Content uploaded by Ali Moshiri
Author content
All content in this area was uploaded by Ali Moshiri
Content may be subject to copyright.
Page 1 of 11
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
Role of tissue engineering in tendon reconstructive surgery
and regenerative medicine: current concepts,
approaches and concerns
A Moshiri
1
2
Abstract
Surgical reconstruction of tendon
injuries is challenging. Classic recon-
structive techniques and tendon
limitations and tissue engineering is a
neering in tendon healing is still
investigated. Researchers have also
focused on in vitro investigations and
because of the differences between
ex vivo and in vivo
great concern and generally hard to
information concerning the structure
the characteristics of biomaterials is
aim to substitute the classic recon-
structive methods with the new tissue
was aimed to introduce the most
between tissue engineering and
tendon regenerative medicine with the
valuable for those who have concerns
about tendon healing.
Introduction
challenging
. Classic surgical recon-
structive methods have significant
large tendon deficits
when the injured tendons cannot be
niques
. Natural grafts can be divided
. All
of them have their own significant
limitations include availability of the
donor site morbidity and cosmetic
. For
infection and transmission of fatal viral
the allografts and ethical concerns
.
tion rate is higher and their value in
regenerative medicine because of
be another major concern
.
neering has been introduced to reduce
dons
and much advancement has been
achieved
with different technologies have been
introduced so that nowadays there
are many commercially available
market
13
in vivo tests and most of the
tissue-engineered researches have
mainly focused on in vitro assays
.
in vivo studies regarding
ucts on regenerative medicine have
and they have only observed the quali-
data
controversies between the results of
the in vivo studies and there are also
low
. Regardless of the efficacy of
are some great concerns that should be
addressed in future studies
13
.
the role of tissue engineering in ten-
don reconstructive surgery and regen-
*
1
2
Page 2 of 11
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
the general guidelines for those
investigations that translate basic to
clinical researches in the field of
tendon tissue engineering.
Classi�ication of tendon injuries
tendon injury and its correlation
with the goals of tissue engineering
1
.
tendon defects
under three classifications
2
transected tendon injuries
to stabilize fractured bones
1
sible
ries have resulted from high stress
forces such as those resulting from
of these injuries
injuries
3
. Based on the nature of the
face different challenges
3
debride these tendon edges and facili-
may have been lost and direct suturing
is of limited value in this condition
.
.
those injuries that have resulted from
the formation of large defects in the
tendon is of great concern
.
Process of tendon healing
21
and there are
which have never been clearly defined
to date
varied. Classic tendon healing could
but characterization of tendon heal-
ing could differ based on the severity
of tendon injury and the treatment
modality
22
characteristics of tendon defects
treated with autografts have some
these differences are larger when the
tissue-engineered grafts are used to
.
In�lammatory phase of tendon
healing
.
Lag stage
ischaemia commences in the injured
area
be due to lysis of the cell membranes
21
.
bility of the un-severed vascular struc-
tures of the injured area
injured area
23
with fibrin strands to form blood
clot
growth factor) and inflammatory medi-
ators to initiate the inflammatory stage
of the wound healing in the injured
area
23
endothelial lining of small venules
cells enter the injured area
clot acts as both a chemotactic medium
and scaffold for the inflammatory cells
so that they can migrate on the fibrin
strands throughout the injured area
23
.
In�iltration and debriding
cells infiltrate the injured area and
start to degrade the necrotic tissues
enzymatic lyses
faster than other inflammatory cells
wound healing
1
and have significant roles not only in
lagen and elastin fibrils and foreign
body material but they also deliver
genic mediators in the injured area
and have a crucial role in further heal-
MMP-13 degrade the necrotic tissues
and are useful in the inflammatory
remodelling at later stages
21
. Cytokines
and other chemo-attractant media-
blasts and endothelial cells into the
injured area and by delivering growth
Page 3 of 11
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
.
Growth factors such as vascular
let-derived growth factors and tissue
tion and tissue maturation and
healing with different mechanisms
.
Fibroplasia phase
are the dominant cells about five days
can be divided into three sub-stages
or granulation tissue stage and late
stage
.
Fibrous response
blasts migrate from the injured tendon
Sheath to the injured area
ing
infiltrate the injured area from the
1
.
don healing
21
may vary based on their origin. Cells
collagen and glycosaminoglycans than
.
gliding mechanism within the tendon
scar tissue results in adhesion forma-
.
mal cells also migrate from the
injured area
30
and differentiated into fibroblasts and
endothelial cells by the local growth
factors
fibroblasts and endothelial cells
23
.
Granulation tissue stage
degeneration and necrosis
23
is the key element which activates
factors and initiate angiogenesis in
the injured area
major role in this regard
endothelial cells aggregate in the
regenerate blood vessels (Fig. 1B)
.
some of them are able to be connected
them die because of insufficient
inflammation changes to chronic
major inflammatory cells
.
been shown that glycosaminoglycans
collagen fibril formation and differen-
tiation
been shown to have a significant role
in subsiding the inflammatory stage of
wound healing
23
. Glycosaminoglycans
ited by immature and mature fibro-
Figure 1:
of the blood vessels have been degenerated. (E) Maturation to consolidation
120 µm).
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
newly regenerated tissue. At this
echogenicity and homogenicity at
uniformly small-sized unimodal col-
lagen fibrils at the ultra-structural
modulus of elasticity at biomechani-
1
Amorphous collagenous stage
Fibroblasts (tenoblasts) mainly start
collagen fibrils
this stage
of the tenoblasts is high
and the transverse diameter of the
newly regenerated collagen fibrils is
(Fig. 3C). Such a granulation tissue is
hazardly distributed and there is no
correlation in the direction of teno-
glycosaminoglycan and collagen con-
tent of the healing tissue gradually
but then they start to decline and
reach their steady state at about five
.
Remodelling phase
of tendon healing can be divided into
mid-remodelling or maturation stage
and late remodelling or consolidation
stage
.
Alignment stage
has filled the injured area so that the
continuity of the injured tendon is
established
1
injured limb so that the weight-bearing
Figure 2:
differentiated from aggregation of the matured collagen fibrils. (E) At the
highly dense and align collagen fibres.
Figure 3:
of the collagen fibrils is low and they are randomly distributed in different
increased and they are highly aligned so that they have been only sectioned
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
affected limb increases and weight-
bearing forces can be transmitted
the collagen fibres and blood vessels
. Accord-
eter of the injured area decrease
the collagen fibrils increases and
are mainly oriented uni-directionally
tissue is seen
1
.
Maturation stage
and hydration of the tissue and the
the new tissue decreases and the
blood vessels degenerate and resorb
. Most of the newly regen-
1
start to aggregate and differentiate
into larger and more mature collagen
fibrils (Fig. 3E)
glycosaminoglycans (e.g. chondroitin
uration and differentiation of collagen
fibrils
30
diameter of the highly aligned colla-
gen fibrils so that their diameter
(Fig. 3E)
still much smaller than that of the nor-
.
they transform into metabolically
inactive tenocytes that are histologi-
cally characterized by longitudinal
tenoblasts
22
the healing tissue so that in a normal
of the normal contralateral tendon’s
characteristics should be achieved at
this stage
.
Consolidation stage
healing and could continue for years
or even to the end of life
. At this
cross-linking of these collagen fibrils.
.
be suggested that tendon healing is
in its final stage
biomechanical characteristics of the
large injury it may never reach its
normal value
is far behind that of the normal con-
organization of the tendon from colla-
vs. 1F)
.
Discussion
Limitations of tendon healing based
on the type of tendon injuries
tations
lyses by the chemical activity of the
MMPs and other degrading enzymes
which are secreted during the inflam-
.
Lack of effective mechanisms to guide
blasts and collagen fibres at the
fashion
tenon and the surrounding fascia that
inhibits the movement of the healing
stress is not transmitted into the heal-
ment and maturation stages of tendon
cal role and function
1
surgery is required
.
tendon injury is more severe and the
more aggressive and the outcome is
limitation that would have a major
.
When the tendon defect is larger than
dinous adhesion substantially increases
because there is no scaffold for the
ate along the stress line of the tendon.
because the fibroblasts migrate in the
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
the migrated fibroblasts in the defect
a reduction in the amount of collagen
area in such a tendon injury may not be
established
deficits have more significant limita-
designed
2
.
Role of tissue engineering in
tendon regenerative medicine
has seen much advancement and sev-
eral manufacturing technologies and
treatment modalities have been intro-
duced to reduce limitations of tendon
neering consists of three different
. A
major advance ment in tendon tissue
engineering is related to the scaffolds.
medicine is to design a suitable envi-
remodelling and maturation
scaffold in this regard including the
molecule(s) from which the scaffold
is manufactured (basic material of the
their biological characteristics and the
.
issues that should be considered in
manufacturing a scaffold
12
tissue engineering should be cyto-
in vitro
ble and biodegradable in vivo
.
.
in
vitro and in vivo and this is the greatest
concern
each of the above characteristics
.
Basic material of the scaffold
Several materials have been used so
effective in tendon tissue engineering
and regenerative medicine
. Gener-
rials
. Biological materials such
effective in tendon healing
.
2
in the injured area
.
1
in vivo
tors
lar scaffolds
. Chitosan is a natural
has been shown that this molecule
. All
these materials are biodegradable
2
.
biodegradable biological materials
such as silk and carbon fibres
usage of carbon fibre did not continue
this regard are in vitro investigations
that have low value in translational
medicine
. Synthetic materials such
with invaluable results
. Many
researches have focused on the in
vitro characteristics of such materials
and those who investigated their in
vivo efficacy have not suggested their
tion
in vascular tissue engineering and
.
cal sciences was in the surgical field
as suture materials
materials when their usage was limited
to surgical sutures
12
merit as a surgical suture can be attrib-
surgical suture do not have consider-
foreign material is considerably less
than the scaffolds constructed from
these materials
were never deleted from the field of
tion in tissue-engineered scaffolds
has greatly reduced
they have been combined with
biological materials to decrease their
in vivo studies
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
regarding their efficacy in tendon
regenerative medicine are rare
.
Dimensions of the scaffolds
Regardless of the different technolo-
engineered scaffolds designed for
tendon tissue engineering are bidi-
mensional
are commercially available in the
.
. For this
injured area of the tendon with a mini-
tridimensional scaffolds are more suit-
in vivo
regenerative medicine is unclear
.
Architecture of the scaffolds
Several technologies have been intro-
more enhanced architectures would
be manufactured in the near future
.
acellularization technologies
.
re-designed in a more effective man-
tendons
ered as tissue grafts
.
.
Each of these technologies has its
es
in vivo
formance when used as a graft in the
injured area
tion rate is fast so that few days after
tory cells and mediators
fibres is randomized and is not suita-
engineering
.
duce both bi- and tridimensional scaf-
cartilage regenerative medicine
12
. By
ment and randomized distribution of
ularity is not desirable in tendon tissue
the newly regenerated tissue is a must
alignment of the newly regenerated
tissue is not a major concern because
of the nature of the tissue that should
be reconstructed
.
nanometric to micrometric scales
.
Other physical characteristics
of the scaffolds
Regardless of the above factors that
are some other issues that should be
addressed
2
. Both these characteristics
can be controlled and ordered when
tendon-engineered scaffolds should
have fibre diameters varying between
nano-scale and micro-scale
been shown that controlling the scaf-
fold fibre diameter is critical in the
Figure 4:
has been used for augmentation of small tendon defects. (F) Scanning electron
(G) Synthetic tridimensional tissue-engineered scaffold for tendon and ligament
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
design of scaffolds for functional and
tissue healing
.
A tendon’s normal architecture is
metric diameters and collagen fibres
and fibre bundles with different micro-
scaffold for tendon tissue engineering
should consist of both micro and nano-
scale moderately to highly aligned
fibres to be effective in guiding both
the nano and microstructure of the
tation
tant factor
cartilage or bone architecturally and
should be smaller than the scaffolds
that are constructed for cartilage and
bone tissue engineering
2
well-designed tridimensional tendon
to reduce the amount of invasion of
acteristic that should be addressed
.
absorb liquids but deliver them slowly
.
tors
structures and healing mediators in its
architecture and maintain them for a
long time
also used for drug delivery
assembled within the scaffold and de-
tation of the graft with the aim of
increasing the efficiency of the treat-
ment modality
2
.
Biological characteristics
of the scaffolds
Biological characteristics are a
major concern in the field of tendon
tissue engineering
. At least five
.
bility and bioefficacy and decreasing
the rejection rate
. Acellulariza-
cally based tissue-engineered grafts
.
materials should be increased and the
should be decreased when designing
a hybrid scaffold. Sterilization is another
factor that should be addressed
2
. By
removing all cellular and microbio-
could be reduced in order to increase
.
molecules in the architecture of the
scaffold could reduce the limitation of
each molecule
scaffold for tendon tissue engineering
should have the following biological
behaviour
chronically be rejected by the host
tissue
initiate the immune reaction and
modulate inflammation because this
can increase the healing rate
of the scaffold
behaviour of a suitable scaffold is to
not been shown for soft tissue scaf-
tendon
don healing and collaborates in differ-
.
Optimization of the scaffolds
as the �inal step
tors
and cell migration. Scaffold matrices
can be used to achieve drug delivery
with high loading and efficiency to
. Several investigations
the efficiency of tissue-engineered
grafts
structures have been shown to signif-
many researches that have shown the
factors
engineered scaffolds with different
there by making it more efficient in
tissue
33
. Glycosaminoglycans have been
the main focus in this regard
ronic acid is one of these agents
23
glycosaminoglycan has been shown
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
of tendon healing and increases the
increases the diameter of the newly
regenerated collagen fibrils and
in vivo
23
. Growth
.
agent that has been shown to decrease
the necrotic tissues in the injured
tendinous adhesions
. Platelet-rich
and tissue maturation
beneficial effects have been suggested
to be due to the growth factors that
.
engineered scaffolds with cells and
tendon reconstructive surgery and
regenerative medicine
12
.
Concerns
most of the researches in the area of
tendon tissue engineering have not
focused on the in vivo conditions and
for this reason the real efficacy of such
biological behaviour is unclear. Such
ucts are introduced as tissue substi-
12
.
in vitro
studies in translational medicine is
clear as to how the cultured stem cells
on tissue-engineered scaffolds would
how these cells remain alive in the
ing when large amounts of degrading
enzymes are delivered by the inflam-
tigations should consider the in vivo
tests and the in vivo researches should
and not just on the observations of the
grafts using different observational
about the mechanism of the host-
tation and host toleration to the for-
ent methodologies including both
ultra-structure)
.
Conclusion
tissue engineering technologies and
engineering is still in its infancy and
immune reaction and in vivo efficacy
Knowledge about the nature of ten-
engineering is needed when tissue
engineering is selected as the alterna-
er should have enough knowledge of
tendon to be able to simulate an
References
functional modulation of early healing of
nous human recombinant basic fibroblast
design for functional and integrative ten-
graft for reconstruction of the Achilles
et al
the shoulder and body wall sites in the rat
et al. Photoactivated
restoration in rodents and in humans.
Page 10 of 11
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
et al.
effect of collagen fiber orientation on cell
et al.
nant basic fibroblast growth factor on the
synthesis in tenocytes from human rotator
cuff tendons with degenerative tears. Am
Tarantula cuben-
sis
glucosamine-chondroitin sulfate on
over and remodeling in the early stages of
healing of tendon injury in rabbit. Arch
®
enhanced
of the tenotomized tendon in rabbits. Cells
glycosaminoglycan (Adequan). Connect
on healing of acute and chronic tendon
ergistic effects of growth factors for use in
et al
fabricated by sectioning tendon using a
microtome for tissue engineering. Nano-
mized scaffold for tendon and ligament
et al. Engineered scaffold-free tendon
ficial graft survival. Biomaterials. 2003
et al. Synthetic col-
lagen fascicles for the regeneration of ten-
Permacolmesh used in abdominal wall
2012 Aug.
characterization of novel bone scaffolds
Page 11 of 11
Critical review
Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moshiri A, Oryan A. Role of tissue engineering in tendon reconstructive surgery and regenerative
tendon and ligament tissue engineering.
et al
zation of biostatic allograft scaffolds.
et al
ing organ regeneration. Biomaterials. 2013
et al. Rigidity of collagen
fibrils controls collagen gel-induced down-
collagen nanofibers reconstituted by
M. Novel biomaterial from reinforced
of collagen-glycosaminoglycan scaffold rela-
lates human tendon fibroblast growth and
et al.
Engineering the growth factor micro
environment with fibronect in domains to
Chemotactic attraction of human fibro-
et al
et al
chymal stem cells seeded on biodegrad-
able scaffolds in a full-size tendon
2012 Oct.