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106
7 Physiolog y of Bone Healing and Fusion
Fi g . 7 . 3 Me s e nch ym al s t e m ce ll d i e re nt iat ion in t o e nd och o nd ra l ve r s u s in t ra m e m b r a n ou s b on e
form at ion.
III. Bon e r e p a ir an d re m od elin g (Fig. 7.4).
A. He m at o m a an d in a m m at or y r e sp on se .
1. Predominant cell types.
a. Macrophages.
b. Platelets.
2. Cytokines.
a. IL-1, IL-6.
b. TGF-b.
c. Prostaglandin E2.
B. Ea rly s t a g e .
1. Predominant cell types.
a. Mesenchymal cells.
b. Fibroblasts.
2. Protein expression.
a. BMP.
b. TGF-b.
C. He m a t o m a m a t u r a t io n .
1. New collagenous matrix is produced and slowly replaced by cartilage
for m at io n (e n d och on d ral o ssi cat ion ).
2. Collagen types I and II are predominant.
D. Conversion o f car tilage t o bon e.
1. The formed hypertrophic cartilage is slowly replaced by bone.
7 Physiolog y of Bo ne Healing and Fusion 107
Fi g . 7 . 4 Proce ss of bone re pair and rem o deling .
2. Protein expression:
a. BMP.
b. TGF-b.
c. IGFs.
d. Collagen types I and V.
e. Osteocalcin.
E. Bon e r e m od elin g.
1. Newly formed bone (woven bone) is then remodeled through tight
regulation between osteoblasts and osteoclasts.
7.2 Physiology of Bone Grafts
I. Typ e s of graft s.
A. Au t ogr a ft .
1. Iliac crest bone graft (ICBG) is the gold standard.
B. All o gr aft s.
1. Fresh, frozen.
2. Freeze dried.
3. Cortical cancellous chips.
4. Demineralized bone matrix (DBM).
II. Bon e g r a ft u se in sp in e su rger y (Fig. 7.5).
A. In d u ce s fu s ion b e t we e n ve r te b r a l s e gm en ts .
B. Re p la ce s b on e d efe ct s s eco n d a r y t o t r a u m a , t u m o r, o r in fe ct io n s .
III. Bon e graft in cor p orat io n .
A. Un d i e r e n tia t e d p ro ge n it o r ce lls a re r e cr u it e d fr o m t h e h ost b e d a n d t h e
implanted autograft.
1. Osteogenic cells from the autograft help to form the initial bone matrix
(osteogenesis).
108
7 Physiolog y of Bone Healing and Fusion
Fi g . 7 . 5 Use o f b on e g ra ft .
B. Ch e m ot a xis o f t h es e p ro ge n it or ce lls is i n d u ce d b y t h e r e le a s e o f in t r a ce llu la r
cytokines and protein expression as a result of the following:
1. Cell death.
2. Surgical trauma.
3. Decortication.
4. Low oxygen tension and low pH.
C. Un d i e r en t iat ed p ro g e n i t or ce lls b e co m e ch o n d r o bla s t s a n d o st e ob la st s
mediated by growth factors and cytokines (endochondral ossi cation).
D. The graft ’s protein m atr ix acts as a sca old for bon y in grow th .
IV. Gen era l cat egories of b on e graft s.
A. Su bst it u t e s: ge n e r a l t e r m s fo r m at e r ia ls o r co m p osit e gr aft s t o b e in t e n de d t o
replace autografts (e.g., allograft, DBM, BMP).
B. Ex t e n d e r s: u se d in c o m b i n a t io n w it h a u t og r a ft t o in cr ea s e t h e a m o u n t o f
osteoconductive and osteoinductive factors for fusion (e.g., calcium phosphate
ceram ics, allograft, DBM).
C. En h an ce r s : m at e r ia ls u se d in co n ju n ct io n w it h a u to g r a ft t o in cr e as e t h e r a t e o f
fusion ; sh ould not be used alone (e.g., DBM, BMP, stem cells).
V. Fa c t o r s a e c t i n g s p i n a l f u s i o n .
A. Pa t ie n t fa c t o r s.
1. Age.
2. Smoking (nicotine consumption).
3. Diabetes mellitus.
4. Metabolic bone disease.
5. Vitamin D de ciency.
B. An a t o m ic a l r e g i o n s.
1. Spine segment.
a. Cervical spine.
(1) Less body m ass to support.
(2) Minimal intervertebral displacem ent and microm otion due to larger
cont act area bet ween adjacent vertebral bodies.
(3) Low strain environm ent optim izes bone form ation.
7 Physiolog y of Bo ne Healing and Fusion 109
(4) Fusion rates are 82 to 100%.
b. Thoracic spine.
(1) Rib attachments provide additional stability and m inim ize exion,
bending, and rotation of vertebral segments.
(a) Associated with high fusion rates.
(2) The thoracolum bar transition (T12–L1), however, is highly m obile.
(a) Susceptible to microm otion, hardware failure, and fusion failure
(pseudarth rosis).
c. Lum bar spine.
(1) High joint reaction forces.
(2) The primary motion is exion and extension, w ith minimal lateral
exion and rotation.
(3) Posterior elem ents dem onstrate greater excursion than the anterior
colum n.
(4) Instrum entation that counteracts the large forces of the lum bar spine
is critical to prom ote spinal fusion.
(5) Fusion rates range from 70 to 100%.
C. Su rgica l p ro ce d u r e s.
1. Primary or revision surgery.
2. Levels of fusion.
3. Instrumentation.
4. Surgical techniques.
a. Meticulous decortication.
b. Graft preparation.
D. Typ es an d quan t it y of bon e graft .
E. Me dicat ion s.
1. Nonsteroidal anti-in ammatory drugs.
2. Chemotherapy.
3. Corticosteroid exposure.
F. Ra d i a t i o n .
G. Ele ct rica l st im u lat ion .
H. Ultrasonography.
I. Spin al a lign m e n t .
110
7 Physiolog y of Bone Healing and Fusion
Sugg este d Reading
Ch e n Y, Gu o Q, Pa n X, Qin L, Zh a n P. Sm o k in g a n d im p a ir e d b o n e h e alin g: w i l l a ct iv a -
tion of cholinergic anti-in ammatory pathway be the bridge. Int Orthop 2011;35(9):
1267–1270
Co h e n MM Jr. Th e n e w b o n e b io lo g y: p a t h o lo gic , m o l ec u la r, a n d c l i n i c a l co r re la t e s . Am J
Med Genet A 2006;1 40(23): 2646–2706
Dod w ell ER, Lato r re JG, Parisin i E, et al. NSAID exp osu re an d r isk of n o n un ion : a m et a-
an alysis of case-control a n d coh or t st udies. Calcif Tissu e Int 2010;87(3):193–2 02
Kn ig h t M N, Ha n ke n s on KD. M es e n c h ym a l s t e m c e ll s in b o n e r e ge n e r a t io n . Ad v W o u n d
Care (New Roch elle ) 2013;2 (6):306 –316
Olabisi R. Cell- based t herapies for sp in al fu sion. Adv Exp Me d Biol 2012;76 0:1 48– 173
Re id JJ, Jo h n s o n JS, Wa n g JC. Ch a l le n ge s t o b o n e fo r m a t i o n i n sp in a l fu s io n . J Bio m e ch
2011;44(2):213–220
8 Bone Grafts, Substitutes, and Biologics
8.1 General Considerations
I. Typ e s of b o n e graft s an d b io lo gics.
A. Au t ogr a ft .
1. Iliac crest bone graft (gold standard).
2. Local bone graft.
B. All o gr aft s.
1. Fresh, frozen, or freeze dried.
2. Cortical cancellous bone chips.
3. Demineralized bone matrix (DBM).
C. Ce r a m ics .
D. Bon e m orp h oge n et ic protein s (BMP-2 , BMP-7).
E. Bon e m a r ro w a sp ir at e a n d s t e m ce lls .
II. Pr o p e r t ies of b on e graft s.
A. Ost e o ge n ic: d ir e c t ly p r o v id e cells t h a t go o n t o p ro d u ce b o n e .
1. Examples include bone marrow aspirate and autologous bone grafts.
B. Os te o in d u c t ive : c o n t a in fa ct o r s t h a t in d u ce p r oge n it or ce lls i n t o b o n e - fo r m i n g c e ll s .
1. Examples include BMPs (BMP-2 and BMP-7).
C. Os t e o co n d u c t ive : p ro v id e a s ca o ld fo r n ew b on e fo r m a t io n .
1. Examples include DBMs.
III. Autograft ve r s u s a llogra ft (Table 8.1).
8.2 Allografts
I. DBM.
A. Pr op e r t ie s.
1. Allograft bone that is treated with acid extraction to isolate grow th factors and
structural proteins (collagen). The resulting bone matrix contains < 8% calcium.
a. DBM does not contain osteoprogenitor cells.
b. Good osteoconductive properties.
2. Biologic e ects vary widely among commercially available DBMs.
a. Preparation.
(1) Dem ineralization.
(2) Sterilization.
(3) Carrier.
(a) Glycerol.
(b) Calcium hyaluronate.
(c) Cellulose.
(4) Am ount and ratios of BMPs.
111
112
8 Bon e Graft s, Subst itute s, and Biologics
Ta b l e 8 . 1 Au t o g r a f t ve r s u s a llo g r a f t
Ty p e o f g r a f t A u t o g r a f t A l l o g r a f t
Osteogenic + –
Osteoinductive + ±
Osteoconductive + +
Donor sit e m orb idit y + –
Im m u n e r e a c t io n − ±
Disease t ra n sm ission − ±
Ty p e s • C o r t i c a l
• Corticocancellous
• Cancellous
• Vascularized
• Bone marrow aspirate
Li m i t a t i o n s • Li m i t e d s u p p l y
• Large defects (tumor,
infe c t io n )
• Fresh
• Frozen
• Freeze dried
• Cortical cancellous chips
• Demineralized bone matrix
• Slow incorporation
• High incidence
of resorption in
posterolateral fusions
b. Donor characteristics.
(1) Patient age and gender.
(2) Bisphosphonate utilization.
B. Ur is t r ep or t e d o n DBM- in d u ce d b o n e fo r m at io n in 1 9 6 5 .
8.3 Synthetic Substitutes
I. Ce ram ics.
A. Pr op e r t ie s.
1. Combination of metallic and nonmetallic inorganic elements held together
by ionic or covalent bonds.
2. Do not provide osteogenic or osteoinductive properties.
3. Provide immediate structural support and are osteoconductive.
B. Bio m e ch a n ic a l s t re n g t h .
1. Low fracture resistance and tensile strength.
2. Questionable indication for anterior grafting without supplemental xation.
C. Bo n d in g a n d r ele a s e o f BMPs .
D. Calciu m –based ceram ics.
1. Hydroxyapatite, tricalcium phosphate.
2. Calcium sulfate.
8 Bon e Graft s, Subst itute s, and Biologics 113
3. Calcium phosphate cements.
4. Calcium phosphate ceramics.
E. Clin ic a l u se o f ce r a m ics .
1. Anterior spinal application.
a. Combination with cages or plates.
2. Filling bony defects (vertebroplasty/kyphoplasty).
3. Graft extenders.
8.4 Growth Factors (Biologics)
I. Bon e m or p h oge n et ic p r ot e in s (BMP-2 an d BMP-7 ) (Fig. 8.1).
A. Pr op e r t ie s.
1. Members of the transforming growth factor-b superfamily.
2. Potent osteoinductive properties.
3. Associated with increased fusion rates compared with allograft.
4. BMPs are soluble, locally acting, and naturally occurring signaling proteins.
a. Induce mesenchymal cells to di erentiate into cartilage and bone-
for m in g cells:
(1) Have the ability to induce bone form ation in both soft tissue (muscle,
tendons) and bone.
b. Tightly controlled regulatory mechanisms cause bone induction only at
the site of BMP and only while BMP is present.
c. The biologic e ect of com m ercially available recombinant human BMPs
will depend on the dose and method of delivery.
B. Fo od a n d Dr u g Ad m in is t ra t io n – a p p r ove d BM Ps .
1. Infuse (BMP-2; Medtronic).
a. Approved for a single-level anterior lumbar interbody fusion (ALIF) from
L4 – S1 t o t r e a t d e g e n e r a t i v e d i s k d i s e a s e .
(1) To be used with a tapered interbody fusion device.
b. Approved for acute, open tibial shaft fractures after initial intramedullary
nail xation.
Fi g . 8 . 1 Re g u l a t o r y m e c h a n i s m s in t h e a c t i o n o f b o n e m o r p h o g e n e t i c p r o t e in s .
114
8 Bon e Graft s, Subst itute s, and Biologics
2. OP-1 (BMP-7; Olympus).
a. Approved for the repair of symptomatic, posterolateral (intertransverse)
lum bar spin e pseudarth rosis in patien ts for whom autologous bone an d/
or bone marrow harvest are not feasible.
b. Patients must have at least one of the following comorbidities:
osteoporosis, diabetes, or nicotine use.
c. Approved for recalcitrant long bone nonunions where the use of
autograft is unfeasible and alternative treatments have failed.
d. Available as sterile dry powder and putty.
C. Co n t rove r s ie s w it h BM Ps .
1. Majority of BMP use is o -label.
2. Reported adverse e ects.
a. Neuroforaminal bone growth.
b. Osteolysis.
c. Retrograde ejaculation.
d. Dysphagia.
e. Airway compromise.
f. Ca n cer.
3. Biased and con icted reports in the literature.
a. Yale Open Data Access (YODA) project.
(1) Questionable underreporting of complications.
(2) Limited random ized, controlled prospective studies.
(3) Lack of consistent reporting and underpowered analyses.
II. Bon e m ar row asp ir at e a n d ste m cells (Fig. 8.2).
A. M o st co m m o n s o u rce s.
1. Iliac crest and vertebral body.
2. The number of stem cells in the bone marrow.
a. One in 50,000 in young individuals.
b. One in 2,000,000 in the elderly.
c. Potency of marrow aspirate may be increased via centrifugation or clonal
expansion.
3. Commercially available stem cell–derived bone graft substitute.
a. Provides a sca old for bony ingrowth.
b. Contains adult mesenchymal cells and osteoprogenitor cells to promote
bone formation.
c. Screened cellular allograft that underwent selective rem oval of
im m unogen ic elem ents (blood cells, w hite blood cells, osteoclast s).
d. Undergoes antimicrobial and antifungal treatment.
e. The processed tissue has a 5-year shelf life, because it is cryopreserved.
B. Po t e n t ia l b e n e t s o f m e se n ch ym a l s t e m c e lls ( M SCs ).
1. Oxidative stress modulation.
2. Autogenous bone contains osteoblastic cells.
a. Spinal fusion is largely mediated by these cells.
b. In patients with reduced cellular stores (chronic illness, elderly,
osteoporosis), MSC may aid in obtaining a solid fusion.
8 Bon e Graft s, Subst itute s, and Biologics 115
ab
Fi g . 8 . 2 ( a , b ) Bo n e m a r r o w a s p i ra t io n .
3. Secretion of cytokines and growth factors:
a. Immunomodulation.
b. Anti-in amm atory e ects.
c. Angiogenesis.
d. Antiapoptotic e ects.
e. Osteogenic properties.
4. Self-renewing.
Sugg este d Reading
Cr a n d a ll DG, Re ve l l a J, Pa t t e r s o n J, H u is h E, Ch a n g M , M cLe m o r e R. Tr a n sfo r a m in a l lu m b a r
in t erbody fu sion w ith rhBMP-2 in spin al defor m it y, sp on dylolist hesis, an d degen era tive disease—part 1: Large series diagnosis related outcomes and complications with
2- to 9-year follow -up. Spine 2013; 38(13):1128–11 36
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morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann
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tu te te chn ology in lu m bar sp in e su rge r y. Glob al Spin e J 2 012;2(4):239–2 48
Sim m o n d s MCBJ, Br ow n JV, He ir s MK, et a l. Sa fe t y a n d e e ct ive n ess o f re co m b i n a n t h u -
man bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individualpar ticip an t d at a. An n Inte r n Me d 2013;158(12):877–8 89
Ya m a d a T , Yo s h i i T , S o t o m e S , e t a l . H y b r i d g r a f t i n g u s i n g b o n e m a r r o w a s p i r a t e c o m -
bined with porous b-tricalcium phosphate and trephine bone for lumbar posterolateral spinal fusion: a prospective, comparative study versus local bone grafting. Spine
2012;37(3):E174–E179
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