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Bone regeneration: current

concepts and future directions


Rozalia Dimitriou1,2, Elena Jones3, Dennis McGonagle3 and Peter V Giannoudis1,2*

Wahyu Prasasti Mutiadesi


1306492995

Introduction

Current clinical
approaches to enhance
bone regeneration

Limitations of current
strategies to enhance
bone regeneration

BMPs (Bone
Morphogenetic
Proteins) and other
growth factors

MSCs (Mesenchymal
Stem Cells)

Scaffolds and bone


substitutes

Gene therapy

Mechanical stability and


the role of mechanical
stimulation in bone
regeneration

Tissue engineering

Systemic enhancement
of bone regeneration

Conclusions

Introduction
Bone regeneration : well-orchestrated series
of biological events
Bone induction and conduction
Involving a number of cell types
Intracellular and extracellular molecular signalling
pathways

Current Clinical Approaches to


Enhance Bone Regeneration
To stimulate or augment bone regeneration
the use of a number of different bone-grafting
methods, such as autologous bone grafts,
allografts, and bone-graft substitutes or
growth factors.

Non-invasive methods of biophysical


stimulation
Low-intensity pulsed ultrasound (LIPUS)
Pulsed electromagnetic fields (PEMF)

Methods to treat bone loss or limb-length


discrepancies and deformities
External fixators and the Ilizarov technique,
intramedullary nails with external monorail
distraction devices, or intramedullary lengthening
device.
* Have several disadvantages (complications,
requirement for lengthy and the consolidation
period and effects on the patients psychology and
well-being.

Bone grafting is a commonly performed


surgical procedure
with autologous bone being considered as the
gold standard bone-grafting material, as it
combines all properties required in a bonegraft
material: osteoinduction (bone morphogenetic
proteins (BMPs) and other growth factors),
osteogenesis
(osteoprogenitor
cells)
and
osteoconduction (scaffold).

A variety of sites can be used for bone-graft harvesting,


with the anterior and posterior iliac crests of the pelvis
being the commonly used donor sites.

Autologous Bone

the patients own tissue


histocompatible
non-immunogenic
reducing to a minimum
the
likelihood
of
immunoreactions
and
transmission of infections.

Allogeneic Bone Grafting


from human cadavers or
living donors
Lack osteoinductive
properties and no cellular
component, because
donor grafts are
devitalised via irradiation
or freeze-drying
processing.
There are issues of
immunogenicity and
rejection reactions,
possibility of infection
transmission, and cost.

Bone-graft Substitutes
They consist of scaffolds
made of synthetic or
natural biomaterials
promote the migration,
proliferation and
differentiation of bone
cells for bone
regeneration.
Ex : collagen,
hydroxyapatite (HA), btricalcium phosphate (bTCP) and calciumphosphate cements, and
glass ceramics , and the
research into this field is
ongoing.

Limitations of Current Strategies to


Enhance Bone Regeneration
Treatment strategies should aim to address all
prerequisites for optimal bone healing,
including osteoconductive matrices,
osteoinductive factors, osteogenic cells and
mechanical stability, following the diamond
concept suggested for fracture healing

BMPs ( Bone Morphogenetic


Proteins) & Other Growth Factors
The most extensively studied.
Potent osteoinductive factors.
Induce the mitogenesis of mesenchymal stem
cells (MSCs) and other osteoprogenitors, and
differentiation towards osteoblasts.
Clinical use: either alone or combined with bone
grafts.
Isues : safety (concentrations of growth factors
needed to obtain the desired osteoinductive
effects), the high cost, and the potential for
ectopic bone formation.

Using recombinant DNA technology, BMP-2


and BMP-7 have been licensed for clinical use
since 2002 and 2001 (ex : non-union, open
fractures, joint fusions, aseptic bone necrosis
and critical bone defects)
Extensive research is ongoing to develop
injectable formulations for minimally invasive
application, and/or novel carriers for
prolonged and targeted local delivery.

Growth factors
Ex :platelet-derived growth factor, transforming
growth factor- b, insulin-like growth factor-1,
vascular endothelial growth factor and fibroblast
growth factor.

MSCs
An adequate supply of MSCs is important for
efficient bone regeneration.
The current approach of delivering osteogenic
cells directly to the regeneration site includes use
of bone-marrow aspirate from the iliac crest,
which also contains growth factors.
It is a minimally invasive procedure to enhance
bone repair, and produces satisfactory results
This strategy is already applied for cartilage
regeneration.

Alternative sources of cells(less invasive) :


Peripheral blood and fat, muscle, or even
traumatised muscle tissue after debridement (are
also under extensive research).

The role of MSCs in fracture repair is still in its


infancy, largely due to a lack of studies into
the biology of MSCs in vivo in the fracture
environment.
Relates to the historical perceived rarity of in
vivo MSCs and also to a lack of knowledge
about in vivo phenotypes.

Scaffolds and Bone Substitutes


Lack osteoinductive or osteogenic.
Synthetic bone substitutes and biomaterials
Synthetic bone substitutes are currently
available, such as HA (hydroxyapatite), b-TCP
and calcium phosphate cements, and glass
ceramics.

As adjuncts or alternatives to autologous bone


grafts, as they promote the migration,
proliferation and differentiation of bone cells for
bone regeneration.
Can be used in combination with autologous
bone graft, growth factors or cells for
regeneration of large bone defects.
There are also non-biological osteoconductive
substrates, such as biocompatible metals (for
example, porous antalum) that offer the potential
for absolute control of the final structure without
any immunogenicity.

Research is ongoing to improve the


mechanical properties and
biocompatibility of scaffolds, to promote
osteoblast adhesion, growth and
differentiation, and to allow vascular
ingrowth and bone-tissue formation.
Improved biodegradable and bioactive
three-dimensional porous scaffolds are
being investigated, using
nanotechnology such as :
magnetic biohybrid porous scaffolds acting
as a crosslinking agent for collagen for bone
regeneration, or injectable scaffolds for
easier application.

Tissue Engineering
A promising strategy in the field of bone
regenerative medicine.
Aims to generate new cell-driven, functional
tissues rather than just to implant non-living
scaffolds.
Combines progenitor cells, such as MSCs or
mature cells (for osteogenesis) seeded in
biocompatible scaffolds and ideally in three
dimensional tissue-like structures (for
osteoconduction and vascular ingrowth), with
appropriate growth factors (for osteoinduction).

Issues of efficacy, safety and cost. Culturedexpanded cells may have mutations or
epigenetic changes that could confer a
tumour-forming potential.
In vitro and in vivo evidences suggests that the
risk of tumour formation is minimal.

Gene Therapy
Another promising method of growth-factor
delivery in the field of bone-tissue engineering
Involves the transfer of genetic material into
the genome of the target cell.
Issues : cost, efficacy and biological safety.
Delivery of growth factors, particularly BMPs,
using gene therapy for bone regeneration has
already produced promising results in animal
studies.

using a viral
(transfection)
Gene transfer

by Vector
non-viral
(transduction)

in vivo

easier method
the genetic material is transferred
directly into the host , however, there are
safety concerns with this approach.

Gene
therapy

requires the collection of cells by tissue


harvest, and their genetic modification in
vitro before transfer back into the host.

Method

Technically more demanding

ex vivo
it is a safer method, allowing testing of the
cells for any abnormal behavior before reimplantation, and selection of those with the
highest gene expression

Mechanical Stability & The Role of


Mechanical Stimulation In Bone
Regeneration
Adequate mechanical stability and use of fixation
devices is also an important element for optimal
bone repair (ex : large bone defects or impaired
bone healing ).
The mechanical loading affects the regeneration
process, with different stress distribution or
inhibiting differentiation of particular tissue
phenotypes.

In early fracture healing, mechanical stimulation


seems to enhance callus formation, but the
amount of callus formation does not correspond
to stiffness.
During the initial stages of bone healing
a less rigid mechanical environment resulted in a
prolonged chondral bone regeneration phase.
a more rigid mechanical environment resulted in a
smaller callus and a reduced fibrous-tissue component

For later stages of bone regeneration, lower


mechanical stability was found to inhibit callus
bridging and stiffness.

Finally, in vitro studies have also shown the


role of the mechanical environment on
different cell types involved in bone
regeneration.

Mechanical stability is also important for local


vascularisation and angiogenesis during bone
regeneration.
An in vivo study, it was shown that smaller
interfragmentary movements led to the
formation of a greater number of vessels within
the callus, particularly in areas close to the
periosteum, compared with larger movements.
Finally, the presence of a mechanically stable
environment throughout the bone-regeneration
process is also essential

Systemic Enhancement of Bone


Regeneration
Using systemic agents.

GH (Growth Hormon)
Current evidence suggests a positive role for
GH in fracture healing
Issues about safety profile and optimal dose.

PTH (Parathyroid Hormon)


PTH administration induces both cancellous
and cortical bone regeneration, enhances
bone mass, and increases mechanical bone
strength and bone-mineral density, with a
relatively satisfactory safety profile. (animal
studies and clinical trials)
Ex : PTH 1-34 (or teriparitide) and PTH 1-84,
are already used in clinical practice as anabolic
agents for the treatment of osteoporosis.

Denosumab RANKL (Receptor Activator of Nuclear


factor Kappa B Ligand)

a new pharmaceutical agent


a fully human monoclonal antibody designed to
target receptor activator of nuclear factor-B
ligand (RANKL),
a protein that selectively inhibits
osteoclastogenesis
in osteoporosis :
decrease bone turnover
increase bone-mineral density
improve bone regeneration

Wnt Pathway
Signalling pathway
Play a role in bone regeneration
Impaired Wnt signalling is associated with
osteogenic pathologies, such as osteoporosis and
osteopenia.
Systemically induce the Wnt signalling pathway or
inhibit its antagonists, such as sclerostin, can
improve bone regeneration.
There are concerns about carcinogenesis

Agonists Of The Prostaglandin Receptors EP2 and EP4

Skeletally anabolic at cortical and cancellous


sites.
Promising results have been seen in animal
models
without adverse effects
these receptors may represent novel anabolic
agents for the treatment of osteoporosis and for
augmentation of bone healing

Conclusions
There are several clinical conditions that require
enhancement of bone regeneration either locally or
systemically.
Various methods are currently used to augment bone
repair, depending on the healing potential and the
specific requirements of each case.
Knowledge of bone biology has vastly expanded with
the increased understanding at the molecular level,
resulting in development of many new treatment
methods, with many others (or improvements to
current ones) anticipated in the years to come.

Phases of Bone Regeneration


(Fracture Healing)
1. Reactive
Phase

i. Fracture and
inflammatory
phase
ii. Granulation
tissue formation

Bone
Regeneration

iii. Cartilage
Callus formation
2. Reparative
Phase
iv. Lamellar bone
deposition

3. Remodeling
Phase

v. Remodeling to
original bone
contour

Fracture and
inflammatory
phase

Remodeling
to original
bone contour

Lamellar bone
deposition

Granulation
tissue
formation

Cartilage
Callus
formation

Reactive Phase
After fracture, the first change seen by light and
electron microscope is the presence of blood cells
within the tissues adjacent to the injury site.
Soon after fracture, the blood vessels constrict,
stopping any further bleeding.
A few hours after fracture, the extravascular blood cells
form a blood clot, known as a hematoma. All of the
cells within the blood clot degenerate and die.
Within this same area, the fibroblasts survive and
replicate. They form a loose aggregate of cells,
interspersed with small blood vessels, known
as granulation tissue.

Reparative Phase
Days after fracture, the cells of the periosteum replicate and
transform.
The periosteal cells proximal (closest) to the fracture gap develop
into chondroblasts which form hyaline cartilage.
The periosteal cells distal to (further from) the fracture gap develop
into osteoblasts which form woven bone.

The fibroblasts within the granulation tissue develop into


chondroblasts which also form hyaline cartilage.
These two new tissues grow in size until they unite with their
counterparts from other parts of the fracture. These processes
culminate in a new mass of heterogeneous tissue which is known as
the fracture callus.
Eventually, the fracture gap is bridged by the hyaline cartilage and
woven bone, restoring some of its original strength.

The next phase is the replacement of the hyaline cartilage and


woven bone with lamellar bone.
The replacement process is known as endochondral
ossification with respect to the hyaline cartilage and bony
substitution with respect to the woven bone.
Substitution of the woven bone with lamellar bone precedes the
substitution of the hyaline cartilage with lamellar bone.
The lamellar bone begins forming soon after the collagen matrix of
either tissue becomes mineralized.

The mineralized matrix is penetrated by channels, each containing


a microvessel and numerous osteoblasts.

The osteoblasts form new lamellar bone upon the recently exposed
surface of the mineralized matrix.
This new lamellar bone is in the form of trabecular bone.
Eventually, all of the woven bone and cartilage of the original
fracture callus is replaced by trabecular bone, restoring most of the
bone's original strength

Remodeling Phase
Substitutes the trabecular bone with compact bone.
The trabecular bone is first resorbed by osteoclasts, creating a
shallow resorption pit known as a "Howship's lacuna".
Then osteoblasts deposit compact bone within the resorption pit.
Eventually, the fracture callus is remodelled into a new shape which
closely duplicates the bone's original shape and strength.
The remodeling phase takes 3 to 5 years depending on factors such
as age or general condition.
This process can be enhanced by certain synthetic injectable
biomaterials, such as cerament, which are osteoconductive and
actively promote bone healing.

References
1.

2.
3.
4.

Brighton, Carl T. and Robert M. Hunt (1986), "Histochemical


localization of calcium in the fracture callus with potassium
pyroantimonate: possible role of chondrocyte mitochondrial
calcium in callus calcification", Journal of Bone and Joint
Surgery, 68-A (5): 703-715
Brighton, Carl T. and Robert M. Hunt (1991), "Early histologic and
ultrastructural changes in medullary fracture callus",Journal of
Bone and Joint Surgery, 73-A (6): 832-847
Brighton, Carl T. and Robert M. Hunt (1997), "Early histologic and
ultrastructural changes in microvessels of periosteal
callus", Journal of Orthopaedic Trauma, 11 (4): 244-253
Ham, Arthur W. and William R. Harris (1972), "Repair and
transplantation of bone", The biochemistry and physiology of
bone, New York: Academic Press, p. 337-399

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