Bone healing, direct bone healing, indirect bone healing, primary and secondary bone healing, stages of bone healing, substitute of bone healing, autografting and allograft, fracture healing

1. Stages of bone healing and madalities
to enhance bone healing
 By Dr surya Vijay Singh

2. Content
 Structure of bone
 Bone healing
 Types of bone healing
 Factors affecting bone healing
 Modalitiesto enhance bone healing
 Complications

3.  Bone is unique structure with several
specific functions
 Major reservoir of calcium
 Support the human frame
 Origin and insertion of muscles
 Protects vitals soft tissues
 Hepls in motion

4. Bone structure
 Periosteum : 2 layers – 1) fibrous layer, 2) cambium layer
 Outer fibrous layer Consist dense irregular connecting tissue.
 Inner cambium layer/ osteogenic layer Consist primitive stem
cells. It is source of new bone cells.
 Periosteal membrane atteched to blood vessels and nerve
fibrous.
 Compact bone/cortical bone : Outer bone made up of dense
bone contain haversian and volksmancanal, osteons, lamellae.
Haversian system or osteon is functional unit of mature bone.
 Spongy bone/cancellous bone: Inner bone, more at ends of bone
contain trabeculae, weaker than compact bone.
 Endosteum : Inner portion of bone marrow cavity is lined with
fibrous sheet called as endosteum.

6. Bone composition
 Water-8%
 Solidmaterial-92%
 Orgenic phase – 21%
 inorganic phase – 71%

7. Fracture healing
 Definition : Fracture healing is complex process that
requires the recruitment of appropriate cell
(fibroblasts, macrophages, chondroblasts, osteobasts,
osteoclast) and
 the subsequent expansion of the appropriate genes
(those control matrix production and organisation,
growth factors, transcription factors)
 at the right time and in the right Anatomical location.

8. Types of bone healing
Two types of bone healing
1) Direct bone healing / primary bone healing / callous
free bone healing.
2) Indirect bone healing / secondary bone healing / callous
formation bone healing.

9. Primary bone healing
 If the fracture is reduced and held absolute rigidity following internal
fixation and fracture Compression, then bone Heals directly with bone.
 Following conditions for primary bone healing ;
 1. Excellent Anatomical reduction
 2. Minimal or no mobility
 3. Good vascular supply
 4. Absolute stability achieved by interfragmentary compression with
lag screw, compression plate or both.
 2 types of direct / primary bone healing.

10. Types of direct bone healing
 1) Gap healing
 2) contact healing
 GAP HEALING : Even with rigid fixation, in some area of fracture,
small gaps occur between the bone segment.
 Blood vessels from periosteum, endosteumor harvesian canals
invade the gaps bringing osteogenic cells into gap.
 Bone is deposited directly over the fracture ends without resorption
or Intermediate cartilage formation.

11. Gap healing of bone
 If Gap is < 0.3mm then lamellar bone forms
directly.
 If 0.5-1 mm then woven bone formation and
lamellar bone subsequently laid down with in
the trabeculae space.
 At the end of 6 weeks lamellar bundles
oriented at right angle to the Longitudinal Axis
of remaining bone. Over several months,
remodeling then leads to change in this
direction.

12. Contact healing of bone
 Contact Healing occurs only when there
is less then 0.01 mm gap at ends and
Interfragmentarystrain is less than 2%.
The fragments are in direct opposition and
osteons are able to grow across the fracture
site parallel to the long axis. Osteoclasts on
one side of the fracture undergo a
tunneling resorptive response(cutting
cone). This develops the penetration of the
capillary loops which establishes the
Haversians systems. The end result of
contact healing is the regenerationof the
bone architecture.
 Osteon forms at rate of 1-2um/day.

13. Cutting cone of contact bone healing
 Cuttingcones are formed at the ends of the osteons
closest to the fracture site. The tips of the cuttingcones
consist of osteoclastswhich cross the fracture line,
generating longitudinalcavities at a rate of 50–100
μm/day.
 These cavities are later filled by bone produced by
osteoblastsresiding at the rear of the cuttingcone. This
results in the simultaneousgeneration of a bony union
and the restoration of Haversian systems formed in an
axial direction.The re-established Haversian systems
allow for penetrationof bloodvessels carrying
osteoblasticprecursors.
 At cutting cone site osteoclastsform a specialized
membrane, the ‘ruffled border’, which adheres to
woven bone, creating Howship‘s lacunae.

14. Parren‘s interfragmentary strain
hypothesis
 Perren‘s Interfragmentary strain hypothesis
states that the local mechanical
environment affects the tissue response. The
interfragmentary strain is defined as the
ratio of the relativedisplacement of
fracture ends verses the initial fracture gap
width.
 Interfragmentary strain governs the type of
tissue that forms between the fracture
fragments.
 It is inverselyproportional to the fracture
gap size.

15. Parren’s strain hypothesis
 If Interfragmentary strain < 2 % = a state of absolute stability, and primary
(direct) healing occurs.
 When 2 to 10 % = state of relativestability and secondary (indirect) bone
healing occurs.
 If strain > 10 % = poor stability at fracture site, granulation tissue toleratethis
elongation

16. Indirect bone healing / secondary
bone healing
 4 phases of fracture healing :
 1) inflammatory phase
 2) soft callus formation
 3) hard callus formation
 4) remodeling phase

17. Inflammatory phase of bone healing
(week 1)
 Injury cause a haematomaand local inflammation. The
fracture hematomacontains seven-foldgreater amount of
membrane-boundtumor necrosis factor alpha (TNF-α) and
IL-1, IL-6, IL-11 and IL-8 also elevated.
 The presence of cellular debris initiates an inflammatory
response mediated by both local and infiltrating
inflammatory cells, including platelets, polymorphonuclear
cells (PMN), macrophages, and lymphocytes from
surrounding soft tissue and granulation tissue formed.
 Neutrophils are the first cells to arrive at the fracture site, and
are present at least as early as 3 hours after fracture.
 Cliniallythere is erythema, heat, swelling and pain (rubor,
calor, tumor and door). The fracture ends are mobileand
may crept us and causing pain.

18. Soft callus phase of bone healing
(weeks 2-3)
 The soft callusstage of fracture healing is the differentiationof progenitor
cells into chondrocytesand osteoblasts.
 Granulation tissueis graduallyreplacedwith fibrous connective tissue (by
fibroblasts) and cartilage (by chondroblasts).
 Blood vessels grows into the callus(neovasularisation).This process is mainly
regulated by two molecularpathways,an angiopoietin-dependentpathway,
and a vascularendothelialgrowth factor (VEGF)-dependentpathway.
 Fragments ends become sticky and sufficient stabilityto prevent shortening,
but not angulation.

19. Hard callus phase of bone healing
(weeks 4-12)
 Hard callus develops when the fracture ends are held together by soft
callus.
 Bone can formedin two ways; by intramembranous ossification (which
occurs under the periosteum away from the fracture site) and by
endochondral ossification (from a cartilage precursor at the fractured bone
ends).
 This progresses centrally across the fracture gap, gradually reducing
movement and strain. Calcium is laid down in the matrix and the callus
then becomes visibleon radiograph.
 Fracture becomes rigidwith this woven bone and is united when there is no
movement or crepitus at fracture site.
 Clinically reduction of pain and increase sense of stability at the site of
fracture.

20. Location of callus formation
 1) Gap callus between the bone ends
 2) medullary (endosteal) callus along the medullary cavity.
 3) periosteal callus under periosteum.
 Medullary callus provides some resistance to bending movements.Use of
intramedullary nail minimizationmedullary callus but abundance periosteal
callus production.
 Periosteal callus is most effective in providing resistanceto bending and
torsional forces, and resisting force is proportional to the fourth power of the
radius of the cross section of bone through the callus mass.
 In plate fixation, there is plenty of medullary callus as well as periosteal callus on
opposite (compression) side of the plate.

21. Stages of bone healing (biochemistry)

22. Remodelling Of bone healing (months
to years)
 During remodeling, the canalicular architecture of bone is reestablished,
and the haversian system with its osteocytes is restored.
 The osteoclasts ream out a tunnel in the dead cortical bone down that a
blood vessels follows,bringing in the osteoblasts that lay down the lamellar
bone.
 Creeping substitutionreplaces the woven bone with lamellar bone. (in
cancellous bone the cells are closet blood vessels and the process of bone
replacement take on the surface of trabeculae, phenomenon referred to
as creeping substitution).
 By Wolff’s law, involves the strengthening of the internal and cortical
architecture of bones in response to applied physiological (dynamic)
loads.
 The activity of bone resorption by osteoclasts and bone formation by
osteoblasts is linked through the actions of RANK, RANKL, and
osteoprotegerin (OPG).

23. Stages of bone healing (graph)

24. Diamond concept of bone healing
 Fracture healing is complex physiological process and requires
the spatial and timely coordinated action of several different
proteins, cell types, and expressions of hundreds of genes
working towards restoring its structural integrity without scar
formation.
 The four sided model of bone fracture healing interaction.
 1) osteogeniccells (multipotent mesenchymal stem cells –
MSCs)
 2) growth factors – fracture hematomawhich consists signalling
molecules (TNF-a, FGF, PDGF, IGF, VEGF, Interleukin IL1, IL-6,).
 3) osteoconductive scaffold – the extracellular matrix provides
a natural scaffold for all cellular events and interactions.
 4) mechanical environment – mechanical stability is a decisive
factor for bone healing.

25. Factors influencing # healing

26. Modalities to enhance bone healing
 Natural Bone graft
 Bone graft substitute
 Electrical and ultrasound stimulus
 Shock wave therapy
Indications for their use include
malunions, nonunions,arthrodesis,
and reconstructive procedures.

27. Autologous bone graft
 It contain 3 required components for formation of bone
 Iliac crest is commonarea for autografting. Posterior
iliac crest offers more bone for grafting than anterior.
Fibulacan be used for a structural graft, ribs, distal end
radius, olecrenon,Greater trochenter and proximal
tibia can also be used.
 Either cancellous or cortical bone can be harvested
depending on the procedure.
 The morbidity associatedwith graft harvesting, such as
donor-site pain, iliac crest fracture, incisional hernia in
iliac bone graft, nerve or arterial injury, and infection
rates of between 8% and 10%.
 For defects up to 6 cm in length where immediate
structural support is desired, nonvascularized cortical
bone graft used. >12 cm are good candidates for
vascularized grafting procedures. 6-12 cm defect have
controversy.
•Refers to the scaffolding
/structural framework that
allows bone growth.
osteoconduction
•Is the ability to induce /stimulate
the production of osteoblasts.
BMP is most common
osteoinductivemediator.
Osteoinduction
•Material directly provides cells
that will produce bone
including primitive
mesenchymal stem cells,
osteobasts and osteoclasts.
Osteogenesis

29. RIA(reamer, irrigator, aspirator)
 This is a novel intramedullary (IM)-reaming
devicethat is used to irrigate and aspirate the
bone marrow canal. A relatively new technique
developedin 2005 to overcome the donor-site
morbidity associated with autologous bone-
graft.
 RIA developedto decrease intramedullary
pressure and fat embolismduring reaming.
 These marrow bony fragments are rich in
mesenchymal stem cells along with rich in FGF-2,
IGF-B1, and TGF-B But not BMP2.
 Overall, RIA appears to be a safe and effective
method for autologous graft harvesting, leading
to less persistent postoperative pain.
 Complications like perforation of ant. Cortex of
femur.

30. Bone graft substitute
 Bone graft substitute classifiedinto 5 major
categories :
 1) allograft based
 2) factor based
 3) cell based
 4) ceramicbased
 5) polymer based

31. 1) Allograft based bone graft substitute
 Allograft bone is prepared and sterilizedvia freeze-drying, freezing, or irradiation.
 Freeze-drying, or lyophilization, viaa removal of water and vacuum packing of the tissue
significantly reduces immunogenicity. Such treatment of the graft reduces its mechanical integrity,
thereby diminishingits load-bearing properties.
 Irradiation has a similar effect on mechanical strength, decreasing it in a dose-dependent fashion.
 Both freeze-drying and irradiation reduce the osteoinductive potential of the allograft by inducing
the death of its osteogenic cells.
 Demineralized bone matrix (DBM) is the decalcified form of allograft that contains the
osteoinductive proteins that stimulate bone formation. It is supplied as a putty, injectable gel,
paste, powder, strips, and mixtures of these.
 Demineralized allograft usually is mixed with a carrier such as glycerol, calcium sulfate
powder, sodium hyaluronate, and gelatin. Sterilization of DBM by gamma irradiation and
ethylene oxide exposure decreases the risk of disease transmission but also may decrease
the osteoinductive activity of the product..
 contraindicated in patients with severe vascular or neurologic disease, fever, uncontrolled
diabetes, severe degenerative bone disease, pregnancy, hypercalcemia, renal compromise,
Pott disease, or osteomyelitis or sepsis at the surgical site.
 Risk of disease transmission like bacterial infection, hepatitis B, C .

32. 2)Factor based bone graft substitute
 Urist first discovered bone morphogenetic protein (BMP) in 1965 when
he recognized its ability to induce enchondral bone formation.
 Most of the BMPs used today are in the bone superfamily
transforming growth factor-beta (TGF-β).
 Presently, only two proteins have been isolated, produced, and
approved for use in humans. Because they are produced by the
recombinant process, they are designated rhBMP-2 and rhBMP-7.
 Other BMPs that have been shown to have osteogenic properties
are BMP-4, -6, and -9.
 FDA) has approved rhBMP-2 for use in anterior lumbar fusion with a
titanium cage.
 BMP-2 and BMP-7 are water soluble and require a carrier to remain
in the operative area to be effective.
 Other proteins bone formation include platelet-derived growth factor
(PDGF) and vascular endothelial growth factor (VEGF).

33. 3) Cell based bone graft substitute
 Cells may be used to stimulate or seed cells for new tissue.Presently,
the most frequently used cell-based graft is autologous bone marrow.
 In the future, adult and embryonic stem cells, somatic stem cells such
as bone marrow stromal cells, dermal stem cells, and cells in fetal cord
blood may be grown for use as grafts.
 Collagen in its denatured form is an osteoinductive material. It is used
as a carrier for BMP.

34. 4)Ceramic based bone graft substitute
 Ceramic and collagen bone substitutes can provide
osteoconduction without the risk of disease transmission.
 ceramics include calcium sulfate, calcium phosphate, and
bioactive glass.
 In addition to osteoconduction these products are
osteointegrative, having the ability to form intimate bonds
with the tissue.
 Calcium phosphate ceramics come in several varieties,
including tricalcium phosphate and synthetic hydroxyapatite.
 Bioactive glass is silicate-based glass that is biologically
active.Presently, it is used with polymethyl methacrylate to
improve bonding.
 Used with other products as a carrier or for protection (such
as cages).

35. 5)Polymer based bone graft substitute
 include both natural and synthetic polymers, biodegradable and
nonbiodegradable.
 Some nonbiodegradable natural and synthetic polymers are
composites of the polymer and a ceramic and can be used in load-
bearing areas.
 Biodegradable natural and synthetic materials include polyglycolic acid
and poly(lacticco-glycolic) acid.

36. Electrical and ultrasound stimulus For
bone healing
 Electromagnetic stimulation has been used since the early 1970s
in the treatment of delayed unions and nonunions, with reported
success rates of 64% to 85%.
 but it has not been proved to be effective in the treatment of
fresh fractures.
 Electromagnetic stimulate bone healing in following ways:
 1) Direct current delivery through implantedelectrodes ( DCES- direct
current electric stimulation).
 2) Alternating current deliveredthrough an external coil used
intermittently ( PEMF- pulsed electromagnetic field).
 3) current Delivered between two plates that form a magnetic field
used continuously for promoting bone healing ( CCS- capacitively
coupled electrical stimulation).
 It helps to stimulate the secretion of numerous growth factors,
including BMP-2 and BMP-4, TGF-β, and IGF-2.

37. Ultrasound Therapy for bone healing
 Low-intensity ultrasound has been shown to increase the incorporation
of calcium ions in cultures of cartilage and bone cells and to
stimulate the expression of numerous genes involved in the healing
process, including IGF and TGF-β.
 Low-intensity ultrasound also has been suggested to enhance fracture
healing in smokers, a group at risk for delayed unions.

38. Shock wave therapy for bone healing
 Sock wave therapy is used in hypertrophic non-union.
 The waves created microfractures in the hypertrophic tissue,
leads to neovasularisation and osteoinduction.

39. Reference
 Campbell’s Operative
Orthopaedics 13th edition
 Rockwood & Green’s fracture in
adult 8th edition
 Muller manual of fracture fixation
AO Group
 McRae’s Orthopaedics trauma