CODI: Cornucopia of Disability Information

New Interventions in Pressure Ulcer Treatment

	    New Interventions in Pressure Ulcer Treatment:
		      Regenerative Skin Healing


				  by
			  Dale Feldman, PhD

        Skin is the largest and the most frequently traumatized organ
system in the body.  Skin injuries are one of the chief causes of
death in North America for people between the ages of 1 and 44.  One
of the most prevalent skin injuries is pressure ulcers.  Pressure
ulcers are localized areas of tissue necrosis that develop when soft
tissue is compressed between a bony prominence and an external surface
for a prolonged period.  They can range from superficial inflammation
that extends into the dermis to an extensive ulcer occasionally
involving underlying bone.

        Pressure ulcers are one of the most debilitating and costly
problems associated with disabling conditions such as spinal cord
injury (SCI).  Pressure ulcers are found in 20-30% of individuals with
SCI, 3-10% of nursing home residents, and 3-11% of persons with acute
injuries.  It is estimated that persons with SCI, who have pressure
ulcers, incur hospital charges three to four times those of other
individuals with SCI and average at least an additional $15,000 per
year in health care costs.  This figure rises to more than $30,000 for
the most severe sores (Grade 4).
        
        Since hospital charges relate directly to the number of days
in treatment, reducing the length of a hospital stay through more
effective treatment of pressure ulcers could mean a savings for the
patient, the health care delivery system, and the third party payer.
        
        Faulty or impaired healing has been labelled the most
prominent factor in these lesions.  Speeding up the rate of
regenerative healing would reduce both the likelihood and effect of
other secondary complications.
        
        Pressure ulcers can interfere with every aspect of the
physically disabled individual s life, from active participation in
the rehabilitation program to returning to an active role in the
community.  A nonsurgical treatment that promotes healing in a shorter
time would reduce the hospital stay, recovery time, costs, and
complications associated with surgical skin grafting.

GOALS

        Until now, very few effective, conservative treatments have
been available for either small or large ulcers other than removing
pressure from the affected area.  The goal of this research is a more
effective treatment of a costly and debilitating secondary
complication of SCI--pressure ulcers.  Specifically, the focus is to
develop and evaluate new interventions to speed up regenerative skin
healing.  This would reduce costs, the length of medical treatment,
and morbidity associated with pressure ulcers.  Optimal intervention
would be the enhancement and optimization of regenerative healing
rather than reparative healing.
        
        Many investigators continue to examine ways to enhance and
control skin healing by changing the wound s environment (oxygen,
magnetic fields, stress, location, etc.) or the wound s biochemical
activity (growth factors or other biochemical agents).  Each treatment
method can significantly affect the progression and rate of healing as
well as the type of tissue formed.

        A wound dressing, when it is used, can enhance healing in a
number of ways .  Skin healing can be altered by changing the
configuration (pore size, porosity, fiber diameter), the surface
(composition, charge, surface energy), the biochemical activity
(incorporation of growth factors or other biochemical factors), or the
degradation or drug delivery rate of the wound dressing.  The goal in
virtually all cases is tissue regeneration and at the fastest possible
rate.  Whenever possible the wound dressing--if there is one--should
be degradable.  Therefore, the optimal solution is a degradable wound
dressing that stimulates regeneration

TYPES of WOUNDS and TREATMENT

        Clinically both deep (full-thickness) and shallow (partial
thickness) pressure ulcers are of concern.  In most cases partial
thickness wounds (Grade 1 and 2) are treated with wound dressings,
rather than skin grafts, since the lost epithelium can regenerate on
its own with little or no dermal contraction.  Immediate concerns with
shallow pressure ulcers include blood loss, bacterial invasion, and
fluid loss in partial thickness wounds.

        The shallow wounds typically heal naturally, however, many of
the skin ulcers can progress to deeper wounds due to pathology or
continual irritation.  In all cases speeding up the regenerative
healing would be beneficial.  Therefore, there is a place for
degradable regenerative systems even for these shallow wounds.
               
        Full thickness wounds (Grades 3 and 4) involve a loss of the
epithelium and dermis.  These usually necessitate more active
treatments than just wound dressings.  The dermis normally does not
regenerate itself.  Healing occurs primarily through the development
of granulation tissue and scar, causing the wound area to contract and
lose its elasticity.  The optimal wound dressing must provide a
scaffold structure that promotes the development of a new dermis over
which the epidermis can grow without any contraction.
        
        Clinical approaches toward healing for both types of wounds
can range from environmental control through dressing applications to
surgery in the form of skin grafting and skin flaps.  Additionally,
cultured epidermal autografts (CEAs) have been used especially for
burn wounds, when the supply of donor sites is limited.  Dressing
change regimens for deep skin ulcers can take from six weeks to six
months of bed rest to heal.  The healing process depends on the size
of the ulcer and patient compliance.
  
        Surgical intervention in the form of pedicle flaps and skin
grafts are not ideal solutions either.  For skin ulcers, skin flaps
(the usual method of choice) do not always take and there are a
limited number of donor sites available for these procedures.  Other
drawbacks include the high cost of surgery and the lengthy post
operative healing time [1,2].

        The use of CEAs have had mixed results and their strength,
durability, and limited neo-dermis formation are concerns.  Even in
the best cases, it takes 5 years to obtain dermal-like tissue [2].  It
appears that formation of a neo-dermis is a critical part of a
regenerative system.
        
        Therefore, researchers have attempted to design dermal
replacements.  The first were non-degradable with Yannas and
co-workers eventually developing a biodegradable wound dressing [3].
This wound dressing is not completely regenerative, however, without
epidermal autografting.  The autografting can be in the form of cell
seeding or partial thickness skin grafts.  In the best cases, however,
these wound dressings have been successful in retarding the scarring
process since the dermal scaffold provides structural integrity until
the epidermal grafting or cell mitosis ensues.  An additional concern,
however, is the take rate of these wound dressings, especially when
compared to the high percentage take of autografts.


RESEARCH at U.A.B.

        Research on wound healing at UAB has focussed on evaluating
optimal bioactivity (cell and tissue stimulation) and the optimal
wound scaffolding.  For optimal bioactivity, both environmental
changes (oxygen and pulsatile electromagnetic fields--PEMF) and
biochemical modifications (growth factors) were assessed in vitro
(cell structure) and in vivo (animal model) in order to optimize the
regenerative response .  For optimizing the scaffold, different
materials with different configurations, degradation rates, and drug
delivery kinetics have been assessed in vitro and in vivo.  The
ultimate goalhas been to design systems suitable for the treatment of
both pressure ulcers and burns that could be used in open wounds as
well as in conjunction with skin grafts.

Optimizing Bioactivity

        Oxygen was initially investigated in vitro on fibroblasts and
macrophages.  Oxygen at twenty percent O2 (160 mmHg) [4] was found to
increase fibroblast activity and fibroblast protein production,
indicating an increase in healing.  Macrophage activity decreased
which is indicative of decreasing inflammation.  Based on this
information, both the oxygen level and oxygen gradient were modified
in an in vivo study to help determine the optimal clinical oxygen
treatment protocol [5].  Oxygen treatment, corresponding to the 160
mmHg in vitro level (70%), significantly accelerated the healing
response with the more occlusive (oxygen impermeable) wound dressing
inducing a more optimum histological response in the early healing
stages.  However, the more oxygen permeable wound dressing provided,
the better cellular and tissue responses at the later healing stages
[5].  A further study, examined a lower oxygen dosage (40%), which is
closer to the clinically acceptable 6 L/min, and found a similar
acceleration in the healing response [1,6].

        The use of low frequency pulsating electromagnetic fields
(PEMF) in the treatment of full thickness defects in the rabbit model
was done to understand more fully the effects of PEMFs on wound
healing [7,8].  It was found that a magnetic field of 2-2.8 mTesla at
a frequency of 75 Hz applied for 240 minutes daily for one week
significantly accelerated the healing response [7,8].  An additional
in vivo study was done to determine the optimum parameters for the
PEMFs to be implemented for soft tissue regeneration and overall wound
healing [9,10].  Although PEMF accelerated the healing response in all
cases, specific combinations of frequency and intensity levels
produced specific cellular responses.  It is possible that the optimal
PEMF system may involve a series of different frequencies and
intensities at various stages of the healing process [9,10].

        In vitro studies done with different growth factors and
scaffolds found maximum values in the nanograms/ml range (optimal
fibroblast proliferation with and without PLA and collagen wound
dressings).  In vivo, these levels showed no significant effects [11].
Therefore, further in vivo studies were done with increased growth
factor concentrations.  One in vivo study compared the effectiveness
of transforming growth factor (TGF-b) and fibroblast growth factor
(FGF-1) treatment of full thickness wounds created on the dorsum of
New Zealand white rabbits [2,12].  The TGF-b incorporated collagen
matrix showed enhanced angiogenesis (development of vessels).  It was
concluded, however, that the wounds treated with the FGF-1 and the
collagen matrix healed slightly better than the ones treated with
TGF-bincorporated in the collagen matrix.

        In another study, FGF-1 was used topically and was also
incorporated into a fibrin matrix [1,6].  In both instances, the FGF-1
(10 mg/cm2) significantly accelerated the healing process and lead to
the best overall healing with complete epithelialization and minimal
contraction.

Optimizing the Scaffold

To optimize the scaffold, different materials have been used:
collagen, PLA, and fibrin.  In these studies, the fibrin systems have
worked the best overall.  Fibrin matrices are adhesives that can set
up in situ (in place), filling voids and irregular shapes.  Another
advantage is that the growth factor is incorporated at the time of
polymerization.  Additionally, the ability to tie the drug delivery
and degradation to cellular infiltration establishes a biofeedback
system, which is tailored to the individual patient s healing rate.
Because of the biological half-life of FGF-1, binding to receptor
sites or the included fibronectin as well as protection within the
matrix is critical for sustained drug deivery [13].

        Although the fibrin matrix, due to its own biological activity
[13], serves as a reasonable scaffold, better scaffolds can be made by
optimizing the configuration as well as the bioactivity.  In a rabbit
ear ulcer model, full thickness defects were treated with the fibrin
matrices in both non-porous and porous (12% porosity and 100-200 mm
pores) forms [14].  Because of the enhancement stimulated by the
porous implants on angiogenesis and fibroblast proliferation, FGF-1 is
currently being incorporated into these porous fibrin systems.  The
level of porosity, the concentration of the growth factor, and the
concentration of the fibrin matrix which effect the drug delivery rate
and degradation rate of the system are currently being optimized.
Even in unoptimized systems, FGF-1 in a non-porous fibrin matrix was
capable of complete epidermal regeneration with dermal filling of the
full thickness defect and minimal contraction (20%) within two weeks.
Controls took at least three weeks to heal and healed mostly by
contraction [1,6].

        Several experiments have also been conducted to determine the
shear adhesive strength of the fibrin matrix at different
concentrations as well as test the clinical efficacy for skin graft
attachment [15-17].  Results indicated that the fibrin matrix is
beneficial as a replacement for sutures or staples used to secure skin
grafts because it reduces operative time and decreases secondary
complications.  Therefore, unmeshed grafts can be used with a better
success rate in areas where cosmetics are important [16].

        For wounds such as skin ulcers; although the adhesiveness, in
situ polymerization, and flexural properties of the fibrin matrix are
very desirable due to the wound topography; pre-molded wound dressings
made of fibrin and other constituents could be clinically attractive.
These systems could be customized to the wound site and adhered with
little manipulation.  Such a wound dressing could be developed and
designed so outpatients could administer it to themselves to
drastically reduce their hospital and medical costs.

RESULTS and FUTURE RESEARCH 

        Based on the preceding studies, it was hypothesized that the
porous fibrin matrix would provide the most versatile and effective
scaffold for the clinical treatment of pressure ulcers and burns.
FGF-1 was chosen as the most effective bioactive factor with fibrin,
although other biochemical factors could be added later.  The use of
oxygen treatments or PEMFs, although believed to be effective, did not
show the promise of the degradable regenerative fibrin system in the
animal models.

        Two planned clinical trials at UAB will use fibrin/FGF-1 for
pressure ulcer and burn healing.  For pressure ulcers, patients with
stage three and four ulcers will be randomized into four groups: 1)
control, 2) topical FGF-1, 3) FGF-1 in a porous fibrin matrix, and 4)
FGF-1 in a non-porous fibrin matrix.

        Clinically, work must be done to further investigate the
dosage requirements and degradation rates of the fibrin for a given
porosity and concentration.  Eventually the appropriate delivery of
the fibrin system must be determined: in situ polymerization as
compared to a premolded packaged system.

        This new treatment program will provide a non-surgical option
to decrease significantly the immobility and its consequences that are
associated with pressure ulcers as well as markedly decrease the costs
of both conservative and surgical care.

Bibliography

1.  Wilson D, Feldman D, Thompson T. Fibrin glue as a matrix for a-FGF
delivery in vivo.  Trans of the 19th Ann Mtg of the Soc for Biomat
1993.

2.  Ashar P. FGF-1 and TGF-B in a collagen matrix for full thickness
defect healing. M.S.  Thesis, University of Alabama at Birmingham
1993.

3.  Yannas I, Burke J. Design of an artificial skin. J of Biomed Mat
Res 1980; 14:65-81.

4.  Estridge T, Feldman D. The use of oxygen for optimal fibroblast
activation. Trans of FASEB 1991;75:7230.

5.  Pandit A, Feldman D, Estridge T. Effect of oxygen and oxygen
permeability on wound healing using polyurethane and polyacrylonitrile
membranes. Trans of the Soc for Biomat 1991;17:138.

6.  Wilson D, Feldman D. Acidic fibroblast growth factor (a-FGF)
delivery through a fibrin matrix with oxygen treatments for full
thickness defects. Trans Wound Healing Soc, European Tissue Repair Soc
1993;3:8.

7.  Andino R, Feldman D. Pulsating electromagnetic fields used to
treat full thickness defects in the rabbit model. Trans of FASEB 1991.

8.  Kelpke S, Feldman D. The acceleration of full thickness defect
healing by using pulsatile electromagnetic fields. Trans of the Wound
Healing Soc 1992;2;102.

9.  Kelpke A, Feldman D. Polyurethane dressing in combination with
pulsed electromagnetic fields to accelerate wound healing. Trans Soc
for Biomat 1993;19:56.

10.  Kelpke S, Feldman D. The effect of frequency and intensity on
PEMF healing of full-thickness defects. Trans Wound Healing Soc 1994.

11.  Estridge T, Feldman D, Pandit A, Andino R. The effect of wound
matrices on the healing of full thickness defects in the rabbit model.
Trans of the 19th Ann Mtg of the Soc for Biomat 1993;19:44.

12.  Pandit A, Ashar R, Feldman D.  Acidic fibroblast growth factor
and transforming growth factor beta in stimulation of healing in full
thickness skin defects. Ann Mtg of the Wound Healing Soc and the
European Tissue Repair Soc 1993.

13.  Feldman D, Sierra D. Tissue adhesives in wound healing. in
Handbook of Biomaterials and Applications. Marcel Dekker 1994 (in
press).

14.  Pandit A, Feldman D. The effect of a porous degradable fibrin
scaffold on wound healing.  Trans Soc for Biomat 1994;20:34.

15.  Flahiff C, Feldman D, Saltz R, Huang S. Mechanical testing of
fibrin adhesives for blood vessel anastomosis. J Biomat Mat Res
1992;26:481-491.

16.  Saltz R, Feldman D, Floyd D, Huang S. Experimental and clinical
applications of fibrin glue. Plast Reconstr Surg 1991;88(6):1005-1015.

17.  Sierra D, Feldman D, Saltz R. A method to determine the shear
adhesive strength of fibrin sealants. J Appl Biomat 1992;3:147-151.


Dale Feldman, Ph.D. is an Associate Professor of Biomedical
Engineering at UAB.  He has served as a principal investigator since
1988 with the Medical RRTC in SCI, conducting research in the
treatment of pressure ulcers, biomaterial enhanced regeneration,
tissue ingrowth into porous implants, drug delivery systems and
biodegradable polymers.  For further information on this research,
call 205-934-8420.


Research Update is published annually by the Medical Rehabilitation
Research and Training Center at the University of Alabama at
Birmingham.
Phone:      205-934-3282 (voice)      205-934-4642 (TDD)
  
1994 Board of Trustees of the University of Alabama This publication
is supported in part by a grant (#H133B30025) from the National
Institute on Disability and Rehabilitation Research, Department of
Education, Washington, D.C. 20202. Opinions expressed in this document
are not necessarily those of the granting agency.  Samuel L. Stover,
MD, Project Director Linda Lindsey, MEd, Editor