This document discusses current trends in the treatment of fractures, including the use of bone morphogenetic proteins, stem cells, bone grafts, scaffolds, platelet rich plasma, tissue engineering, and gene therapy. BMPs enhance bone cell maturation and function, while stem cells can differentiate into bone cells and aid repair. Autologous bone grafts are still the gold standard but alternatives like allografts, biomaterials, and synthetic bone substitutes are increasingly used. Platelet rich plasma and growth factors also help bone healing. Tissue engineering combines cells, scaffolds, and growth factors for regeneration. Gene therapy aims to promote healing by transferring genes into cells to stimulate bone growth.

1. CURRENT TRENDS IN
TREATMENT OF FRACTURES
By
Dr Rekha Pathak and Dr T Sai kumar
Division of Surgery

2. Bone Morphogenetic Proteins
• They are involved in early limb development and enhance
maturation and function of differentiated cells (chondrocyte and
osteoblast).
• They bind to their receptors (serine/threonine kinase receptors)
which are responsible for modulating gene transcription.
• BMP-2 and BMP-7 are the most intensively studied BMPs in the
recombinant technology.

3. • Clinical studies describing the use of BMPs are mainly
dedicated to the treatment of nonunion, and segmental bone
defects
• They induce the mitogenesis of mesenchymal stem cells
(MSCs) and other osteoprogenitors, and their differen-
tiation towards osteoblasts

4. Method of use
• Both the products require a collagen sponge carrier delivery system
-Scaffold for bone ingrowth
-Concentrates BMP locally
• Necrotic & sclerotic tissue shld be debrided
• Should be in contact viable fragment
• ORIF[open reduction and internal fixation] shld be done first
• No irrigation, drains after BMP
Biological adjuct with no mechanical strewithngth

5. Problems with BMP
• Heterotrophic ossification...Boraiah Corr2009
• • Bone resorption: stimulation of osteoclasts Esp in cancellous bone...
Toth spine 2009•
• Local inflammatory response
• • Local immune response
• • Stimulation of cancer cells

6. Stem cells
• A stem cell is a cell that has two essential characters: and ability to
differentiate into a particular cell type and self-renewal.
• Adult stem cells are pluripotent.
• They participate in physiologic remodeling/turnover of normal
tissues and repair of the injured tissue

7. • 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.
• Alterna-tive sources of cells, which are less invasive, such as peripheral blood and
mesenchymal progenitor cells from fat , muscle, or even traumatised muscle
tissue after debridement , are also under extensive research.
• Certain biomolecules, such as bone morphogenic proteins (BMPs), and growth
factors regulate the bone metabolism and stimulate the differentiation of MSCs
to osteoblasts.
• Supplementation with these growth factors further contributes to faster recovery
by activation of resident MSCs and increases their osteoinduction properties

8. • Quarto demonstrated successful healing of large bone defects
(average of 5 cm) in three patients with bone marrow-derived
mesenchymal stem cells (MSCs) seeded on a ceramic scaffold.
• Marcacci used bone marrow-derived MSCs seeded on a ceramic
scaffold to treat four diaphyseal bone defects which were stabilized
with external fixators. All bone defects demonstrated complete
healing at an average of 6 months with no recorded complications.

9. • Novel techniques of MSCs harvesting, in vitro expansion are
encouraging. MSCs in vitro expansion done by growing them in an
osteogenic differentiation media prior to transplantation in the host.
But these approaches add costs and risks of viral or bacterial
contamination, besides time consuming since they require a two-
stage surgery.
• The use of MSCs in fracture healing is still in the beginnings, mainly
due to a lack of studies into the MSCs in vivo biology in the fracture
environment

10. Bone graft
• The current gold standard to treat a segmental or critical
size defects is autologous bone grafting, which has a success
rate considered to be 50–80%.
• The bone segment taken from patient’s body contains
osteoconductive and osteoinductive properties that aid in faster bone
regeneration.
• However, the surgical procedure of autologous bone grafting can be
laborious and present the risk for inherent postoperative infections,
such as bleeding.

12. • Autologus bone graft is a commonly performed surgical maneuver to
enhance bone healing and being considered as the “gold standard” as
it contains all properties required in a bone graft material:
osteoinductive [bone morphogenetic proteins (BMPs) and other
growth factors], osteoconductive (scaffold) and osteogenesis
(osteoprogenitor cells) and has a success rate of 50%-80%.
• The iliac crest is the commonly used donor sites. But harvesting has
its complications and needs an additional surgical procedure

13. • Allogeneic bone graft bypasses the harvesting problems and graft
quantity. It is available in many forms, such as demineralised bone
matrix, cancellous and cortical, corticocancellous, osteochondral and
whole-bone segments.
• But They have decreased osteoinductive properties and with no
cellular component
• Their main drawbacks are the
1 issues of rejection,
2 immunogenicity,
3 transmission of infection, and cost

14. Scaffolds and Bone Substitutes
• The alternative to the grafting approach is the use of a broad range of
bone substitutes, which include biomaterials and scaffolds.
• Biomaterials hold a great potential for clinical application, including
the treatment of nonunion fractures, with the use of scaffolds that
are commonly constituted with collagen, hydroxyapatite,
β-tri-calcium phosphate, bio-ceramics, biopolymer, bioactive glasses,
bioactive composites, etc.,

15. • However, these biological and synthetic scaffolds lack the efficient
osteoinductive and osteogenic properties when compared to bone grafts.
• Alternatively, they provide the structural strength necessary for the
regenerating bone by aiding cellular adhesion, proliferation, and
differentiation, which over time are replaced by the newly generated bone.
• Although biomaterials partially mimic the structural microenvironment
of the bone, the current challenge is to improve their biological aspects.
Next generation biomaterials and scaffolds are being designed to match
the topographical and biological features of bone at the nanoscale to
achieve maximum biofunctionality and faster recovery.

16. • DBM and collagen are biomaterials, used mainly as bone-graft extenders, as they
provide minimal structural Support
• A large number of synthetic bone substitutes are currently available, such as HA,
b-TCP and calcium- phosphate cements, and glass ceramics .
• These are being used as adjuncts or alternatives to autologous bone grafts, as
they promote the migration, proliferation and differentiation of bone cells for
bone regeneration. Especially for regeneration of large bone defects,where the
requirements for grafting material are substantial, these synthetics can be used in
combination with autologous bone graft, growth factors or cells .
• Furthermore, there are also non-biological osteoconductive substrates, such as
fabricated biocompatible metals (for example, porous tantalum) that offer the
potential for absolute control of the final structure without any immunogenicity

17. Platelet Rich Plasma
• Platelet concentration counts in a healthy individual between 1.5-4.5 ×
105/μL. To be labeled as platelet rich plasma (PRP), a platelet count of 4-5
times of the baseline should be present in the platelet concentrate
• .Platelets contain granules which contain multiple growth factors and
cytokines that play an important role in the early responses of bone repair
and also help the regeneration of tissues with low healing potential.
• PRP preparation includes drawing of blood into a tube containing an
anticoagulant followed by centrifugation then treated with calcium
chloride and bovine thrombin which forms a gel-like substance for direct
application

18. • Hakimi compared combined PRP with autologous cancellous graft and
isolated autologous cancellous graft in long bones of minipigs. There
was a significantly better bone regeneration in case of combined PRP
and graft.
• Yamada et al[16] combined mesenchymal stem cells with PRP in a
canine model that resulted in a higher maturation of bone.
• PRP is autologous and nontoxic, with no risks of immunogenic
reactions. However, the use of bovine thrombin leads to the
development of auto-antibodies against factors V and XI, and thus the
risk of life-threatening coagulopathies

19. Tissue Engineering
• Bone tissue-engineering is a strategy combines the principles of
orthopaedics with biology, physics, materials science and engineering,
to generate cell-driven, functional tissues.
• It combines progenitor cells which are seeded in biocompatible
scaffolds with appropriate growth factors, in order to form hybrid
constructs to generate and maintain bone, especially for the
management of large bone defects

21. • The tissue-engineering approach is a promising strategy added in the
field of bone regenerative medicine, which aims to generate new,
cell-driven, functional tissues,rather than just to implant non-living
scaffolds
• the tissue-engineering approach has been used to accelerate the
fracture-healing process or to augment the bone-prosthesis interface
and prevent aseptic loosening in total joint arthroplasty, with
promising results regarding its efficacy and safety

22. Gene Therapy
• This involves the transfer of genetic material into the genome of the
target cell, allowing expression of bioactive factors from the cells
themselves for a prolonged time.
• Gene transfer can be performed using a viral (transfection) or a non-
viral (transduction)vector, and by either an in vivo or ex vivo gene-
transfer strategy.

23. • With the in vivo method, which is technically relatively easier, the
genetic material is transferred directly into the host; however, there
are safety concerns with this approach.
• The indirect ex vivo technique requires the collection of cells by
tissue harvest, and their genetic modification in vitro before transfer
back into the host.
• Although technically more demanding, it is a safer method, allowing
testing of the cells for any abnormal behaviour before reimplantation,
and selection of those with the highest gene expression