TOE

AM

FhI(AN

.JoLRN;5I.

OF in (-I.

(LIxIc.sL

Nuiiurios

\1.

23, N.
VruUd

5, May,

1970, pp

514-519

Original

Communications

Zinc
Effects of Zinc

and
Deficiency

Wound
and
C.
DAVID

Healing
Zinc Supplementation12
H.

HAROLD

H.

SANDSTEAD,3
SHEPHARD,5

M.D.,
M.D.,

VERNE AND

LANIER,

JR.,4

M.D.,

GLENN

D.

GILL.E5PIE,0

B.A.

Downloaded from www.ajcn.org by guest on November 27, 2011

ZINC,
biological l)11t plays nucleic which enzyme oxytibonucleic (2, (1) role ciency strength skin vine The tial of of skill 3) by of

AN

ESSENTIAL and! plants, a)

NUTRiENT

for at a

higher
TI,,

EXCISED DAY ZINC DEFICIENT ZERO

WOUND TO HEALING

THERMAL T 1/2 DAY ZINC DEFICIENT 6 TO 19

BURN OR 23

animals

has
it

least component and role

two
PAIR FED CONTROL

functions: several an
acid!

is

PAIR FED CONTROL

metalloenzymes un!erstood
protein an(!

b)
(1),

it in metallodIeliver
DAYS 5

incompletely be

metai)ohsm

may

ind!epend!ent Its acid the utilization are examples as in a a surgical and delays of the processes, requirement synthesis

of in of of consequence

its for rat amino this zinc

function. and! the for rat Perhaps, in these results of rats (6). practical usefulness patients tiiis
MATERIAlS

acids latter of defitensile in of the boits

function.

metabolic healing (5)

3
DAY 6 TO 23

decreased! incisions healing the poten-

P <

.001

P<

001

implications of with study.

AND

zinc in

treatment healing
arc

Fic.

1. compared
of

/.inc-(lehcient for
an between area

and rate
of

pair-fe(l wound closure

control following

rats

poor wound

of
skin

excision (lifferences

or

thermal
are highly

burn.
signilicant.

The

prolnpte(!

the

means

METHODS
spraye! egg

white, PP
cages, given and!

biotin-cnriched

diet

constainin

Weanhing 1)awlcy rats

From of cine. Surgciv,

female
were

fed
ision

and 150-g a purified.

of No tniversitv tnt 1011 and

male 20%

Spragueprotein,

taillilig less steei

<0.3
l)OttleS,

ziiic

(7,
glass

8),

housed in a
divided

d!istilhed

water

from

he t

1)is

Department
of Medi-

plastic dust-free
groups of

maintained
They were

relatively
into animals.

Vanderbilt
Tennessee

School Foundation (;rant 69-9-42, AM 03411.

and

envirollmemit.

Nashville. Supported Health

Health .ssistant

37203.

pair-fed
of each

ant!
were every

b Ser

Nutrition ice (rant

of

(;rant 397,
and U.S.

One I il)itunl with

member
animals,

ad libitum-fed and each

injectc(I

of

the

ad

Lllite(l Public

Foun(lation
Professor

intraperitoneally

100 Two to

,tg //inC four

signs

other after

(lay.
beginning

Nutrition Assistant in Surgery.

Assistant

wceks

Professor

of

Medicine.

Resident
11

in

when
Fisher

clinical

of

zinc

deficiency
Reference

the diet, (failure of

Solution.

Surgery.
.ssistant

Chief
to 1)r.

Resident Sandstead.

Research Certified Reagent

514

Zinc

and

\\ound

Healing

515

TABLE

Effect

of

zinc

deficiency

on

the

rate

of
the

closure
rat

of

open

surgical

wounds in the

integument

of

Day

0-5

or a

Day

to

healing

of

the

control

Pairs

Ti/?

K
Control
Deficient

Ti?
Control Deficient Control
I)eIicient

K
Con

Deficient

trcl

l
2

2.33 2.66
5.33 2.66
2.50

2.33 2.33
2.66 2.49
1.50

0.258 0261 0.132 0.261 0.346 0.390 0.346 0.308 0.308 0.346 0.288 0.385 0.173 0.288 0.385

0.258 0.258 0.261 0.278 0.462 0.390 0.346 0.390 0.396 0.265 0.389 0.433 0.385 0.408 0.408

6.49
8.66 Positive sloped 6.33 7.75 4.25 2.88 3.75
3.75

5.33 2.66 3.66 4.33 3.00 2.50 3.13 2.50 3.00 250 3.50
2.99

0.107 0090 Positive slope 0.109

0.089

0.132
0.261

3
45
5e

0. 0.

188 1 6()

0.231

Downloaded from www.ajcn.org by guest on November 27, 2011

0.

163

0.346
0.222

7 8 10 11

1.75 2.00
2.25

1.75 2.00
1.75

0.241 0.154 0.154 0.154 0. 145

0. 192

0.346 0.231 0.346 0. 198

0.232 0.224 0.257

2.25 2.00 2.40 1.80 4.00 2.40 1.80 P

1.75
2.62

3.75 4.75 3.60 3.40

5.20

12
1 3 14 15

1.78 1.60 1.80 1.70 1.70 <0.01

3.10
2.70

0.204 0.133 0.192 0.204 P <0.001

3.60 3.40

2.65
2.95

0.261

l6c

0.233

Tli2

K 0.390 0.346 0.346 0.390 0.347 0.385 0.383 0.347 when ad controls. the wound
weanling Adult Iflale

T1i2 3.23 3.23 3.35 3.00 3 At) 3.40 3.00 3.40 closed. rats.
Weanling
a

K 0213 0.213
0.206

AL AL AL3

1 2
.

1 .75 2.00 2.00 1 .75 2.00 1.80 1.80 2.00

AL
AL5 AL6 AL7 AL8 T112 (log 5-16; 2

0.231
0.204 0.204 0.231 0.204 fractional
=

time

in AL libituin

days
=

was one-half female

rats.
C

K = 0-8 Days
female

rate 1-I; Pair

of wound 0-5 3 not days

=

closure groups in

#{247} T112). and ad

libituin-fed
b

groups
rats.
d

included

calculation

of significance.

weight
secretions

gain,
on

scruffy whiskers)

appearance,

and

porphyrin

successive

experiments

in

which was open by Images

a applied and serial

10-sec, to the of

I-cm the pos-

had thickness of

become
animals, a

evident
l/2-cm

in diameter
di-

thermal were

burn left

the
ameter,

nonzinc-supplemented circular,

full

area fascia animals was in the thigh. were

of

skin

excised from rior thigh of hibitum experiment utilizing Seven animals.

tile

the underlying eight pairs After repeated posterior animals

of the and four complete, same

terior thigh. Time wounds was of closure poste-rate from ad the were a standard projected of the and
cut-outs

fractional the wounds the cut

analytical

determined distance. onto wounds

were

photography and then

an

healing

white traced
weighed

paper and
on

outout.

was other of

animals, lines
The

pairs

subjected

to

balance two

their

weights

plotted

on

semiloga-

516

Sandstead

et

al.

a L,

.73

1 /:

Downloaded from www.ajcn.org by guest on November 27, 2011

Fro. cient wounding.

2. rat,

Effect of

zinc

deficiency

on

closure

of

surgical

wounds in

the integument libitum

of

the

rat.

The

zinc-defifollowing

XIIa,

is compared with its pair-fed control, .VIIb, and .\ll wounds were the same size when first excised.

an ad

eOlltrol atintervals

iithimi
of
was

it

ppLI

wound

for losure. (
i)etweeii

dcternmination Ihe fractional

an(! the means

divi(ie(! of tile half-time rate of closure a I)Ove,

of tile
cate tot

into
a 11(1

pails, trea ted! skiim of

houset!

and

fed

ts

(iescrii)ed zinc. l)upliii catbutas

with
were closure

pireimteit1
excised

thc ii

calculated

time significance

areas k. lime

of rate ai)ove.

from

difference

lo
melmta ill

asertain
tion to rats,

time coiitril)ution
teimsile strength

dictermined. of zinc supple.

of Ilcalilig wounds

was

(ieternmiime(!

c!ecribcd

norimma!

200-g

rats water,

were and
were was

fed
divided

Purina
into 400 supple-

rat in Zinc
deficiency pairs closure

Rl-:stLTs

chow,

given

tap
cages.

maintained
injected with i)een
were were

resulted surgically I and < 0.001) of betweeim of

striking protltlce(!

in which when time two

(!uming

delayed
wOtln(!s

galvaimile(! iiicl oile

tg nmente(! tile line

File\ of

of
i)

time
(Figs.

member

each

(Table significant time Time wouix! mals period! tion in

2),

was imighly related control animals. time groups

tile

tiai1. Rer zinc had for 7 days, 4-cmmm incisioims

integunment. stitures and 12 all(I
of

(P of differences closure were of of time

less

to rates of

time of ani-

placet!
closet!

healing

tiotsal

limewounds and days Dunmphv

zinc treatment

by

interrtli)te(! 6
of tile of a

time tensile

strength i)y tile

time

tleternmined
llletimo(! ternliime closure

Savhov
effect

(9).
on

To
wound

de-

initial

normal

rat,

16

adult

maleswere

observation (iata

(P shows

< that

0.01). two

Inspecdeficient

Zinc

and

Wound

Healing

517

animals sure exaggerates

groups

had

marked

delay early differences

this interval.

in

wound

cloand wounds this the 400

CONTROL

during

the the
during

time

periot!, between The

ZINC SUPPLEMENTED

PAIR FED CONTROL

ZINC DEFICIENT

#{149}

of
trol
I).

the

pail-fed!
animals

control
closed!

and
a similar (Table
also

ad

libitum
i-ate (Table

con.

#{149} #{149}

at

The

them-mal
deficient

burns
animals

II)

(Fig.
closed!

I)

of
more

U)

300

. #{149}

#{149}

the
slowly

#{149} #{149}
-

r
#{149} #{149}

(P <

0.001) collti-ols.

tllan

did

the initial neci-osis 6th day

i)Urlls

of

#{149}#{149}.

time
scured with

pair-fe(!
time time

The of until tile of (lay. time fact less pair-fed! of not

scar

ob-

z
I 10

.-.-..

#{149}#{149}

#{149}

#{149}

extent

associated
postburn.

l)w-ns
time from

Consequently,

rate

wound that to or the 3).

closure

was

w
IU)

200

#{149}

#{149}

Downloaded from www.ajcn.org by guest on November 27, 2011

appraised Of 2) wounds
controls.

that is rats

#{149}

#{149}

interest ant! of

wounds of sag ad open clean timan

the
(Fig. the

w
-J
U)

zinc-deficient

tended

appeai-et! time

z
Ed I-

00

libitum-fed chow-fed the tensile

zinc

Zinc animals strength

supplementation t!id of wounds (Fig.

N.S.

<

.001

improve

Similarly,

TABLE

11

Fic.
effect

3. /iimc on the
zinc

supplementation
tensile incisions deficiency postoperative strengtim

had of (lorsunm

no healing

apparent 12 tlays

Effect

of

zinc

deficiency

on

rate

of

closure

of postoperative
coimtrast, similar

in

the

of
tensile

time

rat.

lim
of

a thermal

burn in the
TI!

integument
K
I

of rat a

decreased

strcimgtlm

I 2-day

wouimds.

Pairs Deficient (ontrol Deficient

supplementation
Control

did

not

improve

time

i-ate
rats.

7.0 2
3

3.9 3.3
4.2

0.099 0.105 0.141 0.105 0. 139 0.152 0146 0.163 0132 0.158 0.119 0.132 0.123

0.117 0.210 0.165 0.119 0. 178 0.173 0.277 0.193 0.213 0.192

of wound closure These latter data

catise and were fulness the the sufficient of zinc expei-iment observations to healing

of are
on

time chow-fed not presented

was entirely tensile the as time a

i)enegative stiength nonusemeans aniretensile

and!

6.6 4.9 6.6 3.0 4.33 4.73 4.25

4 3 Ii 7 8
9

3.8 3.9 4.0 2.3 3.6 3.25 3.6 5.25 4.0 3.36

demonsti-ate of ptiiposes,

supplemelmtation

of improving ma 1.
Foi
l)Oite(!

nom-mal previously

comparison
(5)

3.25
4.4 5.8 3.23 3.33

10
11 12

0.132
0.173 0.141

strengths pair-feti

of
coiltmol

l2-t!ay wounds
rats

P05t0i)er;Lti\e
of zinc-d!eficient

are

included!

in

Fig.

3.

13

P <0.001
--

DISCUSSION

These
6-13
the

studies healing demonstrate a normal

show of that animal the

that zinc will

zinc t!eficiency integument. not Thley increase stipplementa-

Pairs
observed

1-5
from

observed

frolu

dais
= =

6-23.
time in

Pairs
days rate

wound
of wotmnd

was

dats one-half

6-19.

T1 closed.

ilupairs also tion

of

K fractional

closure

(log 2 #{247} T1,2).

518

Sandstead

et

a!.

Downloaded from www.ajcn.org by guest on November 27, 2011

I.

FIG.

Conlmectlve

tissue

strain The collagen

of

12-clay zinc

postoperative surgical deficient wound, to the

incisions

in
control wound

the
fewer

dorsal

integulnent fibroblasts

of

zinc-

deficlelst healing

and and

pair-fed decreased

control rate.
density of

the left, has oem

pair-fed

in

the

area

of

compared

on

the right.

teIlsile sure.

strengtim
Previously

of we imealiimg deficiency

wotinds found! incisiolms of

to closure. it

om that

imasteim tensile decreaset! (5). dit! the is

do- t!etreasct! jectivelmess makes strengtim mals (5). Iimis nitely (10,

d!ellsit)

of tlmese
tell tative.

time

collagen.

1lme obviously
are,

sub-

of
t imeimi

observations
1imey

stieimgtim bs
not

of

imowever,

dietary
t!elay

zinc

Calorie consistent

with between study i-efutes Il)

time time neitimer time

differences two groups of

in

tensile aimidefi-

lestrictiolm

Stli)SeqtiCllt woulid

lee(!ing

A!tliotigim
1iirimment

time of is
wount!

explaimation et may closure unknown, i)e protein

of

foi
and!

im-

coimfirmmmsnor of that in
negative /ine

streimgtim timat i-ole ciitive

cient
librobiasts ilmcisioll of

as
acid

tensile we suspect ;ii. to syntimesis. postopzinc-t!efisimows fewer

impressions (12)

Stiain im-

et

and Husain healilmg

()ur

will

time
ill

answer

melatet! 12-day from

rats

nucleic

aimd (Fig.
con

zincs prose wount! int!ividua!s.

support

nonzinc-d!cficient
observations

I-i istologic
incisions

exanmi Imation

time
mel)t)rted

findings timat
zinc
not

of

ORiain
supplementation

et time
(lid! not

(13), al.

-1)
trol

who normal strength

of tensile meas-

aimd

pair-fed
in

rats of

(!id

increase i)ostoi)eriitive
Ct a!.

time

region

of

time aimimal

healing and

7-day ORiain

wounds.

time

zinc-deprived

I..Jlmlorttinately

Zinc
ui-e Their
comparable

and
postoperative. not

Wound

Healing
REFERENCES

519

tensile findings

strength are,
with ours

12

dlays (Fig.
zinc

therefore, 3).

entirely In
on

our dif-

1. UNDERWOOD, Human Academic, 2. FuJI0KA,

ment for liver. rat

E. and 1962, M.,

AND

J.
p.

Zinc.

lim:

Animal 157. I. LIEBERMAN.

of C/tern.

Ti-ace Nutrition. A 1164, A.

aci(l

Elements
New York:

in

studies
tensile

of

the
strength

effect we

of

deficiency

found the strength

control

significant
of zinc defi-

Zim 1964.

requireacid

synthesis

deoxyribonucleic

by

ferences diem days,

ni fican and

between
I)aim-fed!

J. Biol.
H.
of zinc

239: R.
jim

wounds
were

after
not

12
sig-

3.

SANDSTEAD, meimt dietary

H.,
deficiency

-SND

RiN!uol. synthesis

Impairby

whereas thy
therefore,

the d!iflerences different

measured of normal

deoxsriboimucleic

days
tensile

postoperative.
strength

time rat.

J. Cell

Piiysiol.

We,
of

73: 81, 1969.

4. BUCHANAN,

P.

J.,

ANI)

J.
acids

M. iim 1969.

Hsu. ziimc

Oxidation deficient

of rats.

wounds 12 seems normal

ileahing. or

zinc-supplenmented

#{176}C-lab1ed hderation
5. .S-ssosiisn,

anmiimo

animals It a
se (men

days unlikely

postoperative. to us with stiggest

that

Proc. 28: 762. H. deficiency

surgical

that

treatment of zinc will

i-I., SNO

C.

H. SIiEen.sRn.
teimsile jim time strength

Effect
(if of

int!ividual We
animals)

im-

of

/iimc

on time
iimcisioims

Imealiimg time rat.

iimtcgunmeimt

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that
demonstrate to

ind!ividuals
imzinc and 6.

Pioc. W.

Sac.

l!xtl. D.
om MORToN, Effect of

Thai.
\V.

Med.

128:
ANI)

687,

1968. MillER,
C. M. restrictc(l

proved apy are been prior i)e aie adequate

in this

healing
relatively

subsequent
zinc deficient

them-have
zinc in

J.,

J.

J.

Piirs

CiiFioN. feediimg

zinc
heahiilg

deficiency
in bovine.

and

wound
REICH,
dietary

receiviimg to that the local

a institution tissue during

(liet

marginal of therapy. for and becoines

Proc.

Soc.

Exptl. W.
Effect

itiol. N.,
of iron

Med. 118: 427, H.

iroim jim

1965. FRANK AND

level time rat.

It zinc that

may 7.

Pr-sso, Ss1SMvr.
iroim levels

M.

L. gut oim
/.

i-equirements healing intake

increased! d!ietary
situation.

in-

and

al)sorptiolm

Vutr. and 1960.

92: 33, 1967.

R. M.,
AND

crucial 8. FORBES,

M. in

Y0IIE.

Ziimc rat.

requirement 70:

balance E.

studies D., .-sNI) imealing.

the E.

I. Niitr.

53,

SUM

MARY

9.

Ssviov,
of

J.
New

Dusiiiiv. Engi. 1. H.
sttidies wouimd New

Mecimanisms

wouimd
W.

Med. 250: B.
healing.

1062,
.&ND ac-

The tegument
tensile

rate

of

closure

of

d!efects

the in

inand de-are
10.

1954.

(stii-gical
strength of

or
healing

thermal)
wounds

the

STRAIN, C. H.

H.,

A. M.

Durrox, antI

HEY ER
oim the

RAMsEY. of

Experimental burim

celeratioim Rochester
11. Poirs, W. sulfate. H.

Univ.
1953.
ROB AND

creased!

by not

zinc improve

deficiency

in

the

i-at.

Rept.
\V.
STRAIN.

Rochester,

York, C. G.
healing

Zinc
will
tensile

supplementation
the
of strength wounds

of
rate

normal
of closure

rats
or

H.,

J.

H.
165:

HENJEL,
of 432, zinc 1967. sulfate

the 12.
13.

Acceleration
Surg.

witim

zinc

the in

integu-

Ann.
S. 1: 1069, S., Time

HUSAIN,

L.

Oral 1969. H.J. of

iim

leg

ulcers.

ment.
The and Dr. suggestions. authors H. William tlmank Scott Dr. for \Villiam their

I.ancet

J.

ORi-ux, SIAN.

COPENHAGEN

AND

J.
the

S.

CAL-

Darby

effect wounds 1968.

zinc iim

sulphate rats.B,it.

on

healing

comnments

aimd of
21:

incised 240,

J.

Plastic

Surg.