Fracture healing and recent advances

1. FRACTURE UNION AND
RECENT ADVANCES
Prepared by:
Dr Dipendra Maharjan
First year resident

2. • Fracture is defined as a
– break in the continuity of bone
– results in loss of its mechanical stability
– partial destruction of blood supply.
• But following fracture a scar is not formed,
instead a bone has formed
• bone healing the appropriate nomenclature
would be BONE REGENERATION
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What is Fracture?

3. What is a Fracture Healing?
• A complex process that requires the
recruitment of appropriate cells
• the subsequent expression of the
appropriate genes at the right time and
in the right anatomical location.
• A fracture initiates a sequence of
inflammation, repair, and remodeling
that can restore the injured bone to its
original state or near original state.

4. There are 3 major phases with sub divisions:
• Reactive Phase
– Fracture and inflammatory phase
– Stage of hematoma formation
– Granulation tissue formation.
• Reparative Phase:
– Cartilage Callus formation.
– Lamellar bone deposition.
• Remodeling Phase:
– Remodeling to original bone contour.
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STAGES OF FRACTURE HEALING

6. FACTURE UNION
• Union is incomplete repair and the ensheathing
callus is calcified.
• Clinically the fracture site is still a little tender,
the bone moves in one piece, attempted
angulation is painful.
• X-Rays show the fracture line still clearly visible,
with fluffy callus around it.
• Repair is incomplete and it is not safe to subject
the unprotected bone to stress.

7. • Clinical union
– occurs when progressively increasing stiffness and
strength provided by the mineralization process
makes the fracture site stable and pain free.
• Radiographic union
– present when plain radiographs show bone
trabeculae or cortical bone crossing the fracture
site.
• Radioisotope studies have shown increased
activity in fracture sites long after painless
function has been restored and radiographic
union is present, indicating that the remodeling
process continues for years.

8. • Local factors
• Chemical factors
• Vascular factors
• Systemic factors
• Electromagnetic factors
• Treatment factors
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INFLUENCING FACTORS

9. A.Type of bone
B. Degree of Trauma
C.Vascular Injury
D. Degree of Immobilization
E. Type of Fractures
F. others: Bone death caused by
radiation
thermal
chemical burns
infection.
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LOCAL FACTORS

10. 1.MESSENGER 2.GROWTH 3.PERMEABILITY
SUBSTANCES FACTORS FACTORS
-Serotonin -Transforming GF -Proteases
-Prostaglandins -Fibroblast GF -Polypeptides
-Histamines -Platelet derived GF -Amines
-Thromboxane -Insulin like GF
-Bone morphogenic
proteins(BMP)
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2.CHEMICAL FACTORS

11. • MESSENGER SUBSTANCE:
CYTOKINES-
IL-1,4,6,11, macrophage and granulocyte/macrophage
stimulate bone resorption.
IL-1 ,6 synthesis is decreased by estrogen
PROSTAGLANDINS-
Stimulate osteoblastic bone formation and inhibit activity
of isolated osteoclasts.
LEUKOTRINES-
Stimulate osteoblastic bone formation and enhance the
capacity of isolated osteoclasts to form resorption pits.
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12. GROWTH FACTORS
A.Transforming growth factor(TGF):
-Act on serine/threonine kinase cell wall receptors
- Promotes proliferation and differentiation of osteoblasts,
osteoclasts and chondrocytes
- Stimulates both endochondral and intramembranous
bone formation and collagen type 2 synthesis.
B.Fibroblast growth factors(FGF):
-Increase proliferation of chondrocytes and osteoblasts
-Enhance callus formation & stimulates angiogenesis.
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13. C.Platelet derived growth
factor(PDGF):
•Stimulates bone cell growth
•Increases type I collagen synthesis by
increasing the number of osteoblasts.
•PDGF-B stimulates bone resorption.
D.Insulin like growth factor(ILGF):
•Stimulates bone collagen & matrix synthesis and
replicates osteoblasts .
•It also inhibits collagen degradation.
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14. • E.Bone Morphogenic Proteins (BMP):
BMP are Osteoinductive proteins initially isolated from
demineralized bone matrix.
•FUNCTIONS:
–Induce cell differentiation : BMP 3(osteogenin).
–Promote endochondral ossification: BMP 2 & 7.
–Regulate extracellular matrix production :BMP1.
–Increase fusion rates in Spinal fusions (anterior lumbar
interbody fusion): BMP 2
–Non unions: BMP 7 as good as bone grafting .
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15. • 3.PERMEABILITY FACTORS:
-Protease – Plasmin , Kalikrein, Globulin permeability
factor.
-Polypeptides –leucotaxime, Bradykinin, Kallidin
-Amines – Adrenalin, nor-adrenalin, Histamine.
These factors work in ways that :
– Increase capillary permeability
– Alteration in diffusion mechanism in intracellular
matrix
– Cellular migration
– Proliferation & differentiation
– New blood vessel formation
– Matrix synthesis
– Growth & development.
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3.VASCULAR FACTORS
•A. Metalloproteinases:
–Degrade cartilage and bones to allow invasion
of vessels
•B Angiogenic factors:
-Vascular-endothelial growth factors mediate neo-
angiogenesis & endothelial-cell specific mitogens.
•C. Angiopoietin (І & ІІ)
–Regulate formation of larger vessels and branches.

17. A.Age:
Young patients heal rapidly and have a remarkable ability
to remodel V/S old .
B.Nutrition:
An adequate metabolic stage with sufficient carbohydrates
and protein is necessary.
C.Systemic Diseases:
an immunocompromised state will likely delay healing.
Illnesses like Marfan’s syndrome and Ehlers-Danlos
syndrome cause abnormal musculoskeletal healing.
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4.SYSTEMIC FACTORS

18. D.HORMONES:
– Estrogen
• Stimulates fracture healing through receptor mediated
mechanism.
– Thyroid hormones
• stimulate osteoclastic bone resorption.
– Glucocorticoids
• increased osteoclastic bone resorption.
– Parathyroid Hormone
• Accelerates callus formation (+osteoprogenitor cells) with
enhanced remodeling & biomechanical properties of healing #
– Growth Hormone
• Increases callus formation and fracture strength
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19. • In vitro bone deformation produces
piezoelectric currents and streaming
potentials.
• Electromagnetic (EM) devices are based on
Wolff’s Law that bone responds to
mechanical stress: Exogenous EM fields may
simulate mechanical loading and stimulate
bone growth and repair
• TYPES ARE :
– Ultrasound.
– Direct electrical current.
– Pulsed electromagnetic fields (PEMF).
5.ELECTROMAGNETIC FACTORS

20. A.Ultrasound therapy:
• Modulates signal transduction,
increases gene expression
(aggrecan ), increases blood flow,
enhances bone remodeling and
increases callus torsional strength
in animal models.
• Low-intensity ultrasound is
approved by the FDA for stimulating
healing of fresh fractures.

21. • Direct Electrical
current:
– Electric stimulation of
bone has been taught
to be an effective and
non invasive method
for fracture healing
and treating fracture
non union. Studies
shows that electric
field generated helps
in proliferation of bone
cells.

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C. Pulsed electromagnetic fields (PEMF).
• Approved for the
treatment of non-unions
• Efficacy of bone
stimulation appears to be
frequency dependant
– are most effective (15 to 30 Hz
range)

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RECENT ADVANCES
Bone graft
Autogenous (iliac crest, prox. tibia, distal femur)
Scaffold for osteoconduction
Has bone matrix proteins  osteoinduction
Has progenitor stem cells  osteogenesis
(free vascular fibular graft for absent radius/ long bone)
Allogenic (from cadaver)
Synthetic (demineralized bone matrix, collagen, ceramics,
cements, polymers- Si, PMMA)
2 emerging products
Tricalcium PO4 composite (VITROSS, CORTOSS)
Hydroxyapatite compound (pro osteon) – marine coral

24. •Bone Marrow Aspirate
•bone marrow contains mesenchymal stem cells and circulating
progenitors
•Mesenchymal stem cells can differentiate into osteoblasts,
chondrocytes, and other connective tissue cells in vitro under appropriate
conditions.
•circulating endothelial progenitors that can contribute to adult
vasculogenesis.
•some of the effects of bone marrow aspirate on fracture healing could
be due to the local application of osteochondrogenic cells and/or
endothelial progenitor cells during bone healing.

25. • Use of Serological Bone Formation Markers
– Current serum markers of bone formation activity
include
• bone-specific alkaline phosphatase (ALP)
• procollagen type-I N-terminal propeptide (PINP)
• procollagen type-I C-terminal propeptide (PICP)
• osteocalcin (OC)
– to Monitor Callus Development and Fracture
Healing
– PINP is superior in reflecting bone formation
processes when compared with ALP, PICP, and OC.
PINP can also be characterized as an index of
collagen synthesis, a marker of the early stages of
bone formation, and a marker of callus formation.

26. • Laser Photobiomodulation on Bone
– Laser Phototherapy (LPT) is an effective tool to stimulate
bone.
– results show that the use of IR laser results on increased
bone neo-formation.
– LPT effect depends not only on the total dose, but also on
both irradiation time and mode.
– Energy density and intensity are biologically independent
and accounts for the success and the failure of the
treatment.

27. Percutaneous vertebroplasty:
– Vertebroplasty is a minimally invasive, image-guided
therapy used to relieve pain from a vertebral body fracture.
– It has been used for osteoporotic or malignant fractures.
– Vertebroplasty can increase patient mobility, decrease
narcotic needs, and prevent further vertebral collapse.
– Percutaneous vertebroplasty (PVP) usually involves
percutaneous injection of a cement, polymethylmethacrylate
(PMMA), into the vertebral bodies.
– Occasionally, PMMA has been placed manually into vertebral
lesions during open surgical operations.
Percut. Inj. (Fibroblast GF-2 + hyaluronon)   callus
formation & mechanical strength

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• OTHER RECENT ADVANCES:
• GROWTH FACTOR THERAPY
Due to their ability to stimulate proliferation and
differentiation of mesenchymal and osteoprogenitor cells they
have shown great promise for their ability to promote fracture
repair .
• APPLICATION OF PLATELET RICH PLASMA
PRP improves cellular proliferation and chondrogenesis during early
fracture healing and increases the mechanical strength of callus during
late fracture healing
Injecting platelet rich plasma at fracture site helps in fracture healing .
• TISSUE ENGINEERING, STEM CELLS AND GENE
THERAPIES
In past decade tissue culture and stem cells have
been implicated in enhancing fracture healing and articular
cartilage regeneration.

29. • Fracture healing is influenced by
many variables including mechanical
stability, electrical environment,
biochemical factors and blood flow
etc…
• Our ability to enhance fracture
healing will increase as we better
understand the interaction between
these variables.
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SUMMARY

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Thank You

31. • CAMPBELL TEXTBOOK OF ORTHOPAEDICS 11TH EDITION..
• APLEYS PRINCIPLE OF ORTHOPAEDICS
• REVIEW OF ORTHOPAEDICS BY MILLER
• Orthopaedic Knowledge Update 10
• Recent Developments in the Biology of Fracture Repair
• Recent Advances in the Use of Serological Bone Formation
Markers to Monitor Callus Development and Fracture
Healing Marlon O. Coulibaly1, Debra L.
• Recent Advances on the Use of Laser Photobiomodulation
on Bone. A. Pinheiro
• Gene therapy for in vivo bone formation: recent advances
W. LATTANZI1*, E. POLA2*
• The evidence of low-intensity pulsed ultrasound for in
vitro, animal and human fracture healingPilar Martinez de
Albornoz†, Anil Khanna‡,
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BIBLIOGRAPHY