Here is a preliminary study describing the results of a new method of treating a venous stasis leg ulcers. This report shows the outcome in one patient whose ulcer was implanted with acellular dermal matrix after which the treated leg was dressed with pressure dressings for a period of 92 days. The results were quite encouraging. I wish we had been able to study more patients.
ADM treatment of venous stasis ulcers
Use of Acellular Dermal Matrix in the Treatment of
Venous Stasis Ulcers:
A Preliminary Report
ABSTRACT
Chronic leg ulcers are common, but often
intractable wounds which impose significant burdens on patients and society
alike. These wounds negatively impact
the quality of life circumscribing the range of activities and frequently
causing discomfort Standard compression
therapy has only limited effectiveness, but recently success has been reported
using skin substitutes in the treatment of leg ulcers. Skin substitutes are products composed of
biologically derived materials such as collagen, matrix proteins, complex
sugars, and occasionally living cells which are applied to wounds as
dressings. The relative contributions of
the matrix materials and cells comprising the skin substitute remain, however,
undefined. Our study will examine the
efficacy of one type of skin substitute, acellular dermal matrix (ADM), in
treating leg ulcers. ADM is a native
collagen meshwork derived from human skin that has been treated to remove all
cells and cell debris. As with other
skin substitutes, it is applied as a dressing, and serves as a cushion and replacement
for skin dermis lost from the wound.
Comparisons will be made with conventional compression stocking
treatment. Additionally, some subsets of
patients will receive implants of living cells derived from a small biopsy of
their own skin either used alone or in combination with ADM. We expect this investigation to increase the
understanding of how skin substitutes function therapeutically and to provide
an improved method for treating leg ulcers.
Here we report the results of treatment with ADM of a venous stasis leg
ulcer in one patient.
Ulcers of the lower extremities are
extremely common in the United States (>600,000 cases per year) and account
for significant morbidity and loss of productivity (1) with more than 2 million
workdays lost in the US annually due to these persistent wounds. In addition, these wounds frequently have a
deleterious emotional impact on affected patients. The majority of chronic leg ulcers result
from venous disease leading to ambulatory venous hypertension. These wounds, referred to as "venous
ulcers", are generally about 2-5 centimeters in diameter and are usually
located over the medial malleolus.
Improper venous functioning may occur as a result of damage to the veins
themselves, as a sequela of deep venous thrombosis or superficial thrombophlebitis,
or may reflect dysfunction of the surrounding neuromuscular tissues that
normally propel blood through these vascular conduits. Conventional therapy is often arduous and
time-consuming for patients, and healing frequently progresses slowly.
The
most common therapy utilized in the treatment of venous ulcers involves
compression or support stockings, but healing is achieved in only approximately
50% of patients despite 4-6 months of such treatment (2,3).
Therapeutic approaches involving medical (pentoxifylline) (4), or surgical (vein repair) (5) strategies have provided mixed results and small
split-thickness skin grafts or autologous plugs have been used with some
success (6,7). More
recently, certain artificial skin products (Dermagraft, Apligraf) have been
applied to ulcers, including those related to venous insufficiency, to augment
their healing, with generally favorable results (2,8,9). These
skin substitutes are composed of biologically derived materials, which may
include collagen gels or living cells such as keratinocytes or
fibroblasts. They are considered
biological dressings and do not become permanently incorporated into the
wound. These materials are thought to
duplicate properties of the skin vital to healing including the production and
release of growth factors and cytokines.
The
factors pertinent to the healing of venous stasis ulcers are manifold, and may
include the influences of structural
proteins and other macromolecules, cellular elements, or the growth factors
they elaborate. Recent studies have
demonstrated accelerated ulcer healing with the use of artificial skin products
as noted above. However, the mechanism of
this effect is not at all clear, and may involve the infrastructural and space-occupying
properties of the matrices used rather than the cellular components or growth
factors purported to be acting. This question has not been addressed
previously but will be examined more closely in the study proposed here.
In
addition, Dermagraft (Advanced Tissue Sciences) and Apligraft (Novartis)
contain allogeneic epidermal and dermal cellular components. These foreign materials evoke an immune
reaction in the wound and the effect of this host inflammatory response on
wound healing is unclear, but such inflammation may act to undermine
healing. Our study will examine the
impact of autologous epidermal and dermal cellular populations (from
"mini-implants") on the healing response when introduced into venous
ulcers in various contexts. In addition,
ADM appears to be virtually non-immunogenic when it is implanted within the
same species as that from which it was derived so it does not induce an
inflammatory response in the wound. (10,11).
Our objective in this study was to
preliminarily determine the efficacy of acellular human dermal matrix (ADM) and
autologous skin "mini-implants" in the treatment of venous stasis
ulcers of the leg. We intended for this
investigation to increase our understanding of the therapeutic functions of
skin substitutes and to provide an improved method for treating leg
ulcers.
MATERIALS
Acellular
Dermal Matrix (ADM) is a thin sheet of human tissue, approximately 1/100 of an
inch thick, which is composed mainly of native collagen and other extracellular
matrix components such as laminin and keratan sulfate (12). ADM is
treated with enzymes and detergent to remove cells and cell debris. ADM was derived from donors unrelated to
study participants. We used ADM as a
biological cushion to permanently replace lost dermis in venous stasis
ulcers. Cadaver skin was obtained from
the Skin Bank at the University
of Cincinnati Shriner’s Burn
Center which is certified by the American Association of Tissue Banking. This tissue has been thoroughly screened for
human fungal, bacterial, and viral pathogens and has been certified to be
negative for these pathogens. ADM was
prepared by treating 0.012" thick pieces of cadaver skin with Dispase (2.5
U/ml, 24 h @ 4°C) followed by 0.5% Triton X-100 detergent (24 h @ 25°C) as
described previously (10). We have
reported the composition of such ADM analyzed by immunocytochemistry in
conjunction with light microscopy (12). We have
shown greatly improved healing of experimental full-thickness wounds utilizing
ADM with overlying autologous split-thickness skin grafts in rats (10,11). In
addition, we have used ADM successfully in 5 human burn victims, with no
adverse events attributable to this material and with evidence of improved
healing (13). A
commercially available cadaveric acellular dermal matrix (Alloderm) has also
been employed in burn patients and is described in the literature (14,15).
Alloderm, however, has not been studied in venous ulcers. Its preparation and characteristics are
different from those of ADM, thus allaying concerns regarding patent or
proprietary constraints.
As
discussed above, small split-thickness skin grafts or autologous plugs have
also been used with some success in the treatment of venous ulcers (6,7). We have
used a variation on this using "mini-implants", tissue from a
finely-minced autologous 4 mm skin punch biopsy, placed either directly onto
the surface of the ulcer or on top of the ADM in the ulcer and in both cases
held in place by the usual wound dressings and a compression stocking. Keratinocytes and fibroblasts in the
resulting "mini-implants" should readily migrate into and onto the
wound surface or ADM and rapidly populate these regions. These cells may then serve as a source of a
variety of biological factors that can augment wound healing.
STUDY
DESIGN
The
study is a prospective, controlled, parallel-group, comparative trial. There will be 4 groups of 20 patients
studied, with patients receiving:
1) Standard compression therapy only,
2) Autologous "mini-implants" combined
with standard compression therapy,
3) ADM placed onto ulcerated wounds combined
with standard compression therapy,
4) ADM and autologous "mini-implants"
combined with standard compression therapy.
For
analysis of safety and efficacy, the end points of this study will be
prospectively set at 6 months, mirroring the parameters of the study by Falanga
et al. (2) Patients
will be entered into the study after informed consent is obtained. Patients who qualify for participation in the
study will be assigned to one of the above four treatment groups according to
computer generated randomization schedules.
The present preliminary report shows results from one patient.
STUDY
POPULATION
Eventually, there
will be a total of 80 patients enrolled in this study and the clinical aspects
will be conducted entirely at Rush.
Eligible patients aged 18 to 85 years will be offered the opportunity to
enroll in this study, and be randomly assigned in the outpatient setting to a
treatment group. Leg ulcers (3 to 6 cm
in diameter) will be due to venous insufficiency as determined by the criteria
discussed in Section G (below) and inclusion and exclusion criteria set as
described therein.
TREATMENT
PROTOCOL AND FOLLOW-UP
The
ulcer sites of control patients will be dressed with a standard compression
dressing only. Such a dressing will be
comprised of a non-adherent primary dressing (Tegapore, 3M Health Care, St.
Paul MN), gauze bolster, zinc oxide impregnated paste bandage (Unna boot), and
a self-adherent elastic wrap (Coban, 3M Health Care, St. Paul, MN). In the
standard compression plus mini-implant group, patients will have a 4 mm skin
punch biopsy removed from the buttock or thigh.
The tissue will be finely minced, and placed upon the wound bed, after
which the standard compression dressing described above will be applied. Patients assigned to the ADM treatment group
will have ADM placed directly on the ulcer, with the standard compression
dressing applied over the ADM to immobilize it and keep it in place. Patients assigned to the ADM plus
mini-implant group will have ADM
first placed upon the wound,
after which minced tissue derived from the 4 mm skin punch biopsy will be
placed upon the ADM, over which the standard compression dressing will then be
applied.
When
ADM is to be used, it will applied only once, at the start of treatment. The
Coban elastic wrap, when in place, will extend from the metatarsal heads to the
infrapatellar notch and will be secured at midstretch tension with at least 50%
overlap. Compression therapy will be
reapplied weekly for the first 4 weeks.
Dressings will need to remain in place and kept dry until changed during
follow-up visits. After 4 weeks or on complete healing (defined as full
epithelialization of the wound and no drainage from the site), patients will
use graded elastic stockings as a means of compression (Fast Fit,
Beiersdorf-Jobst, Charlotte,
NC) for the remainder of the
study. These graded elastic stockings
will be removed during bathing and while sleeping.
The
overall design of this study is such as to allow ready comparison with the data
presented by Falanga et al. who used multiple applications of Apligraf to treat
venous ulcers of the leg (2).
STUDY
EVALUATIONS
Demographic
characteristics of each treatment group will be tabulated and compared. Parameters will include gender, race, age,
ulcer area at baseline, and ulcer duration.
All patients will be evaluated weekly for the first 4 weeks; thereafter,
examinations will be performed at weeks 12 and 24. At each visit, ulcer status will be recorded
by photographs and wound tracings. Ulcer
size will be determined by computerized planimetry of surface tracings made
with plastic films. The primary efficacy
end points will include incidence of complete healing by 6 months and the time
required for complete healing to occur.
Other efficacy end points to be evaluated will include incidence and
time to 50% and 75% wound closure by 6 months.
Safety will be evaluated by several parameters, including spontaneous
reports of adverse events at each visit, and direct questioning of patients
regarding their experiences with the treatment.
ANALYSIS
OF DATA
Statistical
calculations will employ SAS software (SAS Inc, Cary, NC).
Comparisons between treatment groups for demographics and baseline ulcer
evaluations will use Fisher’s exact test or X2 analysis. Analysis of frequency of wound closure will
be determined by Fisher’s exact test (2-tailed), and time to wound closure
computed using a survival analysis by the Kaplan-Meier life-table method. Statistical significance of the differences
in time to wound closure by treatments will be tested using the log-rank
test. The individual and combined
effects of pre-existing wound size and duration will be subjected to Cox
proportional hazards regression analysis.
RESULTS
One
patient was studied here using the protocol described for group 3, i.e., ADM
implantation with mini-implants of the patients own dermis. The appearance of the leg ulcer at each visit
is shown in the photographs below (Figure 1).
The wound was implanted with ADM and mini-implants and the patient’s
progress followed for 13 weeks. The
wound,which was initially dry, assumed a moister appearance after
implantation. The wound margins began to
close as time progressed and the wound size decreased. In addition, the wound appeared to
re-epithelialize from the wound margins to a large extent. Epithelialization was not complete by the end
of the observation period however.
Wound
area was calculated from these photos and is shown in Figure 2. The wound area decreased by 72% by the end of
the 13 week followup period.
Chronic leg ulcers are common,
but often intractable wounds which are usually treated with compression
therapy, but recent success has been reported using skin substitutes. The
healing seen over the 13 week period studied here suggests that ADM
implantation may be an effective method of treating these long-standing,
hard-to-heal venous stasis ulcers. The
followup period n this patient needs to be extended for at least 6 months to
see if the improvement is lasting and to determine if complete healing
occurs. Of course, additional patients
must be treated and the remaining study groups must be examined to make any
firm conclusions regarding possibilities for treatment of chronic venous stasis
ulcers using ADM.
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al. Rapid healing of venous ulcers and lack of clinical rejection with an
allogeneic cultured human skin equivalent. Arch Dermatol. 1998;134:293-300.
3.
Falanga V, Sabolinski M. A bilayered living skin construct (Apligraf)
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4.
Samlaska C, et al. Pentoxifylline. J Amer Acad Dermatol. 1994;30:603-621.
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