Pilot Study of Early Postoperative Fractional Ablative Laser Treatment of Skin Grafts for Burns
Phase: NA
Conditions: Burn Scar, Skin Graft Scar
Sponsor: Wake Forest University Health Sciences

 
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Official Title:  Pilot Study of Early Postoperative Fractional Ablative Laser Treatment of Skin Grafts for Burns 
NCT04176705 
IRB-Approved Date: 12/30/20 
 

 
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Background: 
The near and long-term functional impact of burn 
scars and the sequelae of skin grafting are well known1. 
The economic burden of this treatment paradigm has also 
been recognized – with the monetary cost of treating burn 
sequelae estimated as over four times that of the in-hospital 
stays for acute burn injury2. In addition to the social and 
psychological burden, burn scars and the contraction of 
skin grafts can not only limit the range of motion (with a 
loss of function), but also lead to skeletal deformation (Fig. 
1). In addition, there has been increased appreciation of the 
incidence and importance of the impact of pruritus3,4.  The 
solution to these symptomatic and functional challenges is 
ongoing. 
 
Modern treatment of the burn patient is multidisciplinary 
and a wide array of management options are available (e.g. 
surgical release and skin grafting, local tissue 
rearrangement, compression garments, laser treatments, and 
steroid injections) to attempt to alter scar formation5,6. The 
paradigm of burn reconstruction (often referred to as a 
reconstructive ladder) reflects recognition of the 
heterogeneity of the problem and subsequent solution.  The 
overall strategy reflected in this metaphorical label is that 
the simplest solution deserves first consideration, and one 
proceeds to the next higher-level solution only when there 
is an identifiable contraindication to utilization of the first 
step (Fig. 2)7.  The rationale for a reasoned, stepwise 
approach is that the risk increases as a progressively higher-
level step is chosen.  As an extreme example, the use of a 
free flap to cover a second-degree burn is illogical.  The 
wound will predictably heal and the risk of the morbidity 
associated with flap loss is unacceptable.  Contrast the 
previous extreme example with a fourth degree burn 
involving exposed bone of sufficient size that there is not 
an alternative to achieving soft tissue coverage.  In the latter 
situation, the potential risk of free tissue transfer is logical 
in order to protect critical deep structures (bone, vessels, or 
nerves).  These steps can be selected for treatment of open 
wounds, as well as during reconstruction.    Just as there 
may be a better choice for coverage of an acute wound, 
there may also be a clear choice for improving function or 
appearance – while minimizing the risk to the patient.  The 
role of the fractional CO2 laser in modifying burn scars in 
not clear. Multiple authors have identified improvement in 
burns scars with treatment with fractional CO2 (FxCO2) laser treatment8-13.  However, a common critique is that 
 
Figure 1. Disabling burn scar, resulting from 
combination of delayed surgical treatment 
and rehabilitation treatment.  Fixed soft 
tissue deformities clinically apparent on 
inspection (A, C, and D) and X-ray of 
affected hand (B). 
 
 
Figure 2.  The reconstructive ladder (used 
for acute wound coverage or delayed 
reconstruction) is a metaphorical approach 
to reconstruction.  Each successive step is 
accompanied by increasing complexity and 
risk.  Understanding for the role of FxCo2 
treatment is incomplete. 

 
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measures were subjective, treatment timing and laser 
settings variable, and study populations were relatively 
small14.  The common approach to solving these 
challenges is to simply focus on planning a larger study.  
However, we note the lasers were also deployed as a 
solution to a quite heterogeneous problem. A common 
challenge to any clinical study is identifying the condition 
being treated as precisely as possible.  Although not 
commonly addressed, the term “burn scar” encompasses 
a heterogeneous group of pathologic skin changes 
associated not only with areas of burn that heal by 
secondary intention (forming scar), but also areas with 
thickened/shrunken skin grafts, hypertrophy at the seams 
along the edges of skin grafts, and delayed healing of skin 
graft donor sites with resultant hypertrophy (Fig.3).  The 
scarring and contracture of split-thickness skin grafts is 
expected without treatment.  Human split thickness skin 
grafts heal with secondary contracture, and this 
contracture can result in decreased function15.  Multiple 
factors have been noted to affect the amount of 
contracture- such as the use of meshed skin grafts or graft 
thickness16-18. The timing between injury and institution 
of both surgical and non-surgical means of treating scars 
is impactful as well.  Non-surgical methods of scar 
prevention are generally accepted to have increased 
effectiveness when applied closer to the time of injury6.  
Even in cases of simple primary closure of surgical 
wounds, mechanical intervention has been shown to be an effective means of decreasing scar formation, and 
these are applied immediately19,20.   Similarly, there is improved effectiveness of compression garments for 
managing burn scars if applied closer to the time of injury21.  These clinical observations appear consonant with 
animal studies of wounding which have confirmed the 
temporal changes in the wound environment and cellular 
architecture.  Surgical procedures are also affected by scar 
characteristics.  More immature scars show evidence of 
inflammation - greater vascularity, less pliability, and 
greater thickness of the tissue creates challenges that weigh 
against early release and graft or local tissue rearrangement 
(z-plasty).  In summary, the choices are about the best 
therapy and also the best time.  There have been clinical 
studies looking at the efficacy of both early versus delayed 
treatment strategies with FxCO2 laser.  However, early 
appears to mean a matter of months22.  This evolution in 
practice has left a critical time period poorly explored, 
especially with regards to the potential impact on burn 
scars – healing split-thickness skin graft in particular.  Of 
note, this pilot study does not seek to establish a new 
indication for the FxCO2 laser.  The FDA approves the 
laser in use at Wake Forest Baptist Medical Center.  It is 
approved for use on “surgical scars” (we are treating the 
resulting scars associated with skin graft surgery).  As mentioned, “burn scars” is a very inclusive term.  This is 
precisely why we will treat only the surgical scars related to burn treatment.  It is also approved for “other soft 
Figure 3.Examples of heterogeneity of 
pathology described as “burn scar”.  Include 
areas allowed to heal by secondary 
intention (A.), areas of contracted skin grafts 
(B.), scarring at the seams of supple full-
thickness skin grafts (C.) and even delayed 
healing with hypertrophy of donor sites (D.) 
 
 
Fig 4. Split-thickness skin graft contraction 
(Identified as “Scar Contraction”) is 
expressed as % original area as a function of 
time.  In this case, the sizes of the skin grafts 
were normalized to day 28 (the first day of 
laser treatment). 

 
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tissue applications”.  Finally, the laser is being applied in an earlier and earlier fashion as it use has become 
more popular and evolved.  The intent of this study is to establish safety and, perhaps efficacy, of use at a 
different time point.  
 
PRELIMINARY STUDIES (Conducted at The Ohio State 
University) 
Efficacy of Early Laser Treatment of Split-thickness Skin Grafts 
in a Porcine Burn Model: 
 Our group has documented the salutary effects of the 
FxCO2 laser treatment on a porcine model of split-thickness 
skin graft applied to excised burns23.  An unexpected finding 
was the improvement in eventual secondary contracture of the 
split-thickness skin graft (Figure 4.).  Although we also found 
improvement in measures important to skin graft appearance, 
the finding of reduced secondary contracture is particularly 
important to functional outcomes.  We have also conducted a 
pulse-chase study to better understand the effects of early (7 
days after grafting) FxCO2 treatment of split-thickness grafts in 
the same porcine burn model.  There was no evidence of slowed 
healing caused by laser treatment.  Healing was measured by 
transepidermal water loss, which is a functional measure of skin 
integrity (Fig. 5). 
 
Relevance to Proposed Clinical Trial: 
In Figure 3 B, the photo is of an axillary contracture created by tension from a skin graft, which underwent 
the normal, expected course of secondary contracture.  The photo is also intraoperative - from the surgical 
procedure necessary to correct the tension created by the secondary contracture.   The promise offered by the 
porcine model findings is that such corrective 
surgery of contracting skin grafts may be reduced 
in frequency, or avoided all together. Further, the 
animal model offers evidence of safety. 
 
Local Clinical Practice Cannot Provide Custom 
Compression Garments Sooner than 19 weeks 
from the time of injury: 
In an effort to better understand how 
measures such as compression therapy were being 
applied at our burn center, we conducted an IRB-
approved chart review to identify how long a delay 
exists between identification of the need for 
compression therapy and actual wearing by the 
patient.  The study has been submitted for 
publication and a surprising 19-week delay was 
identified (Table 1). 
 
Relevance to Proposed Clinical Trial 
 
Table 1.   A quality improvement project was translated 
into an IRB-approved review of the time required for 
patients to successfully don custom-made compression 
garments.  A surprising delay was noted.   
 
Figure 5.  When the porcine split-thickness 
skin graft (meshed 1:1.5) is treated with 
single pass of 70mJ at 5% fractional 
coverage, wound closure (defined by 
transepidermal water loss) is not retarded. 

 
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The noted delay was, and is, concerning from a clinical 
care perspective.  However, the clinicians have been unable to 
change the delays, as the process appears to have multiple 
logistical delays (therapist availability to measure, delays in 
ordering, delays in insurance approval, delays in fitting, delays in 
altering, and delays created by difficulty in contacting patient).  
These challenges notwithstanding, a unique opportunity has been 
created by the inability to offer a timely standard of care.  The 
delay offers an acceptable and ethical justification to apply early 
laser treatment to patients – either as part of clinical care or a 
prospective study. 
 
Limited Early Laser Treatment is Clinically Free of Complication 
 
Due to our inability to offer a timely and effective therapy to mitigate scar formation, our surgical team at 
the Ohio State University has treated skin grafts with FxCO2 during the period of initial hospital admission, when 
patients were returning to the OR for other procedures.  This has been offered as empiric therapy and not part of 
any type of study (Fig. 6).  With recognition of those limitations, 
the treatment is well tolerated, with no clinical evidence of graft 
injury (Fig. 6). Also, there is anecdotal appreciation of efficacy 
(Fig. 6 and Fig 7). We have applied the FxCO2 laser 
successfully in four patients.  We have seen no areas of 
unanticipated graft damage or loss related to its use.   
 
Relevance to Proposed Clinical Trial 
Safety is an essential concern of any proposed clinical trial.  
Although the experience of treating skin grafts at 6-10 days after 
surgery is limited at our Burn Center, it is promising. 
Establishing safety with an appropriately monitored study is an 
important unmet need. However, the preliminary data and 
qualitative observations are supportive that the study can be 
done safely. 
  
 
PROPOSED PILOT STUDY. 
 
This pilot study is being conducted to establish safety, however we will make multiple measures to 
measures of efficacy as well. We hypothesize that human split-thickness skin grafts will safely respond similar to 
the porcine model when treated with the FxCO2 laser and have significantly less secondary contracture than 
control sites. 
 
 
  
Overall Strategy 
 
Figure 6.  Skin grafts (meshed 1:1) on 
nearly entire dorsum of bilateral hands one 
day after fractional CO2 laser treatment. No 
subsequent loss of graft. Displayed flexion 
of digits at patient maximal effort. 
 
Figure 7. At time of presentation for third 
planned laser treatment (not yet wearing 
compression garments).  Note composite fists in 
A. 

 
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The great majority of laser studies have addressed treatment of established scars. Ideally, treatment modalities 
could be moved into the acute period of injury, to shorten the recovery time of thermal burns by decreasing the 
time to maximum recovery, and mitigate scar formation. 
The current study will address the impact on treatment of 
skin grafts applied in the treatment of acute burn wounds.  
Preliminary work completed by our team has confirmed 
that the red Duroc porcine model is a good model of 
hypertrophic scar formation in humans, and early use of 
the FxCO2 on split-thickness skin grafts decreased 
secondary contracture.  Further, we have identified a 
period of 19 weeks between the time custom-made 
compression garments are ordered and actually applied 
with benefit to the patient. We have identified a 
“therapeutic donut hole” in which we have no efficacious 
alternative to offer until about 19 weeks.  In these patients 
who had larger burn returning to the OR for additional 
procedures, we were able to offer FxCO2 treatment as a 
“salvage” therapy.  With this, we have demonstrated 
safety for the skin graft and anecdotal efficacy. We 
propose a pilot study to prospectively demonstrate safety 
in a controlled study and  attempt to establish efficacy of 
early (post grafting day 6-10) FxCO2 laser treatment of 
split-thickness skin graft applied in the treatment of burn 
injuries. 
 
Patient Eligibility 
All patients who are to undergo skin grafting procedures for acute treatment of thermal burns will be screened 
for enrollment.  Although, split-thickness skin grafts placed for reconstruction or coverage of non-burn injuries 
should be expected to heal and respond to treatment in a similar fashion to grafts on acute burn wounds, this 
study will seek to limit these variables and is focused on offering benefits to the acutely injury patient.  Only 
patients with grafts placed over at least 100cm2 will be approached for inclusion in the study so as to minimize 
any paracrine effect that might result from non-treated grafts in proximity of treatment areas.  The 100cm2 need 
not be contiguous.  That is to say, two smaller areas totaling 100cm2 can be used.  Sites will be randomized to 
laser/no laser. If there is a single site of sufficient size, it will 
be divided in to two, roughly equivalent surface area segments 
with the midpoint along the long axis of the 
limb/hand/foot/neck/torso (Fig. 8).  For site assignment 
purposes we will assume the classic anatomic position with 
patient assumed to be in a standing position, gaze forward, 
hands to sides with palms facing the direction of gaze. Areas 
will be labeled: A.(Right, cephalad, or lateral) and B. (left, 
caudad, or medial).  In order to attempt to assess the same 
three locations at each site, a tracing of each site will include a 
tracing of three, individual locations about 1 cm in 
(approximately) in diameter (Fig. 9). Any measures done at the 
time of treatment visits will be done prior to any therapeutic 
intervention. Both sites will have lidocaine 4% topical 
anesthetic cream (Ferndale Laboratories, Ferndale MI) applied 
as thin layer and left for 30-45 minutes to minimize discomfort 
(after any measurements have been taken).  The area to be 
treated (A. vs. B.) will be randomized with opening of an 
 
Figure 8.  Sites will be randomized such that the 
choice between treatment and control will be 
between A.(Right, cephalad, or lateral) and B. (left, 
caudad, or medial).  Extremities include the feet.  To 
avoid confusion regarding medial/lateral we will 
invoke convention of assuming body is in anatomic 
position (i.e. arms extended to the side with palms 
facing in direction of forward gaze of the patient. 
 
Figure 9. Tracings will be obtained of the 
perimeter of each site.  On the first set of 
tracings, we will mark three locations 
(approximately 1 cm in diameter) that will be 
used to help identify the same areas for 
subsequent measures and surveys. 

 
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evelope with assignment to treatment arm after the test sites have been identified.  The treatment area will then 
be cleaned with chlorhexidine gluconate solution 4.0% w/v (Mölnlycke Healthcare, Norcross, GA).  FxCO2 
laser treatment will then be completed with 5% fractional coverage and 70-mJ fluence setting (percentage of the 
total surface area ablated and the energy delivered in each micro-beam –respectively). We will apply 
triamcinolone acetonide (Bristol-Myers Squibb, Princeton, NJ) at a concentration of 20mg/ml immediately after 
treatment to both laser and no-laser sites - as this is often reported and there is some speculation that this may be 
part of the reason improvement is noted.   
For aftercare, patients will be instructed to apply a thin layer of an over-the-counter moisturizing cream such as 
Lubriderm® (Johnson and Johnson, Skillman, NJ) or Aveeno® (Johnson and Johnson, Skillman, NJ). 
 
Study Intervention and Group Assignment 
Sites will be labeled A and B in accordance with Figure 8.  For each patient, one site will be randomized 
to receive laser treatment and the other will be the control. The study statistician will generate a permuted block 
randomization scheme (three blocks of 5 cells). Treatment assignments will be delivered on-demand following 
confirmation of eligibility, patient consent, and identification of test sites. 
 
 
Study Outcome Assessment 
 
Measurements of scar properties, as 
illustrated in Fig. 10, will be made at the time of 
each treatment (immediately prior to treatment) 
and at two additional follow up time points. To 
assess changes in scar development and 
maturation in the control and treatment sites, scar 
appearance and properties will be assessed at 
each clinic visit using non-invasive methods and 
measurements.  Scars will be photographed at 
each session with a scale bar and color palette in 
each photograph so all images can be balanced to 
the same lighting conditions. Scar area at sites A 
and B will be traced onto transparent sheets and 
quantified 
using 
computerized 
planimetry 
following the same methodology used for our 
porcine studies23. The planimetry will also be 
used to digitally estimate graft loss (if any). To 
assess erythema and pigmentation, a Mexameter 
(Courage + Khazaka, Cologne, Germany) will be 
used to quantify the color of the treated and 
control scar. Scar biomechanics, pliability, 
elasticity and viscoelasticity, will be quantified 
using a BTC-2000(SRLI, Franklin, TN) as this 
instrument was shown to have the greatest inter- 
and intra-user reliability in our prior human 
studies.  Scar height and roughness will be quantified using a mold/casting technique using Aquasil Ultra XLV 
dental impression material (DENTSPLY International, Milford, DE) followed by mold imaging and quantitative 
analysis. In addition, the VSS and POSAS (Observer Scale only) will be performed by the research team members 
for scar color, mechanics, height and roughness. These measurements will be collected at each clinic visit (every 
1.5-3 months).  This data collection strategy has been optimized in adult burn patients at OSUWMC (IRB protocol 
#2016H0250) and requires no more than 25 minutes per patient. 
  
 
Figure 10.  Prior to each of three successive laser 
treatments, measures will be taken.  Photography, done at 
each visit, will be important to assessing qualitative graft 
changes, including monitoring for graft loss. Surveys will be 
given at the visit following a laser treatment (to asses for 
adverse events).  As the graft continues to heal, we expect 
measureable differences, color measurements (Mexameter), 
biomechanical measurements (BTC-2000), and casts with 
dental impression material will be taken.

 
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Clinical End Points: The primary endpoint for this pilot study is the contracture of scar (skin grafted) surface 
area at 90 days post-grafting.  A significant reduction in secondary graft contraction in the treatment group 
compared to the control group would prompt the design of a multi-center confirmatory trial.  Secondary endpoints 
include scar roughness, biomechanics as measured by stiffness and elasticity, redness measured by erythema each 
examined at 90 days post-grafting and VSS/POSAS scores along with patient reported satisfaction.  Additional 
secondary endpoints will include the examination of each measurement at mentioned above at 1 year post-grafting 
to examine longer term healing.  
 
Patient Eligibility: Eligible patients are non-emergent, patients with full-thickness burns who were seen at 
Wake Forest Baptist Medical Center and are scheduled for treatment with autografts for burn injury.   Inclusions 
criteria: ages 18- 89, autograft site of at least 100cm2 (not involving the head, neck, hands, buttocks or 
perineum).  All non-burn diagnosis (i.e. chronic wound, Steven-Johnsons/TEN, etc.) prisoners, pregnant 
women, and patients younger than 18 years will be excluded. 
 
Patient Identification: To screen for eligible patients, the operating room schedules and surgeons’ calendars will 
be reviewed by the clinical research coordinator (CRC), and the three burn surgeons will aid in identifying any 
potentially eligible adult (age 18-89) patient who is to undergo skin grafting of a full-thickness burn. After 
identification, study team personnel will then screen the patient for eligibility, by review of clinical information.  
 
Patient Recruitment:  Once eligible patients are identified, a qualified research team member will approach the 
patient and offer the opportunity to learn more about participation in this study.  If the patient is willing, then the 
qualified research team member will proceed to complete the informed consent and enrollment process. This will 
be completed at the conclusion of clinical care, to avoid any duress from the pain of wounds left open to the air.  
In the clinic, the process will be conducted in the patient’s exam room.  Similarly, inpatients will also be consented 
in the quiet of their hospital room so as to allow them time to carefully consider the details of the study and ask 
questions.  
 
Patient Sample Size and Rationale: As this is a pilot study in humans, we used preclinical data from our porcine 
burn model to inform the choice of sample size. For a full clinical study we estimate a need to enroll 29 patients. 
We acknowledge we may not have a large enough sample size to measure significant improvement.  However, 
the data obtained will aide in the more accurate calculation of the needed sample size for further human studies.  
In addition, the prospective documentation of safety will increase our competitiveness for funding for a full study.  
For this pilot study we propose enrolling only 15 patients – the number at which we would have conducted an 
interim analysis and assess safety if we were to proceed with enrollment of 29 patient s (current estimate for full 
study).  The primary endpoint that we will assess is the scar area at 90 days post-grafting.  We will conduct 
analysis for efficacy after the patients have each reached 90 days post-grafting using the spending function of Lan 
and Demets24. There is not an accepted standard for the measure of graft loss or an expected “percent take”.  Some 
have proposed to use less than or greater than 50% of graft loss reflecting the difficulty25.  In an effort to proceed 
in a conservative fashion, an adverse safety outcome (namely graft loss not evident by physical changes visible 
on Day 7-10 photographs, will be defined as a 5% or greater, laser-associated graft loss with a rate in patients of 
15% or greater deemed unacceptable. In a previous study of burn patients with heterogeneous types of scars, it 
was noted that those treated with FxCO2 were most likely to complain of postoperative pain (8/42 patients, or 
19%), followed by reports of fever (2 out of 42 patients, or 4.8%), development of hypopigmentation (2/42 or 
4.8%), rash (1/42, or 2.4%), or blistering (1/42, or 2.4%)26.  
 
Statistical Plan and Data Analysis 
The primary endpoint of the full trial is the burn scar area at 90 days post-grafting.  For the primary 
analysis, we will compare the log transformed area of the scar for the treatment wounds to the control wounds.  
We will use linear mixed effects models that will adjust for fixed effects of the baseline wound surface area 
grafted (prior to the occurrence of any significant contracture) and treatment center.  A random effect will be 

 
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included in the model for each patient to account for dependence between the treatment and control sites.  The 
primary analysis will follow intention to treat principles and will be conducted at the two-sided 0.05 level27,28.   
 
Secondary objective endpoints include scar roughness, biomechanics as measured by stiffness and 
elasticity, redness measured by erythema each, examined at 90 days post-grafting.  Secondary analyses will follow 
the same general framework as outlined for the primary analysis.  Outcome variables may be log transformed to 
satisfy necessary distributional assumptions for the analysis.  Secondary subjective endpoints are the VSS and 
POSAS scores at 90 days post-grafting.  These endpoints will be analyzed within the same framework as described 
for the other primary and secondary endpoints.  In addition, we will examine all endpoints at 1 year post-grafting 
to characterize the effects of treatment on longer term healing. 
 
We will also conduct exploratory longitudinal analyses of the primary and secondary endpoints.  Since 
we will observe each endpoint at multiple visits across time, we will use longitudinal mixed effects models to 
explore the healing profile across time for both the treatment and control group.  
For efficacy, analysis will be interested in assessing the primary endpoint through the error spending 
function approach described by Lan and Demets24,29.  For safety, an adverse safety outcome will be defined as a 
5% or greater, laser-associated graft loss with a rate in patients of 15% or greater deemed unacceptable.  If there 
are 6 adverse safety outcomes within the first 15 patients, we will terminate the study due to an unacceptable 
safety risk to patients.   
Data Collection 
Data will be collected on Case Report Forms (CRF) and individual SD cards (for photographs) kept with 
the CRF for each individual patient.  These CRFs and SD cards will be stored in the locked office of the CRC 
and in a locked file cabinet. 
 
Data and Safety Monitoring Committee 
A Data Safety and Monitoring Committee (DSMC) will be formed and will meet every 6 months 
throughout the period during which patients are being recruited and experiencing follow-up. The DSMC will 
review data provided by the primary study statisticians and other study staff involved in data management and 
analysis. The committee will consist of Martin Avery, MD(a trauma surgeon at WFBMC, Molly J. Thompson, 
PhamD (Specialty Practice Pharmacist – Critical Care at the Ohio State University), and Rachel Penny PA (PA 
at the Ohio State University - experienced with appearance of grafts, laser patient care, and clinical trials.  All 
unexpected non-serious adverse events and serious adverse events relating to participation in the study will be 
reported verbally and in writing to the local IRB and the study PI.. The verbal report will occur within 48 hours 
of the occurrence. The written report of a serious adverse event (e.g., death or life-threatening adverse event) 
will be reported within 7 days. 
 
 
 
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