4

Wound Repair
JA ME S R . HUP P

CHAPTER OUTLINE
crushing, extremes of temperature or irradiation, desiccation, and
Causes of Tissue Damage, 44 obstruction of arterial inflow or venous outflow. Chemicals able
Wound Repair, 44 to cause injury include those with unphysiologic pH or tonicity,
Epithelialization, 44 those that disrupt protein integrity, and those that cause ischemia
Stages of Wound Healing, 45 by producing vascular constriction or thrombosis.
Inflammatory Stage, 45
Fibroplastic Stage, 46 Wound Repair
Remodeling Stage, 46
Surgical Significance of Wound-Healing Concepts, 47 Epithelialization
Factors That Impair Wound Healing, 47 Injured epithelium has a genetically programmed regenerative
Foreign Material, 47 ability that allows it to reestablish its integrity through prolif-
Necrotic Tissue, 47 eration, migration, and a process known as contact inhibition. In
Ischemia, 48 general, any edge of normal epithelium will begin and continue to
Tension, 48 migrate (by proliferation of germinal epithelial cells that advance
Healing by Primary, Secondary, and Tertiary Intention, 48 the free edge forward) until it comes into contact with another
Healing of Extraction Sockets, 48 free edge of epithelium, where it is signaled to stop growing later-
Bone Healing, 48 ally. Note that the other epithelium can be a different type of
Implant Osseointegration, 49 epithelium.
Facial Neuropathology of Traumatic Origin, 52 Although it is theorized that chemical mediators (released from
Nerve Healing, 52 epithelial cells that have lost contact with other epithelial cells
Classification, 53 circumferentially) regulate this process, no definitive evidence for
this is yet available. Wounds in which only the surface epithelium
is injured (i.e., abrasions) heal by proliferation of epithelium across
the wound bed from the epithelium contained in rete pegs and
adnexal tissues. Because epithelium does not normally contain
blood vessels, the epithelium in wounds in which the subepithelial
tissue is also damaged proliferates across whatever vascularized
tissue bed is available and stays under the portion of the superficial

A
n important aspect of any surgical procedure is the prepara- blood clot that desiccates (i.e., forms a scab) until it reaches another
tion of the wound for proper healing. A thorough under- epithelial margin. Once the wound is fully epithelialized, the scab
standing of the biology of normal tissue repair is therefore loosens and eventually dislodges.
valuable for individuals intending to perform surgery. An example of the sometimes detrimental effect of the process
Tissue injury can be caused by pathologic conditions or by of contact inhibition controlling epithelialization occurs when an
traumatic events. The dental surgeon has some control over opening is accidentally made into a maxillary sinus during tooth
pathologic tissue damage such as the likelihood of a wound infection. extraction (see Chapter 11). If the epithelium of both the sinus
In addition, the surgeon can favorably or unfavorably alter the wall and the oral mucosa is injured, it begins to proliferate in both
amount and severity of traumatically induced tissue injury and areas. In this case, the first free epithelial edge the sinus epithelium
thus contribute to promoting or impeding wound healing. may contact is oral mucosa, thereby creating an oroantral fistula
This chapter discusses the ways in which perioperative tissue (i.e., an epithelialized tract between the oral cavity and the maxillary
injury occurs and the events normally occurring during the healing sinus).
of soft and hard tissues. The process of reepithelialization (i.e., secondary epithelialization)
is sometimes used therapeutically by oral-maxillofacial surgeons
Causes of Tissue Damage during certain preprosthetic surgical procedures in which an area
of oral mucosa is denuded of epithelium (i.e., unattached gingiva)
Traumatic injuries can be caused by physical or chemical insults (Box and then left to epithelialize by adjacent epithelium (i.e., attached
4.1). Physical means of producing tissue damage include incision or gingiva) creeping over the wound bed.

44
 CHAPTER 4 Wound Repair 45

Stages of Wound Healing process has been divided into basic stages that, although not
mutually exclusive, take place in this sequence. These three basic
Regardless of the cause of nonepithelial tissue injury, a stereotypical stages are (1) inflammatory, (2) fibroplastic, and (3) remodeling.
process is initiated and, if able to proceed unimpeded, works to
restore tissue integrity. This process is called wound healing. The Inflammatory Stage
The inflammatory stage begins the moment tissue injury occurs
and, in the absence of factors that prolong inflammation, lasts 3
BOX 4.1 Causes of Tissue Damage to 5 days. The inflammatory stage has two phases: (1) vascular
and (2) cellular. The vascular events set in motion during inflam-
Physical mation begin with an initial vasoconstriction of disrupted vessels
as a result of normal vascular tone. The vasoconstriction slows
blood flow into the area of injury, promoting blood coagulation.
Within minutes, histamine and prostaglandins E1 and E2, elaborated
by white blood cells, cause vasodilation and open small spaces
between endothelial cells, which allows plasma to leak and leukocytes
to migrate into interstitial tissues. Fibrin from the transudated
plasma causes lymphatic obstruction, and the transudated plasma—
Chemical aided by obstructed lymphatic vessels—accumulates in the area
of injury, functioning to dilute contaminants. This fluid collection
is called edema (Fig. 4.1).
The cardinal signs of inflammation are redness (i.e., erythema)
and swelling (i.e., edema), with warmth and pain—rubor et tumour
cum calore et dolore (Celsius, 30 BC – AD 38)—and loss of
function—functio laesa (Virchow, 1821–1902). Warmth and

Pericyte

Basement membrane

Endothelial cell

Marginating polymorphonuclear leukocyte

Platelets
A
Histamine

Mast cell

Complement fractions

Prostaglandins

Open gaps between endothelial cells

Polymorphonuclear leukocytes
migrate through gaps into
interstitial space (diapedesis)

B
Fig. 4.1 Early vascular responses to injury. Initial transient vasoconstriction (A) is soon followed by
vasodilation (B). Vasodilation is caused by the actions of histamine, prostaglandins, and other vasodilatory
substances. Dilation causes intercellular gaps to occur, which allows egress of plasma and emigration of
leukocytes. (Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)
46 PA RT I Principles of Surgery

erythema are caused by vasodilation; swelling is caused by transuda- also secrete fibronectin, a protein that performs several functions.
tion of fluid; and pain and loss of function are caused by histamine, Fibronectin helps stabilize fibrin, assists in recognizing foreign
kinins, and prostaglandins released by leukocytes, as well as by material that should be removed by the immune system, acts
pressure from edema. as a chemotactic factor for fibroblasts, and helps guide macro-
The cellular phase of inflammation is triggered by the activation phages along fibrin strands for eventual phagocytosis of fibrin by
of serum complement by tissue trauma. Complement-split products, macrophages.
particularly C3a and C5a, act as chemotactic factors and cause The fibrin network is also used by new capillaries, which bud
polymorphonuclear leukocytes (neutrophils) to stick to the side from existing vessels along the margins of the wound and run
of blood vessels (margination) and then migrate through the vessel along fibrin strands to cross the wound. As fibroplasia continues,
walls (diapedesis). Once in contact with foreign materials (e.g., with increasing ingrowth of new cells, fibrinolysis occurs, which
bacteria), the neutrophils release the contents of their lysosomes is caused by plasmin brought in by the new capillaries to remove
(degranulation). The lysosomal enzymes (consisting primarily of the fibrin strands that have become superfluous (Fig. 4.3).
proteases) work to destroy bacteria and other foreign materials Fibroblasts deposit tropocollagen, which undergoes cross-linking
and to digest necrotic tissue. Clearance of debris is also aided by to produce collagen. Initially, collagen is produced in excessive
monocytes such as macrophages, which phagocytize foreign and amounts and is laid down in a haphazard manner. The poor orienta-
necrotic materials. With time, lymphocytes accumulate at the site tion of fibers decreases the effectiveness of a given amount of
of tissue injury. collagen to produce wound strength, so an overabundance of
The inflammatory stage is sometimes referred to as the lag collagen is necessary to strengthen the healing wound early on.
phase, because this is the period during which no significant gain Despite the poor organization of collagen, wound strength rapidly
in wound strength occurs (because little collagen deposition is increases during the fibroplastic stage, which normally lasts 2 to
taking place). The principal material holding a wound together 3 weeks. If a wound is placed under tension at the beginning of
during the inflammatory stage is fibrin, which possesses little tensile fibroplasia, it tends to pull apart along the initial line of injury.
strength (Fig. 4.2). However, if the wound were to be placed under tension near the
end of fibroplasia, it would open along the junction between old
Fibroplastic Stage collagen previously on the edges of the wound and newly deposited
The strands of fibrin, which are derived from blood coagulation, collagen. Clinically, the wound at the end of the fibroplastic stage
crisscross wounds forming a latticework on which fibroblasts begin will be stiff because of an excessive amount of collagen, erythematous
laying down ground substance and tropocollagen. This is the because of the high degree of vascularization, and able to withstand
fibroplastic stage of wound repair. The ground substance consists 70% to 80% as much tension as uninjured tissue (Fig. 4.4).
of several mucopolysaccharides, which act to cement collagen
fibers together. The fibroblasts transform local and circulating Remodeling Stage
pluripotential mesenchymal cells that begin tropocollagen produc- The final stage of wound repair, which continues indefinitely, is
tion on the third or fourth day after tissue injury. Fibroblasts known as the remodeling stage, although some use the term wound

Scab

Blood clot

Epidermis
Epidermis

Basal epithelial cells Epithelial cells migrating

migrating along cut under scab
edge of dermis
Collagen bundles in dermis Fibroblast migrating
along fibrin strand
Fibroblasts

Leukocytes Collagen bundles

Leukocyte
Leaking capillary
Capillary
Cut capillary
Endothelial buds

Capillary
Fig. 4.2 Inflammatory (lag) stage of wound repair. Wound fills with clotted Fig. 4.3 Migratory phase of fibroplastic stage of wound repair. Continued
blood, inflammatory cells, and plasma. Adjacent epithelium begins to epithelial migration occurs, leukocytes dispose of foreign and necrotic
migrate into wound, and undifferentiated mesenchymal cells begin to materials, capillary ingrowth begins, and fibroblasts migrate into wound
transform into fibroblasts. (Netter illustration from www.netterimages.com. along fibrin strands. (Netter illustration from www.netterimages.com. ©
© Elsevier Inc. All rights reserved.) Elsevier Inc. All rights reserved.)
 CHAPTER 4 Wound Repair 47

Scab sloughs, leaving

depressed scar

Epidermis regains normal

stratification over wound

Proliferation of epithelial Epithelial cell ("nest")

cells under scab trapped in wound

Collagen remodels into pattern

Fibroblast
more able to resist tension

Fibroblast

Capillary
Restored vascular integrity
Capillary budding continues

Fig. 4.5 Remodeling stage of wound repair. Epithelial stratification is

Fig. 4.4 Proliferative phase of fibroplastic stage of wound repair. Prolif- restored, collagen is remodeled into more efficiently organized patterns,
eration increases epithelial thickness, collagen fibers are haphazardly laid fibroblasts slowly disappear, and vascular integrity is reestablished. (Netter
down by fibroblasts, and budding capillaries begin to establish contact illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)
with their counterparts from other sites in wound. (Netter illustration from
www.netterimages.com. © Elsevier Inc. All rights reserved.)
Surgical Significance of
Wound-Healing Concepts
The surgeon can create conditions that augment or impede the
natural wound repair process. Adherence to surgical principles (see
maturation. During this stage, many of the previous randomly laid Chapter 3) facilitates optimal wound healing, with reestablishment
collagen fibers are removed as they are replaced by new collagen of tissue continuity, minimization of scar size, and restoration of
fibers, which are oriented to better resist tensile forces on the function. One should remember that no wound in skin, oral mucosa,
wound. In addition, wound strength increases slowly but not with or muscle heals without scar formation. The surgeon’s goal with
the same magnitude of increase seen during the fibroplastic stage. respect to scar formation is not to prevent a scar but rather to
Wound strength never reaches more than 80% to 85% of the produce a scar that minimizes any compromise of function and
strength of uninjured tissue. Because of the more efficient orientation looks as inconspicuous as possible.
of the collagen fibers, fewer of them are necessary; the excess is
removed, which allows the scar to soften. As wound metabolism Factors That Impair Wound Healing
lessens, vascularity is decreased, which diminishes wound erythema.
Elastin found in normal skin and ligaments is not replaced during Four factors can impair wound healing in an otherwise healthy
wound healing, so injuries in those tissues cause a loss of flexibility individual: (1) foreign material, (2) necrotic tissue, (3) ischemia,
along the scarred area (Fig. 4.5). and (4) wound tension.
A final process, which begins near the end of fibroplasia and
continues during the early portion of remodeling, is wound contrac- Foreign Material
tion. In most cases, wound contraction plays a beneficial role in Foreign material is everything the host organism’s immune system
wound repair, although the exact mechanism that contracts a wound views as “non-self,” including bacteria, dirt, and suture material.
is still unclear. During wound contraction, the edges of a wound Foreign materials cause three basic problems. First, bacteria can
migrate toward each other. In a wound in which the edges are not proliferate and cause an infection in which released bacterial proteins
or will not be placed in apposition, wound contraction diminishes destroy host tissue. Second, nonbacterial foreign material acts as
the size of the wound. However, contraction can cause problems a haven for bacteria by sheltering them from host defenses and
such as those seen in victims of third-degree (full-thickness) burns thus promoting infection. Third, foreign material is often antigenic
of the skin, who develop deforming and debilitating contractures and can stimulate a chronic inflammatory reaction that decreases
if wounds are not covered with skin grafts and aggressive physical fibroplasia.
therapy is not performed. Another example of detrimental contrac-
tion is seen in individuals suffering sharply curved lacerations, Necrotic Tissue
who frequently are left with a mound of tissue on the concave Necrotic tissue in a wound causes two problems. The first is that its
side of the scar because of wound contraction, even when the presence serves as a barrier to the ingrowth of reparative cells. The
edges are well readapted. Contraction can be lessened by placement inflammatory stage is then prolonged while white blood cells work
of a layer of epithelium between the free edges of a wound. Surgeons to remove the necrotic debris through the processes of enzymatic
make use of this phenomenon when they place skin grafts on the lysis and phagocytosis. The second problem is that, similar to
bared periosteum during a vestibuloplasty or on full-thickness foreign material, necrotic tissue serves as a protected niche for
burn wounds. bacteria. Necrotic tissue frequently includes blood that collects in
48 PA RT I Principles of Surgery

a wound (hematoma), where it can serve as an excellent nutrient Healing of Extraction Sockets
source for bacteria.
The removal of a tooth initiates the same sequence of inflammation,
Ischemia epithelialization, fibroplasia, and remodeling seen in prototypic
Decreased blood supply to a wound interferes with wound repair skin or mucosal wounds. As previously mentioned, sockets heal
in several ways. Decreased blood supply can lead to further tissue by secondary intention, and many months must pass before a
necrosis and can lessen the delivery to a wound of antibodies, white socket heals to the degree to which it becomes difficult to distinguish
blood cells, and antibiotics, which thereby increases the chances of from the surrounding bone when viewed radiographically.
wound infection. Wound ischemia decreases the delivery of oxygen When a tooth is removed, the remaining empty socket consists
and the nutrients necessary for proper healing. Ischemia can be of cortical bone (the radiographic lamina dura) covered by torn
caused by several things, including tight or incorrectly located sutures, periodontal ligaments, with a rim of oral epithelium (gingiva) left
improperly designed flaps, excessive external pressure on a wound, at the coronal portion. The socket fills with blood, which coagulates
internal pressure on a wound (seen, such as with hematomas), and seals the socket from the oral environment.
systemic hypotension, peripheral vascular disease, and anemia. The inflammatory stage occurs during the first week of healing.
White blood cells enter the socket to remove contaminating bacteria
Tension from the area and begin to break down any debris such as bone
Tension on a wound is the final factor that can impede wound fragments that are left in the socket. Fibroplasia also begins during
healing. Tension in this case is anything tending to hold wound the first week, with the ingrowth of fibroblasts and capillaries. The
edges apart. If sutures are used to pull tissues together forcefully, epithelium migrates down the socket wall until it reaches a level at
the fine blood vessels in the tissue encompassed by the sutures which it contacts epithelium from the other side of the socket or
will be constricted, producing ischemia. If sutures are removed it encounters the bed of granulation tissue (i.e., tissue filled with
too early in the healing process, the wound under tension will numerous immature capillaries and fibroblasts) under the blood
probably reopen and then heal with excessive scar formation and clot over which the epithelium can migrate. Finally, during the
wound contraction. If sutures are left in too long in an attempt first week of healing, osteoclasts accumulate along the crestal bone.
to overcome wound tension, the wound will still tend to spread The second week is marked by the large amount of granulation
open during the remodeling stage of healing, and the tract into tissue that fills the socket. Osteoid deposition has begun along the
the epithelium through which the sutures ran will epithelialize, alveolar bone lining the socket. In smaller sockets, the epithelium
leaving permanent, disfiguring marks. may have become fully intact by this point.
The processes begun during the second week continue during
Healing by Primary, Secondary, the third and fourth weeks of healing, with epithelialization of most
sockets complete at this time. The cortical bone continues to be
and Tertiary Intention resorbed from the crest and walls of the socket, and new trabecular
Clinicians use the terms primary intention and secondary intention bone is laid down across the socket. Not until 4 to 6 months after
to describe the two basic methods of wound healing. In healing extraction is the cortical bone lining a socket usually fully resorbed;
by primary intention, the edges of a wound in which there is this is recognized radiographically by a loss of a distinct lamina
no tissue loss are placed and stabilized in essentially the same dura. As bone fills the socket, the epithelium moves toward the
anatomic position they held before injury and are allowed to heal. crest and eventually becomes level with adjacent crestal gingiva.
Wound repair then occurs with minimal scar tissue because the The only visible remnant of the socket after 1 year is the rim of
tissues would not “perceive” that an injury had occurred. Strictly fibrous (scar) tissue that remains on the edentulous alveolar ridge.
speaking, healing by primary intention is only a theoretical ideal,
impossible to attain clinically; however, the term is generally used
to designate wounds in which the edges are closely reapproximated.
Bone Healing
This method of wound repair lessens the amount of reepithelializa- The events that occur during normal wound healing of soft tissue
tion, collagen deposition, contraction, and remodeling needed for injuries (e.g., inflammation, fibroplasia, and remodeling) also take
healing. Therefore healing occurs more rapidly, with a lower risk place during the repair of an injured bone. However, in contrast
of infection, and with less scar formation than in wounds allowed to soft tissues, osteoblasts and osteoclasts are also involved to
to heal by secondary intention. Examples of wounds that heal by reconstitute and remodel the damaged ossified tissue.
primary intention include well-repaired lacerations or incisions Osteogenic cells (osteoblasts) important to bone healing are
and well-reduced bone fractures. In contrast, healing by secondary derived from the following three sources: (1) periosteum, (2)
intention implies that a gap is left between the edges of an incision endosteum, and (3) circulating pluripotential mesenchymal cells.
or laceration or between bone or nerve ends after repair, or it Osteoclasts, derived from monocyte precursor cells, function to
implies that tissue loss has occurred in a wound that prevents resorb necrotic bone and bone that needs to be remodeled.
approximation of wound edges. These situations require a large Osteoblasts then lay down osteoid, which, if immobile during
amount of epithelial migration, collagen deposition, contraction, healing, usually goes on to calcify.
and remodeling during healing. Healing is slower and produces The terms primary intention and secondary intention are appropri-
more scar tissue than is the case with healing by primary intention. ate for descriptions of bone repair. If a bone is fractured* and the
Examples of wounds that heal by secondary intention include free ends of the bone are more than 1 mm or so apart, the bone
extraction sockets, poorly reduced fractures, deep ulcers, and large
avulsive injuries of any soft tissue.
Some surgeons use the term tertiary intention to refer to the *The term fracture used with respect to bone repair includes not only traumati-
healing of wounds through the use of tissue grafts to cover large cally injured bone, but also bone cuts purposely made by a surgeon during
wounds and bridge the gap between wound edges. reconstructive surgery.
 CHAPTER 4 Wound Repair 49

heals by secondary intention; that is, during the fibroplastic stage bony fracture site requires a high degree of vascularity (which
of healing, a large amount of collagen must be laid down to bridge carries blood with a normal oxygen content) for eventual ossification.
the bony gap (Fig. 4.6). The fibroblasts and osteoblasts actually If vascularity or oxygen supplies are sufficiently compromised,
produce so much fibrous matrix that the healing tissue extends cartilage, instead of bone, forms. Furthermore, if vascularity or
circumferentially beyond the free ends of the bone and forms what oxygen supplies are poor, the fibrous tissue does not chondrify or
is called a callus (Fig. 4.7). Under normal conditions, the fibrous ossify.
tissue, including the callus, ossifies. During the remodeling stage, Placing bone under continuous or repeated cycles of some tension
bone that was haphazardly produced is resorbed by osteoclasts, stimulates continued osteoblastic bone formation. Bone is formed
and osteoblasts lay down new bone directed to resist low-grade perpendicular to lines of tension to help withstand the forces
tensions placed on the bone (Fig. 4.8). placed on it. This is the basis of the functional matrix concept of
Healing of bone by primary intention occurs when the bone bone remodeling. However, excessive tension or torque placed on
is incompletely fractured so that the fractured ends do not become a healing fracture site produces mobility at the site. This mobility
separated from each other (“greenstick fracture”) or when a surgeon compromises vascularity of the wound and favors the formation
closely reapproximates and rigidly stabilizes the fractured ends of of cartilage or fibrous tissue, rather than bone along the fracture
a bone (anatomic reduction of the fracture). In both of these situ- line; in a contaminated fracture, it promotes wound infection (see
ations, little fibrous tissue is produced, and reossification of the Fig. 4.8).
tissue within the fracture area occurs quickly, with minimal callus
formation. The surgical technique that comes closest to allowing
bone to heal by primary intention is anatomic reduction of the
Implant Osseointegration
application of bone plates that rigidly hold the ends of the bone The discovery of osseointegration in the 1960s forced a reexamina-
together. This minimizes the distance between the ends of a fractured tion of traditional concepts of wound healing. Before acceptance
bone so that ossification across the fracture gap can occur with of these findings it was thought that the body would eventually
little intervening fibrous tissue formation. expel any foreign material placed through an epithelial surface.
Two factors are important to proper bone healing: (1) vascularity Expulsion would occur as the epithelium bordering the foreign
and (2) immobility. The fibrous connective tissue that forms in a material migrated down along the interface with the foreign material,

Disrupted periosteum
Clot in fracture defect
Periosteum

Osteogenic cells of periosteum

Haversian canal and vessel

Lacunae in compact bond

Osteogenic cell of endosteum

Marrow cavity

Fat droplets of marrow

Section
(magnified above)

Bone fracture

Fig. 4.6 Early phase of fibroplastic stage of bone repair. Osteogenic cells from periosteum and marrow
proliferate and differentiate into osteoblasts, osteoclasts, and chondroblasts, and capillary budding begins.
(Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)