Osteobiologics in the Spine

1
Osteobiologics in the Spine

• Physician Name
• Physician Institution
• Date

2
Bone Grafting in the Spine

• Autograft
• Gold standard
• Best fusion rates
• Significant iliac crest pain and morbidity
• Allograft
• Useful for anterior interbody applications,
  pediatric deformity, and as a bone graft extender
  for PLF
• Low fusion rates posteriorly
• Can be used as an extender
• Disease transmission/religious issues
• Lot to lot variability and questionable
  osteoinductivity due to processing methods

3
Autograft The Gold Standard

• Provides a scaffold for bone formation
• Contains the living cells necessary to build new
  bone
• Naturally remodels into a mechanically strong
  fusion mass
• Recognized as the clinical standard that must be
  met by any bone graft substitute

Iliac Crest Autograft Harvesting
4
Limitations of Autograft

• Requires a second surgical procedure to harvest
  the graft
• Results in significant morbidity to the patient
  and increasedsurgical costs
• Quality and quantity can vary from patient to
  patient

Iliac Crest Autograft Harvesting
5
Recreating the Autograft Environment

• Why autograft works
• Provides a matrix for bone formation
• Contains biological stimulants (ie, growth
  factors) embedded in bone
• Brings along the cells necessary to build new bone

Recreating an environment based on 3
dimensions the matrix, the biologic stimulants,
and the cells
Iliac Crest Autograft Harvesting
6
Autograft Is The Gold Standard

• Living bone
• Contains all the necessary materials for bone
  growth
• Cells
• Growth factors
• Matrices
• No risk of disease transmission

7
Autograft Issues
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Incidence of Graft-site Pain

• Younger and Chapman, 1989 2.5
• Schnee et al, 1997 2.8
• Sawin et al, 1998 17
• Fernyhough et al, 1992 29
• Goulet et al, 1997 37
• Summers and Eisenstein, 1989 49

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Key Ingredients for Bone Formation
2. Biological StimulantsOsteopromotion
Osteoinduction
1. Matrix Osteoconduction
Nutrition
3. Cells Osteogenicity
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Bone Grafting in the Spine

• Bone graft extenders
• Demineralized bone matrix
• Putty or gel form
• Tricalcium phosphate
• Granules
• Bone graft substitutes
• Bone morphogenetic protein (BMP)
• Autologous stem cells

Carrier is important
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Bone Grafting in the Spine

• Ideal characteristics of a bone graft substitute
• Same fusion rates as autograft
• Useful for multiple applications
• Ease of handling (stays where you place it)
• Easily transportable (no refrigeration)
• Osteoconductive
• Osteoinductive
• Reasonable cost

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Structure of Bone
Articular Cartilage
Epiphysis
Metaphysis
Periosteum
Diaphysis (shaft)
Medullary Cavity (bone marrow cavity)
Cortical (compact) Bone
Cancellous (spongy) Bone
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Types of Bone
Cortical

• Compact, dense
• Structural
• Proteins, bone morphogenetic proteins (BMPs)
• Source of demineralized bone matrix (DBM)

Cancellous

• Spongy, porous
• Nonstructural
• Marrow, mesenchymal stem cells (MSCs)
• Cancellous chips

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Wolffs Law

• Bone grows in response to mechanical stress
  to better accommodate that stress.
• Wolff, 19th Century German Physician

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Macrostructure of Bone

• Wolffs Law in operation
• Stress follows predictable paths
• Bone responds by increasing mass and density
• Macrostructure adapts to stresses

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Microstructure of Bone

• Mature bone is very organized
• Concentric cylinders of bony material
• Reinforced by parallel collagen fibers
• Interconnected network of channels and capillaries

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Bone Maturity
Woven Bone
Lamellar Bone
Immature, Disorganized Collagen Structure
Mature, Organized, Aligned Collagen Structure
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Bone Maturity
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Bone Composition
Bone
Living Cells Osteoclasts,Osteoblasts, Osteocytes
Matrix
30
70

• Inorganic/Minerals
• Mineral salts
• Hydroxyapatite (HA)

• Organic/Proteins
• 90 Collagen
• 10 Noncollagenous

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Bone Cells

• Osteoblasts These are bone-forming cells they
  are usually found on the surface of the bone
• Osteocytes These are the most common bone cells
  they are encased in mineralized bone matrix
• Osteoclasts These are large multinuclear cells
  that eat bone derived from hematopoietic stem
  cells
• All cells originate from stem cells

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A Review of Stem Cells

• Undifferentiated cells
• Lacking certain tissue-specific differentiation
  marker
• Major activity cell division
• Proliferation
• Maintains the stem-cell population
• Give rise to specialized, functional cells
• Differentiation
• Able to regenerate tissue after injury
• Stem cells are found in embryos and adults

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Types of Stem Cells
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Types of Stem Cells
Embryo one common stem cell

• Embryonic stem cells
• Found in embryos
• Give rise to all other stem cells

Adult multiple tissue-specific stem cells

• Hematopoietic stem cells
• Responsible for blood formation
• Mesenchymal stem cells
• Responsible for connective tissue formation

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Types of Stem Cells

• Hematopoietic stem cells
• Precursor to all blood and immune system cells,
  as well as bone-resorbing cells (osteoclasts)
• Located mostly in bone marrow
• Mesenchymal stem cells
• Precursor to all connective tissue cells (eg,
  bone, cartilage, tendon, fat, muscle)
• Located mostly in bone marrow

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Bone MarrowSource of Osteoprogenitor Cells
Bone
Lymphoid Progenitor Cell
Hematopoietic Stem Cell
Platelets
Red Blood Cell
Osteoclast
Bone or Cartilage
Osteoblast
Mesenchymal Stem Cell
Osteocyte
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Stem-cell Divisions
The number of hematopoietic stem cells remains
stable
Hematopoietic Stem Cell
White Blood Cell
Hematopoietic Stem Cell
Red Blood Cell
Hematopoietic Stem Cell
Intermediate Cell Stages (multipotent)
Platelet
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Mesenchymal Stem-cell Lineages
The number of hematopoietic stem cells remains
stable for most of adult lifedecrease noted
late in life
Fat Cells
Mesenchymal Stem Cell
Skin Cells
Cartilage Cells
Muscle Cells
Mesenchymal Stem Cell
Tendon Cells
Bone Cells
Osteoblasts
Mesenchymal Stem Cell
Intermediate Cell Stages (multipotent)
Osteocytes
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Hematopoietic Stem-cell Lineages
Osteoclast
Hematopoietic Stem Cell
White blood cell
Hematopoietic Stem Cell
Red Blood Cell
Intermediate Cell Stages (multipotent)
Hematopoietic Stem Cell
Platelet
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Bone Formation Cycle
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Bone Formation Microscopic
Osteoprogenitors
Osteoblasts with cuboidal shapes
Osteocytes embedded in matrix
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Bone Remodeling

• Bone formation is a continuous process
• Bone resorption by osteoclasts is also a
  continuous process
• Imbalance in formation versus resorption rate can
  lead to bone diseases (eg, osteoporosis)
• All bones are constantly remodeledfor a long
  bone, like the femur, complete remodeling takes
  about 7 years

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Bone Remodeling
Cutting Cone (Creeping Substitution)
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The 4 Steps of Bone Repair
Step 1Clot Formation

• Bone injury results in signaling of platelets and
  fibrin from plasma to form a clot
• To stop bleeding
• Stabilize the fracture
• Platelets activate and release multiple signaling
  growth factors

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The 4 Steps of Bone Repair
Step 1InflammationRemove Debris

• The released growth factors attract
  (chemoattraction)
• White blood cells
• Mesenchymal stem cells
• White blood cells clear wound of damaged,
  necrotic tissue

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The 4 Steps of Bone Repair
Step 2Tissue Regeneration
Soft calluscartilage is formed, followed by new
vessel formation
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The 4 Steps of Bone Repair
Step 3Tissue Regeneration
Hard calluscartilage begins to be replaced by
woven bone
37
The 4 Steps of Bone Repair
Step 4Tissue Remodeling

• Remodeling
• Converts woven bone to lamellar bone
• Continues to remodel or refresh
• Wolffs Law

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The Role of Growth Factors
TGF tumor growth factor PDGF
platelet-derived growth factor IGF
insulin-like growth factor VEGF vascular
endothelial growth factor.
39
Osteoconduction

• Supports the attachment of osteoblasts to
  scaffold surface
• Allows for the migration of osteoprogenitor and
  vascular cells into scaffolds
• 3-dimensional construct formation optimized when
  matrix has a high degree of porosity and
  interconnectivity

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Osteoconduction Example Tricalcium Phosphate
(TCP)
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Osteopromotion and Osteoinduction

• Can attract cell and affect cell proliferation
  and matrix formation, but does not affect
  differentiation

Osteopromotive
Biological Stimulants

• Affects cell differentiation, in addition to
  chemotaxis, cell proliferation, and matrix
  formation

Osteoinductive
Bone FormationEffectiveness
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Osteopromotion Bone Marrow Technologies

• Osteogenic foundation of autograft
• Rich source of osteoprogenitor cells
• Bone formation and remodeling depends on cells
• Patient derived/inherently safe
• No chance of rejection
• No patient morbidity
• Cost effective

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Osteopromotion Bone Marrow Technologies

• Bone marrow aspirate
• Requires an osteoconductive carrier
• Crosslinking and mineralization creates unique
  shape memory feature

HEALOS Bone Graft Replacement
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HEALOS Composition
Type I Bovine Fibrillar Collagen(70)
360? Hydroxyapatite Coating (30)
Proprietary Porous Crosslinked Matrix
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HEALOS Bone Marrow Aspirate

• HEALOS
• Material closely mimics early phase of natural
  bone formation
• Immediately recognized and remodeled by cells
• Always used with bone marrow
• Bone marrow
• Bodys primary source of MSCs and osteoprogenitor
  cells
• Active ingredient in autograft

Stem cells in marrow attach to HEALOS
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Baboon Interbody Spine Fusion StudyMidsagittal
Histologic Sections

• 3-Month Specimens

Autograft
HEALOS
Griffith et al. Non-human primate evaluation of
an osteoconductive bone substitute in an
interbody fusion Cage. EuroSpine 1999 September
7-11, 1999 Munich, Germany.
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July 2006 Spine Journal

• Overview
• 25 consecutive patient study with interbody
  fusion and posterior instrumentation
• HEALOS on one posterolateral side, Iliac Crest
  Autograft on the contralateral side
• Independent radiographic review with x-ray,
  computed tomography (CT), visual analog scale
  (VAS), Oswestry Disability Index (ODI)

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July 2006 Spine Journal

• IMAGE 2-year sagittal CT of 58-year-old female
  patient with lumbar fusion at L4-L5
• Autograft side rated as nonunion
• HEALOS side rated as a union
• Results
• 2-year autograft fusion rate 84
• 2-year HEALOS fusion rate 80
• No significant difference between both arms
• 2-year ODI reduction 56
• 2-year VAS reductions 76 (Leg), 34 (Back)

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HEALOS-dependent Bone
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Osteogenicity Example Concentrated Bone Marrow
3-4x selective concentration of osteoprogenitor
cells
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Does an Increase in Cells Improve Healing
Response?
Native Levels of Osteoprogenitor Cells
3- to 4-Fold Increase in Osteoprogenitor Cells
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More Cells More Bone
Whole Bone Marrow
Concentrated Bone Marrow
Improved Bone Formation
Connolly
Good Results
Improved Bone Formation
Muschler
Good Results
Improved Bone Formation
Bruder
Good Results
Improved Bone Formation
Brodke
Good Results
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CELLECT

• 1st technology to enrich a graft with a 3- to
  4-fold increase in osteoprogenitor cells
• Based on the concept of SELECTIVE RETENTION
• Developed in conjunction with The Cleveland
  Clinic

CELLECT
Data on file, DePuy Spine.
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How Does It Work?
? Control Specific Variables

• Hematopoietic stem cells
• 99 of cells, no surface receptors
• Osteoprogenitor cells
• 1 of cells, surface receptors

The Input

• Optimized flow parameters
• Time, number of passes, direction
• Optimized matrix
• Porosity, thickness, composition

The Controlled Variables

• 88 of osteoprogenitors
• 50 of hematopoietic cells
• 3- to 4-fold increase in
• osteoprogenitors

The Result
Data on file, DePuy Spine.
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Why Does It Work?
Mesenchymal Stem Cells Have an Affinity for a
Matrix
MSCs (attaching cells) generate osteoprogenitor
cells directly responsible
for bone
formation
Hematopoietic stem cells (suspension cells)
generate blood cells, and do not attach to
matrices
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Proper Technique Is CriticalAspirate Highly
Cellular Bone Marrow
Aspirate 2 cc ofbone marrow per site
Limit dilution of marrow with peripheral blood
Highly Cellular Marrow
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More Bone-forming Cells More Bone
Preclinically shown to accelerate fusion over
whole bone marrow
100
3- to 4-FOLD INCREASE IN CELLS
80
60
Fusion Rate
SOME CELLS
NO CELLS
40
20
0
Matrix CELLECT
Matrix Marrow
Matrix Alone
Autograft
Brodke et al. Canine femoral gap white paper.
Preclinical data presented at ORS 2002.
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Canine Femoral GapHEALOS
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Osteoinduction Example BMPs

• BMPs Bone morphogenetic proteins
• 1965Dr Marshall Urist, University of California,
  Los Angeles, (UCLA) finds that demineralized
  animal bone implants cause the formation of new
  bone coins BMP term
• 1972Dr Hari Reddi, National Institutes of
  Health, reports that BMP is a soluble material
  (protein) in bone matrix
• 1988Dr John Wozney, Genetics Institute, purifies
  the protein, and discovers the genetic sequence
  of several BMPs
• 2000The first rhBMP-2 product for bone formation
  is reviewed by the US Food and Drug
  Administration
• 2002rhBMP-2 commercialized for use
• Today DePuy Spine is developing rhGDF-5
  (BMP-14), a highly potent BMP for commercial use

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rhGDF-5
OP1
Infuse
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BMP

• Fusion rates equivalent to autograft in the
  musculoskeletal system, including the spine
• Correct dosage for each application is still
  being studied
• Some dose-related complications have been
  reported
• Correct carrier for these molecules is still
  being studied
• Leaching from carrier can be problematic in some
  cases which can lead to unwanted ectopic bone
  formation
• Cost is a major issue

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Costs(Single-level Fusions)
Orthopedic Network News. 200415(4).
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Biologics Applications Yesterday
Poor
AUTOGRAFT
Biology
Normal
Small
Large
Bone-defect Size
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Biologics Applications Today
Suggestion guide based on general clinical
scenario
Cell Enriched
Cell Enriched
Cell Enriched BMPs
Poor Good
Bone Biology
Osteogenic (eg, cervical)
Osteogenic/Cell Enriched (eg, posterolateral,
no comorbidity)
Cell Enriched
Osteoconductive iliac crest backfill
(eg, nonmorbidity, IBF patients)
Osteogenic (eg, scoliosis youngpatients)
Osteogenic
Small Large
Defect Size