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Wound Healing
Wound: from the Old English word,
wund
Wound healing consists of an orderly progression of events
that reestablish the integrity of the damaged tissue. The
initial wound touches off a series of programmed, separate yet
interdependent responses to the injury, including
inflammation, epithelialization (growth of new skin),
angiogenesis (blood vessel regeneration), and the accumulation
of matrix, the cells necessary to heal the tissue. Many wounds
pose no challenge to the body's innate ability to heal; some
wounds, however, may not heal easily either because of the
severity of the wounds themselves or because of the poor state
of health of the individual. The Life Extension Foundation has
designed this protocol to support and enhance the healing of
internal and external wounds that fall into this category.
(For related information on
how to support the body's ability to heal and rebuild itself,
refer to the Catabolic
Wasting and Muscle
Building protocols.) Any wound that does not heal
should be examined by a healthcare professional because it
might be infected, might reflect an underlying disease such as
diabetes, or might be a serious wound requiring medical
treatment. Always inform your healthcare provider of all
supplements and treatments you are using.
Types of WounDS
Although all wounds follow roughly the same healing
process, there are many different causes of wounds.
Partial-thickness wounds penetrate the outer layers of the
skin (the epidermis and the superficial dermis) and heal by
regeneration of epithelial tissue (skin). Full-thickness
wounds involve a loss of dermis (deeper layers of skin and
fat) and of deep tissue, as well as disruption of the blood
vessels; they heal by producing a scar. Wounds are classified
by stage. Stage I wounds are characterized by redness or
discoloration, warmth, and swelling or hardness. Stage II
wounds partially penetrate the skin. Stage III describes
full-thickness wounds that do not penetrate the tough white
membrane (fascia) separating the skin and fat from the deeper
tissues. Stage IV wounds involve damage to muscle or bone and
undermining of adjacent tissue. They may also involve the
sinus tracts (red streaks indicating infected lymph
vessels).
One medical term for a wound is an ulcer. An ulcer is an
open sore on the skin (or a mucous membrane) that causes
destruction of surface tissue. An ulcer can be shallow or deep
and crater-shaped. Ulcers are usually inflamed and
painful.
Traumatic
Ulcers
An injury caused by any kind of accident (or trauma) can
result in a wound that affects the skin, blood vessels, bones,
muscles, soft tissue, or organs that may result in development
of an ulcer.
Arterial
Ulcers
The arteries supply blood, which carries vital oxygen
required by cells to live. If arterial circulation is
partially or completely blocked, the tissue will begin to die,
resulting in a painful wound. Impaired circulation of this
type usually occurs in the extremities (arms and legs),
especially on the top of the foot. Impaired circulation is
signaled by lack of pulse; cool or cold skin; skin that
appears shiny, thin, and dry; loss of skin hair; and delayed
capillary return time. (To test capillary return time, briefly
push on a skin area and then release: normal color should
return in 3 seconds or less.) Treatment of arterial ulcers has
two goals: re-establishing circulation with medical treatment
and healing the wound(s).
Venous
Ulcers
Veins carry deoxygenated blood back to the lungs. Veins
contain valves that prevent backflow, but when these valves
become incompetent, too much blood remains in the tissues.
This condition is called congestion. Venous congestion
commonly affects the legs, causing swelling (edema) and a
brownish discoloration from the hemoglobin of the immobile red
blood cells that leak out. Venous ulcers are the most common
wounds affecting the legs and are frequently found on the
ankles. Venous ulcers are shallow and not too painful. They
may have a weeping discharge. Although venous valves cannot be
repaired, the return of blood through the veins can be
improved by physical activity and by compression which can be
supplied by compression stockings, dressings, or mechanical
pumping devices.
Diabetic Foot
Ulcers
Diabetes results in a narrowing of the small arteries which
can cause ulcers. This narrowing cannot be resolved, but it
can be prevented by careful glucose control. Diabetes also
causes peripheral neuropathy and the loss of sensation,
especially sharp/dull discrimination, in the legs and feet.
For this reason, injuries to the feet may go unnoticed and can
progress into serious wounds. In addition, peripheral
neuropathy can cause deformity of the foot (Charcot foot
deformity) because of inappropriate stresses being placed on
the bones, resulting in microfractures; this deformity in turn
results in bony prominences and swelling that contribute to
ulceration. Neuropathy also cannot be cured, but careful
glucose control slows its progress. Diabetics must be
extremely vigilant about foot care and should seek immediate
medical attention for any wounds. Special shoes can help
relieve pressure on the feet.
Pressure
Ulcers
Also known as bedsores, pressure ulcers are very common in
older and immobile persons. When too much pressure is placed
on them, cells do not get enough oxygen. Pressure of this type
occurs when cells are sandwiched between a bony prominence
(elbow, hip, heel, or tailbone) and a hard surface (bed or
wheelchair). Those cells closest to the bone begin to die, and
the wound spreads toward the skin surface. Thus, a pressure
ulcer indicates not only a surface wound, but also a deep
tissue wound. The risk of pressure ulcers can be reduced by
enhancing mobility, maintaining skin and general health,
ensuring good nutrition, and monitoring weight (patients
should be neither too heavy nor too light).
Burns
Most burns occur in the home, particularly from accidents.
Burns can be caused by scalding hot liquids, grease fires, car
accidents, chemical explosions, frayed electrical cords, house
fires, hot objects (stoves, irons, grills, tailpipes), or even
the sun. A first-degree burn results
in a superficial reddened area on the top layer of the skin
(epidermis) like that caused by a mild sunburn. A second-degree burn involves
the epidermis and second layer of the skin. It results in a
blistered injury that heals spontaneously after the blister
fluid has been removed. A third-degree burn
penetrates all layers of the skin and will usually require
surgical intervention in order to heal. Superficial burns
usually heal on their own within 2 weeks with routine wound
care and protection from infection. Deeper burns (second and
third degree) require medical attention, including nutritional
support and assessment of lung function, and may require skin
grafts and vascular or reconstructive surgery. Immediate care
of a burn consists of cooling the affected area with ice or
ice water.
Stages of Wound HealiNG
Wounds with even edges that come together spontaneously
(minor cuts) or can be brought together with sutures usually
heal well with routine wound care. Wounds with rough edges and
tissue deficit (a crater) may take longer to heal. When there
is a crater and the edges of a wound are not brought together
(left open intentionally), bumpy granulation tissue grows from
the exposed tissue. The granulation tissue is eventually
covered by skin that grows over the wound from the cut edges
to the center. When healing is complete, the granulation
tissue develops into tough scar tissue. All wounds heal in
three stages.
Inflammatory
Stage
This stage occurs during the first few days. The wounded area
attempts to restore its normal state (homeostasis) by
constricting blood vessels to control bleeding. Platelets and
thromboplastin make a clot. Inflammation (redness, heat,
swelling) also occurs and is a visible indicator of the immune
response. White blood cells clean the wound of debris and
bacteria.
Proliferative
Stage
After the inflammatory stage, the proliferative stage lasts
about 3 weeks (or longer, depending on the severity of the
wound). Granulation occurs, which means that special cells
called fibroblasts make collagen to fill in the wound. New
blood vessels form. The wound gradually contracts and is
covered by a layer of skin.
Maturation and
Remodeling Stage
This stage may last up to 2 years. New collagen forms,
changing the shape of the wound and increasing strength of
tissue in the area. Scar tissue, however, is only about 80% as
strong as the original tissue. The body's ability to heal
during this stage is diminished in the elderly.
Wound CaRE
There are four basic steps to follow in caring for any
wound. Perhaps the most important factor in wound healing is
compliance: in other words, caring for the wound consistently
and correctly.
Debride and
Cleanse
Debridement means the removal of dead tissue. Debridement can
be accomplished in an autolytic manner, meaning the wound
itself is encouraged to do this task by the use of dressings.
A medical professional may also use biochemical enzymes;
wet-to-dry dressings (in which a wet dressing is allowed to
dry, trapping material in it, and is then carefully removed);
or mechanical implements such as scalpel or scissors to remove
dead tissue from more serious wounds. Cleansing refers to the
removal of any foreign debris from the wound (such as residuum
from previous dressings) and any bacteria. Cleansing is
usually accomplished by irrigating the wound with fluid from a
disposable syringe.
Many previously accepted wound-cleansing solutions have
been found to be toxic to fibroblasts and lymphocytes, the
cells required to heal wounds. These solutions include
povidone-iodine, acetic acid, iodophor, hydrogen peroxide, and
Dakin's solution (sodium hypochlorite). Commercially prepared
solutions are not regulated by the FDA, and many have been
found to be cytotoxic. The only acceptable wound-cleansing
solution is normal saline solution (0.9% sodium chloride, or
salt, in water). Normal saline solution effectively removes
contaminants and has the same salt concentration as the fluid
in cells, so it does not damage cells by pulling water out of
them. Normal saline is also inexpensive and readily
available.
Maintain a Moist
Environment
During wound healing, cells and fluid are slowly exuded (or
discharged). The exudate provides an environment that
stimulates healing because it contains white blood cells,
growth factors, and other special enzymes and hormones. A
moist environment preserves this exudate, speeding wound
healing and promoting skin growth. It also prevents dressings
from adhering to the wound and damaging the fragile tissue
when the dressing is removed. A moist environment can easily
be maintained using gauze moistened with normal saline
solution (or with a Vaseline-based prescribed ointment
obtained from a physician).
Normal saline solution will support autolytic debridement,
absorb discharge, and trap bacteria. For partial-thickness
wounds with no infection, polyvinyl dressings, which are
semipermeable to oxygen and impermeable to bacteria, can also
be used. Polyvinyl dressings have the advantage of
concentrating the cells responsible for healing in the wound
bed, but the disadvantage is that they are adhesive and may
therefore damage the fragile skin surrounding the wound.
Hydrocolloid dressings are not adhesive and are impermeable to
oxygen and bacteria, but may leave a residue in the wound,
which must then be removed. Absorptive dressings are used on
wounds with a lot of discharge.
It is critical that
the first two steps of wound care be performed regularly and
gently. Dislodging the fragile granulation tissue or skin that
is forming in the wound bed will delay healing. For most
wounds, the first two steps can be accomplished easily and
effectively by using gauze that is kept moist with normal
saline solution.
Prevent Further
Injury
In order to prevent further injury, the initial cause of the
wound must be determined and addressed as described above and
the area must be protected from additional trauma.
Provide Materials for
Healing
Proteins, made up of amino acids, are necessary for all
phases of wound healing, including angiogenesis, fibroblast
proliferation, collagen synthesis, and scar remodeling.
Proteins also support the immune system, helping to prevent
infection. One study found that protein depletion before
surgery is a risk factor in wound infection (McPhee et al.
1998). Fats and carbohydrates are also needed to supply the
extra energy used in healing and to prevent proteins from
being used for energy. Water is necessary to replace losses
through vomiting, bleeding, wound discharge, and fever.
Vitamins and minerals also play key roles in the healing
process, as will be discussed later.
The Danger of InfectiON
Infection of a wound with a large number of bacteria, a
process known as colonization, will slow the healing process.
However, all wounds contain some bacteria. This is called
contamination and usually it does not affect the healing
process. The difference between contamination and colonization
is the concentration of bacteria. Signs of infection include
red skin around the wound, discharge containing pus, swelling,
warmth, foul odor, and fever. Healthcare providers can also
conduct laboratory tests to investigate for the presence of
infection. The routine wound care process outlined above is
usually sufficient to prevent infection. Since all wounds are
contaminated, using sterile materials and techniques is not
necessary. The best way to prevent infection is to carefully
wash your hands. Antibiotic creams should be used only if
signs of infection are present. Then only use them sparingly
to prevent bacterial resistance (bacteria develop the ability
to live in the presence of antibiotics). If a wound is
infected and does not respond immediately to over-the-counter
antibacterial creams, it must be evaluated by a healthcare
professional, who may prescribe antibiotics.
Tetanus prophylaxis is essential in wounds. Tetanus used to
be a common cause of death, but is seldom seen now because of
antibiotic treatment and vaccinations. However, in an
unvaccinated person over 60 who develops tetanus, mortality is
in excess of 60% once the disease process begins, regardless
of what treatments are begun at that time. Persons with
uncomplicated wounds who have not been vaccinated for tetanus
in the prior 5 years should receive a tetanus booster. In
complicated wounds--those that are particularly dirty or
contain a large amount of devitalized tissue--tetanus
vaccination should be updated after 5 years. Symptoms of
tetanus include irritability, headache, fever, and painful
muscle spasms resulting in a condition called lockjaw.
With any type of wound, even seemingly minor injuries,
there is always danger of rapid multiplication of bacteria.
The elderly and persons with reduced immunity are at great
risk for wound-related infections. Once bacteria escape from
the primary location of a wound, they enter the blood. This
condition is commonly called blood poisoning, septicemia,
sepsis, or septic shock. Sepsis is always a serious,
life-threatening condition, with 56% mortality. In the United
States, sepsis occurs annually in three cases per 1000
population (Hosac 2002). In sepsis and septic shock,
circulation is reduced; blood pressure is markedly reduced,
causing vital organs to receive reduced blood supply; heart,
kidney, and liver functions are reduced or show signs of
shutdown (multiorgan failure); and abnormal bleeding can
develop. Symptoms of septicemia and septic shock are sudden
onset of illness, high fever, chills, rapid breathing,
headache, and altered mental state. If the infection is
identified promptly and the patient is treated aggressively
(in an intensive care facility), full recovery from sepsis is
possible (Hosac 2002).
In the last quarter of 2001, the Food and Drug
Administration (FDA) approved the use of Xigris (Drotrecogin
Alfa Activated, Eli Lilly) for the reduction of mortality due
to sepsis in adults. Xigris is the only drug that has shown a
survival benefit. Administration of Xigris requires a
continuous 92-hour intravenous infusion with constant
professional monitoring and supportive care. The only adverse
side effect is increased bleeding events. There is no
published information concerning drug interactions and Xigris,
but because of its association with increased bleeding, Xigris
should not be given to patients taking systemic
anticoagulants. Treatment with Xigris is costly: $6720 for a
155-lb person (each additional 20 lb of body weight adds
approximately $1050) (Hosac 2002).
Alternative TreatmenTS
Many alternative treatments are available to help heal
wounds that do not respond to the conventional methods
described above. These treatments should be undertaken in
coordination with your healthcare provider.
Hyperbaric Oxygen
Therapy
In this therapy, used to treat very serious wounds, the
patient breathes 100% oxygen in a pressurized chamber for
90-120 minutes. The oxygen dissolves into the blood and is
distributed throughout the body, providing extra oxygen to the
cells attempting to heal the wound. Hyperbaric oxygen
treatments have been found to increase the rate of collagen
deposition, angiogenesis, and bacterial clearance (Davis 1987;
Heng 1993). Another benefit is that, if the wound environment
has more oxygen, certain types of bacteria that cause serious
infections cannot grow. During hyperbaric oxygen therapy, the
patient is placed in a hyperbaric chamber in which pressure
and oxygen concentration increase.
The patient breathes in higher oxygen concentrations and
the wound itself is exposed to the higher concentration of
oxygen under pressure. With the patient in the chamber, the
pressure is gradually increased and then, after treatment, it
is gradually decreased again. Plastic surgeons and other wound
care specialists have used hyperbaric oxygen therapy for many
years in treating difficult or complicated, nonhealing wounds.
It is well recognized as a very effective treatment. Because
of the equipment involved in maintaining a hyperbaric chamber,
only certain medical centers have a hyperbaric facility.
However, one can usually be found in the larger cities.
Whirlpool
Therapy
Physical therapists use whirlpool therapy once or twice daily
for about 20 minutes during the inflammatory stage of healing
to enhance circulation and bring more oxygen into the wound
area. The whirlpool also softens and loosens dead tissue and
cleanses the wound. Some patients find that whirlpool therapy
relieves wound pain. Whirlpool therapy should not be used on
wounds that are in the proliferative stage of healing because
it will damage the fragile skin cells. It should not be used
on venous ulcers which result from too much blood in the
area.
Ultrasound
Treatment
Ultrasound treatment uses mechanical vibration delivered at a
frequency above the range of human hearing. Physical
therapists report that covering the wound area with a hydrogel
film and applying ultrasound during the inflammatory and
proliferative stages stimulates the cells involved in wound
healing and also warms the tissue, enhancing healing by
improving circulation.
Electrical
Stimulation
The body has its own bioelectric system that influences wound
healing by attracting repair cells, changing the permeability
of cell membranes, and therefore affecting secretions and
orienting cell structures. A current of energy is generated
between the skin and inner tissues when a break in the skin
occurs. This current is enhanced by a moist wound environment
and can be mimicked by electrical stimulation which is
believed to accelerate the healing process. Electrical
stimulation uses electrodes that are positioned around the
wound area. It can be used on most wounds during all three
stages to support, speed, and even improve wound healing. Use
of this therapy results in a smoother, thinner scar. In 1994,
the Agency for Health Care Policy and Research endorsed
electrical stimulation therapy for treating Stage III and IV
pressure ulcers, based on data from five clinical trials
involving 147 patients ( http://www.ahcpr.gov/ ).
Magnetic
Therapy
Magnetic therapy has a rationale similar to that for
electrical stimulation, because the body's magnetic field is
related to its bioelectric system. The use of magnets has been
reported to increase blood flow and enhance cell growth by
transferring energy. Magnets also affect nerve signals in ways
that may relieve pain. A published case study describes the
complete healing of an abdominal wound by using magnet therapy
for one month. Despite traditional approaches to wound care,
the wound had been present for over a year (Szor et al.
1998).
Therapeutic
Touch
Biofield therapy, the "laying on of hands," is a very old
form of healing. Underlying rationales fall into two
categories: (1) that the practitioner modifies, directs, or
amplifies the human biofield; and (2) that the healing force
comes through the practitioner from a supernatural source,
such as God or the cosmos. Biofield practitioners use a
variety of approaches, but have a holistic focus that
incorporates mental, emotional, and physical health. Massage
therapy is thought to enhance healing, both by relieving
stress and by stimulating the nervous and circulatory systems.
One study found that massage therapy improved activity,
vocalizations, and behavior ratings of state, and also
decreased anxiety in burn patients. Long-term effects were
significantly better for the massage-therapy group in
comparison with a control. Benefits of therapeutic touch
included decreased depression, anger, and pain (Field et al.
1998).
Research: Growth Factors and
Immune ResponSE
As the name implies, growth factors are biological
substances that exert their influence by causing cellular
growth and proliferation. In an ideal wound-healing situation,
new tissue growth would replace damaged tissue resulting from
a wound with no functional or cosmetic impairment. In other
words, the newly grown tissue would work as well as the
previous tissue that was damaged, and it also would be
identical in appearance. Understandably, research involving
growth factors in wound care management is among the most
intriguing research being conducted. There is hope that we are
on the eve of learning how to manipulate growth factors, as
well as cytokines, to control wound healing, improving
function and aesthetics.
There are seven major growth factor families: epidermal
growth factor (EGF), transforming growth factor-beta
(TGF-beta), insulin-like growth factor 1 (IGF-1), interleukins
(Ils), platelet-derived growth factor (PDGF), fibroblast
growth factor (FGF), and colony-stimulating factors (CSF)
(Komarcevic 2000). The fine interplay of these factors along
with a host of other chemicals determines the finely balanced
environment that leads to uncomplicated wound healing and a
desirable end result. Chronic wounds, that is, wounds that
persist longer than expected, and complicated wounds may have
lost the finely balanced orchestration of healing and the
interaction of growth factors may have gone awry in some way.
Most growth factors are being used at research institutions
only, although there have been exceptions as noted in the
discussion to follow.
Epidermal Growth
Factor (EGF)
As the name implies, this growth factor promotes epidermal
growth. The epidermis is commonly referred to as the skin.
Other types of epidermal tissue are the mucosal lining of the
various organs of the gastrointestinal (GI) tract. EGF is
commonly found in tears. It has been used in eye surgery to
promote healing. In fact, the concentration of EGF in an
individual's tears has been found to be a positive determinant
for healing following eye surgery (Fagerholm 2000). With
topical application of EGF, corneal wound healing was improved
(Tripathi 1990). Upregulated EGF has been correlated to cancer
progression, so manipulation of EGF also has a role in cancer
therapy as well as wound repair (Wells 1999). EGF is usually
applied topically, although it can also be used intravenously.
When EGF is applied to injured skin, such as burns, ulcers
(skin or GI tract), and surgical corneal (eye) wounds, it does
promote healing. Therefore, EGF has been used for diabetic leg
ulcers and venous stasis ulcers as a topical application. EGF
is expensive, but it is available for use by physicians.
Insulin-Like Growth
Factor (IGF-1 and other IGFs)
When IGF was discovered, it was found to be somewhat
structurally similar to insulin (hence its name).
Interestingly, topical insulin accelerated wound healing,
perhaps because insulin is chemically similar to IGF-1
(Greenway et al. 1999). Growth hormone secreted by the
pituitary gland causes the liver to produce IGF-1, which
encourages cell growth and maintenance and repair in a variety
of tissues. Many tissues in the body (including muscle, GI
tract, skin, as well as many others) have receptors for IGF-1.
IGF-1 and IGF-2 are important in skeletal muscle repair and
regeneration (MacGregor et al. 1996). IGF-1 is available,
usually at medical research institutions or in medical trials.
Topically applied insulin itself accelerates wound healing,
perhaps because of its chemical similarity to IGF-1 (Greenway
et al. 1999). There are also nutrients like
dihydroepiandrosterone (DHEA) that can increase IGF-1
levels.
Human Growth Hormone
(HGH)
HGH is secreted abundantly in children to enable them to
achieve normal growth. In young adults, still-high levels of
HGH help keep them physically healthy and youthful looking.
With aging, growth hormone secretion and IGF-1 production
decline, contributing to a variety of biochemical and physical
degenerative changes, including delayed wound healing.
Synthetically produced HGH is taken intravenously by some
individuals under the supervision of a physician specialist to
slow or in some cases even reverse the effects of aging. HGH
is much more readily available than IGF-1 and has been used in
a variety of clinical studies to improve body composition and
effect healing (Chen et al. 1999).
Antiaging physicians who treat their aging patients with
HGH are accustomed to the accelerated healing time these
patients have compared with age-matched individuals with very
low IGF-1 levels. In general, individuals taking proper dosing
of HGH have adequate levels of IGF-1, so they heal faster.
However, note should be made that many studies have shown a
worsening of outcome when HGH is used in the period of
critical illness. While growth hormone works well to improve
healing if begun before the wound occurred, in the case of a
critical injury (as a burn or renal transplant), growth
hormone begun at the time of the injury has shown a worsening
of outcome.
Fibroblast Growth
Factor-10 (FGF-10)
Application of FGF-10 improves wound strength, collagen
content, and epidermal thickness (Jimenez et al. 1999). The
parameters for wound strength involve fibroblast cells that
produce connective tissue and scarring. At present, FGF-10 is
used in research investigations only. Fibroblast growth factor
is also known as keratinocyte growth factor (KGF-2).
Vascular Endothelial
Growth Factor (VEGF)
VEGF promotes the development of new blood vessels, including
the smooth muscle cells found in the walls of blood vessels.
New blood vessels must form and reconnect to each other for
wound healing to be complete and to provide an adequate supply
of oxygen and nutrients to the newly formed tissue. VEGF is
trapped in blood clots in wounds and begins to act when the
fibrin clot forms (Tezono et al. 2001). Neutrophils (a type of
white blood cell involved in the inflammatory and healing
response) also produce VEGF (McCort et al. 1999). Injection of
VEGF directly into heart muscle damaged by coronary disease
has also induced the formation of new blood vessels, obviating
the need for cardiac bypass. VEGF in wound healing is being
used in research institutions, although increasingly large
cardiac centers are beginning to offer the injection procedure
to revascularize heart muscle.
Modulating the Immune
Response During Healing
Interleukin is a generic term for a family of nonantibody
proteins called cytokines that act as cellular mediators in
generating an immune response. An appropriate immune response
depends upon the proper balance of cytokines, some that induce
antibody action and others that inhibit the action when no
longer needed for healing. IL-6 is a cytokine that stimulates
a number of immune system reactions that promote the healing
action of antibodies at the wound site (Gallucci et al. 2001;
Swartz et al. 2001). However, if not adequately downregulated,
IL-6 may initiate a series of responses that lead to an
overexpressed immune response. Excessive inflammation is one
result of overexpression of IL-6. In rehabilitation of injured
tendons and ligaments, oversecretion of IL-6 during the
rehabilitation exercise phase may cause exaggerated
proliferation of fibroblast cells, leading to scarring and
scar contraction. Conversely, in ligament injuries such as the
medial collateral ligament (MCL) of the knee, a certain level
of fibrous tissue must form in order for the ligament to heal.
The release of IL-6 promotes MCL collagen synthesis leading to
fibrous tissue formation (Hankenson et al. 2000). It has been
suggested that IL-6 levels should be monitored in skeletal
joints, aiming for a certain optimal level that promotes
enough influx of inflammatory cells to encourage healing, but
not so much as to damage healing tissue with excessive
scarring (Skutek et al. 2001; Swartz et al. 2001). (See the Chronic Inflammation
protocol for recommendations on reducing the effects of
inflammation.)
IL-10 is a cytokine that inhibits the inflammatory
response. Some of the most interesting work involving IL-10
relates to fetal healing. The human fetus has the ability to
heal without scarring and, according to some researchers,
IL-10 is "necessary for scarless wound repair to occur"
(Liechty et al. 2000). Hyaluronon (hyaluronic acid) is a
glycosaminoglycan found in lubricating fluids (synovial fluid,
cartilage, blood vessels, skin) and is also present in high
concentrations in the fetal environment (cord blood). It is
theorized that fetal fibroblasts may mute the inflammatory
response to inflammatory cytokines due to the high levels of
IL-10, hyaluronon, and other substances in the fetal
environment (Kennedy et al. 2000).
Nutritional SupplemenTS
Research has shown that certain nutrients such as aloe
vera, arginine, glutamine, zinc, copper, and vitamin C play
key roles in wound healing (Vaxman et al. 1990; Worwag et al.
1999). The typical Western diet is deficient in these
nutrients. Under normal conditions, the 5 grams a day of
arginine found in the typical Western diet would be marginally
sufficient to maintain tissue health. Research has
demonstrated, however, that in patients undergoing gall
bladder surgery, supplementing 15 grams of arginine for 3 days
prior to surgery significantly reduced nitrogen excretion
(evidence that the patients were using, not excreting, amino
acids in order to heal) when compared with patients receiving
conventional nutritional support. In patients undergoing
surgery for gastrointestinal cancer, supplementation with 25
grams of arginine a day for 7 days improved their nitrogen
balance as measured 5-7 days after surgery and led to more
rapid recovery and discharge from the hospital (Daly et al.
1995).
In a study of women being treated for venous leg ulcers, it
was revealed that the women had suboptimal dietary intake of
energy-providing food sources and key wound-healing nutrients
such as vitamin C and zinc even though they had well-organized
food habits (Wissing et al. 1997). Research on other
nutritional supplements has demonstrated encouraging results.
Some of these studies will be presented in the paragraphs that
follow.
Centella
Also known as Gotu kola, centella comes from the Centella
asiatica plant. According to legend, elephants use this plant
as a food source and owe their longevity to its age-defying
properties. (Scientists would likely claim that the elephants'
lifespan falls as expected on the curve relating size,
metabolic oxygen utilization, and lifespan in various
species.) Centella has been found to induce levels of
antioxidants in wounds and newly formed tissue, including
superoxide dismutase, glutathione peroxidase, vitamin E, and
vitamin C. Centella improves collagen formation and
angiogenesis (Shukla et al. 1999a). A review article of
centella noted the most beneficial effects to date involved
the stimulation and mutation of scar tissue by production of
Type I collagen and an inhibition of the inflammatory
reaction. This article reviewed seven other articles about
centella, stating "Centella asiatica has been documented to
aid wound healing in a large number of scientific reports"
(Shukla 1999b; Widgerow et al. 2000).
Aloe Vera
Aloe vera is a plant well-known for centuries to have healing
properties. Aloe contains the major carbohydrate fraction,
acemannan, which also has antiviral properties. Aloe can be
applied topically to wounds and taken internally for both skin
wounds and gastrointestinal ulcers (Chithraet al. 1998).
Aloe's mode of action may be through modulating macrophage
function in the wound, enabling an immune response that
ingests and destroys foreign pathogens (Zhang et al. 1996). It
has been suggested that aloe works as a free radical scavenger
and improves blood flow to the wound (Heggers et al. 1997).
The healing of dermal wounds in rats has been consistently
found to improve with aloe in several studies.
Aloe vera contains up to 200 different substances
beneficial to the human body. These substances include
enzymes, glycoproteins, growth factors, vitamins, and
minerals. Long-chain sugars, or mucopolysaccharides
(especially acemannan), have been of particular interest for
their remarkable properties. Aloe vera is commonly considered
a general tonic for increasing well-being and longevity. It
provides the micronutrients required for protein synthesis.
Its many components work together to reduce inflammation and
pain, promote healing, and stop infection. Some of these
components cause cells to divide and multiply; some stimulate
the growth of white blood cells. Aloe vera also enhances cell
wall permeability, increasing cell access to nutrients and
facilitating the removal of toxins from the cells. Aloe vera
can be used on the skin and can also be taken internally as a
juice (2 ounces of concentrate in a 6-ounce beverage).
Arginine
Injury significantly increases the need for the amino acid
arginine, which is essential for a variety of metabolic
functions. Animal studies have demonstrated that, following
surgical trauma, dietary supplementation with arginine results
in an increase in nitrogen retention and increased body
weight, both of which are essential for successful recovery
(Sitren et al. 1977; Minuskin et al. 1981; Chyun et al. 1984;
Jeevanandam et al. 1997; Mane et al. 2001). In a clinical
study published in a major medical journal, arginine
supplementation significantly increased the amount of
reparative collagen synthesized at the site of a "standard
wound" (an incision 5 cm long and 1 mm in diameter, into which
a catheter was inserted) made in healthy volunteers. The same
study found marked enhancement of the activity and efficacy of
peripheral T-lymphocytes (white blood cells in the
bloodstream) (Kirk et al. 1993).
Other animal and human studies have demonstrated that
arginine stimulates the cell-mediated immune response and
protects against bacterial challenges (Gurbuz et al. 1998). In
animals, dietary supplementation with arginine increases the
weight of the thymus, the master gland of the immune system,
and reduces shrinkage of the thymus following trauma and in
normally aging animals. The benefits of arginine for thymic
function have also been demonstrated. Its ability to restore
thymic endocrine function is evidenced by increased blood
levels of thymulin, one of the hormones secreted by the thymus
gland. Clinical studies have shown improved immune function in
cancer patients fed arginine. Arginine's ability to improve
wound healing and immune-system function is thought to be
related to its stimulation of the release of growth hormone.
Growth hormone plays a critical role in modulating the immune
system and is essential for muscle growth and development.
That growth hormone secretion diminishes progressively with
advancing age is one of the primary reasons for the decline in
immune-system function and muscular strength as we grow older.
To accelerate wound healing, the Life Extension Foundation
recommends 10-22 grams of supplemental arginine daily.
Glutamine
The amino acid glutamine is an important substrate for
rapidly proliferating cells, including lymphocytes (white
blood cells). It is also the major amino acid lost during
muscle protein catabolism in the initial response to injury.
An article documented beneficial effects from supplying burn
patients with glutamine and arginine in amounts 2-7 times
those found in the normal diet of healthy persons (De-Souza et
al.1998). The Foundation recommends 2000 mg of glutamine
daily.
Zinc
Zinc plays a well-documented role in wound healing. Although
zinc is present in the body in only a small quantity, it is
found in many tissues, including bone, skin, muscle, and
organs. It is a component of DNA, RNA, and numerous enzyme
systems that participate in tissue growth and healing. Zinc is
crucial for protein synthesis and is a key part of the
thymulin molecule which enables T-lymphocytes to mature.
A study involving zinc supplementation in inflammatory
bowel disease illustrated the importance of taking adequate
supplementation, but not too much. In this study, excess
amounts of zinc caused tissue injury and impaired wound
healing (Cario et al. 2000). However, relative zinc
deficiencies, especially in the elderly, are common in the
United States (Andrews et al. 1999).
Zinc should be taken
at least 2 hours after copper or the antibiotic
tetracycline..
Copper
A German physician first observed the role of copper in
healing, noting that broken bones seemed to heal faster when
patients were given a copper salt during convalescence. Since
then, the role of copper in the biosynthesis of bone and
connective tissue has been well established, although its
mechanism of action is only partially known (Tenaud et al.
1999). Copper supplementation has enhanced bone healing. It
works with vitamin C to create strong collagen, and it creates
cross-links in collagen and elastin that give strength to
proteins.
- N ote: The Life Extension Foundation
does not recommend high-dose copper as a long-term dietary
supplement because of the preponderance of evidence that
long-term copper supplementation generates too much
free-radical activity throughout the body. On the other hand,
therapeutic, short-term supplementation of copper (8 mg
daily) to enhance wound healing at localized injury sites is
appropriate. Copper supplementation as early as possible
after serious burns has been demonstrated to replenish the
copper depletion that is so typical of burn
victims.
Superoxide Dismutase
(SOD)
Copper also plays a critical role in the synthesis of a
natural antioxidant called copper/zinc superoxide dismutase
(SOD). In the initial phase of wound healing, immune cells are
rushed to the wound site to protect against harmful invaders.
They actually use free radicals to fight bacteria and to
dispose of dead tissue. Once the free radicals have
accomplished their job, however, they must be neutralized so
the actual healing process can begin. SOD and other
antioxidants such as vitamins C and D stop the free-radical
oxidation process and promote the healing and repair process
itself. Injury can deplete SOD and other antioxidants. In
certain antioxidants depletion levels as high as 70% have been
reported following injury (Ballmer et al. 1994). SOD should be
supplemented to encourage new tissue to grow, to enhance
collagen, and to reduce swelling. Wounds treated with SOD have
been shown to heal better and more quickly (Niwa 1989; Misaki
et al. 1990; Eldad et al. 1998). Current research indicates
that SOD taken orally is destroyed in the digestive tract. A
lipid-encapsulated injectable form of SOD (LIPSOD) and a
sublingually administered form currently show the most promise
for direct supplementation.
Vitamin C
Vitamin C is crucial for the proper function of the enzyme
protocollagen hydroxylase which produces collagen, the primary
constituent of the granulation tissue that heals a wound and
the key component in blood vessel walls. A published review
stated that vitamin C plays a variety of roles in the
prevention and treatment of cancer, including stimulating the
immune system and enhancing wound healing (Head 1998). Wound
healing requires more vitamin C than diet alone can easily
provide. It must be replenished daily because it is water
soluble. Any excess is excreted rather than stored. Three
tablets of Life Extension Mix 3 times a day provide the
vitamin C and other nutrients needed for wound healing. For
instance, vitamin A is important for tissue synthesis and
enhances resistance to infection. B vitamins are needed for
cell proliferation and for the replacement and maturation of
red blood cells lost through bleeding. One response to a wound
is a higher rate of metabolism. This leads to higher
energy-level requirements in order to heal a wound, and to
increased requirements for thiamine, niacin, and
riboflavin.
In a topical solution, vitamin C has shown to be very
effective in encouraging healing of the cornea in the wounded
eye (Gonul et al. 2001).
Vitamin
B5
Pantothenic acid (vitamin B5) improves healing by encouraging
the migration of cells into the wounded area, thus
establishing epithelialization (Weimann et al. 1999). At the
same time that new cells are migrating into the wounded area,
cell division is increased and protein synthesis is increased,
improving the efficiency of the healing process. Vitamin B5
also helps prevent an excess of inflammatory response in the
wound and has been shown to improve surgical wound healing
(Kapp et al. 1991).
Vitamin B5 has been demonstrated to speed up wound healing,
increase protein synthesis, and multiply the number of repair
cells available at the wound site (Aprahamian et al. 1985).
Vitamin B5 seems to have the most benefit early on in wound
repair, actually increasing the distance that repair cells can
travel.
Vitamins B5 and C in
Combination
French researchers examined combined supplementation with
vitamins B5 and C before the removal of tattoos. One week
prior to surgery, some patients were administered 200 mg of
vitamin B5 and 1 gram of vitamin C. Scars of all patients were
measured 75 days after surgery. The scars of those who had
been supplemented with vitamins B5 and C were stronger and
thicker and had more color. Researchers concluded that the
vitamins had "recruited" more minerals to the wound areas
(Vaxman et al. 1995). These "recruited" minerals included
copper, magnesium, and manganese, all proven to enhance wound
repair. Vitamins B5 and C also kept iron from the wound areas,
thus enhancing the healing process. The same group of
researchers found that supplementation with vitamins B5 and C
strengthens the healing of wounds incidental to colon
surgery.
Bromelain
Bromelain is found in pineapple and contains a proteolytic
enzyme with the ability to break down or dissolve proteins.
This mechanism of action can be helpful in chronic wounds or
wounds having too much scar tissue. According to the PDR for Nutritional
Supplements (2001, p. 72), bromelain speeds up healing
time after surgical procedures, shows positive effects in the
treatment of athletic injuries, and in at least one study has
reduced swelling and pain from injuries of the musculoskeletal
system. It has also been found to have antitumor properties
(Maurer 2001). Bromelain is commonly taken as a digestive aid
to enhance absorption of proteins.
Curcumin
Curcumin is an extract of the spice turmeric, known to have
antioxidant properties and other health benefits. In Indian
medicine, curcumin is used to reduce inflammation and treat
wounds and skin ulcers. Topical application of curcumin
encourages wound remodeling via effects on transforming growth
factor-beta (TGF-b). It also improves reepitheliazation (new
skin formation) and migration of cells such as myofibroblasts,
fibroblasts, and macrophages, necessary for healing at the
wound site. In animal studies, curcumin has shown
effectiveness in both topical and oral solutions (Sidhu et al.
1999).
Other Substances of Intrest in
Wound HealiNG
Although major studies have not been done with the
following substances, they are of interest and have been used
in wound healing. Some of them have particular interest for
the aging person.
Topical
Estrogen
Compared to youthful skin, in aging skin complications are
more likely to develop, such as the progression of a wound to
a chronic nonhealing state. This is related to an increased
amount of elastase in the wound. Elastase is an enzyme that
breaks down elastic proteins and is upregulated in impaired
wound healing states. In a study by Ashcroft et al. (1999)
involving 36 patients over the age of 70, half male and half
female, topical estrogen was found to decrease delays in wound
healing in both the male and female patients. Wound size,
collagen levels, and fibronectin levels all improved with
topical estrogen, indicating improved wound healing. In this
study, estrogen was delivered to the wound site for 24 hours
as a patch routinely used in female estrogen replacement
therapy (Ashcroft et al. 1999). Fibronectin levels have been
found to be deficient in chronic wounds of the aged, such as
venous ulcers in humans or laboratory wounds in aged animals
(Herrick et al. 1997).
Dilantin
(Phenytoin)
Dilantin is a drug commonly used to treat epilepsy and
seizure disorders. One of the known complications of Dilantin
is gingival overgrowth (overgrowth of tissue at the gum
margins in the mouth), suggesting that Dilantin might have an
ability to alter and improve healing in chronic wounds by the
same mechanism of encouraging tissue growth. Although no
studies have been reported in the United States, Dilantin has
been reviewed in Great Britain and suggested for this use
(Talas et al. 1999). In another study, topical Dilantin was
compared with glucose analogs (honey) in patients with chronic
leg ulcers over a 4-week period and showed superiority
(Oluwatosin et al. 2000). Honey has been recognized as an
agent to improve wound healing for some time. In the United
States, topical agents of glucose analogs are commonly used
for chronic wounds.
Fracture HealiNG
Bone fracture, or a break in a bone, is a very common
wound. Almost all persons experience a bone fracture at some
time in their lives. Because of the tensile strength needed in
bone, particularly the long bones that support the weight of
the skeleton, this type of wound generally takes longer to
heal than soft tissue wounds. Bones that do not support as
much weight, such as the clavicle, take about 6 weeks to heal
after a fracture, but structural bones (such as the femur)
that support skeletal weight can take 3-5 months to heal.
Weight-supporting bones must be well stabilized (or
immobilized) in order to heal. They must remain immobile in a
splint or a cast while new bone forms. New bone formation,
called callus, is evident on an x-ray about 10 days after the
fracture has occurred. At this stage, the new bone is soft and
flexible. Over weeks to months, replacement with hard bony
tissue occurs and the bone is able to function again and
support weight.
The same events of inflammation, proliferation, and
remodeling that occur in soft tissue injury also occur with
fractures, although these stages are spread over a longer time
period.
The same therapeutic and supplement recommendations also
apply to bone injury, although there is a particular
importance for copper and zinc. Copper supplementation is
important in fracture healing and in the early formation of
collagen in the wound.
Copper, 8 mg daily, provides adequate supplementation and
should be taken for 6 weeks for a fracture of a
non-weight-bearing bone. It should be taken for 2-3 months for
a major weight-bearing bone. Because copper is also a
pro-oxidant, supplementation should be stopped after this
period of time.
Zinc should be taken at a dose of 90 mg daily (as
recommended earlier for healing of other wounds). Zinc's
enhancement of fracture healing may be related to its effects
on increasing IGF-1 and TGF-beta, both of which are growth
factors discussed previously.
In an animal study, rats were divided into groups: one
control and one supplemented with vitamin C. All had fractured
tibias. After examination at four 5-day intervals, "It was
seen that the vitamin C-supplemented group went through the
stages of fracture healing faster compared with the control
group" (Yilmaz et al. 2001).
Glucosamine and chondroitin should also be supplemented to
encourage cartilage formation and repair if the fracture has
extended along an articular (joint) surface and there is
likely cartilage injury also.
Growth factors have been studied with respect to fracture
healing. At the present time, most of this work is in the
research stage, although even now synthetic bone grafts
impregnated with growth factors such as IGF-1 are available
(Schmidmaier et al. 2001; Spiroet al. 2001). Administration of
IGF-1 has been found to enhance bone fracture healing, but so
far the evidence for using TGF-beta has been conflicting
(Tielinen et al. 2001). To date, the use of fibroblast growth
factor (FGF) has also been discouraging (Nakajima et al.
2001).
Another growth factor important in bone healing is
osteogenic protein-1 or OP-1. A study of OP-1 to enhance
fracture healing is in its infancy, but preliminary results
are encouraging (Blokhuis et al. 2001). As shown in animal
studies, parathormone (parathyroid hormone) also has promise
in enhancing fracture strength and early callus formation
(Andreassen et al. 2001), although in humans, parathormone is
being used primarily to treat osteoporosis and in fractures
associated with osteoporosis. Several new drugs stimulating
bone healing are being tested, and most of these exert their
effects via various growth factors, especially IGF-1, TGF-b,
and FGF. In the future, stem cells may be used to improve bone
healing (Moutsatsos et al. 2001).
Adequate dietary intake of protein is important. In an
animal model, three groups were studied: controls (20%
protein), malnourished animals (6% protein), and renourished
animals (6% protein, but fed a 20% diet in the postfracture
period). The researchers found that in renourished animals,
the cross-sectional area of the fracture callus (the bony
deposit that forms around broken ends of bones during healing)
was greater than in those in the malnourished and
well-nourished animals. They concluded: "Protein deprivation
has a profound detrimental effect on fracture healing" (Day et
al. 2001). In general, the diet should contain an adequate
amount of protein for healing of all wounds and proteins
should definitely be supplemented. Glutamine and arginine,
amino acids mentioned earlier in this article, should
definitely be supplemented.
Smoking is especially harmful when the body is trying to
provide substrates for adequate wound healing. Smoking has
been shown to "adversely affect bone mineral density, lumbar
disk disease, the rate of hip fractures, and the dynamics of
bone and wound healing" (Porter et al. 2001).
For fractures complicated by a nonunion (the ends of the
fractured bone do not rejoin), work has been done for over 20
years using various types of electrical stimulation on the
bone ends to encourage union of the fracture site.
For additional information on accelerating healing of bone
fractures, the reader is encouraged to refer to the protocol
on Osteoporosis. Bone
healing rates may be enhanced by following some of the
recommendations for preventing and reversing age-associated
bone loss, such as supplementing with the nutrients calcium,
magnesium, boron, vitamin D3, and vitamin K; hormones such as
DHEA and topical natural progesterone; and even a
physician-prescribed bis-phosphonate drug such as Actonel.
SUMMARY
First, the type of wound, its cause, and its severity must
be determined. Serious wounds must be evaluated and treated by
a healthcare professional to prevent infection or development
of serious complications. If there is any indication that the
wound is not healing and has become infected, consult a
healthcare professional immediately.
Next, the stage of healing of the wound should be
identified. Then, follow the four principles of basic wound
care: debride and cleanse, maintain a moist environment,
prevent further injury, and provide supportive dietary
nutrients for healing.
- Arginine and glutamine are
two essential amino acids that are required for protein
synthesis. Take 10-22 grams daily of arginine and 2000 mg
daily of glutamine.
- Zinc and copper have been
documented to promote wound healing. These minerals should be
taken at least 2 hours apart to avoid antagonistic effects.
Take 8 mg of copper daily for a limited time only during
healing; take 90 mg of zinc.
- Life Extension Mix provides
vitamin C, vitamin E, vitamin B5, and other essential
nutrients to support and enhance wound healing: 9 tablets
daily.
- Additional vitamin C may be
supplemented several times daily to promote collagen
formation and provide additional antioxidant protection.
Consult with a healthcare provider for serious wounds.
- Aloe vera has numerous
healing properties in both oral and topical applications. As
a juice, 2 ounces of aloe concentrate may be mixed with a
6-ounce beverage. Topical aloe vera creams may be applied
several times daily.
- The digestive enzyme
bromelain may help promote healing, reduce pain, and prevent
scar tissue formation by helping to break down protein: one
500-mg tablet with meals.
- Curcumin may help promote new
skin growth in both oral and topical solutions. Take one
900-mg capsule daily. A compounding pharmacy should be
consulted for topical applications.
- For skeletal fractures,
glucosamine and chondroitin may promote healing. Four 1000-mg
combination capsules, taken twice daily, are suggested.
Several other nutrients mentioned for wound healing are also
recommended for fracture healing.
- Taken orally, centella may
improve collagen formation and reduce the effects of
inflammation: one 500-mg capsule daily, or applied as an
ointment, 1-2 applications daily.
- In people with adequate
levels of HGH and IGF-1, wounds heal faster than in those
with low levels. HGH supplementation should not be started
during the catabolic period of critical illness because it
increases the risk of mortality. However, people on an HGH
antiaging protocol heal faster than others of their age. If
HGH is not affordable, consider supplementing with 75-100 mg
of DHEA during the healing process. Refer to the DHEA Replacement
protocol for details.
- For chronic or serious
wounds, consider alternative treatments such as hyperbaric
oxygen therapy, whirlpool therapy, ultrasound treatment,
electrical stimulation, magnetic therapy, and therapeutic
touch.
- For wounds and
fractures that do not heal as expected, it might be
beneficial to seek help from a university orthopedic or
plastic surgery section using local application of growth
factors and new drugs that affect growth factors. For
nonunion bone fractures, electrical stimulation is an option
available at university hospitals as well as other
institutions.
To learn what you can do to reduce the risk of medically
induced complications, refer to the Foundation's Anesthesia and Surgical
Precautions protocol.
Product availabiliTY
Cold-pressed, whole-leaf aloe vera juice concentrate;
topical aloe vera ointment;
arginine powder,
tablets, and
capsules;
glutamine powder and capsules;
vitamin B5 powder and capsules;
curcumin with bioperine; bromelain;
zinc;
copper;
vitamin
C;
glucosamine-chondroitin caps; DHEA;
and
Life Extension Mix may be ordered by phoning (800)
544-4440 or by ordering online.
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