speculation on the interrelationship between cells of the

four connective tissues in healing of wounds that involve

them all.

On the Repair Potential of

Periodontal Tissues*

GINGIVA

by
A . H . MELCHER
T E E T H A R E supported by the periodontium. The
periodontium is a connective tissue organ, protected by
epithelium, that attaches the teeth to the bone of the jaws
and provides a continually adapting apparatus for their
support during function. The four connective tissues of
the periodontium are the lamina propria of the gingiva,
the periodontal ligament, the cementum and the alveolar
bone. For the purposes of this discussion, the whole of the
alveolar process, that is alveolar and supporting bone,
will be considered rather than just the alveolar bone,
which in this author's view is a term that should be
restricted to the thimble of bone lining the socket of the
tooth. The lamina propria of the gingiva is protected by
keratinized stratified squamous epithelium on its mas
ticatory surfaces, and by nonkeratinized epithelium on its
crevicular and junctional surfaces. A discussion of the
healing potential of periodontal tissues should include all
of the above connective tissues and epithelium. For
reasons that will be made clear later, it is advisable to
examine the alveolar part of the periodontium, that is the
periodontal ligament, alveolar bone and cementum as a
unit.
THE

The literature concerning healing of periodontal tis

sues will not be reviewed exhaustively, inasmuch as this
was done relatively few years ago. Most of the published
papers report histological evaluation of experiments, and
there appears to be little data available concerning either
the biological processes underlying the response of
periodontal tissues to wounding or the interaction be
tween the cells of the different tissues of the periodontium
when more than one periodontal tissue is involved in the
wound. In vivo experiments generally do not provide
conditions in which questions of this nature can be
answered, and few attempts have been made to examine
the tissues or cells of the periodontium in vitro. This
meeting could provide an ideal opportunity to speculate
about some of the gaps in our understanding against a
background of what is known. Consequently, this paper
will discuss aspects of the potential for healing of, on the
one hand, gingival epithelium and connective tissue and,
on the other, alveolar bone, periodontal ligament and
cementum. Some principles associated with the response
of bone to wounding will also be covered, as well as
1

* Presented at the 50th Anniversary of the Department of Periodontology of New York University College of Dentistry, on May 16-17,
1975, at the Plaza Hotel, New York, New York.
Medical Research Council Group in Periodontal Physiology,
Faculty of Dentistry, University of Toronto, 4384 Medical Sciences
Building, Toronto, Ont., Canada.

256

It is well known that the gingival connective tissue and

epithelium have a marked capacity for regeneration.
There is also evidence that crevicular and junctional
epithelium, together with the internal and external basal
laminae, are regenerated readily; that the junctional
epithelium will reattach to enamel, cementum, dentine
and even, under some conditions, calculus; and, further
more, it is claimed that regenerating crevicular and
junctional epithelium can differentiate from cells taking
origin from the germinative layers of keratinized mas
ticatory epithelium.
The lamina propria of the gingiva regenerates readily
after wounding, and this is accompanied by differentia
tion of gingival fibres. A fascinating question that may
be raised is why gingiva is able to regenerate after
wounding and the architecture of its fibres frequently to
be restored, when most other connective tissues, for
example that of skin, tend to scar after wounding and to
exhibit disorientation of the newly-formed fibres. It may
be conjectured that forces transmitted from the teeth to
the regenerating connective tissue regulate differentiation
and orientation of gingival fibres, or that the attachment
of gingival connective tissue to bone or cementum
prevents contraction, and therefore distortion, during
healing, but it is not known whether or not this is in fact
the case. It is perhaps pertinent at this juncture to
distinguish between the terms regeneration and repair:
regeneration refers to restoration of architecture and
function in a healing wound, whereas repair refers to
healing of a wound by tissue that does not fully restore
the architecture or the function of the part.
2-7

RESPONSE OF BONE TO W O U N D I N G

As regeneration of bone is a matter of some considera

ble concern in the treatment of periodontal disease,
devoting a little attention to some of the principles
associated with bone repair in general, before looking at
alveolar process in particular, could be of interest.
Regeneration of bone after wounding is achieved by cells,
and bone cells are found to occupy different compart
ments which, for the purpose of this discussion, could be
considered to number four, namely: osteocytes, bone
cells in marrow, cells of endosteum and the osteogenic
cells of periosteum. It is worthwhile examining briefly the
contribution of each of these to wound healing.
Although the osteocytes in the vicinity of a wound may
be active, it is unlikely that they make any real
contribution to restoring a bone defect. Similarly, al
though it is claimed that bone marrow contains a highly
potent population of osteoprogenitor cells that may be
distinct from the hemopoietic and endosteal popula
tions, there is no information concerning their contri
bution to healing of wounds in bone. Conceivably, it is
10

11

Volume 47
Number 5

Periodontal Repair

this population of osteoprogenitor cells, termed by

Friedenstein Determined Osteogenic Precursor Cells
(DOP cells), that is responsible for the osteogenic
response that is obtained from transplants of bone
marrow.
Cells of endosteum cover all internal surfaces of bone
including the walls of canals, the wall of the medullary
cavity, and the surfaces of trabeculae of cancellous bone,
and are believed by some authors to be active metabolically. They may play an important role in wound
repair in some sites, including the mandible. It is
interesting to note that cartilage is rarely deposited by
these cells and is not frequently seen in endosteal callus,
whereas cartilage is commonly deposited by cells of
periosteal callus.
It is widely accepted that the cells of periosteum make
a major contribution to healing of bone wounds, espe
cially to fractures of long bones. Periosteum exhibits two
features that are important in any consideration of its
role in healing: (1) It consists of at least two layers, an
outer fibrous layer that does not appear to possess
osteogenic potential and an inner cambium or osteogenic
layer that does. The osteogenic layer appears to be
continuous with endosteum where canals open onto the
surface of the bone. (2) Depending on the state of its
activity, the osteogenic layer may contain varying num
bers of cell strata, and the cells may exhibit different
degrees of maturation.
11

12,13

14

15

16

17

The osteogenic layer of the periosteum of a young

growing bone may be multilayered. The outer layers of
cells adjacent to the fibrous periosteum usually contain
dividing cells and thereby provide the font for a continu
ous supply of new osteoblasts. As the bone surface is
approached, the cells can be seen progressively to exhibit
morphological characteristics consistent with active syn
thesis, whereas the cells on the bone surface can be
recognized as active osteoblasts. The osteogenic layer of
a periosteum in such a state of activity may be in
equilibrium, the rate of production of new cells capable
of differentiating into osteoblasts equalling the loss of
cells from the compartment to the osteocyte popula
tion. Alternatively, a unilateral increase in produc
tion of new cells, or a decrease in the rate of transforma
tion from osteoblasts to osteocytes, will lead to increase
in the thickness of the osteogenic layer or, if the reverse
occurs, to a thinning of the osteogenic layer.
As a given part of a bone approaches the end of its
growth, division of progenitor cells in the osteogenic
layer of the periosteum ceases while differentiation and
osteogenesis continues, until all but the progenitor cells
have become osteocytes. The periosteum then exhibits a
morphological structure consistent with that of mature
bone, and comprises a fibrous layer covering a single
layer of attenuated progenitor cells constituting the
osteogenic layer. These apparently uncommitted progen
itor cells retain their capacity for division, and may be
reactivated by trauma or by the stimuli which are
responsible for remodelling of bone. It is of interest that
17

257

following injury, these progenitor cells may differentiate

into either chondroblasts or osteoblasts. The periosteum
in the vicinity of an actively-repairing wound of an adult
animal may resemble that of a young growing animal.
These two stages in the life cycle of periosteum have
important clinical implications. Tonna has shown that,
shortly after fracture of a long bone in a young animal,
some of the cells in the periosteum divide while others
simultaneously are synthesizing extracellular protein. By
contrast, in an older animal, division of progenitor cells
occurs first, and this is followed later by synthesis of
extracellular protein by their differentiating progeny.
Such a finding is not surprising, as it is evident that the
multilayered osteogenic component of the periosteum of
a young animal is a "going-concern" in which progenitor
cells are dividing and differentiated cells are engaged
actively in osteogenesis. Trauma in such a situation will
be followed by continuation of this activity, perhaps at an
increased rate. On the other hand, if the relatively few
cells of the cambium layer of the periosteum of an adult
were immediately to differentiate into osteoblasts, and to
secrete and surround themselves with extracellular sub
stance of bone without first dividing, there would be no
cells left to divide and provide successors, and the
cambium layer of that area of the periosteum would soon
be lost. Consequently, trauma must be followed first by
division of the progenitor cells of the periosteum. Only
then can some of the daughter cells differentiate into
osteoblasts, backed by a population of other daughter
cells that have remained as progenitors and which
eventually will divide again. In this way, a continual
source of cells that can differentiate into osteoblasts and
finally can be entombed as osteocytes, is assured. Thus,
though osteogenesis is initiated shortly after wounding of
a young animal, it is delayed in an adult.
18

The response of periosteum to surgical treatment is

consistent with what has been described above. The cells
of a flap of periosteum that has been elevated from adult
bone and replaced do not give rise to new bone; the new
bone that is deposited in the site takes origin from cells of
undisturbed periosteum surrounding the flap.
How
ever, if an osteoperiosteal flap is raised, new bone is
deposited by the cells of the flap. These observations
suggest that the surgical maneuvers involved in elevating
a periosteal flap destroy most of the thin layer of cells
that comprises the osteogenic layer of the adult perios
teum, and in consequence the capacity of the replaced
periosteum to produce new bone is lost. On the other
hand, elevation of an osteoperiosteal flap does not
destroy these cells and they can engage in proliferation,
differentiation, maturation and osteogenesis after the
flap is replaced.
16,

1 9

20

ALVEOLAR

PROCESS,

PERIODONTAL

LIGAMENT

AND

CEMENTUM

As far as is known, the fate of the cells of the

osteogenic layer of the mueoperiosteum of gingiva after
elevation and replacement of a full-thickness flap such as

258

J. Periodontal.
May, 1976

Melcher

is used in periodontal surgery has not been investigated,

but it would be surprising if the results differed from that
which occur elsewhere. However, it has been shown that
osteogenesis following elevation and replacement of a
gingival flap may be preceded by necrosis and resorption
of bone, that excision of the mucoperiosteum hinders
the repair process, and that resorption of alveolar
process is less active, osteogenesis more active, and
restoration of alveolar process lost following surgery
more complete under a split-thickness flap than under a
full-thickness flap.
21

22

23

The response of the cells of alveolar bone to trauma is

vigorous, and is exemplified by the extensive osteogenesis
that is stimulated by tooth extraction (see for review).
This is in contrast to the cells of some bones such as, for
example, the flat bones of the skull that do not exhibit a
strong osteogenic response following w o u n d i n g .
In
deed, were it not for the response of the endosteal and
periosteal cells of the alveolar process, and the cells on
the periodontal surface of the alveolar bone, orthodontic
movement of teeth would be difficult if not impossible.
It is inadvisable to consider healing of alveolar bone
separately from periodontal ligament because, although
the cells of the mucoperiosteum and endosteum of the
alveolar process make an important contribution to
healing, deposition and resorption of bone from the
periodontal surface of the alveolar bone is accomplished
by cells that appear to arise in the periodontal ligament.
In this context, it is important to note that the periodon
tal surface of the alveolar bone is not covered by
periosteum, but rather by endosteum, and that therefore
it must be regarded as an internal surface of bone.
Furthermore, cells of the periodontal ligament are re
sponsible not only for osteogenesis and osteoclasis, but
also for fibrogenesis and fibroclasis in the ligament itself,
and cementogenesis and cementoclasis. Consequently,
cells of periodontal ligament must play an important role
in healing of alveolar bone in a wound that involves both
alveolar process and periodontal ligament, and most
wounds inflicted on periodontium during periodontal
therapy do involve both of these two tissues.
1

19,24

Regeneration of periodontal ligament does not appear

to be as aggressive as that of alveolar bone. Regeneration
of periodontal ligament occurs in wounds involving the
periodontal space; however, if the wound is large, it may
be colonized to a varying degree by bone cells, and this
can lead to ankylosis and obliteration of that part of the
periodontal s p a c e .
It may seem strange that a
connective tissue which, in normal function, exhibits a
high rate of turnover of extracellular protein,
and
that possesses cells whose rate of deoxyribonucleic acid
synthesis and mitosis has been shown to respond to
stimulus
should not heal more readily relative to
bone. This question will be discussed further below. It is
also of interest in relation to what appears below, that
regeneration of periodontal ligament in a wound involv
ing the ligament and alveolar bone is accompanied by
25-28

29,

31,32

3 0

regeneration of alveolar bone and reestablishment of the

periodontal space.
Regeneration of cementum in the alveolar part of the
periodontium is achieved by cells that appear to take
origin from periodontal ligament, and seems to occur
quite readily after wounding and tooth movement.
Resorption of cementum may also occur after
wounding.
There does not appear to be any informa
tion on the origin of the cells that differentiate into
functioning cementoblasts and deposit cementum on the
root surface adjacent to lamina propria of gingiva in
healing of wounds in that area. It is reasonable to
suppose that they are derived from progenitors in the
lamina propria of gingiva, but the possibility that cells
from periodontal ligament may have to migrate into this
area of the root to give rise to cementoblasts cannot be
dismissed. Levine and Stahl,
Stahl et a l . and
Listgarten have found that after detachment of gingival
fibres and removal of cementum in a flap procedure,
much of the root becomes covered by epithelium, and not
by cementum. This could mean either that epithelial cells
migrate onto the root surface faster than do cells of
gingival connective tissue or periodontal ligament, or
that gingival connective tissue cells that have migrated
into the area do not attach to the root surface and do not
secrete cementum. It is of interest that in Listgarten's
experiment cementogenesis occurred regularly, but was
most advanced in the most apical part of the wound
adjacent to periodontal ligament; and furthermore, that
it has been shown that cells in the coronal part of
periodontal ligament respond to surgical treatment of
gingiva by increased synthesis of deoxyribonucleic acid
and that they may migrate coronally.
This ques
tion remains to be elucidated.
26

1,3,

2 8

26,28

83

34

21,

INTERACTION

BETWEEN

CELLS

OF

3 5 , 3 6

PERIODONTAL

TISSUES

Periodontal therapy is concerned intimately with re

generation of alveolar process. It is evident from the
above that the cells of alveolar process have the capacity
to effect regeneration after wounding and moreover, it is
claimed that osteogenesis can be enhanced by the use of
bone marrow g r a f t s .
This notwithstanding, restora
tion of alveolar process lost in periodontal disease still
cannot be achieved predictably, a deficiency that may
rest partially in the sequestered and inimicable environ
ment of the periodontium. However, there may be other
reasons for the difficulty, and these could originate in the
behavioral characteristics of the cells of the part. Before
discussing this question there is an important point to be
made. The tissue lost consequent to periodontal disease is
not only bone, but includes lamina propria of gingiva,
periodontal ligament and cementum. Should we not then,
in therapy, be attempting to reconstruct the entire organ
that supports the tooth, that is periodontium, rather than
only one of its constituent tissues, namely bone? If one
accepts this thesis, then it becomes evident that regenera37,38

Volume 47
Number 5

Periodontal Repair

tion of periodontal ligament is of prime importance as it

provides continuity between alveolar bone and cementum
and also because it apparently contains cells that can
synthesize and remodel the three connective tissues of the
alveolar part of the periodontium.
Returning to the question raised earlier, it seems on
the limited experimental evidence available that perio
dontal ligament may not regenerate as readily as bone,
and that this could discourage hopes that regenera
tion of periodontium can be achieved. However, in the
types of experiments reported, the occupation of perio
dontal space by bone may have been due to the fact that
bone cells had a shorter distance to migrate to the center
of the wound, or indeed to most of the wound when much
of the periodontal ligament was destroyed, than the cells
of the surrounding viable periodontal ligament, and that
they could enter the wound ahead of the periodontal
ligament cells despite the fact that bone had to be
resorbed before bone cells could reach the periodontal
space. In general terms it would seem that like cells can
aggregate and occupy a particular territory, possibly
excluding unlike cells; embryonic cells maintained in
vitro have been shown to exhibit this characteristic.
Melcher has suggested that periodontal ligament cells
and their progeny have the capacity to inhibit osteogene
sis, and that it is through this homeostatic mechanism
that the periodontal space is maintained throughout life.
However, this belief now seems to be too restrictive, and
it is possibly closer to the truth to postulate that bone and
soft connective tissue cells of periodontal ligament exert
stimuli upon one another, and are acted upon by external
stimuli that permit them reciprocally to maintain or alter
the balance of their territorial boundaries. If this hypoth
esis can be shown to be credible, and there is some
evidence that may support it, and if the nature of the
regulating stimuli could be determined, then it would be
possible to understand how the integrity of the periodon
tal space is normally maintained throughout life. It
would also be possible to explain why, after wounding,
the periodontal space can be occupied by bone cells, and
why, provided the domain of the bone cells and their
mineralized extracellular substance is sufficiently large to
resist resorption stimulated by the movement of the
functioning tooth, the newly deposited bone will persist
and will not be replaced by periodontal ligament. Thus,
although it may appear to be the case, it is by no means
certain that periodontal ligament has a diminished
capacity for regeneration relative to bone.
39

26

28

As far as is known, no experimental data is available

concerning the interaction between cells of gingival
connective tissue on the one hand and cells of alveolar
process and periodontal ligament, on the other, in healing
of a wound that involves all three tissues. It has been
shown in other situations that osteogenesis in repair of a
bone wound can be inhibited by invasion of the site by
nonosteogenic cells that presumably exclude the migrat
ing osteogenic cells, and it does not seem unreasonable
40

259

to suppose that this could be the case in wounds of

periodontium. For example, if cells derived from gingival
connective tissue occupy the area of the wound adjacent
to the alveolar process and periodontal ligament, it is
likely that no increase in the height of bone or periodon
tal ligament will occur. This is because there is no
evidence that the cells of gingiva exhibit osteogenic
potential. The replacement of gingival flaps raised in
periodontal surgery in direct contact with the crest of the
alveolar process could theoretically favor such a sequence
of events, but such a hypothesis needs to be tested
experimentally. Placing bone, or particularly marrow
grafts possibly assists cells of osteogenic potential to
colonize the grafted area by displacing lamina propria of
gingiva and increasing the distance that the gingival cells
must migrate before they can colonize the wound. If
osteogenic cells are present in the grafted site, or are able
to reach it before the cells of gingival connective tissue,
then it is possible that the height of the alveolar process
will be increased during healing. Unfortunately, such
therapy does not take into account the need for regenera
tion of periodontal ligament, and so does not necessarily
lead to the desirable outcome of a regenerated periodon
tium. If both periodontal ligament and bone could be
regenerated in a coronal direction, then cells apparently
having the capacity to regenerate and maintain the
alveolar part of the periodontium, namely cementum,
periodontal ligament and alveolar bone, will colonize the
wound. Then it should not be overoptimistic to hope that
the four connective tissues of the newly regenerated
periodontium could be maintained in proper relationship
to one another. The foregoing concept is based on
theoretical beliefs about the phenotypic and social behav
ior of cells of the tissues of the periodontium, and
remains to be tested experimentally. However, the suc
cessful isolation and culture of periodontal ligament
cells, and the Finding that periodontal ligament cells
exhibit some characteristics different from skin cells in
vitro,
has made possible the design of in vitro experi
ments to explore some of these phenomena. From the
clinical standpoint, the design of surgical procedures
that will allow colonization of wounds coronal to the
alveolar crest by cells derived from periodontal ligament
and bone rather than by cells derived from lamina pro
pria of gingiva or bone alone could provide a fruitful
field for investigation.
41

42

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Melcher

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3