Bone Research (2013) 3: 216-248.
www.boneresearch.org
REVIEW
Bo ne Re g e ne ra tio n Ba se d o n Tissue Eng ine e ring
C o nc e p tio ns – A 21st C e ntury Pe rsp e c tive
Jan Henkel
1
, Maria A. Woodruff
1
, Devakara R. Epari
1
, Roland Steck
1
, Vaida Glatt
1
, Ian C. Dickinson
2
, Peter
F.M. Choong
3,4,5
, Michael A. Schuetz
1,6
, Dietmar W. Hutmacher
1,7
*
1
Institute of Health & Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia;
2
Orthopaedic Oncology Service, Princess Alexandra Hospital, Brisbane, Australia;
3
Department of Surgery, University of
Melbourne, St. Vincent's Hospital, Melbourne, Australia;
4
Department of Orthopaedics, St. Vincent's Hospital, Melbourne,
Australia;
5
Bone and Soft Tissue Sarcoma Service, Peter MacCallum Cancer Centre, Melbourne, Australia;
6
Orthopaedic and
Trauma Services, Princess Alexandra Hospital, Brisbane, Australia;
7
George W Woodruff School of Mechanical Engineering,
Georgia Institute of Technology, Atlanta, GA, USA
The role of Bone Tissue Engineering in the field of Regenerative Medicine has been the topic of subst
antial
research over the past two decades. Technological advances have improved orthopaedic implants and surgical
techniques for bone reconstruction. However, improvements in surgical techniques to reconstruct bone have
been limited by the paucity of autol
ogous materials available and donor site morbidity. Recent advances in the
development of biomaterials have provided attractive alternatives to bone grafting expanding the surgical
options for restoring the form and function of injured bone. Specifically,
novel bioactive (second generation)
biomaterials have been developed that are characterised by controlled action and reaction to the host tissue
environment, whilst exhibiting controlled chemical breakdown and resorption with an ultimate replacement by
regenerating tissue. Future generations of biomaterials (third generation) are designed to be not only osteo-
conductive but also osteoinductive, i.e. to stimulate regeneration of host tissues by combining tissue engineer-
ing and in situ tissue regeneration
methods with a focus on novel applications. These techniques will lead to
novel possibilities for tissue regeneration and repair. At present, tissue engineered constructs that may find
future use as bone grafts for complex skeletal defects, whether from post-
traumatic, degenerative, neoplastic or
congenital/developmental “origin” require osseous reconstruction to ensure structural and functional integrity.
Engineering functional bone using combinations of cells, scaffolds and bioactive factors is a promisin
g strategy
and a particular feature for future development in the area of hybrid materials which are able to exhibit suitable
biomimetic and mechanical properties. This review will discuss the state of the art in this field and what we can
expect from future generations of bone regeneration concepts.
Keywords: bone tissue engineering; regenerative medicine; additve manufacturing; clinical translation; s
caffolds
Bone Research (2013) 3: 216-248. doi: 10.4248/BR201303002
Intro d uc tion
Afte r 15 ye a rs o f Tissue Eng ine e ring & Re g e ne ra tive Me d i-
c ine 1.0 a nd a no the r 10 ye a rs o f 2.0 ve rsio ns (
1) the e ra
o f tissue e ng ine e ring 3.0 ha s b e g un. This re vie w will d e s-
*C o rre sp o nd e nc e : Die tma r W. Hutma c he r
E-ma il: d ie tma r.hutma c he r@ q ut.e d u.a u
Re c e ive d 11 June 2013; Ac c e p te d 20 July 2013
c rib e the sta te o f the a rt o f the b o ne tissue e ng ine e ring
fie ld a nd p re se nt a p e rsp e c tive o f its ro le in Tissue
Eng ine e ring & Re g e ne ra tive Me d ic ine 3.0. O ve r the la st
te n ye a rs re ma rka b le p ro g re ss ha s b e e n ma d e in the
d e ve lo p me nt o f surg ic a l te c hniq ue s fo r b o ne re c o ns-
truc tio n. Altho ug h the se so p histic a te d te c hniq ue s ha ve
tra nsfo rme d re c o nstruc tive surg e ry a nd sig nific a ntly im-
p ro ve d c linic a l o utc o me s, the y ha ve a lre a dy re a c he d a
numb e r o f the ir p ra c tic a l limits to furthe r imp ro ve he a lth-
Jan Henkel et al.
www.boneresearch.org | Bone Research
217
c a re o utc o me s. To da y ma jo r re c o nstruc tive surg e rie s
(d ue to tra uma o r tumo ur re mo va l) a re still limite d b y the
p a uc ity o f a uto lo g o us ma te ria ls a va ila b le a nd d o no r
site mo rb id ity. Re c e nt a d va nc e s in the d e ve lo p me nt o f
sc a ffo ld -b a se d Tissue Eng ine e ring (TE) ha ve g ive n the
surg e o n ne w o p tio ns fo r re sto ring fo rm a nd func tio n.
The re a re no w b io a c tive b io ma te ria ls (se c o nd g e ne r-
a tio n) a va ila b le tha t e lic it a c o ntro lle d a c tio n a nd
re a c tio n to the ho st tissue e nviro nme nt with a c o ntro lle d
c he mic a l b re a kd o wn a nd re so rp tio n to ultima te ly b e
re p la c e d b y re g e ne ra ting tissue . Third -g e ne ra tio n b io -
ma te ria ls a re no w b e ing d e sig ne d to stimula te re g e n-
e ra tio n o f living tissue s using tissue e ng ine e ring a nd in situ
tissue re g e ne ra tio n me tho d s. Eng ine e ring func tio na l
b o ne using c o mb ina tio ns o f c e lls, sc a ffo ld s a nd b io -
a c tive fa c to rs a re se e n a s a p ro mising a p p ro a c h a nd
the se te c hniq ue s will und o ub te dly le a d to c e a se le ss
p o ssib ilitie s fo r tissue re g e ne ra tio n a nd re p a ir. The re a re
c urre ntly tho usa nd s o f re se a rc h p a p e rs a nd re vie ws
a va ila b le o n b o ne tissue e ng ine e ring , b ut the re is still a
ma jo r d isc re p a nc y b e twe e n sc ie ntific re se a rc h e ffo rts o n
b o ne tissue e ng ine e ring a nd the c linic a l a pp lic a tio n o f
suc h stra te g ie s. The re is a n e vid e nt la c k o f c o mp re -
he nsive re vie ws tha t c o ve r b o th the sc ie ntific re se a rc h
a sp e c t a s we ll a s the c linic a l tra nsla tio n a nd p ra c tic a l
a p p lic a tio n o f b o ne tissue e ng ine e ring te c hniq ue s. This
re vie w will the re fo re d isc uss the sta te o f the a rt o f
sc ie ntific b o ne tissue e ng ine e ring c o nc e p ts a nd will a lso
p ro vid e c urre nt a pp ro a c he s a nd future p e rspe c tive s fo r
the c linic a l a pp lic a tio n o f b o ne tissue e ng ine e ring .
Bo ne bio log y
Bo ne a s a n o rg a n ha s ne xt to its c o mp le x c e llula r c o m-
p o sitio n a hig hly sp e c ia lise d o rg a nic -ino rg a nic a rc hi-
te c ture whic h c a n b e c la ssifie d a s mic ro - a nd na no -
c o mp o site tissue . Its mine ra lise d ma trix c o nsists o f 1) a n
o rg a nic p ha se (ma inly c o lla g e n, 35% d ry we ig ht) re s-
p o nsib le fo r its rig id ity, visc o e la stic ity a nd to ug hne ss; 2) a
mine ra l p ha se o f c a rb o na te d a p a tite (65% d ry we ig ht)
fo r struc tura l re info rc e me nt, stiffne ss a nd mine ra l ho me o -
sta sis; a nd 3) o the r no n-c o lla g e no us p ro te ins tha t fo rm a
mic ro e nviro nme nt stimula to ry to c e llula r func tio ns (2).
Bo ne tissue e xhib its a d istinc t hie ra rc hic a l struc tura l o r-
g a niza tio n o f its c o nstitue nts o n nume ro us le ve ls inc lud -
ing ma c ro struc ture (c a nc e llo us a nd c o rtic a l b o ne ),
mic ro struc ture (Ha rve rsia n syste ms, o ste o ns, sing le tra b e -
c ula e ), sub -mic ro struc ture (la me lla e ), na no struc ture
(fib rilla r c o lla g e n a nd e mb e d d e d mine ra ls) a nd sub -
na no struc ture (mo le c ula r struc ture o f c o nstitue nt e le -
me nts, suc h a s mine ra l, c o lla g e n, a nd no n-c o lla g e no us
o rg a nic p ro te ins) (Fig ure 1) (3). Ma c ro sc o p ic a lly, b o ne
c o nsists o f a d e nse ha rd c ylind ric a l she ll o f c o rtic al b o ne
a lo ng the sha ft o f the b o ne tha t b e c o me s thinne r with
g re a te r d ista nc e fro m the c e ntre o f the sha ft to wa rd s
the a rtic ula r surfa c e s. C o rtic a l b o ne e nc o mpa sse s
inc re a sing a mo unts o f p o ro us tra b e c ula r b o ne (a lso
c a lle d c a nc e llo us o r sp o ng y b o ne ) a t the p ro xima l a nd
d ista l e nd s to o p timise a rtic ula r lo a d tra nsfe r (2). In
huma ns, tra b e c ula r b o ne ha s a p o ro sity o f 50-90% with
a n a ve ra g e tra b e c ula r spa c ing o f a ro und 1mm a nd a n
a ve ra g e d e nsity o f a p p ro xima te ly 0.2 g ·c m
-3
(4-6). C o rti-
c a l b o ne ha s a muc h d e nse r struc ture with a p o ro sity o f
3-12% a nd a n a ve ra g e d e nsity o f 1.80 g ·c m
-3
(5, 7).
O n a mic ro sc o p ic sc a le , tra b e c ula r struts a nd d e nse
c o rtic a l b o ne a re c o mp o se d o f mine ra lize d c o lla g e n
fib re s stac ke d p a ra lle l to fo rm la ye rs, c a lle d la me lla e
(3–7 µm thic k) a nd the n sta c ke d in a ±45° ma nne r (2). In
ma ture b o ne the se la me lla e wra p in c o nc e ntric la ye rs
(3–8 la me lla e ) a ro und a c e ntra l p a rt na me d Ha ve rsia n
c a na l whic h c o nta ining s ne rve a nd b lo o d ve sse ls to
fo rm wha t is c a lle d a n O ste o n (o r a Ha ve rsia n syste m), a
c ylind ric a l struc ture running ro ug hly p a ra lle l to the lo ng
a xis o f the b o ne (3). C a nc e llo us b o ne c o nsists o f inte r-
c o nne c ting fra me w o rk o f ro d a nd p la te sha p e d tra b e -
c ula e . O n a na no struc tura l le ve l, the mo st p ro mine nt
struc ture s a re the c o lla g e n fib re s, surro und e d a nd infil-
tra te d b y mine ra l. At the sub -na no struc tura l le ve l thre e
ma in ma te ria ls a re b o ne c rysta ls, c o lla g e n mo le c ule s,
a nd no n-c o lla g e no us o rg a nic p ro te ins. Fo r furthe r d e ta ils
the re a d e r is re fe rre d to (3).
Mine ra lise d b o ne ma trix is p o p ula te d with fo ur b o ne -
a c tive c e lls: o ste o b la sts, o ste o c la sts, o ste o c yte s a nd
b o ne lining c e lls. Ad d itio na l c e ll typ e s a re c o nta ine d
within the b o ne ma rro w tha t fills the c e ntra l intra -
me d ulla ry c a na l o f the b o ne sha ft a nd inte rtra b e c ula r
spa c e s ne a r the a rtic ula r surfa c e s (8). Bo ne ha s to b e
d e fine d a s a n o rg a n c o mp o se d o f d iffe re nt tissue s a nd
a lso se rve s a s a mine ra l d e p o sit a ffe c te d a nd utilise d b y
the b o d y’ s e nd o c rine syste m to re g ula te (a mo ng o the rs)
c a lc ium a nd p ho sp ha te ho me o sta sis in the c irc ula ting
b o d y fluid s. Furthe rmo re , re c e nt stud ie s ind ic a te tha t
b o ne e xe rts a n e nd o c rine func tio n itse lf b y p ro d uc ing
ho rmo ne s tha t re g ula te p ho sp ha te a nd g luc o se ho me o -
sta sis inte g ra ting the ske le to n in the g lo b a l mine ra l a nd
nutrie nt ho me o sta sis (9).
Bo ne is a hig hly d yna mic fo rm o f c o nne c tive tissue
whic h und e rg o e s c o ntinuo us re mo d e lling (the o rc he s-
tra te d re mo va l o f b o ne b y o ste o c la sts fo llo we d b y the
fo rma tio n o f ne w b o ne b y o ste o b la sts) to o ptima lly a d a p t
its struc ture to c ha ng ing func tio na l d e ma nd s (me c ha ni-
c a l lo a d ing , nutritio na l sta tus e tc .). Fro m a ma te ria l sc i-
e nc e p o int o f vie w b o ne ma trix is a c o mp o site ma te ria l
o f a p o lyme r-c e ra mic la me lla r fib re -ma trix a nd e a c h o f
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Bone Research | Vol 1 No 3 | August 2013
218
the se d e sig n a nd ma te ria l a spe c ts influe nc e the me -
c ha nic a l p ro p e rtie s o f the b o ne tissue (10). The me -
c ha nic a l p ro p e rtie s d e p e nd o n the b o ne c o mp o sitio n
(p o ro sity, mine ra lisa tio n e tc .) a s we ll a s the struc tura l
o rg a nisa tio n (tra b e c ula r o r c o rtic a l b o ne a rc hite c ture ,
c o lla g e n fib re o rie nta tio n, fa tig ue d a ma g e e tc .) (11).
C o lla g e n p o sse sse s a Yo ung ’ s mo d ulus o f 1-2 G Pa a nd
a n ultima te te nsile stre ng th o f 50-1 000 MPa , c o mpa re d
to the mine ra l hyd ro xya p a tite whic h ha s a Yo ung ’ s
mo d ulus o f ~130 GPa a nd a n ultima te te nsile stre ng th o f
~100 MPa . The re sulting me c ha nic a l p ro pe rtie s o f the
two typ e s o f b o ne tissue , na me ly the c o rtic a l b o ne a nd
c a nc e llo us b o ne , a re sho wn in Ta b le 1. Ag e a nd re la te d
c ha ng e s in b o ne d e nsity ha ve b e e n re p o rte d to sub -
sta ntia lly influe nc e the me c ha nic a l p ro p e rtie s o f c a nc e -
llo us b o ne (12). As o utline d a b o ve , b o ne sho ws a d istinc t
hie ra rc hic a l struc tura l o rg a niza tio n a nd it is the re fo re
imp o rta nt to a lso d e fine the me c ha nic a l p ro p e rtie s a t
mic ro struc tura l le ve ls (Ta b le 2). Altho ug h the c a nc e llo us
a nd c o rtic a l b o ne ma y b e o f the sa me kind o f ma te ria l,
the ma tura tio n o f the c o rtic a l b o ne ma te ria l ma y a lte r
the me c ha nic a l p ro p e rtie s a t the mic ro struc tura l le ve l.
Bo ne tissue is a lso kno wn to b e me c ha no -re c e p tive ;
b o th no rma l b o ne re mo d e lling a nd fra c ture o r d e fe c t
he a ling a re influe nc e d b y me c ha nic a l stimuli a p p lie d a t
the re g e ne ra ting d e fe c t site a nd surro und ing b o ne tissue
(17-20). In c o ntra st to mo st o the r o rg a ns in the huma n
b o d y, b o ne tissue is c a p a b le o f true re g e ne ra tio n, i.e .
he a ling witho ut the fo rma tio n o f fib ro tic sc a r tissue (21).
During the he a ling p ro c e ss b a sic ste p s o f fe ta l b o ne
d e ve lo p me nt a re re c a p itula te d a nd b o ne re g e ne ra te d
in this wa y d o e s no t diffe r struc tura lly o r me c ha nic a lly
fro m the surro und ing und a ma g e d b o ne tissue (22). Ho w-
e ve r, d e spite this tre me nd o us re g e ne ra tive c a p a c ity,
Table 1 Mechanical properties of compact (cortical)
and spongy (cancellous) bone. Reproduced and modi-
fied from (13).
Pro p e rty Co rtic al
b o ne
Ca nc e llo us
b o ne
Co mp re ssive stre ng th/ MPa 100-230 2-12
Fle xura l, te nsile stre ng th/ MPa 50-150 10-20
Stra in to fa ilure / % 1-3 5-7
Fra c ture to ug hne ss/ MPa m
1/ 2
2-12 -
Yo ung ’ s mo dulus/ G Pa 7-30 0.5-0.05
Table 2 Young’s modulus (GPa) (according to various
levels of architecture). Modified from (14-16) as listed in
the table.
Arc hite c ture Yo ung ’ s mo d ulus
We t sp e c ime n (ma c ro struc tura l) (14) 14-20
We t sp e c ime n (mic ro struc tura l) (15) 5.4
Dry sp e c ime n (sub mic ro struc ture ) (16) 22
Figure 1 Hierarchical structural organization of bone: (A) cortical and cancellous bone; (B) osteons with Haversian systems; (C) lamellae; (D) collagen
fibre assemblies of collagen fibrils; (E) bone mineral crystals, collagen molecules, and non-collagenous proteins. Reproduced with permission from (3),
©1998 IPEM.
Jan Henkel et al.
www.boneresearch.org | Bone Research
219
5-10% o f a ll fra c ture s a re p ro ne to d e la ye d b o ny unio n
o r will p ro g re ss to wa rd s a no n-unio n a nd the d e ve lo p -
me nt o f a p se ud a rthro sis (23-24). To g e the r with la rg e
tra uma tic b o ne d e fe c ts a nd e xte nsive lo ss o f b o ne
sub sta nc e a fte r tumo ur re se c tio n o r re visio n surg e ry a fte r
fa ile d a rthro p la stie s, the se p a tho lo g ic a l c o nd itio ns still
re p re se nt a ma jo r c ha lle ng e in to d a y’ s c linic a l p ra c tic e .
The ra ng e o f b o ne g ra ft ma te ria ls a va ila b le to tre a tsuc h
p ro b le ms in mo d e rn c linic a l p ra c tic e e sse ntia lly inc lud e
a uto lo g o us b o ne (fro m the sa me p a tie nt), a llo g e ne ic
b o ne (fro m a d o no r), a nd d e mine ra lise d b o ne ma tric e s,
a s we ll a s a wide ra ng e o f synthe tic b o ne sub stitute
b io ma te ria ls suc h a s me ta ls, c e ra mic s, p o lyme rs, a nd
c o mp o site ma te ria ls. During the la st d e c a d e s, tissue
e ng ine e ring stra te g ie s to re sto re c linic a l func tio n ha ve
ra ise d c o nsid e ra b le sc ie ntific a nd c o mme rc ia l inte re st in
the fie ld o f o rtho p a e d ic surg e ry a s we ll a s re c o nstruc tive
a nd o ro ma xillo fa c ia l surg e ry. Ye t, the tre a tme nt o f b o ne
d e fe c ts a nd the se a rc h fo r b o ne sub stitute ma te ria ls is
no t just a mo d e rn d a y p he no me no n, with its histo ry
re a c hing b a c k thro ug h mille nnia .
Bo ne g ra fting a nd b o ne sub stitute s in the la st
4 000 ye a rs
The q ue st fo r the mo st e ffic ie nt wa y to sub stitute fo r lo st
b o ne a nd to d e ve lo p the b e st b o ne re p la c e me nt
ma te ria l ha s b e e n p ursue d b y huma ns fo r tho usa nd s o f
ye a rs.
In Pe ru, a rc ha e o lo g ists d isc o ve re d the skull o f a trib a l
c hie f fro m 2000 BC in whic h a fro nta l b o ne d e fe c t
(p re suma b ly fro m tre p a na tio n) ha d b e e n c o ve re d with
a 1 mm-thic k p la te o f ha mme re d g o ld (25). Tre p hine d
Inc a n skulls ha ve b e e n fo und with p la te s ma d e fro m
she lls, g o urd s, a nd silve r o r g o ld p la te s c o ve ring the
d e fe c t a re a s (26). In a skull fo und in the a nc ie nt c e nte r
o f Ishtkunui (Arme nia ) fro m a p p ro x. 2000 BC, a 7 mm
d ia me te r skull d e fe c t ha d b e e n b rid g e d with a p ie c e o f
a nima l b o ne (27). The se p ursuits a re no t limite d to skull
surg e rie s invo lving b o ne sub stitute s. Anc ie nt Eg yp tia ns
ha ve b e e n sho wn to ha ve p ro fo und kno wle d g e o f
o rtho p a e d ic und tra uma to lo g ic a l p ro c e d ure s with Sur-
g e o ns ha ving imp la nte d iro n p ro sthe se s fo r kne e jo int
re p la c e me nt a s e a rly a s 600 BC , a s a na lyse s o f p re se rve d
huma n mummie s ha ve re ve a le d (28).
The first mo d e rn e ra re p o rt o f a b o ne xe no g ra ft p ro -
c e d ure is b e lie ve d to b e the Dutc h surg e o n Jo b Ja ns-
zo o n va n Me e ke re n in 1668 (29-30). A skull d e fe c t o f a
Russia n no b le ma n wa s suc c e ssfully tre a te d with a b o ne
xe no g ra ft ta ke n fro m the c a lva ria o f a d e c e a se d d o g .
The xe no g ra ft wa s re p o rte d to ha ve b e c o me fully
inc o rp o ra te d into the skull o f the p a tie nt. In the 1800s,
p la ste r o f Pa ris (C a lc ium sulpha te ) w a s use d to fill b o ne
c a vitie s in p a tie nts suffe ring fro m Tub e rc ulo sis (31).
Atte mp ts we re a lso ma d e to fill b o ne d e fe c ts with
c ylind e rs ma d e fro m ivo ry (32). In 1820 the G e rma n sur-
g e o n Phillip s vo n Wa lte rs d e sc rib e d the first c linic a l use o f
a b o ne a uto g ra ft to re c o nstruc t skull d e fe c ts in p a tie nts
a fte r tre p a na tio n (33). Wa lte rs suc c e ssfully re pa ire d tre -
p a na tio n ho le s, fo llo wing surg e ry to re lie ve intra c ra nia l
p re ssure , with p ie c e s o f b o ne ta ke n fro m the p a tie nt’ s
o wn he a d . In 1881, Sc o ttish surg e o n Willia m Ma c Ewe n
d e sc rib e d the first a llo g e nic b o ne g ra fting p ro c e d ure :
He use d tib ia l b o ne we d g e s fro m thre e d o no rs tha t ha d
und e rg o ne surg e ry fo r ske le ta l d e fo rmity c o rre c tio n
(c a use d b y ric ke ts) to re c o nstruc t a n infe c te d hume rus
in a 3-ye a r-o ld c hild (34)
Ma jo r c o ntributio ns le a ding to the d e ve lo p me nt o f
mo d e rn d a y b o ne g ra fting p ro c e d ure s a nd b o ne sub -
stitute s ha ve b e e n ma d e b y Ollie r a nd Ba rth in the la te
1800s. Lo uis Lé o p o ld O llie r c a rrie d o ut e xte nsive e xp e ri-
me nts to stud y the o ste o g e nic p ro p e rtie s o f the p e ri-
o ste um a nd o the r va rio us a p p ro a c he s to ne w b o ne fo r-
ma tio n, ma inly in ra b b it a nd d o g mo d e ls. He a lso me ti-
c ulo usly re vie we d the lite ra ture o n b o ne re g e ne ra tio n
a va ila b le a t tha t time a nd in 1867 he p ub lishe d his
1 000-p a g e te xtb o o k ‘ Tra ite e xp e rime nte l e t c liniq ue de
la re g e ne ra tio n d e s o s e t de la p ro duc tio n a rtific ie lle du
tissu o sse ux’ , in whic h he d e sc rib e d the te rm ‘ b o ne g ra ft’
(“ g re ffe o sse use ” ) fo r the first time (35). In 1895 the G e r-
ma n surg e o n Arthur Ba rth p ub lishe d his tre a tise ‘ Ue b e r
histo lo g isc he Be funde na c h Kno c he nimp la nta tio ne n’
(‘ O n histo lo g ic a l find ing s a fte r b o ne imp la nta tio ns’ )
p re se nting his re sults o f va rio us b o ne g ra fting p ro c e d ure s
invo lving the skull a nd lo ng b o ne s (hume rus, fo re a rm
b o ne s) o f d o g s a nd ra b b its inc lud ing histo lo g ic a l a sse ss-
me nt (36). To d a y, b o th O llie r’ s a nd Ba rth’ s wo rk a re c o n-
sid e re d to b e mile sto ne s in the d e ve lo p me nt o f p re se nt
d a y b o ne g ra fting p ro c e d ure s a nd b o ne sub stitute
ma te ria ls.
With the d e ve lo p me nt o f ne w o rtho p a e d ic te c hniq ue s
a nd inc re a se d numb e rs o f jo int re p la c e me nt p ro c e d ure s
(p ro sthe se s), the d e ma nd fo r b o ne g ra fts inc re a se d in
the 20
th
c e ntury, le a d ing to the o p e ning o f the first b o ne
b a nk fo r a llo g e nic b o ne g ra fts in Ne w Yo rk in 1945 (37).
But the risk o f a n immuno lo g ic a l re a c tio n fro m tra nsp la nt-
e d a llo g e nic b o ne ma te ria l wa s so o n re c o g nize d a nd
a d d re sse d in va rio us stud ie s (38-39). Se ve ra l p ro c e d ure s
suc h a s the use o f hyd ro g e n p e ro xid e to ma c e ra te
b o ne g ra fts (“ Kie le r Sp a n”) in the 1950s a nd 1960s to
o ve rc o me a ntig e nity we re no t suc c e ssful (40-41). To d a y,
b o ne sub stitute ma te ria ls suc h a s (b o vine ) b o ne c hip s
a re ro utine ly use d in c linic a l p ra c tic e a fte r b e ing p re -
tre a te d to re mo ve a ntig e n struc ture s. Ho we ve r, d ue to
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the p ro c e ssing ste p s ne c e ssa ry to a b o lish a ntig e nic ity,
mo st o f the se g ra fts d o no t c o nta in via b le c e lls o r g ro wth
fa c to rs a nd a re the re fo re infe rio r to via b le a uto lo g o us
b o ne g ra ft o p tio ns. Whe n a llo g ra fts with living c e lls a re
tra nspla nte d , the re is a risk o f tra nsmitting vira l a nd b a c -
te ria l infe c tio ns: Tra nsmissio n o f huma n immuno d e fic i-
e nc y virus (HIV), he p a titis C virus (HC V), huma n T-lymp ho -
zytic virus (HTLV), unspe c ifie d he p a titis, tub e rc ulo sis a nd
o the r b a c te ria ha s b e e n d o c ume nte d (ma inly) fo r a llo -
g ra fts (ma inly fro m tho se c o nta ining via b le c e lls) (42).
As e a rly a s 1932, the wo rk o f the Swiss H. Ma tti p ro ve d
the p a ra mo unt me a ning o f a uto lo g o us c a nc e llo us b o ne
g ra fts fo r b o ne re g e ne ra tio n a p p ro a c he s (43). Ha ving
c o nd uc te d va rio us e xpe rime nts o n the o ste o g e nic
p o te ntia l o f a uto lo g o us a nd a llo g e nic b o ne , Sc hwe i-
b e re r c o nc lud e d in 1970 tha t the a uto lo g o us tra nsp la nt
re ma ins the o nly re a lly re lia b le tra nsp la nta tio n ma te ria l
o f the future , if a p p lie d to b ring a b o ut ne w b o ne fo rma -
tio n o r c ruc ia lly to sup p o rt the b ridg ing b o ne d e fe c ts
(44). Eve n tho ug h this sta te me nt wa s ma d e mo re tha n
50 ye a rs a g o , it still re ma ins va lid to d a y, whe n b o ne is still
the se c o nd mo st tra nsp la nte d ma te ria l, se c o nd o nly to
b lo o d . Wo rld wid e mo re tha n 3.5 millio n b o ne g ra fts
(e ithe r a uto g ra fts o r a llo g ra fts) a re p e rfo rme d e a c h ye a r
(45). Re c e nt a d va nc e s in te c hno lo g y a nd surg ic a l
p ro -c e d ure s ha ve sig nific a ntly inc re a se d the o p tio ns fo r
b o ne g ra fting ma te ria l, with no ve l p ro d uc ts d e sig ne d to
re p la c e b o th the struc tura l p ro p e rtie s o f b o ne , a s we ll a s
p ro mo te fa ste r inte g ra tio n a nd he a ling . The numb e r o f
p ro c e d ure s re q uiring b o ne sub stitute s is inc re a sing , a nd
will c o ntinue to d o so a s the p o p ula tio n a g e s a nd p hysi-
c a l a c tivity o f the e ld e rly p o p ula tio n inc re a se s. The re fo re ,
while the c urre nt b o ne g ra fting ma rke t g lo b a lly is e sti-
ma te d to b e in e xc e ss o f $2.5 b illio n US e a c h ye a r, it is
e xpe c te d to inc re a se a t a c o mp o und a nnua l g ro wth
ra te o f 7-8% (45).
Altho ug h the la st d e c a d e s ha ve se e n nume ro us inno -
va tio ns in b o ne sub stitute ma te ria ls, the tre a tme nt o f
b o ne d e fe c ts with a uto lo g o us b o ne g ra fting ma te ria l is
still c o nsid e re d to b e the ‘ G o ld Sta nd a rd ’ a g a inst whic h
a ll o the r me tho ds a re c o mp a re d (46). Auto lo g o us b o ne
c o mb ine s a ll the p ro p e rtie s d e sire d in a b o ne g ra fting
ma te ria l: It p ro vid e s a sc a ffo ld fo r the ing ro wth o f c e lls
ne c e ssa ry fo r b o ne re g e ne ra tio n (=o ste o c o nd uc tive ); it
p ro mo te s the p ro life ra tio n o f ste m c e lls a nd the ir d iffe re n-
tia tio n into o ste o g e nic c e lls (=o ste o ind uc tive ) a nd it
ho ld s via b le c e lls tha t c a n fo rm ne w b o ne tissue (= o ste o -
g e nic ) (22, 47). Ho we ve r, the a va ila b le vo lume o f a uto -
lo g o us b o ne g ra ft fro m a p a tie nt is limite d a nd a n
a d ditio na l surg ic a l p ro c e d ure is re q uire d to ha rve st the
g ra fting ma te ria l whic h is a sso c ia te d with a sig nific a nt
risk o f d o no r site mo rb id ity. 20-30% o f a uto g ra ft p a tie nts
e xpe rie nc e mo rb id ity suc h a s c hro nic pa in o r d ysa e sthe -
sia a t the g ra ft-ha rve sting site (48). La rg e b o ne d e fe c ts
(>5 c m) ma y b e tre a te d with b o ne se g me nt tra nsp o rt o r
fre e va sc ula rize d b o ne tra nsfe r (49), a s the use o f a n
a uto lo g o us b o ne g ra ft a lo ne is no t re c o mme nd e d
b e c a use o f the risk o f g ra ft re so rp tio n d e sp ite g o o d so ft
tissue c o ve ra g e (50). The va sc ula rise d fib ula a uto g ra ft
(51) a nd the Iliza ro v me tho d (52-54) a re the mo st c o m-
mo nly use d tre a tme nt me tho d s fo r la rg e r b o ne d e fe c ts;
ho we ve r, c o mp lic a tio ns a re c o mmo n a nd the p ro c e ss
c a n b e la b o rio us a nd p a inful fo r the p a tie nt a s she / he
ma y b e re q uire d to use e xte rna l fixa tio n syste ms fo r up
to o ne a nd ha lf ye a rs (49, 55-56).
The limita tio ns o f e xisting b o ne g ra fting p ro c e d ure s,
e ithe r a uto lo g o us o r a llo g e nic in na ture , a nd the in-
c re a se d d e ma nd fo r b o ne g ra fts in limb sa lva g e sur-
g e rie s fo r b o ne tumo urs a nd in re visio n surg e rie s o f fa ile d
a rthro p la stie s ha ve re ne we d the inte re st in b o ne sub -
stitute ma te ria ls a nd a lte rna tive b o ne g ra fting p ro c e -
d ure s (57). In 1986, Ma sq ue le t a nd c o lle a g ue s (58) first
d e sc rib e d a ne w two -sta g e te c hniq ue ta king a d va n-
ta g e o f the b o d y’ s immune re sp o nse to fo re ig n ma te ria ls
fo r b o ne re c o nstruc tio n. The a utho rs c a lle d it the ‘ c o n-
c e p t o f ind uc e d me mb ra ne s’ – so o n to b e c o me kno wn
a s the ‘ Ma sq ue le t te c hniq ue ’ : In a first ste p , a ra d ic a l
d e b ride me nt o f ne c ro tic b o ne a nd so ft tissue is fo llo we d
b y the filling o f the d e fe c t site with a p o lyme thylme tha -
c ryla te (PMMA) sp a c e r a nd sta b ilisa tio n with a n e xte rna l
fixa to r. Afte r the d e finitive he a ling o f the so ft tissue , a
se c o nd p ro c e d ure is p e rfo rme d 6-8 we e ks la te r, whe n
the PMMA sp a c e r is re mo ve d a nd a mo rc e llise d c a n-
c e llo us b o ne g ra ft (fro m the ilia c c re st) is inse rte d into
the c a vitiy (59-60). The c e me nt sp a c e r wa s initia lly
tho ug ht to p re ve nt the c o lla p se o f the so ft tissue into the
b o ne d e fe c t a nd to p re p a re the spa c e fo r b o ne re c o n-
struc tio n. Ho we ve r, it wa s so o n d isc o ve re d tha t the
PMMA sp a c e r d o e s no t o nly se rve a s a p la c e ho ld e r, b ut
tha t a fo re ig n b o d y re a c tio n to the spa c e r a lso ind uc e s
the fo rma tio n o f a me mb ra ne tha t p o sse sse s hig hly
d e sira b le p ro p e rtie s fo r b o ne re g e ne ra tio n (60-61): The
ind uc e d me mb ra ne wa s sho wn to b e ric hly va sc ula rise d
in a ll la ye rs; the inne r me mb ra ne la ye r (fa c ing the c e -
me nt) c o mp o se d o f syno via l like e p ithe lium a nd the o ut
p a rt is ma d e fro m fib ro b la sts, myo b la sts a nd c o lla g e n.
The ind uc e d me mb ra ne ha s a lso b e e n sho wn to se c re te
va rio us g ro wth fa c to rs in a time -d e p e nd e nt ma nne r:
Hig h c o nc e ntra tio ns o f va sc ula r e nd o the lia l g ro wth
factor (VEGF) as well as transforming growth factor β
(TGF β) are secreted as early as the second week after
imp la nta tio n o f the PMMA sp a c e r; b o ne mo rp ho g e ne -
tic p ro te in 2 (BMP-2) c o nc e ntra tio n p e a ks a t the fo urth
we e k. The ind uc e d me mb ra ne stimula te s the p ro life ra -