Biomedical Engineering Reference
In-Depth Information
bone cortices (see the middle microphotograph
in Fig.
MSCs may also originate in the surrounding
muscle or marrow space. Data to support a
muscle origin come from studies showing that
demineralized bone powder or purifi ed BMPs,
when implanted or injected into muscle tissue,
induce bone formation [
A, B, and E). At the same time, a
crescent-shaped region of intramembranous
bone formation appears at the proximal and
distal ends of the area of periosteal response
and tapers inward toward the fracture line deep
in the cartilage ring. Thus, endochondral and
intramembranous bone formation both con-
tribute to bone healing.
During bone repair, cell interactions are ini-
tiated between the external soft tissues that
surround the injured bone, the underlying
cortical bone and marrow, and the developing
endochondral and intramembranous bone
tissues (Fig.
2
.
1
]. Other
studies have shown that a variety of premyo-
genic cell lines can differentiate into chondro-
genic or osteogenic cells when treated with
BMPs [
92
,
96
,
203
]. Marrow stroma also can
differentiate into osteoblasts and chondrocytes
[
41
,
70
,
104
]. Once recruited, their numbers
increase as a result of other morphogenetic
factors. It is important to identify the source of
the stem cells, because they make up much of
the callus tissue and may make up as much as
30
20
,
94
,
188
,
189
A). The origin of the MSCs that
contribute to bone repair and the identity of the
cells that initiate morphogenetic signals are
still unresolved. Figure
2
.
1
% of the original volume of the uninjured
long bone
Vascular tissues grow into the developing
callus as new periosteal bone develops and pro-
gresses toward the fracture line from the proxi-
mal and distal edges. The interaction of the
vascular elements and the initiation and propa-
gation of the periosteal response thus appear
to be the primary driving mechanisms that
facilitate intramembranous bone formation.
Perivascular mesenchymal cells in blood-vessel
walls may also contribute to this process [
shows potential
sources of cells and signals that lead to the con-
struction of these developmental fi elds.
MSCs involved in fracture repair may origi-
nate in the periosteum, the surrounding tissues,
or both (Fig.
2
.
1
A). The periosteum appears to
be the primary source of MSCs that then give
rise to the intramembranous bone that forms
in the callus [
2
.
1
]. If the periosteum is removed,
callus development is diminished [
154
], because
periosteal cells robustly produce BMPs during
the initial phases of fracture healing [
29
27
].
]. These
observations suggest that morphogens recruit
stem cells locally and induce them to
differentiate.
26
Figure
summarizes the mesenchymal
lineage and types of morphogens that are
involved in lineage selection, expansion, sur-
vival, and programmed cell removal.
2
.
2
Figure 2.1.
Anatomic characterization of fracture repair. Left panels (A-C) show an overview of the morphogenetic fields of
tissue development and the proximate tissue interactions. (A) Histological section of the fracture site immediately postfracture.
Potential tissue origins of mesenchymal stem cells (MSCs) and morphogenetic signals are denoted by the arrows and denoted in
the figure. (B) Histological section of the fracture site at 7 days postfracture. The two types of bone-formation processes are
denoted as endochondral bone (ECB) and intramembraneous bone (IMB) formation. The two proceed in a symmetrical manner
around the fracture site. (C) Histological section of the fracture site at 28 days postfracture. Secondary bone formation and coupled
remodeling predominate in the late stage of bone repair. Right panels (D-G) show a summary of the multiple stages of fracture
healing. Histological sections are presented for each stage, and the various processes associated with each stage are summarized.
All histological specimens are from sagittal sections of mouse tibia transverse fractures and were stained with safranin O and fast
green; micrographic images are at 200
×
magnification. (D) Section for the initial injury was taken from the fracture site 24 hours
postinjury. (E) Section depicting the initial periosteal response and endochondral formation is from 7 days postinjury. Arrows
denote vascular ingrowth from the peripheral areas of the periosteum. (F) Section depicting the period of primary bone formation
is from 14 days postinjury. Arrows denote neovascular growth areas in the underlying new bone. Inset depicts images of an
osteoclast (*chondroclast) resorbing an area of calcified cartilage. (G) Sections depicting the period of secondary bone formation
are from 21 days postinjury. Callus sites. Inset depicts 400
×
images of an osteoclast resorbing an area of primary bone. Reproduced
with permission from Gerstenfeld LC, Cullinane DM, Barnes GL, et al. Fracture healing as a post-natal developmental process:
molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003 Apr 1;88(5):873-84. Copyright © 2003 Wiley-Liss,
Inc., A Wiley Company.
