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