Wound Healing

Tyler Jacobs
Topics for discussion
• General concepts of wound healing
• Normal soft tissue healing
• Abnormal soft tissue healing (keloids vs. hypertrophic scars)
• Wound repair in other tissues of the head and neck
• Normal bone healing
• Complications in bone healing
• Normal cartilage healing
• Nerve healing
• Skin grafting
• Factors in suboptimal wound healing
• Wound management
Normal soft tissue healing (repair)
3 phases:
1) Inflammation (0-5 days)
2) Proliferation (5 days – 3 weeks)
3) Remodeling (3 weeks – 1 year)
Inflammatory phase
• Lasts from time of injury to 3-5 days post injury
• Begins with vasoconstriction → clot formation (fibrin + platelets)
• Primary hemostasis = platelet plug (stops bleeding)
• Secondary hemostasis = crosslinked fibrin (strengthens platelet plug + acts as
scaffold for wound healing)
• Vasoactive changes and inflammation follow hemostasis
Primary Hemostasis
• Platelets have 3 actions:
1) Adhesion to subendothelium
2) Aggregation (platelet-platelet binding) Can also be vWF

3) Secretion (release of granule contents)

Primary Hemostasis
• Platelets release:
• Interleukins → inflammatory
mediators
• Growth factors (TGF-B, PDGF, VEGF)
→ inflammatory mediators +
fibroblast activators
• Serotonin → vasoactive
• Thromboxane A2 → activates
platelets
• ADP → activates platelets
• Prostaglandins → vasoactive +
inflammatory mediator
• Calcium → activates clotting factors
• vWF → platelet aggregation +
coagulation
• PF4
• Fibrinogen → platelet aggregation
 Secondary Hemostasis PTT test
PT/INR test
Link between coagulation
and inflammation:
Inflammation
• Degranulation of mast cells + platelets
→ vasoactive changes (vasodilation +
increased vascular permeability +
production of cellular adhesion
molecules) + chemoattraction of
leukocytes
Inflammation
• Neutrophils enter wound first
via diapadesis, concentration
peaks by 24 hours
• Neutrophils are activated by
local immune mediators →
degranulate & phagocytose
foreign invaders in the wound
Inflammation
• Monocytes follow and transform into macrophages, concentration
peaks around 2-3 days
• Macrophages phagocytose microbes that infiltrate into wound
• Macrophages secrete numerous inflammatory mediators and
enzymes → continues wound debridement → stimulate formation of
granulation tissue
• Enzymes such as collagenases, elastases, cathespins → activate plasmin to
begin clot breakdown
• TGF-a, TGF-B1, PDGF, EGF, FGF, TNF-alpha, IL1 → stimulate granulation tissue
formation
Proliferative Phase
• Characterized by growth of granulation tissue
• Granulation tissue = fibroblasts + myofibroblasts + new blood vessels +
new epithelial cells + leukocytes (macrophages/lymphocytes)
• Fibroblasts arrive at wound on 3rd day and reach peak concentration ~1 week →
produce proteoglycans and type 3 collagen
• Neovascularization enhanced by local factors (hypoxia, elevated lactate) and
cytokines (FGF, VEGF, PDGF)
• Myofibroblasts = contract the scar
• Epithelialization promoted by EGF, TGFa and keratinocyte growth factor
• 3 phases: epithelial migration, proliferation, and differentiation
• Skin-grafting open soft tissue wound can limit amount of granulation tissue
produced thereby reducing scaring and tissue contracture
• Re-epithelialization occurs faster on mucosa than skin because its moist
Tissue remodeling
• Scar tissue becomes stronger as type 3 collagen becomes replaced by
type 1 collagen
• Replacement of collagen type 3->1 and subsequent cross-linking
increases scar’s tensile strength to 75-80% of preinjury tensile
strength
• Decrease in number of fibroblasts and macrophages, and vascularity
occurs over time
Abnormal soft tissue healing
Keloid Hypertrophic Scar
Excess production of scar tissue that is out of Excess production of scar tissue that is localized to the
proportion to the wound wound
Made of type 1 and type 3 collagen Made of mostly type 3 collagen
Frequent Recurrence (event after treatment) Infrequent Recurrence
Can take months after initial trauma to develop Develop shortly after wound
Classically affects earlobes, face, upper extremities
Genetic predisposition (more common in African
Americans)
Treatment: Treatment:
- First line is intralesional injection of corticosteroids - First line treatment is intralesional corticosteroids
- Localized pressure therapy, interferon, or 5-
florouracil can be used in combination with
steroids
- Can be surgically excised or treated with radiation,
cryosurgery, or topical imiquimod
Normal Bone Healing
3 phases just like soft tissue healing:
1) Inflammation
2) Proliferation
3) Remodeling

Bone healing also undergoes calcification

Inflammation
• Stimulated by vessel injury in haversian canals and periosteum and by
presence of necrotic material in fracture site
• Hematoma is formed within fractured bone and necrotic bone edges
are resorbed
Proliferation
• Mesenchymal cells and fibroblasts enter site of injury and lay down fibrous
tissue, cartilage, and immature bone fibers → granulation tissue forms
• If fracture segments are not precisely reduced to preinjury anatomic
position or if bone is avulsed leaving a residual space between the two
bony segments → bone will heal by secondary intention
• Greater cartilage deposition is required to bridge the gap, resulting in the formation
of a callus
• Callus offers fractured bone some minor stability against bending in torsion.
However, immobilization is required for healing to proceed otherwise a fibrous union
results
• Cartilage callus calcifies into woven bone as osteoblasts and osteocyte
concentrations increase within the fracture site
• Osteoblasts deposit osteoid on spicules of calcified cartilage
• No cartilaginous callous forms when fractures heal under immobilization or
the segments are anatomically reduced without a gap → this healing is
called primary intention
Remodeling stage
• Callus completely ossifies as osteoclasts resorb immature bone and it
becomes remodeled into lamellar bone
Dental extraction site healing
• Heals by secondary intention
• Socket fills with blood → blood clot forms → inflammation
• During first week, leukocytes debride fracture site + phagocytose
bacteria, osteoclasts resorb marginal bone along extraction socket,
epithelial cells migrate along socket wall to reepithelialize socket
surface
• During second week of healing, granulation tissue is generated while
osteoid is deposited by osteoblasts to form woven bone
• By 4th week of healing, full reepithelialization is achieved
• Alveolar bone is remodeled over 4-6 months
Complications in Bone healing
• Repeated trauma to an area undergoing bone healing can result in
malunion or nonunion of bony fracture
• Malunion: bony fracture segments heal in an incorrect or nonanatomic
position which can lead to a deformity
• This occurs when the fracture segments do not form bone to bone contact, but
instead remain bridged by fibrous tissue.
• Bony nonunion most commonly seen in inadequately treated mandible
fractures in maxillofacial region.
• Nonunion requires open surgical treatment, with removal of fibrous callous
and adequate fixation of fracture segments for stability. If defect between
fractures is large, a bone graft may be needed to help bridge the gap.
Complications in Bone healing
• Open fractures are at risk for infection
• One feared infection = osteomyelitis (infection of bone that extends
to medullary space)
• More common in mandible than in maxilla because of poorer vascular supply
• Commonly occurs as a result of chronic odontogenic infection that spreads
• Usually requires surgical debridement of involved area and chronic antibiotic
therapy
Normal Cartilage healing
• In the maxillofacial region, cartilage is found on the articular surfaces
of the TMJ and in the auricular and nasal cartilages.
• Cartilage repair is challenging because it has a limited intrinsic
capacity to repair due to low cellular density and minimal vascular
supply.
• Minimal vascular supply means poor inflammatory response after injury
• Large defects typically require autogenous grafting
• In areas where cartilage and bone are in direct contact (i..e articular
cartilage):
• If there is damage that extends down to bone → bleeding from bone will
initiate healing process → fibrous tissue will be laid down (won’t have same
structure/function as cartilage)
• If there is damage that doesn’t extend down to bone → no healing process
Normal Nerve Healing
Normal Nerve Healing
Seddon classification describes three types of nerve injury:
• Neuropraxia: Transient interruption in nerve conduction (“nerve bruise”).
Axonal continuity is preserved, nerve sheath preserved.
• Recovery is spontaneous, but may take weeks to months
• Axonotmesis: Individual axons are damaged within the nerve, entire nerve
sheath is preserved.
• Distal to injury there is Wallerian degeneration (degradation of distal axons with
concomitant loss of Schwann cells)
• As long as proximal nerve body survives, axonal regeneration may occur (but slowly)
• Neurotmesis: Complete transection of nerve (axon and entire nerve sheath
continuity is lost)
• Rarely recover spontaneously, requires surgical intervention
• Neuromas often form after injury as axons attempt to regenerate in a random fashion
Normal Nerve Healing
Sudderland classification encompasses 5 types of nerve injury:
• 1st degree = nerve conduction block
• 2nd degree = some nerve fibers are damaged without damage to
endoneurium
• 3rd degree = endoneurium involvement without perineurium damage
• 4th degree = perineural damage with intact epineurium
• 5th degree = complete transection injury

Surgical intervention is recommended for 4th and 5th degree injuries

Skin Grafting
• Skin grafts can be used to cover traumatic defects that cannot be
adequately repaired with primary closure or defects that are not
expected to close quickly.
• Full thickness vs. split thickness skin graft
• Full thickness = epidermis + entire dermis
• Split thickness = epidermis + variable thickness of partial dermis (thin 0.2-
.3mm, intermediate 0.3-.5mm, thick 0.5-.8mm)
• Full thickness and split thickness skin grafts have different properties
Skin Grafting
• Primary contraction = immediate reduction in size of skin graft
• Secondary contraction = due to wound bed contraction (reduces size of
graft at interface with recipient bed and circumference of the graft at its
periphery)
• Full thickness skin grafts undergo more primary contracture but less
secondary contracture. Therefore, these grafts are placed in areas in which
tissue contraction would otherwise cause a deformity (i.e. face)
• Split thickness grafts have less primary contracture but undergo more
secondary contracture than full thickness grafts.
• Thinner split-thickness grafts have better survival than thicker grafts
because the epithelium is in closer contact with the underlying graft bed
vasculature.
• Split thickness grafts are easier to harvest and much larger grafts can be
obtained.
Skin Grafting
• Skin graft initially adheres to graft bed by fibrin
• Days 0-3: skin graft survival is dependent upon the diffusion of
nutrients from the underlying graft bed capillaries.
• Neovascularization of graft occurs and capillaries of skin graft and
graft bed renastomose in a process known as inosculation
• Full thickness grafts are slower to revascularize than split-thickness grafts due
to the presence of a thicker dermal component
• Reinnervation follows as nerve fibers grow into the graft (takes 2mo
for return of skin sensation)
Factors in suboptimal wound healing
• Aging = poorer perfusion
• Diabetes = poorer perfusion
secondary to microvascular
disease & hyperglycemia
impairs neutrophil and
lymphocyte function
• Smoking = vasoconstrictor →
hypoperfusion
• Malnutrition → lack of
necessary vitamins/minerals
for proper wound healing (i.e.
Vitamin C, Zinc)
• Radiation: destroys cells,
suppresses bone marrow,
obliterate vessels, induce
fibrosis
Wound Management
• Properly debride and clean wound
• Debridement: removal of nonvital tissue, foreign bodies, and biofilm
• Debridement can be done surgically with sharp excision or hydrodynamically with
irrigation
• Type of wound closure is dependent on level of contamination of the
wound
• Clean or clean-contaminated wounds usually closed primarily
• Delayed primary closure recommended in wounds that require extensive
decontamination or debridement (clean first then close primarily)
• Large wounds with tissue loss or avulsion so that wound edges cannot be apposed
heal by secondary intention (very slow healing and notable scarring)
• If you are closing a wound primarily, should be tension free closure
Wound Management
• Dressings are used to maintain a moist environment that allows faster
reepithelialization
• Dressings also aid in delivery of topical agents
• Dressings can be used as a form of debridement with frequent
changes
• Moist dressings are preferred. Dry dressings are not recommended
because they allow tissues to desiccate easily and form dry scabs
Wound Management
• Many types of dressings: open (e.g. no dressing), semiopen,
occlusive, semiocclusive, and biologic
• Tegaderm is a semiocclusive dressing
• Skin grafts are biologic dressings
• “skin equivalents” are another form of biologic dressings. AlloDerm is an
example, and it can be used when patient has inadequate or insufficient skin
graft donor sites
Wound Management
• Negative-pressure
dressings apply
subatmospheric
pressure to a wound
• Promotes wound
healing by a pressure
gradient that allows
for fluid egression
from the wound and
by increasing blood
flow into the wound
Wound Management
• Topical agents can be beneficial as an adjunctive
• Can use antimicrobial topical agents
• Bacitracin zinc ointment has gram positive coverage
• Silver sulfadiazine has broad gram negative and gram positive coverage
Wound Management
• Use of recombinant growth factors are becoming increasingly
common practice for improving healing in chronic wounds
• Recombinant PDGF has been shown to reduce periodontal defects
(GEM 21 contains PDGF within an onsteoconductive matrix)
• Recombinant BMP2 has been used to regenerate mandibular defects
and to augment maxillary sinuses