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REVIEW OF LITERATUREIndia is considered as diabetic capital of the world. Diabetes is growing alarmingly in our
country. Diabetes gained a status of epidemic in India with more than 65 million diabetic
individuals currently diagnosed with the disease and its rapid growth in country.
Approximately 9% of urban and 3% of rural population is estimated to have diabetes21.
The etiology of diabetes in India is multifactorial and includes genetic factors coupled
with environmental influences such as obesity associated with rising living standards,
steady urbanization and lifestyle changes. Delayed wound healing is one of the most
common complications of diabetes which increase the chance of amputation by
compared to normal people. People with diabetes has 50 times more likely to undergo
amputations than people without diabetes22.
Why diabetic wounds delay in healing?
Diabetic wounds pose a challenge to even to most experienced health professional.
There are many factors responsible for delayed healing and chronicity of wounds:
Figure 1: factors contributing for delayed wound healing in diabetics
DELAYED WOUND HEALING
WOUND INFECTIONS
ISCHEMIA
FAULTY WOUND HEALIN
G
IMMUNOPATHY IN DIABETES:
Diabetics have impaired polymorphonuclear function with decreased capacity to migrate
to the site of infection, decreased capacity to phagocytosis14. A significantly lower
chemotaxis has been found in polymorphonucleocytes of diabetic patients (type 1 and
type 2) than in those of controls15, 16, 17. The mean HbA1c concentration was lower
(better regulation) in patients without impaired phagocytosis18 than in those with
impaired phagocytosis19. Polymorphonucleocytes of diabetic patients have shown lower
phagocytic capacity compared to polymorphonucleocytes of controls.
NEUROPATHY IN DIABETES:
In diabetics there will be decreased sensitivity to pain, leading to small wounds due to
trauma. These wounds later gets infected and become chronic. Initially when patient get
injured, they do not notice wound as it is not painful. This makes wound more prone to
get infected6. Localized pressure also plays major role in diabetics, for example bed
sore, infected corn in the foot, if not treated properly can progress into chronic ulcer.
VACULOPATHY IN DIABETICS:
Diabetics will have micro and macroangiopathy. Decreased oxygenation and ischemia
activates inflammation at the site of wound that attracts neutrophils. Neutrophils release
inflammatory cytokines, proteolytic enzymes, reactive oxygen species (ROS) which
damage cells at wound site, prevent proliferation and wound healing. Neutrophils stay
for longer time in diabetic wounds compared to other acute wounds, leading to fact that
chronic diabetic wounds have higher levels of inflammatory cytokines and reactive
oxygen species (ROS) 7.
INADEQUATE LEVELS OF GROWTH FACTORS:
In chronic wounds, compared to acute wounds the levels of proteolytic enzymes
(elastase, matrix metallo proteinases) are high, while the concentration of growth factors
(platelet derived growth factor, keratinocyte growth factor etc.) are low. Inadequate
growth factors play a major role in defective wound healing in diabetics8.
Figure 2:
BACTERIA AND BIOFILMS:
In diabetics chronic wounds affects patients quality of life more than vision loss or renal
failure. Recently alteration in skin microbiota is emerging to have an impact on delayed
healing of diabetic wounds. Diabetic wounds will have high microbial burden. 85% of
amputations in patients with diabetes are preceded by infected wounds. Diabetic ulcers
are polymicrobial and multi drug resistant with ability to form biofilms. Biofilm forming
bacteria are 1000 times more resistant to antibiotics9. So biofilm formation is a very
important virulence factor and main reason for treatment failure. Most common
organism that infect chronic diabetic foot ulcer is Staphylococcus aureus13, followed by
Escherichia coli, Pseudomonas aeruginosa, Citrobacter species, Klebsiella oxytoca,
Proteus respectively. Among the above mentioned bacteria Staphylococcus aureus is
the most common biofilm former followed by Pseudomonas aeruginosa and Citrobacter.
80% of bacterial species isolated from diabetic foot ulcers were multi drug resistant.
Most commonly used antibiotic is amoxicillin + clavulanic acid followed by clindamycin.
50% of gram negative bacterial organisms show resistance to amoxicillin + clavulanic
acid. Imepenum, piperacillin + tazobactum, cefaperazone + sulbactum reported as most
effective drugs against diabetic foot ulcer infections.
Biofilm structure has been analyzed microscopically and biochemically. Biofilm is made
up of multilayered matrix containing water, bacterial cells, proteins, DNA and
polysaccharides.
Figure 3: Composition of Biofilm.
Close cell to cell contact in biofilms always allow easy transfer of plasmid containing
multi drug resistance (MDR) genes amongst one another. Organisms which form
biofilms are also characterized by tolerance which is temporary and non-heritable
character. Mechanism for tolerance:
a) Antibiotics that prevent cell division are ineffective against organisms producing
biofilms.
b) Drug penetration is hindered by polysaccharide matrix.
c) Drug efficacy is altered by pH of microenvironment of biofilm.
d) Biofilms hide microorganisms from host defense
Effective debridement of chronic wounds can overcome this problem.
FAULTY FIBROBLASTS:
Fibroblasts in diabetics have a reduced capacity to produce extra cellular matrix
proteins and keratinocytes that epithelize the wound11.
Epithelial progenitor cells (EPC’s) which are derived from bone marrow travel to the site
of injury and help in formation of blood vessels and wound healing. In study by Omaida
et al, EPC’s that are essential for wound healing are decreased both in circulation and
at wound site. They also found that impaired nitric oxide synthase (NOS) activation and
decreased stromal cell derived factor - 1 alpha (SDF-1 alpha) at wound site is also a
main reason for impaired wound healing.
In diabetics every scratch on skin is a matter of concern, as they have impaired wound
healing. Every small wound has potential to become infected chronic wound leading to
sepsis, amputation and even death.
OTHER CAUSES:
Many factors affect wound healing in diabetics such as age, comorbidities, Wound
etiology, size of wound, location of wound, heavy bio burden, nutritional status etc.
stress also plays a major role in wound healing. Diabetics with non-healing wounds are
at tremendous stress which will have negative effect on wound healing. Stress increase
cortisol levels that lowers immunity and inflammation, thereby increase chance of
infections12. Co-morbid conditions always contribute for wound to become chronic in
Diabetics e.g. diabetics with chronic disease are more prone to methicillin resistant
staphylococcus aureus (MRSA) 10.
Figure 4: multiple factors contributing to diabetic foot ulcers
IMPACT OF DELAYED WOUND HEALING:
Chase et al introduced the concept of “FOREVER HEALING AND PERMANENT WOUNDING” in diabetics. Patients with chronic diabetic wounds will have poor quality
of life. It involves loss of time because of multiple hospital visits over months, time off
work or loss of employment with significant financial burden on patient and his family.
Also affects the social wellbeing of the patient. Diabetic wounds resulting in amputation
increase threefold risk of death in next 18 months to 2 years5. Diabetic wounds are most
common cause of disabling chronic and expensive complication of diabetes.
Figure 5: Increased chance of mortality after amputation in diabetics
MANAGEMENT OF CHRONIC DIABETIC WOUNDS
It is estimated that 15% of diabetes patients will develop Diabetic foot ulcer once in their
life time, and approximately 14% of diabetic ulcers lead to amputation unless a prompt,
rational, multidisciplinary approach to therapy is taken. Factors that affect development
and healing of diabetic patient’s foot ulcer include the degree of metabolic control, the
presence of ischemia or infection, and continuing trauma to feet from excessive plantar
pressure or poorly fitting shoes. Appropriate wound care for diabetic patients addresses
these issues and provides optimal local ulcer therapy with debridement of necrotic
tissue, provision of a moist wound healing environment and applying topical agents
locally that help in healing. During the prolonged healing process of a chronic wound,
rapid and accurate evaluation of the healing progress is critical so that unsuccessful
treatments can be discontinued and alternate treatments be initiated as soon as
possible.
The “TIME” framework in diabetic wound management encompasses tissue
management, inflammation and infection control, moisture balance, and epithelial
(edge) advancement20. Tissue management aims to remove the necrotic tissue burden
via various methods of debridement. Infection and inflammation control by reduction of
bacterial biofilms, antibiotic use, local topical agents, Achieving a moist wound healing
environment without excessive wound moisture or dryness will result in moisture
balance. Epithelial advancement is promoted via removing the physical and biochemical
barriers for migration of epithelium from wound edges. These systematic and holistic
approaches will potentiate the healing abilities of the chronic diabetic ulcers, including
those that are recalcitrant.
Figure 6: “TIME” acronym for management of chronic diabetic wounds.
Adequate debridement, application of topical wound healing agents and dressings is
needed for chronic diabetic ulcers. Many techniques are available for wound dressing
and all essentially reduce infection and improve granulation tissue growth. In this study
the wound healing potential of topical placental extract was evaluated and compared
with topical ionic silver.
Importance of placental extracts in chronic diabetic
wounds:
It is known from traditional folk knowledge that the placenta, supporting the baby's
growth and development in the mother’s womb, contains a wide range of biologically
active components. Research over decades has been uncovering more and more of
these compounds. Indeed, it is claimed that the placenta is capable of producing just
about any substance found in any organ of the body. This biochemical treasure house
supplies the growing fetus with substances that the fetus itself cannot synthesize.
Though a rich source of bioactive components unless recovered, placenta becomes a
biomedical waste immediately after childbirth. Use of human placenta as a therapeutic
agent in no way hampers ecological balance rather promotes resource recovery from a
designated biomedical waste. Research on human placental extract gained a
momentum with the description of the preparation of its extract by Russian
ophthalmologist Prof. V.P. Filatov, he used placental extracts in grafting human corneas
in the year 1912.
Placenta serves as a natural storehouse of many biologically active components with
significant healing attributes. It actually involves in almost every stage of healing. Only
aqueous form is biologically active. Modern indigenous aqueous placental extract is
prepared employing Filatov’s procedure. Fresh placenta retrieved after baby’s birth is
tested for HIV, HBsAg and HCV. Single hot and cold aqueous extractions were done
after incubating placenta at 90oC and 6oC respectively. This was followed by sterilization
of extract under saturated steam (pressure 15-lbs/sq. inch at 120oC for 40 min). After
filtration and addition of 1.5% benzyl alcohol as preservative, ampoules were filled and
sterilized once again under the said condition for 20 minutes24. Each milliliter of drug
was derived from 0.1 g of fresh placenta. A single batch was prepared from pool of
several placentae.
Figure7: Cellular mechanism of wound repair in placental extract therapy.
MECHANISM OF ACTION OF PLACENTAL EXTRACT
IN HEALING WOUNDS:
Aqueous extract of placenta contains nucleotides like Polydeoxyribonucleotides
(PDRNs), known for their regenerative effect28. Placental extract is rich in enzymes like
alkaline and acid phosphatases, glutamic oxaloacetic acid transaminase; RNA, DNA,
and ATP; Vitamins like B1, B2, B6, pantothenic acid, biotin, Folic acid, B12, choline, and
inositol; Amino acids like alanine, aspartic acid, cysteine, histidine, leucine,
phenylalanine, proline, serine, threonine, tryptophan, valine and tyrosine; steroids;
elements like Na, K, Ca, Mg, Cu, Fe, P. All these components may exert multiple
biological activities. Placental extract also has Corticotropin Releasing Factor (CRF)
which is proven to be promoter of Human Epidermal Keratinocyte Proliferation29.
Placental extract increases collagen synthesis, increases tissue protein, accelerates
neoangiogenesis, and epithelialization. Has immunotropic effect on EGF (Epidermal
Growth Factor) and Fibroblast growth factor. It reduces surrounding tissue inflammation
and edema. Studies have shown that use of topical placental extract increases the rate
of wound healing and patients have an early recovery25.
Chakraborty et al. studied the role of placental extracts on the growth of different
bacteria26. They found that placental extracts prevents the growth of bacteria such as
E.coli from urine and blood culture. They found placenta to also have an inhibitory role
in the growth of bacteria such as Staphylococcus aureus, fungi such as Saccharomyces
cerevisae, Kluyvero-myces fragilis, and Candida albicans. Sudhir et al studied the effect
of topical placental extract dressing over various diabetic ulcers and had similar
results27. No side effect has been noted with placental therapy.
Importance of Ionic silver in chronic Diabetic wounds:
Silver is a precious metal, its medicinal properties were known from ages (over past 200
years) as silver coins and vessels were used for drinking water purification. Most of the
diabetic wounds are infected. Topical ointments containing ionic silver are used to
prevent and manage infection in wide range of wounds. The topical antimicrobial agent
silver has been used for hundreds of years in wound care. For example, silver has been
used to prevent or manage infection in its solid elemental form (e.g. silver wire placed in
wounds), as solutions of silver salts used to cleanse wounds (e.g. silver nitrate solution),
and more recently as creams or ointments containing a silver–antibiotic compound
(silver sulfadiazine (SSD) cream).
Silver is found in a number of forms35:
■ Elemental silver: e.g. Nano crystalline silver.
■ Inorganic compound: e.g. silver oxide, silver phosphate, silver chloride, silver-
calcium-sodium phosphate, silver zirconium compound, Silver sulfadiazine.
■ Organic complex: e.g. silver-zinc allantoinate, silver alginate, silver
carboxymethylcellulose.
Mechanism of action of silver at wound site:
In metallic (elemental) form, silver is unreactive and cannot kill bacteria. To become
bactericidal, silver atoms (denoted as Ag ) must lose an electron and become positively
charged silver ions (Ag+). Elemental silver ionizes in air, but ionizes more readily when
exposed to an aqueous environment such as wound exudate. Silver ions are highly
reactive and affect multiple sites within bacterial cells, ultimately causing bacterial cell
death. They bind to bacterial cell membranes, causing disruption of the bacterial cell
wall and cell leakage. Silver ions transported into the cell disrupt cell function by binding
to proteins and interfering with energy production, enzyme function and cell
replication36. Silver ions are active against a broad range of bacteria, fungi and viruses,
including many antibiotic-resistant bacteria, such as meticillin-resistant Staphylococcus
aureus (MRSA) and vancomycin-resistant Enterococci (VRE) 37. Ionic silver reduce
bacterial adhesion and destabilize the biofilm matrix, as well as kill bacteria within the
matrix and increase susceptibility of bacteria to antibiotics38. Ionic silver have be found
to have anti-inflammatory effect, increase neovascularization at wound site39.
Antibiotics act only at single site on target bacterial cell, which is the main reason for
increasing antibiotic resistance. Compared to antibiotics, ionic silver acts at multiple
sites on a target cell30. Therefore, chance of developing resistance to ionic silver is less.
So it can play a potential role in controlling infection and limiting antibiotic use, thereby
decreasing further chance of developing antibiotic resistance.
The aim of treatment with silver dressings is to reduce wound bioburden, treat local
infection and prevent systemic spread. Their main purpose is not to promote wound
healing directly. Clinical guidelines recommend that silver dressings are used for
wounds where infection is already established or an excessive wound bioburden is
delaying healing31, 32. Silver dressings should not be used on wounds where bioburden
is not a problem, i.e. they should be reserved for use in wounds with or at risk of high
bioburden or local infection34.
Figure 8: Mechanism of action of ionic silver on bacterial cell- attachment to the
bacterial cell wall, its diffusion into bacterial cell and coagulating bacterial
proteins/enzymes.
Silver dressings occasionally cause local skin discoloration or staining which is
harmless and usually reversible. This discoloration is not true systemic argyria, which is
rare and usually related to oral ingestion of silver solutions as an alternative health
practice. So ionic silver preparations are non-toxic and few studies even found that ionic
silver promotes wound healing in chronic wounds33. Studies show ionic silver have
antimicrobial activity against a wide range of microorganisms, including resistant forms
such as MRSA and VRE, and fungi and anaerobes40, 41.
.