^27,32,36 described sequence generation; 2 of them^27,32 used proper methods, while the other³⁶ did not generate the sequence properly. The others^{21-26,28-31,33-35} provided no description of how randomization was achieved. None of the 16 RCTs reported any concealment of allocation, blinding of outcome evaluation, blinding of participants and personnel, or other bias. Furthermore, 6 trials^{26,30,32,33,35,36} did not provide complete results. The others^{21-25,27-29,31,34} depicted the data appropriately and comprehensively. The overall risk of bias was found to be low.

Primary outcome: total efficacy rate. All included trials^21-36 provided the primary outcome. The number of wounds collected in all was 620 in the rhEGF group and 586 in the control group. The heterogeneity was 0.00%; thus, a fixed effects model was chosen. The average total efficacy rate to heal PIs (calculated by averaging the total efficacy rate of each included study) in the intervention group was 97.18%, which was significantly superior to 83.38% in the control group (OR: 5.69, [95% CI: 3.61, 8.97], z=7.49, P< .001) (Figure 3A). The Begg’s test (z=.32, P= .753) and the Egger’s test (t=1.02, P= .324) indicated no significant publication bias among these included studies. No obvious asymmetry was found in the funnel plot (Figure 3B).

Secondary outcomes

Proportion of complete healing. For the outcome of the proportion of complete healing, 15 trials^21-29,31-36 were included in the analysis. The sample size of the wounds was 595 in the rhEGF group and 561 in the control group. The heterogeneity was 0.00%; therefore, a fixed effects model was chosen. The proportion of complete healing in the intervention group was 73.30% (436/595), which was significantly higher than 39.52% (222/561) in the control group (OR: 3.88, [95% CI: 3.01, 5.01], z=10.39, P< .001) (Figure 4A). The Begg’s test (z=2.38, P= .018) and the Egger’s test (t=3.88, P= .002) demonstrated publication bias. Figure 4B showed an obvious asymmetry. The publication bias may be due to the small sample size and low quality of included studies.

Time to complete healing. Ten trials^{21-24,27-31,34} were included in the analysis, with a sample size of 406 in the rhEGF group (mean time ranges= 3.5 to 23.07 days) and 380 in the control group (mean time ranges= 10.3 to 38.57 days). The I² of the time to complete healing was 85.20%, which is higher than the 75% seen in previous research.²⁰ The random effects model thus was chosen. Figure 5A showed that the rhEGF group had a shorter time to complete healing compared to the control group (SMD: -2.14 days, [95% CI: -2.60, -1.67], z=9.07, P< .001). The Begg’s test (z=1.61, P= .107) and the Egger’s test (t= -2.85, P= .022) showed a significant publication bias. The funnel plot showed an asymmetry (Figure 5B). As above, the publication bias may be due to the small sample size and low quality of included studies.

Sensitivity analyses. Sensitivity analyses were performed by excluding one of the included studies. The authors did not find significant heterogeneity among the included studies for the total efficacy rate to heal PIs (OR: 5.69, [95% CI: 3.61, 8.97]) (Figure 6), the proportion of complete healing (OR: 3.88, [95% CI: 3.01, 5.01]) (Figure 7), or the time to complete healing (SMD: -2.14 days, [95% CI: -2.60, -1.67]) (Figure 8). The results were relatively robust.

The meta-analysis of RCTs in the current study showed that rhEGF treatment increased the total efficacy rate (97.18% vs. 83.38%) and the complete healing rate (73.30% vs. 39.52%), thus promoting wound healing. Meanwhile, the use of rhEGF significantly reduced wound healing time (SMD: -2.14 days, [95% CI: -2.60, -1.67], z=9.07, P< .001) and accelerated wound healing. Some studies^12,37 have found that rhEGF can accelerate the proliferation and granulation of wound epithelial cells and shorten the healing time by promoting the synthesis of RNA, DNA, and hydroxyproline. Several reviews have demonstrated the effect of rhEGF on the healing of wounds such as diabetic foot ulcers^15,16 and burns.³⁸ Li et al³⁸ evaluated the efficacy and safety of rhEGF on deep second-degree burns using 5 indicators: duration of wound healing, rate of wound healing, rate of scar hyperplasia, positive rate for wound bacteria, and the rate of adverse reactions, which represents a more comprehensive evaluation than was conducted in the current study. However, the 12 original studies included were all published in Chinese and had relatively small sample sizes.

EGF was first discovered in 1962 in the mouse salivary gland.³⁹ It is secreted by fibroblasts, mononuclear cells, macrophages, and platelets, and has been found to increase the synthesis of some endogenous growth factors and collagen synthesis, accelerating the rate of wound healing.³⁷ Human EGF was discovered later and is found in most body fluids. In 1989, EGF was applied locally to heal various peripheral wounds.⁴⁰ However, rhEGF can be degraded by protease within the biofilm formed on the surface of the wound; additionally, EGF can promote the proliferation of malignant cells.⁴⁰

The results of the current study supported the efficacy of rhEGF use for the treatment of PIs. Adverse events such as hypertrophic scarring or malignant changes were rarely noted,¹⁴ and as such, rhEGF may be considered a viable therapeutic option for healing PIs. The current meta-analysis may also provide suggestions for future research in this area; for example, by highlighting the fact that prospective, large-scale, multicenter clinical trials are needed.

This study has some limitations. First, all included studies were performed in China, and it is debatable that the conclusions drawn are applicable in other countries. Furthermore, even though all useful data from current studies were included, the total sample size is still small and the quality is poor. As such, the authors cannot ensure equal randomized controlled trials with equal depths of participation and discussion of comorbid conditions, which may affect the precision of the results. Several of the studies included for analysis exhibited methodological shortcomings. As such, high-quality studies with more accurate randomization and blinding are indicated in order to reduce the risk of bias. Furthermore, rhEGF was administered in combination with other treatments in many of the studies included in this meta-analysis and the effect was significant, which impacts the ability to determine the effectiveness of rhEGF alone.

A meta-analysis of the use of rhEGF in the healing of PIs found it may increase the wound healing rate and reduce the time to complete healing with few harmful effects. These results may provide new evidence for the clinical practice of treating PIs. More large-scale clinical trials and high-quality studies conducted in more than one country are warranted.

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Affiliations: ¹Nantong University Medical School, Jiangsu, China; ²Nantong University Public Health School, Jiangsu, China

Address all correspondence to: Hong-Lin Chen, PhD; 9 Seyuan Road, Chongchuan Area, Nantong City, Jiangsu Province, 226000, China; honglinyjs@126.com

Potential conflicts of interest: None.