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CHAPTER 14 Cellular Injury
281
Diseases of Increased Apoptosis
• HIV (CD4+ cells die through programmed cell death).
• Neurodegenerative diseases.
Diseases of Decreased Apoptosis
• Neoplasia.
• Autoimmune disease.
THE PROCESS OF HEALING
Regeneration and Repair
• Regeneration refers to total healing of a wound with restitution of the original tissues in their usual amounts,
arrangements and with normal function.
• Repair refers to the process where the original tissue is
not totally regenerated and the defect is made good to a
variable extent by scar tissue.
Cell Renewal
e regenerative capacity of cells varies. Cells can be classied according to their potential for renewal:
• Labile cells:
• good capacity for regeneration
• e.g. surface epithelial cells constantly being replaced
from deeper layers, e.g. skin, oesophagus, vagina.
• Stable cells:
• divide at slow rate under physiological conditions
• replaced by mitotic division of mature cells and lost
cells are rapidly replaced
• e.g. liver, renal tubular epithelium.
• Permanent cells:
• never divide in post-natal life
• cannot be replaced if lost
• e.g. nerve cells, striated muscle cells, myocardial cells.
Repair
Organization is the process whereby specialized tissues are
repaired by the formation of mature connective tissue, i.e.
brous scar. Organization occurs by:
• brinous exudate
• removal of brin and dead tissue and phagocytes
• migration of broblasts and capillaries forming granulation tissue
• replacement of exudate by vascularized brous tissue
• eventually a collagen-rich scar develops.
Granulation tissue
• A combination of capillary loops and myobroblasts.
• Capillary endothelial cells grow into the area to be
repaired.
• Fibroblasts are stimulated to divide.
• Fibroblasts secrete collagen and matrix components.
• Fibroblasts acquire muscle laments and attach to adjacent cells and become myobroblasts.
• Myobroblasts cause wound contraction.
• Granulation tissue appears red and granular: hence the
name.
• Excessive granulation tissue protruding above the
wound surface is called ‘proud esh’.
Clinical Problems with Organization and Wound
Contraction
Organization
• Fibrous adhesions in the peritoneum may cause intestinal obstruction.
• Obliteration of the pericardial space with scarring may
cause constrictive pericarditis.
Wound contraction
• Stenosis (narrowing at an orice), e.g. anal stenosis
aer haemorrhoidectomy, pyloric stenosis aer peptic
ulceration.
• Stricture (a narrowing in a tube), e.g. narrowing in the
colon aer ischaemic colitis.
• Scarring in a muscle causing a contracture.
• Contractures following burns, especially around
joints.
INJURIES TO SPECIFIC TISSUES
Skin
Healing depends upon the size of the defect. It depends
on whether it is an incised wound (surgical incision) or
whether there is tissue loss.
Skin Anatomy (Fig. 14.1)
• Skin is composed of epidermis and dermis.
• Beneath the dermis lie subcutaneous fat, fascia and
muscle.
• e blood supply to the skin arises from blood vessels
which perforate the muscle (perforator vessels) and
travel through the subcutaneous tissue to form the subdermal and dermal vascular plexus.
Incised Wound (Surgical Incision) – Healing by First
Intention
• Edges of incision apposed.
• Fibrin ‘sticks’ edges together.
• Capillaries bridge tiny gap.
• Fibroblasts invade brin network.
• Aer 10 days wound is strong and sutures can be
removed.
• Remodelling occurs from then on.
282
e
Segmental artery and perforatin
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SECTION III Pathology
Epidermis
Dermis
Dermal vascular plexus
Subcutaneous tissu
Muscle
Anterior fascia
Subdermal vascular plexus
branch through muscle
Fig. 14.1 The structure of skin with vascular plexus, fat, fascia and muscle.
Tissue Loss – Healing by Second Intention
• Tissue loss, e.g. trauma, or wound le open, e.g. grossly
g
• Does not extend beyond the wound itself.
• Usually settles spontaneously in up to 18 months.
infected wound.
• Phagocytes remove any debris.
• Formation of granulation tissue in base of wound.
• Myobroblasts cause wound contraction
• Centripetal growth of epithelium from wound edges
(re-epithelialization) to cover defect.
• Eventually tissue decit made good by scar tissue.
• Final cosmetic result depends on degree of tissue loss
and amount of scarring.
Anatomy of Repair of Defects
• Wherever possible, scars from any wound should be
placed in the lines of relaxed skin tension (Fig. 14.2),
which are seen in the older patient as wrinkle lines.
• ese lines lie perpendicular to the underlying muscle
contraction.
• ese are dierent to Langer's lines, which were anatomically derived using cadaver experiments and dier
slightly due to lack of mechanical forces.
Abnormalities of Skin Healing
Keloid
• Excessive broblast proliferation and collagen production.
• Particularly common in black Africans.
• Collagen deposition occurs beyond and above the
wound itself.
• Occurs aer surgery and injury, particularly burns.
• Covered by normal epithelium.
• Does not settle.
Hypertrophied scar
• Wound broad and raised.
Reconstructive Ladder (Fig. 14.3)
• When assessing any wound or defect, the principles of
the reconstructive ladder can be utilized.
• Employing the simplest options rst, the ladder outlines
dierent steps for closure of a wound or defect.
• e ladder can be ‘climbed’ as the complexity of the
reconstructive situation increases.
• More recently the concept of a ‘reconstructive elevator’
is employed, where the appropriate reconstruction is
selected for the specic defect or situation, which is not
Posterior fascia
Fig. 14.2 Lines of relaxed skin tension.
Free flap
Regional/pedicled flap
Local/random pattern flap
Full-thickness skin graft
Split-thickness skin graft
Delayed primary closure
Primary closure
Fig. 14.3 The reconstructive ladder.
CHAPTER 14 Cellular Injury
283
always the simplest option: e.g. a large area of exposed
bone without periosteum will need a ap of some sort.
Grafts
• Common option for closure of defects that cannot be
primarily closed.
• Commonly composed of skin, but may contain a variety
of tissue including:
• skin
• cartilage
• tendon
• bone
• or can be composite, using a combination of the above.
• Are not transferred with their own blood supply.
• Rely on the formation of a new vascular system at a new
site.
• Dierent types of gra include:
• autogra: own tissue; most common
• allogra, e.g. cadaver bone
• xenogra, e.g. animal tendon; rare.
Skin grafts
• A full-thickness skin gra consists of epidermis and the
whole of the dermis.
• A split-thickness skin gra consists of epidermis and a
variable thickness of dermis.
Mechanism of skin graft take
Skin gras take in a series of steps, which can be broken into:
• Adherence:
• brin bonds the gra to the recipient site
• occurs in <12 h.
• Plasmic imbibition:
• gra absorbs essential nutrients from recipient bed
• occurs at 24–48 h.
• Inosculation:
• revascularization of the gra via growth of vascular
buds
• occurs at 48–72 h.
Split-thickness skin grafts (Fig. 14.4)
• Common donor sites include:
• thigh
• buttocks.
• Result in more contraction at the recipient site.
• Can be meshed for large areas needing gras.
• Result in pale, square scar at healed donor site (takes
10–14 days).
• Usually ‘take’ well as are thinner, helping them survive
the imbibition phase.
Full-thickness skin grafts (Fig. 14.5)
• Common donor sites include:
• groin
• pre-/post-auricular areas
• supraclavicular region.
284
Thigh
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SECTION III Pathology
Buttock
Post-auricular
Fig. 14.4 Split-thickness skin graft donor sites.
• Result in less contraction at recipient site.
• Limited to relatively smaller areas due to direct closure
of donor site.
• Result in linear scar at donor site.
• Less reliable ‘take’ due to thicker nature.
Flaps
• Unit of tissue transferred with its own blood supply.
• Used for:
• large defects
• where a gra would produce a poorer cosmetic
result, e.g. face
• where the base of a defect could not support a gra,
i.e. bare bone, exposed tendon or poorly vascularized bed.
Classification
Can be classied in several ways:
• by composition: cutaneous, fasciocutaneous, myocutaneous, osteofasciocutaneous, etc. (Fig. 14.6)
• by vascular supply: random pattern, axial, island (Fig. 14.7)
• by location of donor site to defect: local, regional/pedicled, distant/free (Fig. 14.8)
• by design: transposition, Z-plasty, rotation, advancement (Fig. 14.9).
Pre-auricular
Supraclavicular
Groin
Fig. 14.5 Full-thickness skin graft donor sites.
CHAPTER 14 Cellular Injury
e
e
e
285
Fig. 14.6 Flaps by composition.
Epidermis
Dermis
Subcutaneous tissue
Fascia
Muscle
Bone
Cutaneous flap
Epidermis + dermis
Fasciocutaneous flap
Epidermis + dermis + subcutaneous tissu
+ fascia
Myocutaneous flap
Epidermis + dermis + subcutaneous tissu
+ fascia + muscle
Osteofasciocutaneous flap
Epidermis + dermis + subcutaneous tissu
+ fascia + muscle + bone
Local flaps
• Local aps are composed of tissue raised adjacent to the
defect to be covered.
• Can be a useful method of closing defects without tension or gras.
• Can be utilized for scar revision, by changing the length
or direction of a scar.
• is can be useful at cosmetically important sites, such
as the face.
Below are some general examples of random pattern
local ap options.
Transposition flap (Fig. 14.9A)
• A transposition ap can be of varying shape and is
moved laterally into an adjacent defect.
• e angle of movement can be varied, but must leave
signicant breadth at the base of the ap to ensure
vascularity.
• e transposition results in a secondary defect, which
can be primarily closed, but oen requires another
method of closure, such as a skin gra.
Rotation flap (Fig. 14.9B)
• A rotation ap is usually a semi-circular shaped ap,
which is rotated into the defect along the outer line of
the semi-circle.
• is oen necessitates a ‘back-cut’ to allow sucient movement, but as with all aps there must be signicant width
of tissue le at the base of the ap to ensure its survival.
• e rotation results in a secondary defect, which can
oen be primarily closed.
Advancement flap (Fig. 14.9C)
• An advancement ap moves tissue into a defect without
the use of lateral transposition or rotation.
• ey can be of varying shapes, some of which produce:
• a primary defect to be closed
• or excess tissue at the ap base which requires exci-
sion (Burow’s triangles)
• neither of the above aects the width of the ap base.
Z-plasty (Fig. 14.9D)
• A Z-plasty is composed of two interposing triangular
transposition aps.
286
d
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SECTION III Pathology
Random pattern flap: relies on dermal/subdermal plexus,
therefore has maximum length:width ratio of 2:1 for safety
Non-random axial pattern flap: based on specific artery
Non-random island flap: isolated on a vascular pedicle an
can be moved to another site
Fig. 14.7 Flaps by vascular supply.
• ese can be used to alter the direction of a scar or the
length of a scar contracture, depending upon the angles
within the triangles of the Z-plasty.
Free flaps (Fig. 14.10)
Free aps are used in a variety of reconstructive situations
including:
• Traumatic reconstruction:
• open fractures with so tissue loss
• injuries with severe degloving or tissue loss
• burn scar revision.
• Neoplastic/cosmetic reconstruction:
• post-cancer surgery, e.g. breast reconstruction, man-
dibular reconstruction
• tissue coverage post-debridement for necrotizing
infections.
• Functional reconstruction:
• facial or limb re-animation surgery using neurotized
aps.
• Below are some common aps used in the situations
described above.
Radial forearm flap
• Vascular supply from perforating vessels of the radial
ar tery.
• Based on the exor aspect of the forearm.
• Donor site can be directly closed, but for larger skin
requirements needs skin graing.
• Can be taken with a segment of radius: e.g. for mandibular reconstructions.
Anterolateral thigh flap
• Vascular supply from myocutaneous/septocutaneous
perforating vessels of the descending branch of the lateral circumex artery.
• Based on a line drawn from anterior superior iliac spine
to lateral patella.
• Donor site is directly closed.
• Can give large skin paddle.
Deep inferior epigastric perforator (DIEP)/transverse
rectus abdominis myocutaneous (TRAM) flap
• Vascular supply from myocutaneous perforating vessels
of the deep inferior epigastric artery.
Local:
flap
mobilise adjacent
tissue, e.g. rotation
flap
Regional/pedicled:
mobilise tissue
on its blood
supply, e.g.
gastrocnemius
muscle flap
CHAPTER 14 Cellular Injury
287
• DIEP ap dissects out perforating vessels to preserve
rectus muscle and function, in eort to reduce donor
site morbidity, i.e. hernias.
• TRAM aps take varying amount of muscle with the ap.
• Donor site is directly closed.
• Can give a large skin paddle with an acceptable abdominoplasty donor scar.
Bone
• Haematoma resulting from ruptured bone vessels and
periosteal vessels forms between the ends of the fracture.
• Macrophages invade the haematoma together with polymorphs and broblasts; new vessels form, brosis occurs
and by the end of the rst week the clot is organized.
• Osteoblasts grow into the haematoma and form trabeculae of woven bone.
• e new bone (sometimes with islands of cartilage
formed by chondroblasts) is called callus.
• Internal callus lies within the medullary cavity.
• External callus is related to the periosteum and envelops
the fracture site, acting as a ‘splint’.
• By 2–3 weeks the repair tissue reaches its maximum girth
in long bone, but is still too weak to support weight.
• Woven bone is subsequently replaced by lamellar bone.
• Remodelling takes place according to the direction of
mechanical stress.
• Restoration to normal may take up to 1 year.
Factors Affecting Bone Healing
• Movement.
• Misalignment.
• Interposition of so tissues.
• Infection.
• Pre-existing bone disease.
Fig. 14.8 Flaps by location.
Distant/free:
free tissue transfer
using microvascular
surgery, e.g. ALT
Liver
• Hepatocytes have excellent regenerative capacity.
• Following surgical resection of areas of the liver for
trauma, regeneration is rapid and full recovery of the
organ’s mass occurs and the architecture is maintained.
• When the injurious agent persists – e.g. viral damage,
alcohol abuse, autoimmune disease – brosis occurs,
cirrhosis develops and the architecture is lost.
• Damage that destroys hepatocytes only may be followed
by complete restitution.
• Damage that destroys hepatocytes and the architecture
may not be followed by complete restitution.
Kidney
• Epithelium can regenerate.
• Architecture cannot regenerate.
288
Pivot flaps (A and B)
allow advancement
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SECTION III Pathology
Transposition flap
A
Advancement flap
C
Broken lines show ‘Burow’s triangles’
which may need to be excised to
B
D
Rotation flap
Z-plasty
A
B
B
A
Fig. 14.9 Local flaps by design. Pivot flaps: (A) transposition flap and (B) rotation flap (these flaps are termed
pivot flaps as they move around a pivot point). (C) Advancement flap. (D) Z-plasty.
• Loss of tubular epithelium, e.g. ischaemia, toxins, will
recover provided enough normal epithelial cells are le
to regenerate.
• Loss of glomeruli (glomerulonephritis) is likely to be
permanent.
• Perivascular connective tissue cells in the base of the
defect grow towards the surface and dierentiate into
new mesothelial cells.
• Centripetal growth from the wound margins contributes little to mesothelial healing.
• Healing of the unsutured peritoneum is rapid and com-
Cardiac Muscle
• Permanent cells and therefore no regeneration.
• Damaged muscle replaced by scar tissue.
• Important in myocardial infarction
• May result in ventricular aneurysm due to weakening of
wall.
plete, irrespective of the size of the defect, and occurs
with little risk of adhesion formation.
Gastrointestinal Tract
Mucosal Erosions
An erosion is loss of part of the thickness of the mucosa.
• Erosions regenerate rapidly from adjacent viable epithe-
Neural Tissue
• Permanent cells; regeneration does not occur in the central nervous system.
• Peripheral nerves undergo Wallerian degeneration distal to the site of trauma. Recovery is variable depending
upon alignment and continuity.
lial cells.
• Erosions can repair in a matter of a few hours if the
cause is removed.
• Erosions can cause signicant gastrointestinal (GI)
bleeds but escape detection by endoscopy a few hours
later as rapid healing has occurred.
Mucosal Ulcers
Peritoneum
• Sutured peritoneum may result in local ischaemia,
which acts as a stimulus to adhesion formation, especially if contaminated with foreign material.
• A clean unsutured defect, no matter how large, will usually heal without adhesions.
• Loss of full thickness of the mucosa.
• Repaired by granulation tissue in base and centripetal
growth of surface epithelium.
• If cause persists, the ulcer may become chronic with
considerable brous scarring, e.g. pyloric stenosis with
chronic duodenal ulceration.
Free radial forearm
branches of the deep
paddle
flap—branches of
radial artery and
skin paddle
Anterolateral thigh
flap—branches of
lateral femoral
circumflex artery and
skin paddle
DIEP/TRAM flap—
inferior epigastric
artery and skin
Fig. 14.10 Free flaps.
Gastrointestinal Anastomoses
• Healing better in upper GI tract; stomach and small
bowel heal better than colon.
• Very dependent upon blood supply.
CHAPTER 14 Cellular Injury
289
• Interrupted sutures with suturing of only the sero-muscular layers prevent ischaemia of the mucosa and allow
good mucosal healing.
Factors Affecting Wound Healing
Local
• Inadequate blood supply.
• Haematoma.
• Infection.
• Early movement (especially delayed fracture healing).
• Foreign material, e.g. sutures, extraneous foreign bodies.
• Irradiation.
• Denervation, e.g. peripheral neuropathy (diabetes, neuropathic ulcers).
• Leprosy.
• Charcot’s joints (joint does not repair).
Systemic
• Nutritional problems, e.g. malnutrition, vitamin C deciency (required for collagen synthesis), zinc deciency.
• Drugs, e.g. steroids, immunosuppressive drugs, cytotoxic agents.
• Neoplasia.
• Diabetes mellitus: aects polymorph function, microvascular disease, neuropathy.
• Age: younger patients heal better than older patients.
• Jaundice.
• Uraemia.
INJURY DUE TO IONIZING RADIATION
Biological response to irradiation depends on:
• physical factors, i.e. dose, character, time of exposure
• chemical factors, e.g. substrates for generation of free
radicals
• biological factors, i.e. phase of cell cycle at time of exposure.
Individuals may be exposed to irradiation in several ways:
• Background:
• natural sources:
• cosmic
• terrestrial
• airborne
• food sources
• articial sources
• diagnostic X-rays
• nuclear power industry.
• Accidental:
• Chernobyl disaster.
• Occupational:
• radiologists
• mining of uranium.
• Medical:
• diagnostic tests.
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SECTION III Pathology
Mode of Action
Following the passage of ionizing radiation through tissues,
several types of free radicals are formed from water in the
cells. Short-lived and highly reactive free radicals (e.g. H•
and OH•) are formed. In well-oxygenated cells, oxygen free
radicals (e.g. HO
cals interact with macromolecules (e.g. membrane lipids
•
and O
2
•−
) are also formed. ese radi-
2
and DNA) and cause damage.
e types of radiation-induced DNA damage include:
• strand breaks
• base alterations
• cross-linking.
e resulting DNA damage may have three possible
consequences:
• cell death, either immediately or at the next attempted
mitosis
• repair and no further damage
• a permanent change in genotype.
e outcome will depend upon the dose given and the
radiosensitivity of the cell. Rapidly dividing cell populations are the most sensitive.
Effects on Tissues
ese may be acute or chronic.
• Acute:
• result in cell death
• most marked in cells that are dividing rapidly, e.g.
gut epithelium, bone marrow, skin, gonads
• vascular endothelial damage results in uid and pro-
tein leakage into the tissue, causing inammation.
• Chronic:
• damage to endothelium results in exposure of under-
lying collagen with platelet adherence and thrombosis
• results in intimal proliferation and development of
endarteritis obliterans
• this results in long-term vascular insuciency and
consequent atrophy and brosis
• radiation-induced mutation of the genome increases
risks of neoplasia.
Effect on Individual Tissues
Bone Marrow
• Suspends renewal of all cell lines.
• Granulocytes are reduced before erythrocytes, which
survive longer.
• Outcome depends on dose used.
• Varies from complete recovery to aplastic anaemia.
• Increased incidence of leukaemia in long-term survivors.
Skin
• Cessation of mitosis in epidermis with desquamation
and hair loss.
• Regrowth will occur if enough basal stem cells survive.
• Damage to melanocytes results in melanin release into
tissues, where it is ingested by phagocytes, which remain
in the tissue, resulting in hyperpigmentation.
• Destruction of dermal broblasts results in inability
to produce collagen, and therefore thinning of the
dermis.
• Damage to small vessels results in thinning of the
wall, dilatation and tortuosity, and the formation of
telangiectasia.
Intestines
• Loss of surface epithelium results in diarrhoea.
• Damage of full thickness with brosis will result in stricture formation.
Gonads
• Extremely radiosensitive.
• Sterility may result with low doses.
• Mutations may occur in germ cells, with resultant teratogenic eect.
Lung
• Progressive pulmonary brosis may occur.
• Inhaled radioactive materials may induce pulmonary
tumours.
Kidney
• Gradual loss of parenchyma results in impaired renal
function.
• Endarteritis obliterans of small vessels will cause intrarenal renal artery stenosis and hypertension.
Whole-Body Irradiation
• As the dose increases, so does the severity and rapidity
of the onset of the eects.
• Total body irradiation may be used therapeutically to
ablate the bone marrow prior to marrow transplantation
with either autologous stored marrow or from another
donor.
• A very high dose results in CNS damage, with coma
and convulsions occurring within hours. As the dose
reduces, gut damage occurs within a few days; with further reduction, marrow failure can occur in weeks; and
at low doses there are no immediate eects, although
there is a long-term risk of neoplasia.
Ultraviolet Light
• Non-ionizing radiation does not penetrate deeply.
• Has a range of wavelengths.
• May act by inducing thymine dimers in DNA, nondimer damage, or inhibiting DNA repair processes.
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