Professional Documents
Culture Documents
MANAGEMENT OF CHRONIC
WOUNDS
Usually heal in anticipated time frame Wounds fail to heal in anticipated time frame and often
reoccur
Eg. Acquired due to trauma or surgical procedure Occur as a result of an underlying condition like extended
pressure on tissues, poor circulation or poor nutrition.
2. Stage of Inflammation
3. Stage of Proliferation
4. Stage of Remodelling
Timeline of wound healing- 4 phases do not follow
linear order but overlap in time
STAGES OF WOUND HEALING
I) HEMOSTASIS
• Injury → lacerated vessel → transient vasoconstriction. (minutes to few hours)
• Thromboplastic tissue products (subendothelium) exposed.
• These toxic agents can be released to the outside of the cell (attack normal
tissue).
Inflammatory Phase
• In a healing wound, neutrophil infiltration ceases after a few days of injury.
• Expended neutrophils are Phagocytosed by Macrophages.
• Most macrophages at the wound site are recruited from the peripheral
circulation (Extravasation)
• Factors that guide the extravasated monocyte to the wound site include
• growth factors and chemotactic proteins
• proinflammatory cytokines, and chemokines (macrophage inflammatory protein 1α, MCP-1, and RANTES)
• The source of these chemo-attractants includes
• clot-associated platelets
• wound edge hyperproliferative keratinocytes
• wound tissue fibroblasts
• leukocyte already at the wound site.
ROLE OF MACROPHAGES
• Mediators in the microenvironment receptors on the monocyte cell surface, bringing major
changes make of the cell.
• Major examples of such receptors present on the monocyte surface include
• Toll-like receptors (TLRs)
• complement receptors
• Fc receptors.
• Mast cell activation helps initiate the inflammatory phase of wound healing.
(degranulate within hours)
• Activated mast cell controls the key events of the healing phases:
• triggering and modulation of the inflammatory stage
• proliferation of connective cellular elements
• final remodeling of the newly formed connective tissue matrix.
Role Of Macrophages
• Macrophages represent the predominant cell type in a healing wound 3–5 days
following injury.
2. GRANULATION
3. CONTRACTION
4. EPITHELIALIZATION
FIBROPLASIA
• Fibroblasts are activated and present at the wound by 3 to 5 days after
injury.
• Migration starts from the wound edges as well as from epidermal cell nests
(sweat glands and hair follicles)
• Intergrins – transmembrane receptors with extracellular membrane and intracellular protein
domains (composed of alpha and beta subunits) .
• Ligands to integrins include growth factors and ECM components such as collagen, elastin, etc.
• Integrins + ligands→ BINDING→ change in gene expression and new cellular function ensues.
• The ratio of type I collagen to type III collagen in normal skin is 4-5:1.
• Hypertrophic and immature scars contain ratios of 2:1 or less.
Major fibrillar collagens composing ECM in skin and scar are collagen types I and III. Ratio of
collagen I : III is 4:1 in both scar and skin. Although type III collagen is initially deposited in
relatively greater amounts in wound, its amount is always less than type I collagen in mature
scar.
STAGE OF PROLIFERATION - Granulation
• Granulation tissue is dense population of blood vessels, macrophages,
and fibroblasts within a loose provisional matrix of fibronectin,
hyaluronic acid, and collagen.
• During the proliferative phase granulation tissue is light red or dark pink in
color (perfusion by new capillary loops).
• This repair process speeds wound closure compared with epithelialization and
scar formation alone. Additionally, area of insensate scar is smaller.
• Contractile forces are likely generated by myofibroblasts (fibroblast with alpha
smooth muscle actin and microfilaments in cytoplasm).
• This new epithelial cell layer forms a stratum germinatum and undergoes mitosis
as in normal skin.
Cellular differentitation
• The normal structure of stratified squamous epithelium is re-
established.
• Morphologic changes in keratinocytes at the wound margin are evident within hours
after injury.
• The epidermal cell layer thickens and marginal basal cells migrate over the wound
defect.
• Once these keratinocytes begin migrating, they do not divide until epidermal
continuity is restored.
• New epithelial cells for wound closure are provided by fixed basal cells in a zone near
the edge of the wound.
• The keratinocytes become columnar and divide to restore the layering of the
epidermis and re-form a barrier to further contamination and moisture loss.
• Proteins called tissue inhibitors of matrix metalloproteinase specifically inactivate the matrix
metalloproteinases.
• As the collagen matrix forms, densely packed fibers fill the wound site. The ultimate pattern
of collagen in scar is one of densely packed fibers and not the reticular pattern found in
unwounded dermis.
Wound tensile strength as a function of time. Maximal tensile strength is 75%-80% of the
unwounded skin.
• Wound scar remodelling occurs during months to years to form a "mature" scar.
• Early scar appearance is red due to dense capillary network induced at the injury site.
When closure is complete, capillaries regress until relatively few remain.
• As the scar redness dissipates during a period of months, the true scar pigmentation
becomes evident.
• Scars are usually hypo-pigmented after full maturation. Scars can become hyper-
pigmented in darker-pigmented patients and in those lighter-pigmented patients whose
scars receive excess sun exposure.
• Sun protection measures are recommended for patients with early scars on sun exposed
areas such as the scalp, face, and neck.
• During remodelling, wounds gradually become stronger with time but never becomes as strong
as unwounded skin.
• Wound tensile strength increases rapidly from 1 to 8 weeks after wounding and correlates
with collagen cross-linking by lysyl oxidase. Thereafter, tensile strength increases at a slower
pace and increase up to 1 year after wounding.
• Tensile strength of wounded skin at best reaches only approximately 80% that of unwounded
skin.
• Presence of foreign body and foreign body reactions • Chemotheraphy and radiotherapy
CAPILLARY
DECREASE
LEAKAGE
VALVULAR VENOUS INCREASED IN
BACKFLOW OF PLASMA
INCOMPET INSUFFICIE VENOUS COLLAGEN
OF BLOOD CONSTITUE
ENCE NCY PRESSURE PRODUCTI
NTS LIKE
ON
FIBRIN
PATHOPHYSIOLOGY OF VENOUS
ULCERS
DETECTED BY
ELEVATED SECRETING BEGINS THE
ENDOTHELIAL
VENOUS VASOACTIVE INFLAMMATORY
CELLS(ICAM-
PRESSURE MOLECULES CASCADE
1,CD54)
ARTERIAL ULCERS
•OCCURS DUE TO ARTERIAL INSUFFICIENCY
EMBOLISM
DM
VASCULITIS
PYODERMA GANGRENOSUM
SICKLE CELL DISEASE AND THALESSEMIA
DIABETIC FOOT ULCERS
• OCCURS IN ABOUT 15% OF INDIVIDUALS
• FACTORS THAT CONTRIBUTE TO ABERRANT HEALING-
a) Abnormal and chronic inflammatory response
b) Hyperglycemia
c) Microvascular abnormalities
d) Hypoxia
e) Changes of ECM scaffold
PATHWAY OF DIABETIC ULCER
HYPERGLYCAEMI
CELL APOPTOSIS
A LEADS TO NON FORMATION OF
DECREASE & DISRIPTION OF
ENZYMATIC ADVANCED
SOLUBILITY OF NORMAL
BINDING OF GLYCATION END
THE ECM WOUND
SUGAR RESIDUES PRODUCTS
HEALING
TO PROTEINS
PRESSURE INJURIES
• CAUSES INCLUDE- Pressure, friction, shearing forces between tissue
planes and moisture
LATE EFFECT-
IONIZING RADIATION REDUCED PROLONGED
ACUTELY DISRUPTS INCREASED VASCULAR
CAUSES BOTH ACUTE OEDEMA NEOVASCULARIZATION INLAMMATORY PHASE
BASEMENT MEMBRANE PERMEABILITY
AND LATE EFFECTS. OF WOUNDS CAUSES FIBROSIS AND
CONTRACTION
NUTRITION
• CAUSES INCLUDE- General malnutrition state, inadequate caloric
intake, and deficiencies in vitamins, micronutrients, macronutrients.
• MALNUTRITION prolongs the inflammatory phase of wound healing
by reducing the proliferation of fibroblasts and formation of
collagen ,altering the function of immune cells, such as reducing
phagocytosis & decreasing complement levels.
MICRO-ORGANISMS
• Bacteria predominantly exist in biofilms in clinical and natural
settings, as opposed to planktonic states (single organisms/free-
floating).
• Biofilms describe adherent populations of microbes that form
three-dimensional populations and are organized on extracellular
polymers.
• Chronic wounds develop biofilms, as complex interactions
between the host wound microenvironment and heterogeneous
bacterial populations
• They delay and inhibit wound healing by not only producing
toxins and damaging enzymes, but also promoting the complex
chronic inflammatory pathways.
• Proteases released from bacteria impede growth factors and
wound healing proteins. Large levels of microbial exudate have
also been shown to affect cell proliferation and wound healing.
MANAGEMENT OF BIOFILM INFECTED
WOUNDS
• PRESSURE OFF LOADING
• APPROPRIATE DRESSINGS
• SYSTEMIC ANTIBIOTICS
• TISSUE DEBRIDEMENT
• VAC DEVICES
OBESITY AND METABOLIC
SYNDROMES
• CAUSES WOUND INFECTION, IMPAIRED WOUND HEALING, PRESSURE
INJURIES, VENOUS ULCERS, HEMATOMA FORMATION, SEROMA
FORMATION
• OBESITY HAS LOWER LEVELS OF LYMPHOCYTE PROLIFERATION,
ALTERED CYTOKINE LEVELS & PERIPHERAL IMMUNE FUNCTION.
ADVANCED WOUND HEALING
• BIOLOGICAL THERAPIES - GROWTH FACTORS
PDGF & PRP
STEM CELLS
HYPERBARIC OXYGEN
CELL CULTURED PRODUCTS
• SCAFFOLDS
• BIOPHYSICAL FORCES- NEGATIVE PRESSURE WOUND THERAPY
EXTRACORPOREAL SHOCK WAVE THERAPY
ELECTROMAGNETIC THERAPIES
GROWTH FACTORS
• Growth factor–related wound repair has been of immense interest in
wound healing science.
• Commercially marketed growth factors currently available include
recombinant human fibroblast growth factor, recombinant human
platelet-derived growth factor, and recombinant human epidermal
growth factor.
• They can be applied topically or injected
PDGF AND PRP
• Platelet-rich plasma (PRP) and PDGFs obtained from centrifugation of
blood.
• The first commercially available topical PDGF in the United States is
becaplermin gel (Regranex®) & was studied in chronic diabetic foot
ulcers but has increased risk of rate of mortality secondary to
malignancy.
STEM CELLS
• Stem cells are undifferentiated cells that possess the ability to mature
into differentiated cells of either one embryonic germ layer
(multipotent) or all three embryonic germ layers (pluripotent).
• One of the most widely studied multipotent adult stem cells in wound
healing research has been mesenchymal stem cells (MSCs)
HYPERBARIC OXYGEN
• HBOT utilizes compression chambers to deliver high levels of oxygen
concentration at raised atmospheric pressures.
• HBOT aims to promote oxygen-dependent wound healing pathways
and has particularly been a treatment strategy when revascularization
in vascular insufficiency has been unsuccessful.
CELL CULTURED PRODUCTS
• Cell cultured products, also known as tissue-engineered constructs, include
Apligraft, Epicel, and Dermagraft.
• Apligraft utilizes a bovine collagen matrix incorporated with human neonatal
fibroblasts and neonatal keratinocytes to act as a scaffold as well as providing
cells that produce growth factors and ECM components.
• Dermagraft comprises a polyglactin scaffold with dermal neonatal fibroblasts.
• Cultured epithelial autografts using patients’ own keratinocytes, such as Epicel,
have been utilized to treat large burns and take 2 to 3 weeks in culture to grow.
SCAFFOLDS
• Scaffolds act as a platform for cell migration and angiogenesis and are a key
therapeutic modality.
• Scaffolds can be of human origin (donated tissue or cadaveric) and nonhuman
origin (porcine or synthesized through extraction and cross-linking).
• Integra™ is a bilayer matrix of bovine collagen and glycosaminoglycan derived
from shark skin that is lyophilized to form a highly porous scaffold. Integra™
has been used with considerable success in burns, and clinical trial data have
attested its use in the healing of chronic wounds, specifically decreasing time
to wound closure in diabetic foot ulcers.
• Allopatch®, which is a decellularized scaffold derived from human cadaveric
tissue, has demonstrated efficacy in closure of nonhealing diabetic foot ulcers.
BIOPHYSICAL FORCES
• NPWT effectively ensures wound drainage, aids granulation tissue
development, and expedites wound contraction.
• ESWT delivers high-energy acoustic pulses to tissues and is the
standard of care in treating nephrolithiasis and various
musculoskeletal conditions. It has been reported to improve
cutaneous wound healing through increasing cell proliferation and
stimulating angiogenesis.
• Electromagnetic therapies are thought to interact with endogenous
electric fields in the skin to increase expression of growth factors and
nitric oxide and also promote angiogenesis