EGF-loaded Chitosan to Facilitate Healing and Prevent Scar Formation of Cesarean Wound

Study Overview
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Brief Summary
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Cesarean section (CS) is a major surgical intervention that affects women at childbearing age. Scarring from CS potentially causes discomfort and psychological distress. Emerging evidence indicates that epidermal growth factor (EGF) plays crucial roles in wound healing with the potential of minimizing scar formation. This study aims to investigate the effect of microencapsulated recombinant human EGF (Me-EGF) in scar prevention. Silicone gel was incorporated as part of the routine scar treatment. Healthy women scheduled for cesarean delivery will be enrolled and randomized to three groups: (1) no scar treatment, (2) silicone gel only, or (3) silicone gel plus Me-EGF. Vancouver Scar Scale (VSS) will be used for scar assessment at the 6th month and 9th month after CS.

Detailed Description
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Objective: Cesarean section (CS) is a major surgical intervention that affects women at childbearing age. Scarring from CS is expected but certainly not desirable, potentially causes discomfort and psychological distress. Emerging evidence indicates that epidermal growth factor (EGF) plays crucial roles in wound healing with the potential of minimizing scar formation. This study aims to investigate the effect of microencapsulated recombinant human EGF (Me-EGF) in scar prevention. Silicone gel was incorporated as part of the routine scar treatment. Materials: The investigational dressing in this study: the microencapsulated polysaccharide and oligopeptide-1 is provided by Good-Care Biotech, Ltd. (brand NewEpi®: 10 mcg Me-EGF/ml, Taipei, Taiwan). The investigational dressing NewEpi® was formulated in spray solution with a proprietary drug delivery system in which rhEGF was encapsulated in chitosan as nanoparticles. Silicone-based scar therapy has shown the beneficial effects of improving the appearance of scars. Dermatix® (Dermatix® Ultra, Menarini Asia-Pacific, Taiwan) is a Taiwan-FDA approved topical silicone gel and commercially available. It is transparent, odorless and quick drying. Concerning the applicability over lower abdomen area, silicone gel (Dermatix®) was selected to be part of the routine care in this study. Study Procedures: Healthy women scheduled for cesarean delivery were enrolled and randomized to three groups: (1) no scar treatment, (2) silicone gel only, or (3) silicone gel plus Me-EGF. Vancouver Scar Scale (VSS: vascularity, pigmentation, elasticity, and height) was used for scar assessment at the 6th month and 9th month after CS. Eligibility was determined at the screening visit. Details of the study regarding eligibility, purpose, study procedure, scope of care and potential risks were explained. Upon enrollment, full medical history of the participants was obtained, including history of hypertrophic scar or keloid. Scars from previous injuries or surgical incisions were evaluated and recorded. Each patient was randomized to one of the three treatment arms: Group 1 (receiving no scar treatment), Group 2 (silicone gel only), and Group 3 (silicone gel plus Me-EGF). Enrolled participants underwent Cesarean delivery performed by one of the four obstetricians at the Department of Obstetrics and Gynecology of CGMH, as part of their prenatal care. Other than routine surgical wound care, participants in Group 1 did not receive any treatment pertaining to scar prevention. The day of Cesarean delivery was recorded as Day 0. For participants in Group 3, on day 0 prior to final dermal closure, 4ml of Me-EGF (containing 40mcg microencapsulated polysaccharide and rhEGF) was sprayed evenly along the incision site, subsequently covered with antibiotic ointment and sterile gauze. Another 0.5 ml (5 mcg of Me-EGF) was sprayed during dressing change on day 1 and day 5 respectively. At each dressing change, the sutured wound was cleaned by sterile normal saline, followed by Me-EGF sprays, and waited for two minutes to allow for absorption, then covered with dry sterile gauze. Each participant in Group 2 and Group3 brought home two tubes of silicone gel when they returned for their follow-up visits on day 14. They were instructed to start applying silicone gel evenly to the wound twice a day for two months. Study Participants: This study is approved by the Institutional Review Board at Chang-Gung Memorial Hospital (CGMH, Linkou, Taiwan). All practitioners and research staffs are in compliance with Good Clinical Practice guidelines. A total of 60 females scheduled for cesarean birth will be recruited by their primary obstetricians at the Department of Obstetrics and Gynecology of CGMH. Prior to their enrollment, the study procedures will be explained to obtain written informed consents. The inclusion criteria are: (1) Age of 18 or older; (2) planned for cesarean delivery with Pfannenstiel-incision, which is one common method of performing Caesarian sections today; (3) had not received any treatment for scars at least one month before enrollment; and (4) capable of understanding study protocol in order to sign the informed consent voluntarily. Patients will be excluded if: (1) currently taking any medication that might affect outcome evaluation of this study, including but not limited to: systemic corticosteroids or immunosuppressants; (2) currently undergoing any treatments involving lower abdomen, or planning to have such treatments; (3) having active infection involving abdomen at the time of recruitment; (4) concomitant severe or poorly-controlled illness (e.g., cardiovascular, renal, hepatic, pulmonary or gastrointestinal disease, malignancy or history of HIV infection); (5) with any abdominal tumor; (6) undergoing urgent cesarean delivery without proper pre-op standard procedure, or (7) having known allergy to any of the ingredients in any of the products used in this study. Clinical Evaluation and Outcome Measures: There were a total of four time points at which data were collected and photos taken using the same digital camera with fixed settings: day 0 (completion of suture on Cesarean incision), day 1, day 5 before discharge from the hospital, and at follow-up visits in month 3, month 6, and month 9. After enrollment and before day 0, baseline photos of old Cesarean scars were taken from participants who had prior Cesarean childbirth, in addition to photos of other scars from those who had reported history of hypertrophic scar or keloid. Scars were assessed using Vancouver Scar Scale. The VSS consists of 4 parameters: vascularity (0-3), pigmentation (0-3), elasticity (0-5), and height (0-3). Prior to the study commencement, all personnel involved had received mandatory training on scar assessment and VSS scoring. At month 3, 6, and 9, a nurse practitioner took photos and evaluated the incision scar on each patient with VSS. Photos of each healing wound were taken with a ruler placed adjacent to the scar to measure the height raised above skin level. Subsequently all scores were validated twice by different research staffs by using the photos on record. No significant discrepancies were found. At each follow-up visit, the primary obstetrician also assessed each patient for any side effect or adverse event. Statistical Analysis: Clinical data and all scar measurements were recorded on case report forms and entered in Microsoft Excel database, later validated by different research staffs as the final scores. Data were analyzed using jamovi statistical software (Version 0.9). Means and standard deviations were presented for interval variables of baseline characteristics. Categorical data at baseline were presented in frequency and analyzed with Chi-Square tests. Nonparametric Kruskal-Wallis tests were performed on VSS scores for between group comparisons. A p-value < 0.05 was considered statistically significant.

Official Title
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EGF-loaded Chitosan to Facilitate Epithelial Healing And Prevent Scar Formation of Cesarean Wound

Conditions
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Cesarean Wound, Scar; Previous Cesarean Section, Complicating Pregnancy or Childbirth, Affecting Fetus or Newborn

Intervention / Treatment
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* Other: Control
* Other: Silicone gel
* Other: microencapsulated polysaccharide and oligopeptide-1(Me-EGF) 40 mcg & 5 mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 or older Planned for cesarean delivery with Pfannenstiel-incision Had not received any treatment for scars at least one month before enrollment Capable of understanding study protocol in order to sign the informed consent voluntarily Exclusion Criteria: Currently taking any medication that might affect outcome evaluation of this study, including but not limited to: systemic corticosteroids or immunosuppressants Currently undergoing any treatments involving lower abdomen, or planning to have such treatments Having active infection involving abdomen at the time of recruitment Concomitant severe or poorly-controlled illness (e.g., cardiovascular, renal, hepatic, pulmonary or gastrointestinal disease, malignancy or history of HIV infection) With any abdominal tumor Undergoing urgent cesarean delivery without proper pre-op standard procedure Having known allergy to any of the ingredients in any of the products used in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Upon enrollment, full medical history of the participants was obtained, including history of hypertrophic scar or keloid. Scars from previous injuries or surgical incisions were evaluated and recorded. Each patient was randomized to one of the three treatment arms: Group 1 (receiving no scar treatment), Group 2 (silicone gel only), and Group 3 (silicone gel plus Me-EGF).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Group 1: Control<br>Participants receive no scar prevention and treatment for Cesarean wounds. | Other: Control<br>* No scar prevention or treatment.<br>|
| Active Comparator: Group 2: Silicone gel<br>Each participant in Group 2 brought home two tubes of silicone gel when they returned for their follow-up visits on day 14. They were instructed to start applying silicone gel evenly to the wound twice a day for two months. | Other: Silicone gel<br>* Dermatix® (Dermatix® Ultra, Menarini Asia-Pacific, Taiwan FDA approved)<br>|
| Experimental: Group 3: Silicone gel plus Me-EGF<br>The day of Cesarean delivery was recorded as Day 0. For participants in Group 3, on day 0 prior to final dermal closure, 4ml of Me-EGF (containing 40mcg microencapsulated polysaccharide and rhEGF) was sprayed evenly along the incision site, subsequently covered with antibiotic ointment and sterile gauze. Another 0.5 ml (5 mcg of Me-EGF) was sprayed during dressing change on day 1 and day 5 respectively. At each dressing change, the sutured wound was cleaned by sterile normal saline, followed by Me-EGF sprays, and waited for two minutes to allow for absorption, then covered with dry sterile gauze. Each participant in Group 3 brought home two tubes of silicone gel when they returned for their follow-up visits on day 14. They were instructed to start applying silicone gel evenly to the wound twice a day for two months. | Other: Silicone gel<br>* Dermatix® (Dermatix® Ultra, Menarini Asia-Pacific, Taiwan FDA approved)<br>Other: microencapsulated polysaccharide and oligopeptide-1(Me-EGF) 40 mcg & 5 mcg<br>* 4ml (40 mcg) of Me-EGF spray will be given by the operating physician prior to wound closure, followed by daily application of 5 mcg until day +5 after delivery. Starting from day +14, participants will receive FDA approved Silicone gel to be applied to the Cesarean wound twice a day for two months. Participants also receive routine post-partum care as usual.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vascularity | Vascularity is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Pink; 2: Red; 3: Purple | Evaluation of Vascularity is done at: month 3+ follow-up visit. | 
| Pigmentation | Vascularity is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Hypo-pigmentation; 2: Mixed-pigmentation; 3: Hyper-pigmentation | Evaluation of Pigmentation is done at: month 3+ follow-up visit. | 
| Pliability | Pliability is one the the four subscales in Vancouver Scar Scale (VSS). Score range: 0-5. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Supple; 2: Yielding; 3: Firm; 4: Banding; 5: Contracture | Evaluation of Pliability is done at: month 3+ follow-up visit. | 
| Height | Height of the scar is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: flat; 1: 0-2mm; 2: 2-5mm; 3: > 5mm | Evaluation of Height is done at: month 3+ follow-up visit. | 
| Vascularity | Vascularity is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Pink; 2: Red; 3: Purple | Evaluation of Vascularity is done at: month 6+ follow-up visit. | 
| Pigmentation | Vascularity is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Hypo-pigmentation; 2: Mixed-pigmentation; 3: Hyper-pigmentation | Evaluation of Pigmentation is done at: month 6+ follow-up visit. | 
| Pliability | Pliability is one the the four subscales in Vancouver Scar Scale (VSS). Score range: 0-5. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Supple; 2: Yielding; 3: Firm; 4: Banding; 5: Contracture | Evaluation of Pliability is done at: month 6+ follow-up visit. | 
| Height | Height of the scar is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: flat; 1: 0-2mm; 2: 2-5mm; 3: > 5mm | Evaluation of Height is done at: month 6+ follow-up visit. | 
| Vascularity | Vascularity is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Pink; 2: Red; 3: Purple | Evaluation of Vascularity is done at: month 9+ follow-up visit. | 
| Pigmentation | Vascularity is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Hypo-pigmentation; 2: Mixed-pigmentation; 3: Hyper-pigmentation | Evaluation of Pigmentation is done at: month 9+ follow-up visit. | 
| Pliability | Pliability is one the the four subscales in Vancouver Scar Scale (VSS). Score range: 0-5. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: Normal; 1: Supple; 2: Yielding; 3: Firm; 4: Banding; 5: Contracture | Evaluation of Pliability is done at: month 9+ follow-up visit. | 
| Height | Height of the scar is one of the four subscales in Vancouver Scar Scale (VSS). Score range: 0-3. It is a Likert-type scale of which score 0 indicates normal or none, and a higher score indicates the severity of the specific condition. Assessed at 3 time points: Month 3+, Month 6+ and Month 9+ postpartum visits. A trained nurse practitioner evaluates participant's Cesarean wound scar and assigns a score when the participant returns to the follow-up appointment. 0: flat; 1: 0-2mm; 2: 2-5mm; 3: > 5mm | Evaluation of Height is done at: month 9+ follow-up visit. |