Review

The effects of drugs on wound healing: part 1

Sree R. K. Karukonda, MD, PhD, Timothy Corcoran Flynn, MD, Erin E. Boh, MD, PhD,
Elizabeth I. McBurney, MD, Glenn G. Russo, MD, and Larry E. Millikan, MD

From the Department of Dermatology, Tulane University School of

Medicine, New Orleans, Louisiana
Correspondence
Timothy Corcoran Flynn, MD, Tulane University School of Medicine,
Department of Dermatology, 1430 Tulane Avenue TB36, New Orleans,
LA 70112

An understanding of basic wound healing physiology is

important when discussing the effects of drugs on wound
healing. Major advances have occurred within the eld of
wound healing in the last 20 years.18 In Part 1 of ``The effects
of drugs on wound healing'', the phases of wound healing are
discussed, the importance of local factors are outlined, and
the effects of pharmacologic agents on specic phases of
wound healing are presented. Part 2 details specic classes of
drugs and their impact on the healing wound.
Wound healing involves ve phases. These sequential
phases are termed: injury, coagulation, inammation,
tissue formation, and tissue remodeling.914 Each phase
lasts a specic length of time and has characteristic cellular
elements and extracellular agents, as well as cytokines and
growth factors which act as signals, suppressors, and
promoters. Figure 1 shows the wound healing cascade and
documents the phases. Table 1 details the cellular and
extracellular elements involved.
Phases of wound healing

250

The rst phase of wound healing is injury. A variety of

agents, such as surgery, trauma, infection, drugs, and the
immune system, can injure tissue. The injured cells release
soluble cellular products termed cytokines. Cytokines are
polypeptides allowing for communication between cells,
causing major changes in cell behavior.16 Platelet-derived
growth factor (PDGF), transforming growth factor-beta
(TGF-b), and transforming growth factor-alpha (TGF-a)
are cytokines released in injured cells. These cellular factors
initiate events that lead to subsequent phases of wound
healing. Table 2 lists the effects of these cytokines and
growth factors in wound healing. Normal wound healing
necessitates prompt removal or arrest of the injurious
agent.
International Journal of Dermatology 2000, 39, 250257

The second wound healing phase is coagulation and

occurs immediately after injury. Platelets agglutinate at the
site of injury and a brin clot forms via the activation of the
coagulation cascade. Thrombin induces platelet degranulation, leading to the release of growth factors PDGF, TGFb, epidermal growth factor (EGF), and TGF-a, as well as
adhesive glycoproteins such as bronectin. In addition to
providing hemostasis, the brin clot acts as a matrix for
colonization by inammatory cells which are attracted to
the wound site via chemotaxis from PDGF and TGF-a.
Inammation, the third phase of wound healing, occurs
15 days after injury. Migrating inammatory cells
accumulate in the healing wound with neutrophils predominating in the early hours of inammation. Neutrophils help decontaminate the wound through phagocytosis
of bacteria and foreign bodies.13 By the third day,
macrophages outnumber neutrophils (Table 1).
Macrophages are the most important inammatory cell
in wound healing.13,17,18 Impaired wound healing has been
demonstrated in experimental animals depleted of monocytes,19,20 but wounds can heal in neutropenic or
lymphopenic animals.18,21 Macrophages provide wound
decontamination and tissue debridement through phagocytosis of microbes and tissue debris. Macrophage-derived
cytokines are essential for the initiation and propagation of
new tissue formation at the wound site. These include
PDGF,22 TGF-b,23 broblast growth factor (FGF),24 TGFa,25 interleukin-1 (IL-1),26 EGF, and tumor necrosis
factor-alpha (TNF-a). Macrophages facilitate the transition from the inammatory phase to the tissue repair
phase.13
Tissue formation, the fourth phase of wound healing,
occurs between days 312. Re-epithelialization begins at
the wound edges as early as 24 h post-injury, and
granulation of the wound starts around post-injury day 5
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Effects of drugs on wound healing: Part 1 Review

Contraction of the wound is mediated by myobroblasts.31,32 Smooth muscle-like contraction by myobroblasts is stimulated by 5-hydroxytryptophan, prostaglandin
F1a, angiotensin, vasopressin, bradykinin, epinephrine, or
norepinephrine.33 TGF-b promotes wound contraction.34
Wound contraction continues through the tissue formation
phase and into the remodeling phase.
The phase of tissue remodeling occurs as early as day 3
and continues for up to 540 days. In an attempt to return
toward normal tissue structure, net accumulation of
collagen ceases and net loss of collagen begins by day
21.12,35 Although new collagen continues to be deposited,
net resorption occurs due to increased degradation of old
collagen by collagenases. As macrophages begin to
disappear, angiogenesis and broblast proliferation decrease. The extracellular matrix is also remodeled by
metalloproteinases which include interstitial collagenases,
type IV collagenases, and gelatinases. Tensile strength
increases for 6 months to 1 year as a result of the formation
of increased cross-linkages in the remodeled collagen.36

Cytokine therapy in wound healing

Figure 1 Cascade of wound healing processes (modied from

Cohen et al.,12 with permission)

for the re-establishment of the integrity of the epidermis

and dermis at the wound site. Re-epithelialization of the
wound is important as rapid re-establishment of the
epidermal barrier is protective for the organism. Epithelial
cells begin migrating within hours of injury from wound
edges, hair follicles, and sebaceous glands. Proliferation of
epithelial cells begins within the rst 24 h27,28 under the
mitogenic and chemotactic inuence of TGF-a and EGF.29
Granulation tissue is formed as macrophages, broblasts,
and endothelial cells move into the wound space. Fibroplasia
begins with broblast proliferation and collagen deposition
stimulated by TGF-b. Basic broblast growth factor (bFGF)
induces endothelial replication and mobilization.30 As
macrophages continue to remain a source of cytokines for
broplasia and angiogenesis, broblasts construct a new
extracellular matrix to support cell growth while the newly
formed blood vessels meet metabolic needs for the formation
and maintenance of tissue.
Wound contraction occurs in full thickness injuries and
reaches a peak between 5 and 15 days after injury.
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Therapeutic use of growth factors, either exogenous or

endogenous, is currently being investigated in wound
healing.15,30,3739 A rational approach dictates that the
processes involved in a specic wound (coagulation,
inammation, epithelialization, broplasia, angiogenesis,
contraction, and tissue remodeling) be identied. Then the
appropriate growth factor(s) needed to enhance or facilitate the process are applied topically or increased locally at
the appropriate time.
Acute wounds may be helped by growth factors involved
in the initial phases of wound healing (Fig. 1). Acute
wound uid harvested up to the third postoperative day
was demonstrated to stimulate in vitro growth of human
dermal broblasts and umbilical vein endothelial cells.40
PDGF or similar peptides are chemotactic to inammatory
cells and stimulated broblasts.41 The presence of TGF-b
and EGF in wound uid is critical for cell migration and
matrix formation. In addition to promoting angiogenesis
and regulating collagen synthesis, TGF-b stimulates bronectin production by both broblasts and keratinocytes.
EGF stimulates keratinocyte proliferation and migration,
while inhibiting broblast proliferation. EGF lays down a
thick epidermis over a sparse dermis.42 Skin graft donor
sites predominantly heal by re-epithelialization. Separate
clinical trials of growth factors EGF12 and bEGF43 did not
signicantly improve wound healing of skin graft donor
sites. bFGF has been used in a rat model to stimulate
angiogenesis in cryo-injured skin grafts, but had no
signicant effect on noninjured skin grafts.44
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Karukonda et al.
15

Table 1 Role of cellular and extracellular elements in healing (modied from Rothe et al. )
Wound element

Appearance after injury

Major effects on wound healing

Platelets

Immediate

Neutrophils
Macrophages

6 h, peak at 24.48 h, begin to

disappear at 72 h
Most abundant at 35 days

Hemostasis; release of growth factors: PDGF, TGF-b, EGF, and TGF-a;

release of proteolytic enzymes
Wound debridement, bacterial and foreign body clearance

Fibroblasts

Between 4872 h

Keratinocytes

Epidermal migration begins during

Endothelial cells

Between 4872 h

Fibronectin
Collagen

Early
Type III: after 2 days
Type I: after several weeks
Maximum synthesis by 2 weeks
Early; maximum by 4 days

Proteoglycans
Hyaluronic acid

Wound debridement; release of growth factors: PDGF, TGF-b, TGF-a;

FGF, IL-1, EGF, and TNF-a
Synthesis of collagen, proteoglycans, and elastin; release of growth
factors: TGF-b, PDGF, KGF, FGF, IGF-1, and IFN; wound contraction;
wound remodeling
Epidermal healing secondary to migration and mitosis; synthesis of
fibronectin; production of growth factors: TGF-a, TGF-b, EGF
Synthesis of fibronectin; angiogenesis to provide nutrients and oxygen;
production of growth factors: PDGF, TGF-b, and IGF-1
Structural support for cell migration; organization of collagen
Structural support and strength; regulate cellular interactions
Regulation of collagen synthesis, cellular interactions, matrix component
Enhancement of cell motility

EGF, epidermal growth factor; FGF, fibroblast growth factor; IFN, interferon; IGF-1, insulin-like growth factor; IL-1,
interleukin-1; KGF, keratinocyte growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor;
TNF-a, tumor necrosis factor-alpha.
Table 2 Growth factors in wound healing
Growth factor

Source

Wound healing related functions

PDGF

Chemotaxis, fibroblast proliferation, collagenase production

TNF-a
IGF-1

Platelets, macrophages, endothelial cells,

injured cells
Macrophages, platelets, neutrophils, lymphocytes
fibroblasts, epithelial and endothelial cells, injured
cells
Plasma, platelets, macrophages, epithelial cells
Activated macrophages, platelets, epithelial cells,
injured cells
Fibroblasts
Macrophages
Pituitary, macrophages, fibroblasts,
endothelial cells
Macrophages, T lymphocytes
Plasma, liver, fibroblasts

IFNs

Lymphocytes, fibroblasts

TGF-b

EGF
TGF-a
KGF
IL-1
FGF

Fibroblast proliferation, chemotaxis, collagen metabolism

Epithelial cell proliferation, granulation tissue formation

Epithelial cell proliferation, granulation tissue formation
Epithelial cell proliferation
Fibroblast proliferation
Fibroblast proliferation, matrix deposition, wound contraction,
angiogenesis
Fibroblast proliferation
Synthesis of sulfated proteoglycans and collagen, fibroblast
proliferation
Inhibition of fibroblast proliferation and collagen synthesis

For definition of abbreviations, see Table 1.

Chronic wound uid, such as that found in pressure

ulcers, venous stasis ulcers, and diabetic foot ulcers,
inhibits cell proliferation.45 Wound uid from chronic
lower extremity ulcers inhibits dermal broblast proliferation.46 Keratinocyte migration may be inhibited by
degradation products of bronectin and vitronectin in
chronic wound uid.47
Pressure ulcers heal by angiogenesis, deposition of
extracellular matrix, and contraction.40 In addition to a
International Journal of Dermatology 2000, 39, 250257

deciency in cytokines, the ulcer base contains senescent

broblasts.48 Effects of specic growth factors in the
healing of pressure ulcers have been investigated.49,50
Topical PDGF-BB (the homodimer made from polypeptide
B chains) was noted to accelerate the wound closure,
causing up to a 71% decrease in ulcer volume in a phase
two multicenter trial of 45 patients with pressure ulcers.49
Effects of PDGF that are attributable to the ulcer healing
are the initiation of chemotaxis of monocytes and
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Karukonda et al.

broblasts, proliferation of broblasts and endothelial

cells, and induction of extracellular matrix. bFGF is
mitogenic and chemotactic to broblasts and endothelial
cells and causes angiogenesis. In randomized, blinded,
placebo-controlled phase one and two trials,50 recombinant bFGF was noted to decrease 70% of the ulcer volume
in 21 of 35 patients receiving topical bFGF compared to 4
of 14 patients in the placebo group. Topical IL-1b has been
evaluated for its effect on pressure ulcers as it stimulates
monocytes and granulocytes. It is also chemotactic to
macrophages and may stimulate macrophages to secrete
other growth cytokines.39 No signicant improvement was
noted as compared to the control group. These results were
not surprising as proinammatory cytokines are a component of wound chronicity.51
The appropriate dosage of growth factors should be
considered for a given wound. Higher doses of PDGF
(300 mg/mL) produced superior results compared to a
lower dose (100 mg/mL) when used in pressure ulcers.49
The higher dose decreased ulcer volume by 71% and the
lower dose by 60%. Prolonged exposure of pressure ulcer
broblasts to high-dose IL-1b overcame senescence.48
Therapeutic use of specic growth factors to enhance reepithelialization in venous stasis ulcers has been investigated. As EGF enhances epithelial proliferation and
granulation tissue formation, a randomized, double-blind,
placebo-controlled study was conducted to evaluate its
effectiveness in venous stasis ulcers.52 Although ulcer size
was reduced, EGF failed to cause wound re-epithelialization. The results were attributed to the lack of signicant
keratinocyte migration and differentiation under the
inuence of EGF.39 This study underscores the relative
importance of keratinocyte migration and differentiation
compared to keratinocyte proliferation in achieving effective re-epithelialization in wounds such as venous stasis
ulcers, partial thickness burns, and skin graft donor sites.
Primarily, EGF promotes keratinocyte proliferation.
The effect of TGF-b2 on chronic venous stasis ulcers
delivered in a collagen sponge vehicle was evaluated in an
open trial.53 After 6 weeks of treatment, the ulcer area
decreased by 73% compared to an increase of 9% in
controls. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expected to be more useful in pressure and
diabetic ulcers with its stimulatory activity on leukocytes
and macrophages. It was observed to be more effective
than topical silver sulfadiazine cream or placebo in venous
ulcer therapy after 4 weeks.39
Angiogenesis, deposition of extracellular matrix, wound
contraction, and epithelialization are necessary for healing
of diabetic foot ulcers. Whether neuropathic or ischemic,
the cause of the ulcer must be considered, as some growth
factors were noted to be ineffective in ischemic wounds.54
Patients with neuropathic diabetic ulcers were treated with
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Effects of drugs on wound healing: Part 1 Review

daily recombinant human PDGF-BB (rhPDGF-BB) topical

applications. After 20 weeks, 48% of treated patients
had healed ulcers compared to 25% with placebo.55
Becaplermin (Regrane 0.01% gel) is a topical rhPDGFBB that has recently been approved by the Food and Drug
Administration (FDA) for diabetic neuropathic ulcers.
RGD (a peptide complex of arginineglycineaspartic
acid), when complexed with hyaluronate, is believed to
stimulate cell migration and attachment with accelerated
epithelialization.39 Of 65 patients with diabetic neuropathic ulcers, complete healing was noted after 10 weeks in
35% of patients treated with RGD peptide matrix
compared to 8% of patients in the control group.56
Pharmacologic interaction with wound
healing phases
Drugs can affect wound healing by assisting or interfering
with specic phases. The coagulation phase of wound
healing may be affected by anti-platelet drugs, such as
aspirin or nonsteroidal anti-inammatory agents. Aspirin
irreversibly inhibits platelet aggregation. The anticoagulants warfarin and heparin can inhibit proper coagulation
and can adversely affect wounds by increasing the risk of
hematoma and seroma formation (Fig. 2). Several drugs
may affect the inammatory phase of wound healing.
Aspirin and nonsteroidal anti-inammatory drugs
(NSAIDs) inhibit inammatory mediators derived from
arachidonic acid metabolism and platelet aggregation.
Corticosteroids suppress the inammatory phase by
inhibiting prostacyclin synthesis57 and the recruitment of
leukocytes.58 Antibiotics such as tetracycline and erythromycin demonstrate anti-inammatory properties through
the inhibition of leukocyte chemotaxis.59,60 Dapsone has
anti-polymorphonuclear leukocyte activities.61 Colchicine
impedes granulocyte migration to the wound and the
release of cellular contents.62 Antiseptics can be toxic to
keratinocytes63 and broblasts, leading to decreased
epithelialization,64 wound strength, and contraction.6466
Tissue formation can be affected by drugs that inuence
re-epithelialization, broplasia, or angiogenesis. Corticosteroids inhibit these processes, impede keratinocyte proliferation, and suppress macrophages.67 The use of topical
uorinated corticosteroids can reduce re-epithelialization.
Colchicine and antineoplastic drugs may impede collagen
synthesis.68 Vasoconstrictors, such as epinephrine, nicotine, and cocaine, can cause tissue hypoxia affecting the
microcirculation and tissue formation. Smokers have an
increased incidence of ap necrosis (Fig. 3). Wound
contraction is suppressed by corticosteroids, Dilantin,
cytochalasin B, colchicine, and vinblastine.18 Combining
topical corticosteroids with oral vitamin A has been
suggested as a therapeutic option to inhibit wound
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Effects of drugs on wound healing: Part 1

Figure 2 A large hematoma is seen at the seventh

postoperative day underlying the patient's sutures. He had

inadvertently taken aspirin prior to the surgery

Figure 3 Central necrosis of a bilateral advancement ap is

seen in this 66-year-old patient who smokes greater than

two packs of cigarettes per day

Karukonda et al.

contraction without adversely affecting re-epithelialization

to a signicant degree.18
The phase of tissue remodeling can be affected by
pharmaceuticals. Corticosteroids suppress the gene expression necessary for the biosynthesis of collagen. Secretion of
procollagen into the extracellular space required for
collagen synthesis is prevented by colchicine and vinblastine by blocking the formation of microtubules.69 bAminonitrile (BAPN) and D-penicillamine affect cross-link
formation of collagen in the extracellular space by
inhibiting lysyl oxidase.69 Collagen degradation is inhibited by glucocorticoids, TGF-b, retinoids, interferon-g, and
progesterone through the suppression of metalloproteinase
expression.70
Ascorbic acid (vitamin C) is essential for normal collagen
synthesis as a required cofactor for the hydroxylation of
proline and lysine.71,72 Deciency of ascorbic acid presents
as scurvy (Fig. 4) with cutaneous manifestations of
ecchymoses, poor wound healing, capillary fragility,
perifollicular hemorrhage, and corkscrew hairs. Capillary
fragility is due to the breakdown of connective tissue
around blood vessel walls. Gastrointestinal blood loss,
conjunctival hemorrhage, and bleeding gingiva can develop
as a result of weakened vessels.73 Poor wound healing is
due to impaired collagen synthesis. Symptoms of scurvy
appear when the total body pool of ascorbic acid drops
below 300 mg.74 Nutritionally deprived states, such as
starvation, acute or chronic illness and dietary fads,
increase the risk of scurvy.
Alcoholism predisposes patients to nutritional deciencies, but alcohol as a drug as not been felt to seriously
affect wound healing. With alcohol, cell migration is
slowed during the initial phases of wound healing.75 After
an initial lag, cells move into the healing wound and, by
day 30, there is no appreciable difference in cellular or
collagen content.
Local factors in wound healing

Figure 4 Perifollicular hemorrhage is seen as a result of

weakened connective tissue around blood vessel walls in this

alcoholic patient with scurvy
International Journal of Dermatology 2000, 39, 250257

Specic local factors at the site of the healing wound have

important effects. Local factors detrimental to wound healing
include anoxia, abnormal pH, necrosis, infection, hematoma, foreign body, and desiccation. Tissue oxygen levels are
correlated with morphologic ndings in wound healing.7678
Hypoxia favors cell migration and angiogenesis, while
impairing cell proliferation, collagen synthesis, and bacterial
resistance. Many drugs have vasodilatory or vasoconstrictive
effects that impact tissue oxygenation and nutrient supply
and may affect wound healing. Epinephrine may compromise
blood supply and oxygenation. Extreme changes in tissue pH
from the physiologic range cause severe damage to tissue.
Bacteria that alter tissue pH can cause signicant tissue
damage. Lactic acid from anaerobic metabolism lowers pH as
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Karukonda et al.

tissue and bacteria compete for substrates and oxygen. Tissue

abscesses are usually encapsulated with an acid pH that
makes drug delivery to the center difcult, necessitating
incision and drainage. Pseudomonas, Klebsiella, and Proteus
organisms thrive in an alkaline environment. Wounds
infected with P. aeruginosa respond to topical treatment
with dilute solutions of acetic acid. Necrosis can affect wound
healing. Anoxia, severe inammation, and the increased
potential for infection in a necrotic environment lead to poor
wound healing. The use of antiseptics in open wounds may
devitalize tissue.
Infections are an important cause of delayed wound
healing.79 Although all cutaneous wounds are contaminated by resident ora, pathogenic organisms must be
present in an excess of 100,000 bacteria per gram of tissue
for a clinical infection to occur.80 Bacteria compete with
the host for substrates such as oxygen and glucose.
Infection can produce local tissue hypoxia and accumulation of lactic acid, leading to cell lysis and the release of
proteolytic enzymes.12 In addition, direct tissue injury is
also caused by the toxins and proteases produced by
bacteria.57 The inammatory phase of wound healing may
be prolonged by bacteria through the activation of the
alternative complement pathway, resulting in further tissue
destruction.9 Antibiotics are often needed to adequately
treat infected wounds.
Hematomas and seromas can have unfavorable effects
on healing wounds. A hematoma is an excellent medium
for microorganism growth,79 and can disrupt tissue
structures, causing poor wound healing from the hypoxic
environment of the surrounding tissue. Drugs that may
enhance hematoma formation include anticoagulants and
anti-platelet drugs.
Foreign bodies are detrimental to wound healing. Tissue
oxygen tension and pH76 are lowered by the presence of a
foreign body. Wound healing may be delayed by the
prolonged inammatory response caused by the activation
of the alternative complement pathway.57,79 Foreign
bodies provide an excellent site for bacterial adherence
and proliferation. In addition to the removal of the foreign
body, antibiotics may be needed for proper wound healing.
A dry, desiccated wound will not heal as well as a moist
wound. Benets of a moist environment. Benets of a moist
environment included enhanced re-epithelialization,81,82
increased dermal repair,83 and promotion of angiogenesis.84 Topical ointments and occlusive dressings provide a
moist wound environment which aids in wound healing.
Conclusions
The physiology of wound healing is divided into ve
sequential phases. Each phase as characteristic cells and
cytokines which play important roles in coordinating the
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Effects of drugs on wound healing: Part 1 Review

events leading to a successfully repaired injury. Understanding of the events in wound healing provides a
framework to comprehend the benecial impact of some
drugs and the negative aspects of other pharmacologic
agents in wound healing. Drugs which benet wound
healing must be used at the appropriate time to have the
benecial effect. Cytokines are now being successfully used
as benecial topical agents in healing wounds. Local
factors such as infection, hypoxia or foreign bodies are
important in the healing wound and should be corrected or
controlled.
References
1 Bernstein E. Wound healing. Clin Dermatol 1994; 12:
1191.
2 Falanga V, Zitelli JA, Eaglstein WH. Periodic synopsis
wound healing. J Am Acad Dermatol 1988; 19: 559562.
3 Telfer NR Moy RL. Drug and nutrient aspects of wound
healing. Dermatol Clin 1993; 11: 729737.
4 Hom DB, Szachowicz EH (guest editors). Wound healing
for the otolaryngologisthead and neck surgeon.
Otolaryngol Clin North Am 1995; 28: 8351091.
5 Koopman CF Jr, Chvapil M (guest editors). Symposium on
wound healing. Otolaryngol Clin North Am 1984; 17:
243453.
6 Nemeth AJ. Wound healing. Dermatol Clin 1993; 11:
783789.
7 Zitelli J. Wound healing for the clinician. Adv Dermatol
1987; 2: 243268.
8 Hunt TK, ed. Wound Healing and Wound Infection:
Theory and Surgical Practice. New York: AppletonCentury-Crofts, 1977: 110.
9 Clark RAF. Cutaneous tissue repair: basic biologic
considerations part I. J Am Acad Dermatol 1985; 13: 701
725.
10 Hunt TK. Basic principles of wound healing. J Trauma
1990; 30: S122S128.
11 Fine NA, Mustoe TA. Wound healing. In: Greeneld LI,
editor-in-chief. Surgery. Scientic Principles and Practice,
2nd edn. Philadelphia: Lippincott, 1997: 6783.
12 Cohen IK, Diegelmann RF, Crossland MC. Wound care
and wound healing. In: Schwartz SI, editor-in-chief, 6th
edn. Principles of Surgery. New York: McGraw-Hill,
1994: 279303.
13 Clark RAF. Mechanisms of cutaneous wound repair. In:
Fitzpatrick TB, Eisen AZ, Wolff, et al., Dermatology in
General Medicine, Vol. 1. New York: McGraw-Hill,
1993: 473486.
14 Kirsner RS, Eaglstein WH. The wound healing process.
Dermatol Clin 1993; 11: 629640.
15 Rothe MJ, Falanga V. Growth factors and wound healing.
Clin Dermatol 1992; 9: 533559.
16 Elias PM, Jackson SM. What does normal skin do? In:
Arndt KA, Robinson JK, Le Boit PE, Wintroub BU, eds.
International Journal of Dermatology 2000, 39, 250257

255

256

Review

17

18

19

20

21

22

23

24

25

26

27

28
29
30
31

32

33

Effects of drugs on wound healing: Part 1

Cutaneous Medicine and Surgery. Philadelphia: W.B.

Saunders, 1996: 4657.
Ongenae KC, Phillips TJ. Leg ulcers and wound healing.
In: Arndt KA, Robinson JK, Le Boit PE, Wintroub BU, eds.
Cutaneous Medicine and Surgery, Vol. 1. Philadelphia:
W.B. Saunders, 1996: 558573.
Zitelli JA. Wound healing by rst and second intention. In:
Roenigk RK, Roenigk HH, eds. Dermatologic Surgery.
Principles and Practice, 2nd edn. New York: Marcel
Dekker, 1996: 101130.
Leibovitch SJ, Ross R. The role of macrophages in wound
repair: a study with hydrocortisone and antimacrophage
serum. Am J Pathol 1975; 78: 71100.
Riches DWH. The multiple roles of macrophages in
wound healing. In: Clark RAF, Henson PM, eds.
Molecular and Cellular Biology of Wound Repair. New
York: Plenum, 1988: 213.
Simpson DM, Ross R. The neutrophilic leukocyte in
wound healing: a study with antineutrophilic serum. J Clin
Invest 1972; 51: 20092023.
Shimakado K, Raines EW, Madtes DK, et al. A signicant
part of macrophage-derived growth factor consists of two
forms of PDGF. Cell 1985; 43: 277286.
Assoian RK, Fleurdelys BE, Stevenson HC, et al.
Expression and secretion of type b transforming growth
factor by activated human macrophages. Proc Natl Acad
Sci USA 1987; 84: 60206024.
Baird A, Mormede P, Bohlen P. Immunoreactive broblast
growth factor in cells of peritoneal exudate suggests its
identity with macrophage growth factor. Biochem Biophys
Res Commun 1985; 126: 358364.
Madtes DK, Raines EW, Sakariassen KS, et al. Induction
of transforming growth factor-a in activated human
alveolar macrophages. Cell 1988; 53: 285293.
Dinarello CA. Interleukin-1 and the pathogenesis of the
acute-phase response. N Engl J Med 1984; 311: 1413
1418.
Winter GD. Epidermal regeneration studied in the
domestic pig. In: Maibach HI, Rovee DT, eds. Epidermal
Wound Healing. Chicago: Yearbook, 1972: 71.
Krawczyk WS. A pattern of epidermal cell migration
during wound healing. J Cell Biol 1971; 49: 247253.
Burgess AW. Epidermal growth factor and transforming
growth factor alpha. Br Med Bull 1989; 45: 401424.
Hom DB. Growth factors in wound healing. Otolaryngol
Clin North Am 1995; 28: 933953.
McGrath MH, Hundahl SA. The spatial and temporal
quantication of myobroblasts. Plast Reconstr Surg
1982; 69: 975985.
Singer II, Kawka DW, Kazazis DM, Clark RAF. In vivo
codistribution of bronectin and actin bers in granulation
tissue: immunouorescence and electron microscope
studies of the bronexus at the myobroblast surface. J Cell
Biol 1984; 98: 20912106.
Gabbiani G, Hirschel BJ, Ryan GB, et al. Granulation
tissue as a contractile organ: a study of structure and
function. J Exp Med 1972; 135: 719734.

International Journal of Dermatology 2000, 39, 250257

Karukonda et al.

34 Montesano R, Orci L. Transforming growth factor beta

stimulates collagen matrix contraction by broblasts:
implication for wound healing. Proc Natl Acad Sci USA
1988; 85: 48944897.
35 Hunt TK, Goodson WH. Wound healing. In: Way LW, ed.
Current Surgical Diagnosis and Treatment, 9th edn.
Norwalk, CT: Appleton & Lange, 1991: 95108.
36 Diegelmann RF, Rothkopf LC, Cohen IK. Measurement of
collagen biosynthesis during wound healing. J Surg Res
1975; 19: 239243.
37 Clark RAF. ed. The Molecular and Cellular Biology of
Wound Repair, 2nd edn. New York: Plenum, 1996:
1611.
38 Lawrence WT, Diegelmann RF. Growth factors in wound
healing. Clin Dermatol 1994; 12: 157169.
39 Robson MC. Exogenous growth factor application effect
on human wound healing. Prog Dermatol 1996; 30: 17.
40 Katz MH, Alvarez AF, Krisner, RS, et al. Human wound
uid from acute wounds stimulates broblast and
endothelial cell growth. J Am Acad Dermatol 1991; 25:
10541058.
41 Duel TF, Kawahra RS, Mustoe TA, Pierce GF. Growth
factors and wound healing: platelet-derived growth factor
as a model cytokine. Ann Rev Med 1991; 42: 567584.
42 King LE, Carpenter GF. Epidermal growth factor. In:
Goldsmith LA, ed. Biochemistry and Physiology of the
Skin. New York: Oxford University Press, 1983: 269281.
43 Greenhalgh DG, Rieman M. The effect of bFGF on the
healing of partial thickness skin graft donor sites. A
prospective randomized, double-blind study. Wound Rep
Reg 1994; 2: 113121.
44 Lees VC, Fan TP. A freeze-injured skin graft model for the
quantitative study of basic broblast growth factor and
other promoters of angiogenesis in normal healing. Br J
Plast Surg 1994; 47: 349359.
45 Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell
proliferation by chronic wound uid. Wound Rep Reg
1993; 1: 181186.
46 Bucalo B, Eaglstein WH, Falanga V. The effect of chronic
wound uid on cell proliferation in vitro (abstr). J Invest
Dermatol 1989; 92: 408.
47 Grinell F, Ho CH, Wysocki A. Degradation of bronectin
and vitronectin in chronic wound uid: analysis by cell
blotting, immunoblotting and cell adhesion assays. J Invest
Dermatol 1992; 98: 410416.
48 Vandeberg JS, Robson MC, Mihail RJ. Extension of life
span of pressure ulcer broblasts with recombinant human
interleukin-1B. Am J Pathol 1995; 146: 12731282.
49 Mustoe TA, Cutler NR, Allman RM, et al. Phase II study
to evaluate recombinant PDGF-BB in the treatment of
pressure sores. Arch Surg 1994; 129: 213219.
50 Robson MC, Phillips LG, Lawrence WT, et al. The safety
and effect of topically applied recombinant basic broblast
growth factor on the healing of chronic pressure sores.
Ann Surg 1992; 216: 401408.
51 Bennett NT, Schultz GS. Growth factors and wound
2000 Blackwell Science Ltd

Karukonda et al.

52

53

54

55

56

57

58

59

60

61
62

63
64

65

66

67
68

healing: Part II. Role in normal and chronic wound

healing. Am J Surg 1993; 166: 7481.
Falanga V, Eaglstein WH, Bucalo B, et al. Topical use of
human recombinant epidermal growth factor (h-EGF) in
venous ulcers. J Dermatol Oncol 1992; 18: 604606.
Robson MC, Phillips LG, Cooper DM. The safety and
effect of transforming growth factor-B2 for the treatment
of venous stasis ulcers. Wound Rep Reg 1995; 3: 157167.
Mustoe TA, Ahn ST, Tarpley JE, et al. Role of hypoxia in
growth factor responses: differential effects of basic
broblast growth factor and platelet derived growth factor
in an ischemic wound model. Wound Rep Reg 1994; 2:
227283.
Steed DL. The Diabetic Ulcer Study Group: clinical
evaluation of recombinant human platelet growth factor
for the treatment of lower extremity diabetic ulcers. J Vasc
Surg 1995; 21: 7181.
Steed DL, Ricotta J, Prendergast JJ, et al. Promotion and
acceleration of diabetic ulcer healing by RGD peptide
matrix. Diabetic Care 1995; 18: 3946.
Reed BR, Clark RAF. Cutaneous tissue repair: practical
implications of current knowledge II. J Am Acad Dermatol
1985; 13: 919941.
Clark RAF, Gallin JI, Fauci AS. Effect of in vivo
prednisone on in vitro eosinophil and neutrophil adherence
and chemotaxis. Blood 1979; 53: 633641.
Esterly NB, Furey NL, Flanagan LE. The effect of
antimicrobial agents on leukocyte chemotaxis. J Invest
Dermatol 1978; 70: 5155.
Eady EA, Holland KT, Cunliffe WJ. The use of antibiotics
in acne therapy: oral or topical administration?
J Antimicrob Chemother 1982; 10: 89115.
Dahl MV. Clinical Immunodermatology, 3rd edn.
St Louis: Mosby, 1996.
Flower RJ, Moncada S, Vane JR. Analgesics, antipyretics
and anti-inammatory agents: drugs employed in gout. In:
Gilman LS, Gilman A, eds. The Pharmacologic Basis of
Therapeutics. New York: Macmillan, 1980: 718720.
Hirschman JV. Topical antibiotics in dermatology. Arch
Dermatol 1988; 124: 16911700.
Custer J, Edlishc R, Prusak M, et al. Studies in the
management of the contaminated wound. Am J Surg 1971;
121: 572575.
Camisa C, Eisenstat B, Ragaz A, Weissmann G. The effects
of retinoids on neutrophil function in vitro. J Am Acad
Dermatol 1982; 6: 620629.
Ballin A, Leong I, Carter DM. Effect of mupirocin on the
growth and lifespan of human broblasts. J Invest
Dermatol 1987; 88: 736.
Ehrlick HP, Hunt TK. Effects of cortisone and vitamin A
on wound healing. Ann Surg 1968; 167: 324328.
Bauer EA, Valle KJ. Colchicine-induced modulation of
collagenase in human skin broblast cultures: I.
Stimulation of enzyme synthesis in normal cells. J Invest
Dermatol 1982; 79: 398403.

2000 Blackwell Science Ltd

Effects of drugs on wound healing: Part 1 Review

69 Hunt TK, Dunphy JE. Fundamentals of Wound

Management. New York: Appleton-Century-Crofts, 1979;
103107.
70 Eisen AZ, Goldberg GI. The role of extracellular matrix
metalloproteinase inhibitors in connective tissue
remodeling. In: Fitzpatrick TB, Eisen AZ, Wolff, et al.,
Dermatology in General Medicine, 4th edn, Vol. 1. New
York: McGraw-Hill, 1993: 315328.
71 Mussini E, Hutton JJ Jr, Udenfriend S. Collagen proline
hydroxylase in wound healing, granuloma formation,
scurvy, and growth. Science 1967; 157: 927929.
72 Levine M. New concepts in the biology and biochemistry
of ascorbic acid. N Engl J Med 1986; 314: 892902.
73 Case records of the Massachusetts General Hospital.
Weekly clinicopathological exercises. Case 39-1995.
A 72-year old man with exertional dyspnea, fatigue, and
extensive ecchymoses and purpuric lesion. N Engl J Med
1995; 333: 16951702.
74 Jorizzo JO, Callen JP. Dermatologic manifestations of
internal disease. In: Arndt KA, Robinson JK, Le Boit PE,
Wintroub BU, eds. Cutaneous Medicine and Surgery.
Philadelphia: W.B. Saunders, 1996: 18631888.
75 Benveniste K, Thut P. The effect of chronic alcoholism on
wound healing. Proc Soc Exp Biol Med 1981; 166: 568
575.
76 Hohn DC. Host resistance to infections: established and
emerging concepts. In: Hunt TK, ed. Wound Healing and
Wound Infection: Theory and Surgical Practice. New
York: Appleton-Century-Crofts, 1980: 264279.
77 Pai MP, Hunt TK. The effect of varying oxygen tensions
on healing open wounds. Surg Gynecol Obstet 1972; 135:
756758.
78 Niinikoski J. The effect of blood and oxygen supply on the
biochemistry of repair. In: Hunt TK, ed. Wound Healing
and Wound Infection, New York: Appleton-CenturyCrofts, 1980: 5671.
79 Golsen JB. Wound healing for the dermatologic surgeon.
J Dermatol Surg Oncol 1988; 14: 959972.
80 Krizek TH, Robson MC. Evolution of quantitative
bacteriology in wound management. Am J Surg 1975; 130:
579584.
81 Winter GD. Formation of the scab and the rate of
epithelialization of supercial wounds in the skin of the
young domestic pig. Nature 1962; 193: 293294.
82 Hinman CD, Maibach MI, Winter CD. Effect of air
exposure and occlusion on experimental human skin
wounds. Nature 1963; 200: 377379.
83 Dyson M, Young SR, Penele L, et al. Comparison of moist
and dry conditions on dermal repair. J Invest Dermatol
1989; 92: 434439.
84 Dyson M, Yung SR, Hart J, et al. Comparison of moist and
dry conditions on the process of angiogenesis during
dermal repair. J Invest Dermatol 1992; 99: 729733.

International Journal of Dermatology 2000, 39, 250257

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