A Multi-centre Randomised Controlled Trial to Compare Epidermal Grafting With Split Skin Grafting for Wound Healing
Phase: NA
Conditions: Ulcer, Skin Ulcer, Wounds and Injuries
Sponsor: University College, London

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1.0 
Protocol title & version details 
 
1.1 Titles 
 
Full Title 
A Randomised Controlled Trial to Compare Epidermal Grafting with Split Skin Grafting for Wound 
Healing 
 
Short Title 
Epidermal grafting in wound healing 
 
1.2 Protocol version details 
 
Version 1.2 
October 18 2016 
 
 
 
 
 
 
 
 
 
 

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1.3 Names, roles and contact details 
Chief Investigator &  
Clinical Academic 
Supervisors 
1) Professor Toby Richards,                                                                 
Professor of Surgery and Consultant Vascular Surgeon,                          
UCL Division Surgery and Interventional Science,                         
Fourth floor, 74 Huntley Street, London, WC1E 6AU 
2) Mr Afshin Mosahebi,                                                              
Consultant Plastic Surgeon and Senior Lecturer,                                       
Department of Plastic and Reconstructive Surgery, Royal Free 
Hampstead NHS Trust Hospital, Pond Street, London, NW3 2QG 
Principle researchers 
1) Mr Muholan Kanapathy,  Research Fellow,                                            
UCL Division of Surgery and Interventional Science,                           
Fourth floor, 74 Huntley Street, London, WC1E 6AU 
2) Miss Nadine Hachach-Haram, Specialist Registrar,                               
Department of Plastic and Reconstructive Surgery, Royal Free 
Hampstead NHS Trust Hospital, Pond Street, London, NW3 2QG 
3) Miss Nicola Bystrzonowski, Specialist Registrar,           
Department of Plastic and Reconstructive Surgery, Royal Free 
Hampstead NHS Trust Hospital, Pond Street, London, NW3 2QG 
Laboratory Academic 
Supervisor 
Professor Toby Richards, Senior Lecturer,  
Professor of Surgery and Consultant Vascular Surgeon                   
UCL Division Surgery and Interventional Science 
Fourth floor, 74 Huntley Street, London, WC1E 6AU 
Contact on behalf of sponsor 
(NHS sponsored) 
Research and Development, University College London Hospital 
1st Floor Maple House, London, W1T7NF 
02076792000 
Host Trusts & Study Site(s) 
1) Mr Afshin Mosahebi,                                                                     
Consultant Plastic Surgeon and Senior Lecturer,                                       
Department of Plastic and Reconstructive Surgery, Royal Free 
Hampstead NHS Trust Hospital, Pond Street, London, NW3 2QG 
2) Professor Keith Harding, Head of Wound Healing Research Unit,     
Cardiff University, School of Medicine, Upper Ground Floor, Heath 
Park, Cardiff CF14 4XN 
Clinical Laboratory 
UCL Division of Surgery & Interventional Science,                      
Centre for Nanotechnology & Regenerative Medicine,                
Royal Free NHS Trust Hospital Campus, Pond St,  London, NW3 2QG 
 
 
 
 

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2.0 
Signature Page 
 
Signatures of all healthcare professionals involved in the study are documented below: 
 
Chief Investigator &  
Clinical Academic Supervisors 
 
Professor Toby Richards, Professor of Surgery and Consultant Vascular 
Surgeon, UCL 
________________________ 
 
______________ 
Signature  
                                           Date 
Mr Afshin Mosahebi, Consultant Plastic Surgeon and Senior Lecturer, 
Royal Free Hampstead NHS Trust Hospital  
________________________ 
 
______________ 
Signature  
                                           Date 
 
Principle researchers 
Mr Muholan Kanapathy, Research Fellow, UCL Division of Surgery and 
Interventional Science 
_____________________                         ____________ 
Signature                                                          Date 
Miss Nadine Hachach-Haram, Specialist Registrar in Plastic Surgery, 
Royal Free Hampstead NHS Trust Hospital 
________________________ 
 
______________ 
Signature  
                                           Date 
Miss Nicola Bystrzonowski, Specialist Registrar in Plastic Surgery, Royal 
Free Hampstead NHS Trust Hospital 
 
 
________________________ 
 
______________ 
Signature  
                                           Date 
 

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3.0 Contents page 
 
1.0 
Protocol title & version details ....................................................................................................1 
1.1 Titles ................................................................................................................................................1 
1.2 Protocol version details ..................................................................................................................1 
1.3 Names, roles and contact details ....................................................................................................2 
2.0 
Signature Page ..............................................................................................................................3 
3.0 
Contents page ...............................................................................................................................4 
4.0 
Summary .......................................................................................................................................6 
4.1 Aim(s) and reason of the study .......................................................................................................6 
4.2 Primary and secondary objectives ..................................................................................................6 
4.3 Description of methods and assessments ......................................................................................6 
5.0 
Background ................................................................................................................................ 13 
5.1 Literature search and review of epidermal graft ......................................................................... 13 
5.2 Justification .................................................................................................................................. 14 
6.0  
Specific aims of the study ......................................................................................................... 15 
7.0  
Study design .............................................................................................................................. 15 
9.0  
Study setting .............................................................................................................................. 17 
10.0 
Participants recruitment and consent ...................................................................................... 17 
10.1 Recruitment of participants ....................................................................................................... 17 
10.2 Gaining participant consent ....................................................................................................... 17 
11.0 
Outcome measures ................................................................................................................... 17 
12.0 
Data ............................................................................................................................................ 18 
12.1 Data to be collected ................................................................................................................... 18 
12.2 Data handling and record keeping ............................................................................................. 18 
13.0 
Study assessment ...................................................................................................................... 19 
14.0 
Statistical Considerations .......................................................................................................... 19 
14.1 Sample size ................................................................................................................................. 19 
14.2 Statistical analysis ...................................................................................................................... 20 
15.0 
Subject Compliance & Withdrawal of Subjects ........................................................................ 20 
15.1 Subject Compliance .................................................................................................................... 20 
15.2 Withdrawal of Subjects .............................................................................................................. 21 

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16.0 
Ethical Considerations ............................................................................................................... 21 
16.1 Benefits, risks and burdens to study participants ...................................................................... 21 
16.2 Approvals from relevant groups ................................................................................................ 22 
17.0 
Finance, Insurance & Harm ....................................................................................................... 22 
17.1 Finance details ........................................................................................................................... 22 
17.2 Insurance details ........................................................................................................................ 22 
17.3 Cover for non-negligent and negligent harm ............................................................................. 23 
18.0 
Reporting and Dissemination ................................................................................................... 23 
19.0 
List of relevant references ........................................................................................................ 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.0 
Summary 
 
4.1 Aim(s) and reason of the study 
 
Split thickness skin grafting is the normal standard of care for wound closure. However, this is an 
invasive procedure and associated with pain also there can be additional donor site morbidity. 
Epidermal grafting is an emerging clinical alternative that is gaining clinical practise. Epidermal 
grafting (EG) is an alternative method of autologous skin grafting that ‘harvests’ a finer layer of 
skin than traditional Split Skin grafting (SSG). This potentially results in less pain and reduced 
donor site morbidity but only delivers several cell layers to the wound so may be less effective 
at healing a wound. It is not known if EG is an effective alternative to SSG. 
Further the mechanism to achieve wound healing may be different. EG promotes wound healing 
by expressing growth factors that accelerates wound healing and encourages keratinocyte 
migration. Whereas SSG is a transplant of several skin layers that integrated to the existing 
wound bed as a formal skin covering. 
We wish to compare these two clinical practises; epidermal grafting and split thickness skin 
grafting in wound healing.  
 
4.2 Primary and secondary objectives 
 
Our primary objective is to determine the efficacy of epidermal grafting to split thickness skin 
grafting in wound healing at 6 weeks and 3 months. 
Our secondary objective is to gain information on the biology of wound healing with EG and SSG, 
specifically to compare the expression of cytokeratin (keratinocyte marker) and Connexin 43 (gap 
junctional protein) before and after grafting. 
 
 
4.3 Description of methods and assessments 
 

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Research participant design and methodology 
1) The Population of patients will be those referred, following assessment and review, by a 
Consultant Plastic Surgeon for split thickness skin grafting or Epidermal grafting. Patients 
will be identified, from both the outpatient clinic and inpatient referrals. 
2) Patients will undergo a ‘run in phase’ to ensure the wound bed is ready and appropriate 
for grafting. This will include negative microbiology. Wound will be deemed ‘ready’ by 
two trial clinicals. Baseline three dimensional wound photographs will be taken. 
3) Patients will be offered participation in the study, provided with the Patient Information 
Sheet (PIS) and will be allowed time (at least 24 hours) prior to obtaining informed 
consent. 
4) Patient will be consented and randomised to either an epidermal graft or a split thickness 
skin graft group. 
5) The interventional procedures will be undertaken within 7 days of randomisation 
6) Baseline assessment will include;  
a. Wound assessment using the Wound Assessment Form (Appendix 4) 
b. Photographs of the donor site and wound site 
c. Wound exudate sampling. 
d. Punch biopsies at the wound edge and the centre of the wound. 
7) Patient will then receive treatment (either epidermal graft or split thickness skin graft) 
and immediate follow up assessments 
a. Pain scores relevant to the procedure 
b. Time of the Procedure – start to finish 
8) Patient will be reviewed at day 7 ± 2 post grafting in an outpatient plastic surgery clinic 
a. Wound assessment using the Wound Assessment Form (Appendix 4) 
b. Photographs of the donor site and wound site 
c. Wound exudate sampling. 
d. Punch biopsies at the wound edge and centre of the wound. 
9) Wounds will be reviewed weekly in the outpatient clinic for 6 weeks or until wounds are 
healed.  
a. Health resource utilisation will be collected of dressing changes. 
b. Photographs of the donor site and wound site 

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c. Documentation of any adverse events  
 
10) 6 week review 
a. Wound assessment using the Wound Assessment Form (Appendix 4) 
b. Photographs of the donor site and wound site 
c. Patient’s satisfaction using the Patient Skin Graft Satisfaction Questionnaire 
(Appendix 5) 
d. Documentation of any adverse events 
 
11) 3 month review 
a. Health resource utilisation will be collected of dressing changes 
b. Photographs of the donor site and wound site 
c. Patient’s satisfaction using the Patient Skin Graft Satisfaction Questionnaire 
(Appendix 5) 
d. Documentation of any adverse events 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1.0 Flow chart illustrating patient journey throughout the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wound Bed preparation  
Patient screening & patient information leaflet given 
Patient consents & enrolment 
Biopsy 
sample for 
laboratory 
analysis  
Patient followed up weekly for 6 weeks in clinic or until wound heals 
Patient reviewed on day 7 ± 3 and undergoes wound exudate 
sampling and 4-mm wound punch biopsies 
 
Patient undergoes wound exudate sampling and 4-mm 
wound punch biopsies followed by treatment 
Split thickness 
skin graft (n=22) 
Epidermal graft 
(n=22) 
Randomisation 
(n=44) 
Final Review 3 months 
Patient referred by a consultant plastic surgeon for EG or SSG 

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Wound bed preparation 
All patients will be reviewed by a consultant plastic surgeon and assessed then referred to the 
department of plastic surgery for SSG or EG. Normal clinical practise is that all wounds will be 
assessed clinically and prepared with either negative pressure wound therapy (NPWT) or 
appropriate wound dressings to achieve wounds with healthy granulating bed. Wound swabs 
will be performed to ensure no infection as per normal clinical practise. During this time period 
of wound bed preparation patients will be flagged to the research team. When the wound bed 
is deemed ‘ready for grafting’ agreed between two treating clinicians, patients will then screened 
and where appropriate be offered a patient information sheet for inclusion into the trial.  Once 
the patients are ready for intervention, following review by the study team, patients will undergo 
informed consent and randomisation. 
Ppunch biopsy procedure – technical aspects 
Prior to any intervention, the patient will be assessed clinically to confirm ‘inclusion and exclusion 
criteria’ are met (see Section 8.0) and informed consent form will be completed (see Appendix 
2). Wound assessment will be documented in the ‘wound assessment & biopsy form’ (see 
Appendix 4).  
Punch wound biopsies (4mm) will be taken from two locations, at the centre of wound and at 
the wound edge, after administering adequate local anaesthesia. This procedure will be done at 
the start of the study and at day 7 post-grafting. The punch biopsy procedure is a routine 
dermatological procedure, and is a safe and efficient method of obtaining a tissue sample 
appropriate for laboratory research. Punches are circular cutting instruments of various 
diameters (4mm in this case) that cut cylindrical pieces of tissue from the skin to the underlying 
fat. The punch is withdrawn and the specimen removed using small forceps and scissors. The 
specimen is then placed in a specimen pot containing paraformaldehyde and transferred to the 
laboratory.  Following the procedure, any bleeding (if present) will be controlled by direct 
pressure over the site of biopsy.  
Study investigators are experienced clinicians and care will be taken to ensure good quality 
wound biopsy samples, appropriate for histological analysis and further laboratory studies. Study 
documentation and biopsy procedure will take approximately 5-10 minutes. 

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Epidermal graft harvesting – technical aspects 
Prior to grafting, the wound and donor sites are cleaned by the operating surgeon. The harvesting 
device will be applied to the donor site (thigh) for 40-50 minutes to harvest the epidermal graft 
as per existing normal clinical practise. The harvested epidermal graft will then be transferred 
onto the wound using Adaptic Touch (non-adhering silicone dressing, measuring 5cm x 5cm) or 
another appropriate dressing. The wound is dressed with Aquacel (hydrofiber dressing) followed 
by gauze or another appropriate dressing as deemed by the treating clinician. The wound will be 
secured with either a crepe bandage if appropriate or mefix. The donor site will be dressed with 
Tegaderm (a semi permeable, adherent dressing) or another appropriate dressing as deemed by 
the treating clinician. The wound will be reviewed on day 7 ± 3 post-grafting as per normal clinical 
practise. 
 
Split thickness skin grafting – technical aspects 
Patients will undergo this procedure in the operating theatre or in minor operations designated 
clinic room under general or local anaesthetic. The wound will be initially debrided by the 
treating clinician. The split thickness skin graft will be harvested from the thigh using an air 
dermatome, set to cut at the thickness of 5-10/1000 inch. The split thickness skin graft will then 
be applied onto the wound and dressed with Adaptic Touch or another appropriate dressing as 
deemed by the treating clinician. The donor site will be dressed with Kaltostat (Alginate dressing) 
or another appropriate dressing as deemed by the treating clinician, with a 2.5cm overlay beyond 
the wound margin and secured with mefix. As per standard clinical practise, the graft will be 
checked at day 7 ± 3. 
 
 
 

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Laboratory studies methodology summary: 
1. We will determine the type and concentration of growth factors expressed by the epidermal 
graft and its response to the wound, both pre- and post-grafting, comparing it with split 
thickness skin graft. 
2. We will compare the expression of cytokeratin (keratinocyte marker) and Connexin 43 (gap 
junctional protein) before and after grafting. 
 
Follow up protocol 
Participants are reviewed at day 7 ± 3 post grafting and then weekly, for 6 weeks. On every 
follow-up visit, photographs and measurements of the wound and donor site will be taken.  
Pain score as reported by patient will be recorded using Numerical Rating Scale at day 1, 2, 3, 4, 
5, 6, 7, 14, 21, 28, 35, and 42. A validated ‘patient skin graft satisfaction questionnaire’ (see 
Appendix 5) will be completed by participants at the end of the study. In all cases two 
questionnaires will beundertaken one for the donor site and one for the wound itself. 
As per current clinical practise, patients are allowed to change the dressing at home every 3-7 
days after the first week review. 
 
 
 

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5.0 
Background 
 
5.1 Literature search and review of epidermal graft 
 
Epidermal grafts are made of multi-layered keratinocytes, in which a variety of other cell types 
with specialised functions are embedded, such as the melanin pigment-producing melanocytes, 
the immune-competent Langerhans cells, the neuroendocrine Merkel cell and the basal layer 
contain epidermal stem cells (1). In normal wound healing, keratinocytes begin to migrate from 
the wound edges within 24 hours to the wound bed where they proliferate and form new 
epithelium (2).  
Traditionally, various, relatively cumbersome, techniques have been used to harvest EG, 
however these harvesting techniques have not been easily reproducible, limiting its potential to 
be used in the clinical setting (3). 
CelluTome (from Acelity), a novel automated EG harvesting device, produces an array of 
epidermal microdomes immediately available for transfer to the recipient site. Migrating 
keratinocytes synthesise and deposit a variety of extracellular matrix components, such as 
laminin, fibronectin, and type IV collagen (4). In addition, numerous growth factors are also 
produced, namely, the epidermal growth factor (EGF), transforming growth factor alpha (TGF-a), 
and heparin-binding growth factor (HB-EGF) which act on epidermis to promote wound healing 
(5). During this process, epidermal grafts simulate bioengineered skin, stimulating the 
endogenous process of wound healing that has yet to be fully understood. 
In a similar study protocol we have previously found that gap junctional protein, Connexin 43 (Cx 
43), plays a pivotal role in wound healing (REC reference: 11/LO/1483, IRAS Project ID: 79542). 
Abnormal Cx43 expression results in delayed wound healing (6). Cx43 is normally down-
regulated in wound-edge keratinocytes in the first 24-48 hours as they change to a migratory 
phenotype. In abnormal rat skin with increased Cx43 expression, wound-edge keratinocytes fail 
to change to a migratory phenotype, resulting in a bulb of non-migratory keratinocytes. By 
inhibiting the up-regulation of Cx43, rat wounds healed at a normal rate. Our recent clinical pilot 
data suggests that greatly elevated levels of Cx43 protein are a feature of both keratinocytes in 
a wide variety of human chronic wounds (pressure, venous, diabetic and unhealed surgical 

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wounds) (7). These observations are supported by the findings of both Abdullah et al. who 
reported elevated gap junctional coupling in cultures of fibroblasts and Brandner et al. who 
reported the presence of Cx43 in keratinocytes at the edge of chronic wound biopsies (8, 9). 
Connexins are regulated by growth factors affecting the Connexin levels, cellular distribution, 
channel open probability and conductance/permeability (10). It is therefore plausible that the 
epidermal grafts express an array of growth factors which encourage the migratory activity of 
keratinocytes by down regulating the expression of Connexin 43 and accelerating wound healing. 
Understanding the cellular biology will enable a better evaluation of the efficacy of epidermal 
grafts in acute and chronic wound management. 
 
5.2 Justification 
 
The total cost of wound management to the NHS is estimated to be about £2.3-3.1 billion per 
year (11) with up to half a million patients suffering from debilitating peripheral vascular disease 
and wounds significantly affecting their quality of life (12). 
Most wounds are managed in the outpatient setting with protocols that vary according to 
geography, institution and speciality. Currently, wound requiring split thickness skin grafts often 
requires hospital admission, at least 12 hours, a period of immobility for some patients, attentive 
donor site wound care and pain management. Cutting edge alternatives such as tissue 
engineered skin grafts carry their own challenges; namely the cost, relatively long cultivation 
time, and are limited to specialised facility. 
This study evaluates the efficacy of EG, as an alternative to current wound management therapy, 
SSG. In a pilot study carried out in our centre (unpublished data), we noted that this technique 
offers a method of autologous skin harvesting with minimal or no pain and a scar free donor site. 
Moreover, complete wound epithelialisation was achieved while maintaining patient 
independence. Therefore, this device has the potential to save NHS resources, by eliminating the 
need for theatre space and a hospital bed, and result in better Patient Reported Outcomes 
Measures. 
 

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6.0  
Specific aims of the study 
 
Our primary endpoint is to determine the efficacy of EG in wound healing at 6 weeks. This will 
be done via measurement of the wound at each review, using expert clinical assessment, the 
trust wound assessment criteria, and analysis of photo diaries. An independent blinded analysis 
of the photo diaries will be carried out by 2 plastic surgeons.  Inter and Intra rater reliability will 
also be assessed.  
Our secondary objective is to determine the type and concentration of growth factors expressed 
by the EG, as well as to compare the expression of cytokeratin and Connexin 43 before and after 
grafting. 
 
7.0  
Study design 
 
A prospective, randomised, multicentre study, in 2 parallel groups. The centre involved is the 
Royal Free Hospital, London. The sample size will be 44 patients, 22 patients in the EG group and 
22 patients in the SSG group. The study participants are to be recruited between October 2015 
and June 2018 and participants in both groups are to be followed up for 6 weeks. Groups are to 
be compared with respect to age, sex, BMI, and comorbidities.  
 
Study type 
 
 
:  
Investigational 
Estimated enrolment  
:  
44 patients 
Study start date 
 
: 
1 October 2015 
Estimated study end date 
: 
1 June 2018 
Study design: Allocation 
 
: 
Randomised 
 
 
Endpoint 
 
: 
Efficacy study 
 
 
Intervention Model 
:  
Parallel Assignment 
 
 
Primary Purpose 
: 
Treatment 

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Randomisation process 
After obtaining informed consent, patients will be randomly assigned to either the epidermal 
graft group or split skin graft group using computer randomisation.   
 
8.0 
Study participants 
Subject inclusion and exclusion criteria for the study are shown in Table 1 below: 
Inclusion Criteria 
Exclusion Criteria 
1. Male or female 
2. Age 18-90 at time of consent 
3. Wound measuring more than 1cm x 
1cm and lesser than 5cm x 5cm (1% 
TBSA) 
4. Wound with clean, healthy granulating 
bed, with minimal adherent slough 
5. Patient understands and is willing to 
participate and can comply with 
weekly visits and follow-up regime 
1. Wound with active infection 
2. Wound at plantar of the foot 
3. Patients unsuitable for Split Skin Grafting 
in the opinion of the investigator 
4. Previous history of excessive bleeding 
associated with surgical biopsies or trauma 
5. Allergies to tegaderm (and other dressings 
used in the study) 
6. Known uncontrolled Diabetes Mellitus, as 
measured by an HbA1c > 10%. 
7. Presence of one or more medical 
conditions, including renal, hepatic, 
hematologic, active auto-immune or 
immune diseases that, would make the 
subject an inappropriate candidate for this 
ulcer healing study 
8. Patient not fit for surgery (ASA 
classification > 4) 
Table 1: Inclusion and Exclusion Criteria for Study Participants 
 

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9.0  
Study setting 
 
Participants will be recruited at one centre, namely the Royal Free Hospital (RFH), London. 
Trial will be conducted in accordance to the Declaration of Helsinki and the recommendations of 
Good Clinical Practice. 
 
10.0 
Participants recruitment and consent 
 
10.1 Recruitment of participants 
All patients will be reviewed by a consultant plastic surgeon and assessed then referred to the 
department of plastic surgery for SSG or EG. During normal routine wound care in preparation 
for intervention patients will be flagged to the research team and where appropriate be offered 
a patient information sheet and screened for inclusion into the trial.  Once the patients are ready 
for intervention, following review by the study team, patients will be offered participation in the 
study and informed consent will be obtained.  
 
10.2 Gaining participant consent 
Written informed consent will be sought prior to enrolment in the study. This process will include 
an explanation of the aims, methods of skin harvesting and subsequent wound management, 
anticipated benefits and potential hazards of the study. Patients are given sufficient time (offered 
a period of 24 hours or more if needed) to consider whether they wish to participate.  
Consent will also be obtained for serial clinical photography of the wound and donor site for each 
review, to document the condition and wound healing process. There will be no financial 
payments offered to patients. 
 
11.0 
Outcome measures 
 
Primary outcome measures: 
- 
Wound healing at 6 weeks post grafting. 

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- 
Time for donor site healing. 
Secondary outcome measures:  
- 
Time for wound healing 
- 
Pain score as reported by the patients at day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, and 42 using 
Numerical Rating Scale.  
- 
Patient satisfaction for the donor site measured using a Patient Skin Graft Satisfaction 
Questionnaire. 
- 
Patient satisfaction for the wound measured using a Patient Skin Graft Satisfaction 
Questionnaire. 
- 
Incidence of adverse events. 
 
12.0 
Data  
 
12.1 Data to be collected 
Prior to grafting, wound will be assessed and recorded in the ‘Wound Assessment and Biopsy 
Form’ (Appendix 4). Details on patient’s co-morbidity, previous surgery to the wound, number 
and type of previous wound dressings will be recorded. Photographic documentation of the 
wound and donor site is performed before and after grafting, as well as at each wound review.  
The appearance and measurement of the wound is recorded at each visit. Pain score as reported 
by the patients will be recorded at day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, and 42. Data on number 
of outpatient visits and cost for each visit is recorded. Patient satisfaction will be measured at 
the end of the study using a ‘Patient Skin Graft Satisfaction Questionnaire’ (Appendix 5). 
 
12.2 Data handling and record keeping 
 
The multidisciplinary healthcare professionals at the outpatient clinic will have access to 
participants’ personal data to enable them to provide patient care. The data extracted for the 
purposes of this study would be anonymised. All personal data extracted will be stored on trust 
computers, which can only be accessed by research investigators, and are password protected.  

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The NHS computers and university computers, which will store the data, are encrypted and kept 
in a secure building with swipe card access. Access to all computers will be via secure login. All 
personal and study data will be stored on NHS secure servers and will be password protected 
with restricted access to unauthorised individuals. All handling, processing and storage of 
personal identifiable data and study data will be in accordance with the Data Protection Act 1998 
and the NHS Code of Confidentiality.   
We will store research data generated by the study for five years at UCL. The chief investigator 
will have long term access to research data after the study has ended. 
 
13.0 
Study assessment 
 
The primary outcome analysis is made based on the measurement of the wound taken at each 
visit. The wound and donor site will be assessed using a standardised wound assessment tool, 
the ‘PUSH Tool’ (Appendix 4), at each visit. The wound area will be measured with a sterile 
centimetre ruler as length of long axis x greatest width perpendicular to long axis, as per normal 
clinical practise. Wound healing at 6 weeks and time for donor site healing will be recorded. The 
PUSH Score for the wound and donor site will be statistically analysed. If the primary intervention 
had failed at week 6 ± 2, re-grafting and repeat of biopsy as per protocol will be considered after 
discussing with patient. Failed intervention is defined as increasing wound size or failure of 50% 
reduction in wound size at week 6 ± 2. 
Image analysis 
The wound and donor site will be photographed at each visit using a 3-dimensional camera, 
LifeViz (from Quanticare), to obtain high quality, accurate and standardised images for analysis. 
These images will be stored in patient’s photo diary. 
 
14.0 Statistical Considerations 
 
14.1 Sample size 
 

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We will recruit a total of 44 patients into this study, with 22 patients randomised into each study 
arm. Preliminary data suggests that both techniques offer same healing rate at 6 weeks post 
grafting, however donor site morbidity is present in 40 % of patients with split thickness skin 
graft while only 5% is seen in patients with epidermal graft. Sample size calculation with power 
of 80% at 5% significance level indicates that 22 patients per group are necessary 
 
14.2 Statistical analysis 
 
All analysis will be conducted according to the intention-to-treat principle with the use of SPSS 
version 22 (IBM, Armonk, NY, USA). Patients are evaluated for analysis if they received a study 
treatment. If the clinical course cannot be fully evaluated, the last point of visit is considered as 
the last data analysed. Baseline characteristics of the two groups will be recorded. The 
continuous variables will be compared using Student t-test. The categorical variables will be 
compared using Pearson’s chi-square or Fisher’s exact test depending on the number of events.  
The proportion of wounds healed with each treatment will be compared using chi-square test or 
Fisher’s exact tests depending on the number of events. Mean time to wound healing will be 
determined on the bases of the number of days until complete re-epithelialisation, using Kaplan-
Meier analysis of cumulative wound healing, followed by a log rank test. 
Secondary outcomes will be compared between groups using a chi-square test for categorical 
variables. Non-normally distributed continuous variables will be compared using Mann-Whitney 
U test. A p value of less than 0.05 will be considered significant and all tests will be two-sided.  
 
15.0 
Subject Compliance & Withdrawal of Subjects 
 
15.1 Subject Compliance 
 
Participants who are undergoing an operation will be verbally re-consented at the time of surgery 
to confirm they wish to remain in the study and for the biopsies to be performed.   
 

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15.2 Withdrawal of Subjects 
 
Subjects will be withdrawn from the study under the following circumstances: 
• Participant develops serious life threatening illness and is admitted to hospital. 
• Participant who has given informed consent, loses capacity to consent during the study 
for any other reason. 
All subjects withdrawing from the study will be recorded along with reasons for withdrawal and 
details of planned follow up.   
 
16.0 
Ethical Considerations 
 
16.1 Benefits, risks and burdens to study participants 
 
Information obtained from this study will benefit wider scientific research in particular with 
regards to the role of grafting in wound healing. The information obtained from this study may 
improve future treatment of patients.  
The risks to study participants will be minimized.  This study is to be undertaken in a university 
teaching hospital.  Two small 4-mm punch biopsies will be taken, by an experienced surgeon, 
one from the participants’ wound edge and the other from the centre of the wound, before 
treatment and 7 days post grafting. Contraindications to undergoing this procedure are clearly 
specified in the exclusion criteria.  Should a complication of biopsy occur, immediate treatment 
can be provided as the patient is in the surgical environment. Participants will be asked prior to 
informing their GP of involvement in the study.  Patients will be reviewed weekly at the 
outpatient specialist clinic. 
Participants in the study will have the opportunity to discuss their current wound-healing 
progress with study investigators.  To minimize bias and conflict of interest, participants’ future 
treatment options will not be discussed by investigators.   
 

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16.2 Approvals from relevant groups 
 
Patients, service users, carers and members of the public will be involved in the research process 
through Royal Free Hospital patient focus group discussion.  For patients attending these groups, 
it will provide opportunity for them to express their views about this research project and the 
current service.  They will also receive published information regarding the results of this study.  
Patients who do not attend these groups will be informed of the groups’ involvement and will 
also be invited to take part in the study. Specifically we have asked patients undergoing EG or 
SSG about the protocol to be studied and their willingness to participate in such a trial.  
Formal approvals are to be sought from NHS/HSC, Trust Research and Development offices and 
Research Ethics committee.  
 
17.0 
Finance, Insurance & Harm 
 
17.1 Finance details 
 
This study is part of Dr Muholan Kanapathy’s doctoral research project. The study itself is not 
funded specifically. MK is funded from UCL by his supervisor Mr Toby Richards. 
 
17.2 Insurance details 
 
University College London holds insurance to cover participants for injury caused by their 
participation in the clinical study. Participants may be able to claim compensation if they can 
prove that UCL has been negligent. However, as this clinical study is being carried out in a 
hospital, the hospital continues to have a duty of care to the participant of the clinical study. 
University College London does not accept liability for any breach in the hospital’s duty of care, 
or any negligence on the part of hospital employees. This applies whether the hospital is an NHS 
Trust or not.  This does not affect the participant’s right to seek compensation via the non-
negligence route.  

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17.3 Cover for non-negligent and negligent harm 
 
The study will be conducted in compliance with the protocol, GCP and the applicable regulatory 
requirement(s). 
Participants may also be able to claim compensation for injury caused by participation in this 
clinical trial without the need to prove negligence on the part of University College London or 
another party.  Participants who sustain injury and wish to make a claim for compensation should 
do so in writing in the first instance to the Chief Investigator, who will pass the claim to the 
Sponsor’s Insurers, via the Sponsor’s office.  Hospitals selected to participate in this clinical study 
shall provide clinical negligence insurance cover for harm caused by their employees and a copy 
of the relevant insurance policy or summary shall be provided to University College London, upon 
request. 
 
18.0 
Reporting and Dissemination 
 
The results of the study will be reported and disseminated in peer reviewed scientific journals, 
conference presentations, website/online publications as well as internal reports. Reporting will 
be based on CONSORT guideline for reporting randomised trial. All publications will be forwarded 
to participants. 
 
 
 
 
 
 
 

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19.0 
List of relevant references 
1. 
Potten CS. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. 
International review of cytology. 1981;69:271-318. 
2. 
Ortonne JP, Loning T, Schmitt D, Thivolet J. Immunomorphological and ultrastructural aspects of 
keratinocyte migration in epidermal wound healing. Virchows Archiv A, Pathological anatomy and 
histology. 1981;392(2):217-30. 
3. 
Jung KE, Kim MH, Kim JY, Park BC. Comparison of modified Korean cupping method and 
conventional respiratory suction unit for epidermal graft. International journal of dermatology. 
2014;53(8):e384-e6. 
4. 
Kirfel G, Herzog V. Migration of epidermal keratinocytes: Mechanisms, regulation, and biological 
significance. Protoplasma. 2004;223(2-4):67-78. 
5. 
Barrandon Y, Green H. Cell migration is essential for sustained growth of keratinocyte colonies: 
the roles of transforming growth factor-alpha and epidermal growth factor. Cell. 1987;50(7):1131-7. 
6. 
Wang CM, Lincoln J, Cook JE, Becker DL. Abnormal connexin expression underlies delayed wound 
healing in diabetic skin. Diabetes. 2007;56(11):2809-17. 
7. 
Becker DL, Thrasivoulou C, Phillips AR. Connexins in wound healing; perspectives in diabetic 
patients. Biochimica et biophysica acta. 2012;1818(8):2068-75. 
8. 
Abdullah KM, Luthra G, Bilski JJ, Abdullah SA, Reynolds LP, Redmer DA, et al. Cell-to-cell 
communication and expression of gap junctional proteins in human diabetic and nondiabetic skin 
fibroblasts: effects of basic fibroblast growth factor. Endocrine. 1999;10(1):35-41. 
9. 
Brandner JM, Houdek P, Husing B, Kaiser C, Moll I. Connexins 26, 30, and 43: differences among 
spontaneous, chronic, and accelerated human wound healing. The Journal of investigative dermatology. 
2004;122(5):1310-20. 
10. 
Schalper KA, Riquelme MA, Branes MC, Martinez AD, Vega JL, Berthoud VM, et al. Modulation of 
gap junction channels and hemichannels by growth factors. Molecular bioSystems. 2012;8(3):685-98. 
11. 
Posnett J, Franks PJ. The burden of chronic wounds in the UK. Nursing times. 2008;104(3):44-5. 
12. 
Franks PJ, Morgan PA. Health-related quality of life with chronic leg ulceration. Expert review of 
pharmacoeconomics & outcomes research. 2003;3(5):611-22.