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Chronic Wound Healing Wound
Search Articles - Jason P. Hodde, MS, ATC/L and Reynald Allam, MD, MBA Infectio
Manag
Subscribe to Wounds Risks,
Abstract: Chronic wounds represent a state where healing Treatin
Industry News Problem
has stagnated. Venous, diabetic, and pressure ulcers are
New Products typically difficult to heal and are at high risk of becoming Consen
chronic. In an attempt to restart the healing of chronic Statem
Classifieds Negativ
wounds, many biologically important molecules, such as Pressu
Continuing Education collagen, hyaluronic acid, and growth factors have been Wound
used to treat these wounds with varying degrees of success. Therap
Supplements the
Until recently, the idea of replacing the failing extracellular Manage
Enewsletters matrix (ECM) with an intact and biologically complex of Diab
substitute was unknown. Small Intestinal Submucosa Wound
Editorial Board
Wound Matrix (SISWM) is both a biologically complex and
Supple
Contact Us intact ECM, and an effective therapy for treating chronic
wounds. A drop in replacement for the ECM of difficult to
Author Instructions
heal or chronic wounds helps to stimulate tissue ingrowth, Special Publication:
Rapid Review deposition of new matrix, and rapid epithelialization The following is a collection of
publications from Healthpoint inten
potentially leading to improved quality of life for patients. facilitate expeditious, cost-effective
About Us
wound care management. There w
nine publications total.

Hot Topics: Decem

Bioengineered skin equivalent Disclosure: This work was supported by Cook Biotech Newly
Funded
Incorporated. Dr. Allam is a paid consultant for Healthpoint, Selectiv
Negative pressure wound
therapy Ltd. Non-Se
Debride
Acellular dermal matrix CPT Co
The native dermis is normally able to direct wound Impact
Diabetic neuropathy
healing following damage but in chronic wounds, the dermal Hospita
Silver dressings extracellular matrix (ECM) and cells within it are diseased Owned
Enzymatic debridement Outpati
and unable to provide the correct signals needed to Wound
stimulate and coordinate healing.1,2 In deep, chronic Departm
Keywords: diabetic foot ulcers, pressure ulcers, or venous leg ulcers,
Novem
the dermal ECM may be completely absent and wounds may Clinical
Autolytic debridement
not efficiently epithelialize because the wound healing Experie
Wound necrosis signals that are usually present in the dermis have been with Oa
Surgical debridement Wound
lost. Functional ECM is essential to wound healing. The for the
Mechanical debridement healing process is stalled if functional ECM is absent in Treatm
Wound fibroblasts chronic wounds. In these particular situations, therapeutic Venous
Diabeti
Delayed wound healing strategies must include the use of exogenous factors to act Ulcers:
Impaired wound healing
as a surrogate for the native dermis if healing is expected to Series
occur. Cases
Compression stockings
View Al
Diabetic foot wounds
Pressure dressing
The Chronic Wound Problem

The extent of the chronic wound problem and its


Related Links:
impact on quality of life and financial impact on the Symposium on Advanced W
worldwide economy is immense. For example, in individuals Care (SAWC)

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The Buck Stops Here
65 years and older, venous leg ulcers affect approximately
Association of Advanced Wo
1.69%3 of the population in the United States and cost Care
approximately $9,600 to treat.4 In addition to the economic
Ostomy/Wound Manageme
costs, most patients with chronic venous leg ulcers report
pain (81%), itching (69%), and loss of sleep (67%) as a Podiatry Today
result of their wounds,5 as well as a significantly lower Vascular Disease Managem
quality of life.6 Of the 13.8 million people in the United Wound Healing Society
States diagnosed with diabetes,7 6% may develop foot
ulcers over a 3-year period8 with an estimated annual cost
of approximately $6 billion.9 More than 50% of people with Article Submission:
diabetes and a foot ulcer are expected to develop a wound All submissions for
infection, and up to 20% will require some degree of consideration should be
amputation during the course of their disease.10 Pressure submitted online using th
ulcers afflict approximately 15% of patients in acute care Rapid Review Web-Based
facilities11 and up to 29% in long-term care facilities,12 Review System at
www.rapidreview.com.
burdening the healthcare system with more than $8.5 billion
Authors should scroll dow
in annual costs.13 Pressure ulcers are often associated with HMP Communications an
fatal septic infections and are reported to cause thousands click on Author.
of deaths each year in the United States.14
Observed together, these data indicate that chronic
wounds are prevalent, costly, and have a significant
negative impact on quality of life. Therefore, effective
treatment strategies for chronic wounds could provide
tremendous benefits to both patients and society as a
whole. Unfortunately, complete healing rates for diabetic
foot ulcers, venous leg ulcers, or pressure ulcers remain at
approximately 25% to 50% following up to 20 weeks of
treatment when standard wound care therapies and
traditional synthetic dressings are used.1517 These low
rates suggest that standard of care is inadequate for many
patients while highlighting the need for more aggressive
management strategies in this population. Significant cost
savings, decreased morbidity, and substantial increases in
quality of life can be achieved with more rapid and complete
ulcer healing.

Matrix Strategy for Healing

One aggressive management strategy that has been


studied recently in randomized clinical trials is the
application of an intact ECM material to the chronic wound
bed.1820 While other advanced strategies have
concentrated on the delivery of individual matrix factors,
such as collagen,16 hyaluronic acid,21 or growth factors,22,23
the application of an intact exogenous ECM that can supply
many of the necessary factors in a single weekly treatment
is a recent advance in effective care of chronic wounds. An
intact, functional ECM is essential to achieving wound
closure and restoring native tissue architecture.24 Materials
that closely recapitulate the complex tissue structure and
composition of the dermal ECM may fare better in
stimulating the healing of chronic wounds than single,
purified components.
An intact, biologically-derived ECM provides a complex
of collagens, glycoproteins, glycosaminoglycans, growth
factors and proteoglycans25 needed to direct all stages of

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wound healing. Unlike single proteins or reconstituted


collagen dressings, these structural proteins and associated
bioactive molecules are dispersed in a unique and natural
spatial distribution. This complex of structural collagens and
matricellular proteins provides signals to direct the cells
present in the wound to migrate into the open scaffold,
synthesize new matrix, and encourage epithelialization, all
while protecting the bioactive growth factors from rapid
inactivation and degradation due to the proteolytic nature of
chronic wound bed fluid.
These biologically-derived ECM materials can be
obtained from a number of tissues. In addition to the
dermis, the submucosa of the small intestine, urinary
bladder, pericardium, basement membrane of the liver,
decellularized Achilles tendon, artery, vein, ureter, and renal
capsule can be isolated and used as sources of ECM
materials. Of these tissues, the wound graft material
derived from the small intestinal submucosa of pigs has
been the most extensively characterized.2533

SIS Wound Matrix

Small Intestinal Submucosa Wound Matrix (SISWM)


consists of the tunica submucosa of the small intestine.26
The tunica submucosa is the layer of connective tissue
arranged directly under the mucosa layer of the intestine
and is 100200 mm thick. In the living intestine, the
submucosa supports the mucosal structures and is secreted
and maintained by connective tissue fibroblasts. This tissue
layer supports the growth and differentiation of the rapidly
proliferating mucosal and glandular cells while maintaining a
connective tissue structure that gives the intestine its
integrity and strength.
As in the case of all clinical grade biomaterials derived
from animals, SISWM must be purified to ensure its safety.
SISWM is harvested from the mammalian small intestine by
mechanically separating it from its outer muscular layers
and internal mucosal layers.26 It is rinsed in highly purified
water, treated with an aqueous solution of peracetic acid to
ensure viral safety,27 and is then rinsed in sequential
exchanges of water and buffers to yield a neutral pH. It is
freeze-dried to stabilize the proteins within it and is later
sterilized using ethylene oxide gas. When SISWM is
implanted surgically or applied topically as a naturally
occurring ECM graft, it stimulates angiogenesis, connective
and epithelial tissue growth and differentiation, as well as
deposition, organization, and maturation of ECM
components that are functionally and histologically
appropriate to the site where it has been applied.26,28,29 In
chronic ulcers, the SISWM shifts the local wound
environment from a chronic state, characterized by high and
variable levels of pro-inflammatory cytokines and matrix
metalloproteinases (MMPs), to a more acute state
characterized by lower and more stable levels of these
inflammatory proteins and proteolytic enzymes (J.P.H,
unpublished observations, 2006).
Similar to skin, SISWM is comprised primarily of

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fibrillar collagens and adhesive glycoproteins, which serve


as a scaffold into which cells can migrate and multiply.26,30
The SISWM layers also contain potent regulatory factors,
such as glycosaminoglycans, proteoglycans, and growth
factors, which regulate cellular processes that maintain
tissue homeostasis and respond to injury and infection.
These components are retained in the SISWM matrix
following processing and also retain their biological
activity.3033 Since SISWM contains many of the same
components naturally seen in the dermis and is not
reconstituted but supplied in its natural 3-dimensional state,
it recapitulates the complex tissue structure and
composition of the dermal ECM and provides bioactive
wound healing factors that contribute to tissue restoration
following extensive tissue loss or failed ulcer healing.

Clinical Applications

The SISWM material is easy to use, can be stored for


up to 2 years at room temperature, and only needs to be
applied to the wound once weekly. Two recently published,
randomized, controlled, clinical trials have shown the
effectiveness of SISWM (Oasis Wound Matrix, Healthpoint
Ltd, Fort Worth, Tex) in healing chronic diabetic foot
ulcers18 and venous leg ulcers.19,20 Niezgoda et all8
compared SISWM and becaplermin gel in a clinical trial of
73 patients with chronic diabetic foot ulcerations. The ulcers
had to be present for more than 30 days, resistant to
conventional therapy with debridement, offloading, and
moist wound healing. SISWM was applied at the clinic on a
once-weekly basis and becaplermin gel was applied daily as
directed on the package insert for the 12-week trial period.
All wounds in both groups were debrided as needed,
secondary dressings were changed as needed, and patients
were given a pressure-relief device. Healing was tracked
over the course of 12 weeks. In the SISWM-treated group,
18/37 (49%) SISWM-treated patients had complete wound
closure compared with 10/36 (28%) in the becaplermin gel-
treated group. Although the sample size was not large
enough to demonstrate that the incidence of healing in the
SISWM group was statistically superior (P = 0.055), results
showed treatment with SISWM to be at least as effective as
becaplermin gel in leading to ulcer healing by 12 weeks. In
addition, survival plot analysis showed that patients in the
SISWM were twice as likely to heal at 7, 9, and 12 weeks
than the becaplermin-treated group. Subgroup analysis
further revealed that SISWM was more effective than
becaplermin gel in healing plantar foot ulcers, some of the
most difficult diabetic ulcers to heal (52% versus 14%; P =
0.014), and was also more effective in healing patients with
type 2 diabetes (63% versus 29%; P = 0.034). These rates
of improvement are significant in that it has been reported
that even a modest (9%) increase in the healing rate by 20
weeks would lead to a cost savings of $189 per episode,
based on an analysis of Medicare expenditures published in
2000.34 In this study, the average cost of the product
needed to achieve closure in the SISWM group was $250 as

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compared to $1,070 in the becaplermin gel group, yielding a


cost-per-patient savings of approximately $820.18
Mostow et al20 studied 120 patients suffering from
chronic (> 1 month) venous leg ulcers. SISWM plus
compression therapy was randomized against compression
therapy alone. Patients were enrolled into the study only if
their ulcers were nonhealing for at least 1 month and were
unresponsive to compression therapy during a 2-week
screening period. In this study, SISWM was applied on a
once-weekly basis for up to 12 weeks or until wound healing
occurred. All wounds in both groups were debrided as
needed and secondary dressings were changed at weekly
clinic visits. After 12 weeks of treatment, 34/62 (55%) of
the wounds in the SISWM group were healed as compared
to 20/58 (34%) in the standard care group (P = 0.0196). It
was concluded that SISWM, as an adjunct therapy,
significantly improved healing of venous leg ulcers over
compression therapy alone.
Even in these initial studies of difficult-to-treat
populations with chronic wounds, SISWM as an adjunctive
therapy led to complete wound healing in a significant
proportion of patients. Subgroup analysis also suggested
that certain patient populations may show higher than
average healing rates with SISWM, including those with
type 2 diabetes18 and those with venous leg ulcers debrided
at baseline.20 The latter finding suggests that the simple
step of debriding chronic venous leg ulcers prior to
application of an intact ECM material may increase the
likelihood of healing. This observation fits with the function
of an ECM material as a scaffold for the migration of the
bodys own viable cells, which the presence of necrotic
debris theoretically would be expected to hinder, along with
the need for functional, nonsenescent cells to respond to
biochemical signals initiated by the ECM replacement.

Summary

Diabetic foot ulcers, venous leg ulcers, and pressure


ulcers often fail to heal quickly and ultimately become
chronic as a result. These wounds are prevalent and costly,
and negatively impact the quality of life of many patients.3
14
Standard of care is frequently insufficient to promote
healing of these wounds and many require aggressive,
active treatments to stimulate epithelialization.
Chronic wounds are characterized by high levels of
matrix-degrading enzymes,35 pro-inflammatory
cytokines,36 and senescent cells,2 which become
unresponsive to their surrounding environment and are
unable to effectively remodel their ECM. In these chronic
wounds, the body fails to generate a functional ECM. A
functional ECM is central to wound healing,37 and acts as a
scaffold for the migration of fibroblasts and other cells,
regulates cell-to-cell communication, and directs the
development of a biochemical environment that is conducive
to healing. The absence of an ECM impedes granulation
tissue deposition and epithelialization. Strategies to replace

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the failing ECM may be beneficial in stimulating closure of


chronic wounds.
SISWM is an active, intact, biologically-derived ECM
that recapitulates the complex structure and composition of
the dermal matrix. It contains the major components
present in the dermal ECM during normal wound healing. It
also contains bioactive growth factors, which remain bound
to the matrix during its isolation and processing for clinical
use.32,33,38 Preclinical studies have confirmed capillary
ingrowth into the matrix, as well as the migration,
attachment, and proliferation of cells. Clinically, SISWM has
been found to significantly enhance the healing of chronic
wounds compared with standard care alone20 and to work
as well as becaplermin gel at a fraction of the cost in
diabetic foot ulceration.18 As compared to other aggressive
treatments available for chronic wounds, SISWM offers an
effective combination of matrix and signals in a single
weekly application while minimizing costs.18
When treating high-risk wounds, aggressive, active
interventions, such as SISWM are likely to be most
beneficial if pursued early as part of a consistent treatment
algorithm. Evidence indicates that the reduction in the area
of the chronic wound during the first 4 weeks of treatment
is a predictor of complete healing at 12 weeks for diabetic
foot ulcers,39 and at 24 weeks for venous leg ulcers.40 Thus,
for chronic wounds, a lack of response at 34 weeks to
conventional therapy should prompt the re-evaluation of the
patient and consideration of advanced therapies.41 Clinical
evidence shows that sharp debridement can shift a chronic
wound toward a more acute state and is associated with
better outcomes if performed prior to ECM replacement with
SISWM.20 Rapid wound closure minimizes the detrimental
effects of these chronic ulcers on patients daily lives and in
some cases avoid hospitalization, life-threatening
complications, and amputations.
As a treatment that includes both matrix and signals in
the form of growth factors, cell attachment factors, and
matrix binding sites, SISWM provides the elements needed
to address the ECM deficiencies that characterize chronic
wounds. Its clinical efficacy, reasonable cost, and ease of
storage and use suggest that SISWM may be advantageous
as an early and potentially cost effective intervention for
chronic wounds.

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Wounds - ISSN: 1044-7946 - Volume 19 - Issue 6 - June
2007 - Pages: 157 - 162

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