ArticlePDF Available

Role of tissue engineering in tendon reconstructive surgery and regenerative medicine: Current concepts, approaches and concerns

Authors:
  • Dr. Moshiri Veterinary Center

Abstract and Figures

Surgical reconstruction of tendon injuries is challenging. Classic reconstructive techniques and tendon transplantation have some significant limitations and tissue engineering is a newer option. Despite significant development in tissue engineering technologies, the role of tissue engineering in tendon healing is still unclear. There are many tissueengineered products that are commercially available in the market, but most of them have not passed animal and clinical studies, and the behaviour of host immune response to these types of products has not been investigated. Researchers have also focused on in vitro investigations and because of the differences between ex vivo and in vivo situations, translation of their results to clinical practice is of great concern and generally hard to follow. To increase the impact of tissue engineering in tendon healing, more information concerning the structure of tendons, their injuries, healing and host immune response together with the characteristics of biomaterials is needed to produce a more effective tissue-engineered product with the aim to substitute the classic reconstructive methods with the new tissue engineering approaches. This review was aimed to introduce the most important issues in the relationship between tissue engineering and tendon regenerative medicine with the hope that this information would be valuable for those who have concerns about tendon healing.
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.
 
    

      

   
     

 



 
   
    


... These factors have led to introducing and testing various alternative choices 7,8 . Allografts are a different option, although they have significant drawbacks such as rejection, disease transmission, and expense 9,10 . Allografts have less integrating qualities with the host's recovering tissues than autografts. ...
... Allografts have less integrating qualities with the host's recovering tissues than autografts. Moreover, the drawbacks of allografts are that xenografts risk spreading zoonotic illnesses, and graft refusal is more common and severe 10,11 . The last ten years have seen the introduction of tissue engineering in response to these issues. ...
... The methodology of tissue development includes the use of appropriate scaffolds, the addition of appropriate growth stimulants and cells, and, in recent times, the use of appropriate stem cells. To lessen the limitations of traditional grafts and improve graft acceptance, osteogenicity, osteoconductivity, and osteoinductivity, innovative scaffolds and tissue grafts can be made utilizing tissue engineering techniques 10 . ...
Article
Full-text available
Herbal medicines are plant-based medicines and have been documented 4000 years back. Great results have beenextracted from several studies with a minimum amount of side effects. These medicines help osteogenesis as the bone graftsobtained from such are utilized as a filler and scaffold. Such grafts are bioresorbable and do not possess any reaction like antigenantibodies. The aim is to have a comprehensive review study on bone grafts. This review article covers a combination of allaspects regarding bone grafts and their different forms of availability. The Objectives of this review are to explore various bonegrafts and to summarize them so that the reader can have enough information just by reading this article. The article givesthorough information about bone grafts and mainly focuses on several ethnopharmacological studies collected using databasessuch as Pubmed, Medline, Scopus, and Google Scholar. Regarding their osteogenic, angiogenic, anti-inflammatory, and remodelingeffects, acting on bone receptors, promoting bone metabolism, increasing mineral uptake, and supporting free radical oxidation,Chenopodium ambrosioides, Piper sarmentosum, Quadrangularis Cissus, Ricinus communis, and Radix salviae miltiorrhizaeplants were the most extensively studied in several works of literature. This article concludes that using herbal bone grafts onthe site of a defect holds promise for bone regeneration and offers an alternative to conventional therapies when they areimpractical. Very few studies have been conducted to date and this has raised interest in using herbal bone grafts.
... Allografts present themselves as an alternative, albeit with significant limitations pertaining to the risks of rejection, disease transmission, and financial implications. Studies have shown that allografts exhibit reduced integration with the healing tissues of the host when compared to autografts [47,50,51]. In addition to the drawbacks associated with allografts, xenografts pose additional risks such as the potential transmission of zoonotic diseases and a higher likelihood of graft rejection, which tends to be more severe and aggressive [52]. ...
... Tissue engineering of bone is a complex and dynamic process that begins with the migration and recruitment of osteo-progenitor cells and continues with their proliferation, differentiation, matrix production, and bone remodeling. Tissue engineering techniques can be employed to develop novel scaffolds and tissue grafts with the objective of mitigating the drawbacks associated with conventional grafts and enhancing graft incorporation, osteogenicity, osteoconductivity, and osteoinductivity [42,50]. ...
... (34) However, transmission of zoonotic diseases, high graft rejection rates and aggressive immune response are its major disadvantages contributing to its low value in the reconstructive medicine. (35) To overcome potential immunogenicity and morbidity at donor sites, antigenicity, risk of disease transmission, artificial synthetic bone substitute materials, i.e., Alloplasts are generated to closely mimic the biological properties of natural bone. They have osteointegrative and osteoconductive properties. ...
Article
Full-text available
ABSTRACT: Background: Several dental procedures currently necessitate the use of bone grafts to replace or regenerate bone volume that has been lost to disease, trauma or surgery. However, it is essential to consider the patient's opinions and preferences before administration of any such procedure. Our study aims to investigate patients' perspectives on the commonly used bone grafts in dentistry and examine its correlation with variables such as gender, age, level of education, or religious faith. Methods: An anonymous, self-administered cross-sectional based questionnaire form was distributed to 200 individuals. The responses for acceptance, conditional acceptance, refusal and the reasons for the choice for each type of bone graft were obtained. The observed responses were compared with the participants’ demographics. Descriptive statistical analysis was performed for the collected data with P < 0.05 considered statistically significant. Results: Autografts had the highest acceptance rate followed by alloplast, with the least acceptance seen for xenografts. The overall acceptance rate of bone grafts was found to be 90%, 63%, 32%, and 72% for autografts, allografts, xenografts, and alloplasts respectively. A statistical influence was seen with various demographic variables at different levels to the various types of grafts.
... Any metabolic abnormalities that disturb this equilibrium result in an imbalance between osteogenesis and osteoclastogenesis and may cause bone fractures [1]. Bone tissue engineering (BTE) introduced the creation of 3D scaffolds and constructs with specific structural, mechanical, and biological characteristics to favor the bone regeneration process [2]. The main polymeric categories used for the fabrication of scaffolds in BTE are natural and synthetic polymers [3]. ...
Article
Full-text available
The in vitro evaluation of 3D scaffolds for bone tissue engineering in mono-cultures is a common practice; however, it does not represent the native complex nature of bone tissue. Co-cultures of osteoblasts and osteoclasts, without the addition of stimulating agents for monitoring cellular cross-talk, remains a challenge. In this study, a growth factor-free co-culture of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and human peripheral blood mononuclear cells (hPBMCs) has been established and used for the evaluation of 3D-printed scaffolds for bone tissue engineering. The scaffolds were produced from PLLA/PCL/PHBV polymeric blends, with two composite materials produced through the addition of 2.5% w/v nanohydroxyapatite (nHA) or strontium-substituted nanohydroxyapatite (Sr-nHA). Cell morphology data showed that hPBMCs remained undifferentiated in co-culture, while no obvious differences were observed in the mono- and co-cultures of hBM-MSCs. A significantly increased alkaline phosphatase (ALP) activity and osteogenic gene expression was observed in co-culture on Sr-nHA-containing scaffolds. Tartrate-resistant acid phosphatase (TRAP) activity and osteoclastogenic gene expression displayed significantly suppressed levels in co-culture on Sr-nHA-containing scaffolds. Interestingly, mono-cultures of hPBMCs on Sr-nHA-containing scaffolds indicated a delay in osteoclasts formation, as evidenced from TRAP activity and gene expression, demonstrating that strontium acts as an osteoclastogenesis inhibitor. This co-culture study presents an effective 3D model to evaluate the regenerative capacity of scaffolds for bone tissue engineering, thus minimizing time-consuming and costly in vivo experiments.
... But artificial materials has certain drawbacks such as increased inflammatory responses, antigenic reactions, failure at the fixation sites, and lack of long-term biocompatibility [2]. Autografts have limited availability and cause donor site morbidity while allo-and xenografts have the chance to be acutely or chronically rejected by the host [10]. In the present case, there is formation of a gap between the ruptured tendon ends, due to loss of the tendon and the high contractility of the associated muscles, which also prevents bringing together the cut ends by simple tenorrhaphy. ...
Article
Full-text available
The study aimed to a clinico-histopathological evaluating the benefit of using autologous platelets rich plasma (PRP) in healing of Achilles tendonitis in rabbits. Twenty adult male rabbits were used. Five ml of blood was withdrawn from the rabbits marginal ear vein and mixed with sodium citrate for preparation of PRP. Rabbits were randomly allocated into two groups (10 of each). The first group, serve as a control group and the second group, considered as treatment group. Tendonitis was induce under the effect of general anesthesia. Lateral longitudinal incision on the skin over the Achilles tendon was made. The tendon was isolated by blunt dissection from the surrounding tissue. Tendonitis was induced by splitting of the tendon with surgical blade. The first group (treated with one ml normal saline). In contrast, the second group (treated with one ml of PRP). Both saline and PRP were injected intra-lesional after that the surgical skin wounds was re stitched in routine manner. After clinical follow-up of the treatment rabbits, certain secondary complications were happened represented by lameness, swelling and infection. Histo-pathological evaluation was performed at 8 and 16 weeks post-surgery (10 rabbits/group) (5 rabbits/period). Grossly, adhesion was noticed in most rabbits of control group. Microscopical examination reflect perfect orientation and organization of collagen fibers in treatment group in comparing with control group. Based on the results obtain from this study, PRP enhanced and promote tendon healing. ‫اكيلس‬ ‫وتز‬ ‫التهاب‬ ‫عالج‬ ‫في‬ ‫الذاتية‬ ‫الذمىية‬ ‫تالصفيحات‬ ‫الغنية‬ ‫الثالسما‬ ‫دور‬ ‫االرانة‬ ‫في‬ ‫تجزيثيا‬ ‫المستحث‬ ‫انقاضً‬ ‫كاظى‬ ‫خٍشٌه‬ ‫تغذاد‬ ‫ظايؼح‬ / ‫انثٍطشي‬ ‫انطة‬ ‫كهٍح‬ ‫الخالصة‬ ‫انًشضً‬ ‫و‬ ‫انسشٌشي‬ ‫انرقٍٍى‬ ‫انى‬ ‫انحانٍح‬ ‫انذساسح‬ ‫هذفد‬-‫انُسعً‬ ‫فً‬ ‫انزاذٍح‬ ‫انذيىٌح‬ ‫تانصفٍحاخ‬ ‫انغٍُح‬ ‫انثالصيا‬ ‫السرؼًال‬ ‫سحة‬ ‫تانغا.‬ ‫اسَثا‬ ‫ػششوٌ‬ ‫نهثحس‬ ‫اسرخذو‬ ‫االساَة.‬ ‫فً‬ ‫ذحطًٍه‬ ‫تؼذ‬ ‫اكٍهس‬ ‫وذش‬ ‫شفاء‬ 5 ‫يغ‬ ‫ويضض‬ ‫االرًَ‬ ‫انىسٌذ‬ ‫يٍ‬ ‫و‬ ‫د‬ ‫يم‬ (‫تىاقغ‬ ‫يعًىػرٍٍ‬ ‫انى‬ ‫االساَة‬ ‫قسًد‬ ‫انذيىٌح.‬ ‫تانصفٍحاخ‬ ‫انغٍُح‬ ‫انثالصيا‬ ‫نرحضٍش‬ ‫سرشٌد‬ ‫انصىدٌىو‬ 10 ‫نكم‬ ‫اساَة‬ ‫انرخذٌش‬ ‫ذأشٍش‬ ‫ذحد‬ ‫انىذش‬ ‫انرهاب‬ ‫احذاز‬ ‫ذى‬ ‫انًؼايهح.‬ ‫يعًىػح‬ ‫وانصاٍَح‬ ‫سٍطشج‬ ‫يعًىػح‬ ‫االونى‬ ‫انًعًىػح‬ ‫ػذخ‬ ‫يعًىػح).‬ ‫احذز‬ ‫ته.‬ ‫انًحٍطح‬ ‫االَسعح‬ ‫يٍ‬ ‫انىذش‬ ‫وػضل‬ ‫انعهذ‬ ‫طٍح‬ ‫واصٌحد‬ ‫انىحشٍح‬ ‫انعهح‬ ‫يٍ‬ ‫طىنٍا‬ ‫نهىذش‬ ‫انًغطى‬ ‫انعهذ‬ ‫شق‬ ‫شى‬ ‫انؼاو‬ ‫تأ‬ ‫االساَة‬ ‫فً‬ ‫انىذش‬ ‫انرهاب‬ ‫تاسرؼًال‬ ‫االونى‬ ‫انًعًىػح‬ ‫ػىنعد‬ ‫انعشاحٍح.‬ ‫تانشفشج‬ ‫انرششٌظ‬ ‫سهىب‬ 1 ‫انًحهىل‬ ‫يٍ‬ ‫يهٍهٍرش‬ ‫نها‬ ‫فاسرؼًم‬ ‫انصاٍَح‬ ‫انًعًىػح‬ ‫ايا‬. ‫انفسهعً‬ 1 ‫شى‬ ‫انىذش‬ ‫داخم‬ ‫انًادذٍٍ‬ ‫حقُد‬ ‫انذيىٌح.‬ ‫تانصفٍحاخ‬ ‫انغٍُح‬ ‫انثالصيا‬ ‫يٍ‬ ‫يهٍهٍرش‬ ‫سشٌشٌا‬ ‫انحٍىاَاخ‬ ‫ذىتؼد‬ ‫انشوذٍٍُح.‬ ‫تانطشٌقح‬ ‫انعهذ‬ ‫اغهق‬ ‫انؼشض‬ ‫ػهى‬ ‫شًهد‬ ‫انصاَىٌح‬ ‫انًضاػفاخ‬ ‫تؼض‬ ‫سعهد‬ ‫حٍس‬ ‫انًشضً‬ ‫انفحص‬ ‫اظشي‬ ‫وانخًط.‬ ‫وانرىسو‬-‫تؼذ‬ ‫انُسعً‬ 8 ‫و‬ 11 ‫اسرخذو‬ ‫حٍس‬ ‫انعشاحٍح‬ ‫انًذاخالخ‬ ‫اظشاء‬ ‫يٍ‬ ‫أسثىع‬ 10 ‫(تىاقغ‬ ‫يعًىػه‬ ‫نكم‬ ‫اساَة‬ 5 ‫حٍىاَاخ‬ ‫اغهة‬ ‫فً‬ ‫ته‬ ‫انًحٍطح‬ ‫واالَسعح‬ ‫انىذش‬ ‫تٍٍ‬ ‫انرصاقاخ‬ ‫ػٍاٍَا‬ ‫نىحع‬ ‫فرشج).‬ ‫نكم‬ ‫اساَة‬ ‫تًعًىػح‬ ‫يقاسَح‬ ‫انؼالض‬ ‫يعًىػح‬ ‫فً‬ ‫انكىالظٍٍ‬ ‫انٍاف‬ ‫اذعاهاخ‬ ‫واَرظاو‬ ‫ذؼظً‬ ‫انًعهشي‬ ‫انفحص‬ ‫اظهش‬ ‫انسٍطشج.‬ ‫انىذش‬ ‫شفاء‬ ‫فً‬ ‫ػعهد‬ ‫انذيىٌح‬ ‫تانصفٍحاخ‬ ‫انغٍُح‬ ‫انثالصيا‬ ‫تاٌ‬ ‫ذثٍٍ‬ ‫انذساسح‬ ‫يٍ‬ ‫انًسرخهصح‬ ‫انُرائط‬ ‫ػهى‬ ‫اػرًادا‬ ‫انسٍطشج.‬ ‫انسٍطشج.‬ ‫يعًىػح‬ ‫يغ‬ ‫تانًقاسَح‬ ‫المفتاحي‬ ‫الكلمات‬ : ‫ة‬-‫الذمىية‬ ‫تالصفيحات‬ ‫الغنية‬ ‫الثالسما‬-‫أكيلس‬ ‫وتز‬ ‫التهاب‬-‫ارانة‬ AL
Article
Background Tendinopathy refers to conditions characterized by collagen degeneration within tendon tissue, accompanied by the proliferation of capillaries and arteries, resulting in reduced mechanical function, pain, and swelling. While inflammation in tendinopathy can play a role in preventing infection, uncontrolled inflammation can hinder tissue regeneration and lead to fibrosis and impaired movement. Objectives The inability to regulate inflammation poses a significant limitation in tendinopathy treatment. Therefore, an ideal treatment strategy should involve modulation of the inflammatory process while promoting tissue regeneration. Methods The current review article was prepared by searching PubMed, Scopus, Web of Science, and Google Scholar databases. Several treatment approaches based on biomaterials have been developed. Results This review examines various treatment methods utilizing small molecules, biological compounds, herbal medicine‐inspired approaches, immunotherapy, gene therapy, cell‐based therapy, tissue engineering, nanotechnology, and phototherapy. Conclusion These treatments work through mechanisms of action involving signaling pathways such as transforming growth factor‐beta (TGF‐β), mitogen‐activated protein kinases (MAPKs), and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), all of which contribute to the repair of injured tendons.
Article
Full-text available
This study investigated the relationship between the structure and mechanical properties of polycaprolactone (PCL) nanocomposites reinforced with baghdadite, a newly introduced bioactive agent. The baghdadite nanoparticles were synthesised using the sol–gel method and incorporated into PCL films using the solvent casting technique. The results showed that adding baghdadite to PCL improved the nanocomposites’ tensile strength and elastic modulus, consistent with the results obtained from the prediction models of mechanical properties. The tensile strength increased from 16 to 21 MPa, and the elastic modulus enhanced from 149 to 194 MPa with fillers compared to test specimens without fillers. The thermal properties of the nanocomposites were also improved, with the degradation temperature increasing from 388 °C to 402 °C when 10% baghdadite was added to PCL. Furthermore, it was found that the nanocomposites containing baghdadite showed an apatite-like layer on their surfaces when exposed to simulated body solution (SBF) for 28 days, especially in the film containing 20% nanoparticles (PB20), which exhibited higher apatite density. The addition of baghdadite nanoparticles into pure PCL also improved the viability of MG63 cells, increasing the viability percentage on day five from 103 in PCL to 136 in PB20. Additionally, PB20 showed a favourable degradation rate in PBS solution, increasing mass loss from 2.63 to 4.08 per cent over four weeks. Overall, this study provides valuable insights into the structure–property relationships of biodegradable-bioactive nanocomposites, particularly those reinforced with new bioactive agents.
Article
Full-text available
Tendon healing is generally a time-consuming process and often leads to a functionally altered reparative tissue. Using degradable scaffolds for tendon reconstruction still remains a compromise in view of the required high mechanical strength of tendons. Regenerative approaches based on natural decellularized allo- or xenogenic tendon extracellular matrix (ECM) have recently started to attract interest. This ECM combines the advantages of its intrinsic mechanical competence with that of providing tenogenic stimuli for immigrating cells mediated, for example, by the growth factors and other mediators entrapped within the natural ECM. A major restriction for their therapeutic application is the mainly cell-associated immunogenicity of xenogenic or allogenic tissues and, in the case of allogenic tissues, also the risk of disease transmission. A survey of approaches for tendon reconstruction using cell-free tendon ECM is presented here, whereby the problems associated with the decellularization procedures, the success of various recellularization strategies, and the applicable cell types will be thoroughly discussed. Encouraging in vivo results using cell-free ECM, as, for instance, in rabbit models, have already been reported. However, in comparison to native tendon, cells remain mostly inhomogeneously distributed in the reseeded ECM and do not align. Hence, future work should focus on the optimization of tendon ECM decellularization and recolonization strategies to restore tendon functionality.
Article
Full-text available
It is envisaged that we will imagine all the developments that will occur. At no moment in our history is this so far from the truth, there is no status quo and the only real constant is change. Perhaps we will see developments beyond our imagination as something that has happened over the past century. Every time a new scientific and medical journal is launched, we keep wishing that someday clinical sciences could become a completely mature subject without daily change. However, this has always proven to be far from the truth. Medicine is an immense discipline, and only now we are beginning to realise the depths of our ignorance. Lately, many new techniques and technologies have been introduced through translational research that was built on the knowledge acquired from the application in the discipline of basic sciences over the last two centuries. The new knowledge has brought many benefits, including improvement in human health. Meanwhile, it has led to controversies and ethical debates over many issues, including balancing of environmental risks with benefits, genetic testing, human reproductive cloning, and so on. This translational change allowed the introduction of interconnected scientific and clinical principles rather than separate phenomena. The change was welcomed and has allowed the fast progression of science which has changed every aspect in our lives, as we are now living in the digital age and potentially progressing to the nano age. Nowadays, almost all laboratory based scientific research is being translated into a corresponding research in a clinical discipline. This has shown to improve our understanding of the physiological and pathological pro cesses affecting or controlling the human body and later on the understanding of this highly organised structure as a whole.
Article
Full-text available
Most of the exogenous biomaterials for tendon repair have limitations including lower capacity for inducing cell proliferation and differentiation, poorer biocompatibility and remodeling potentials. To avoid these shortcomings, we intend to construct an engineered tendon by stem cells and growth factors without exogenous scaffolds. In this study, we produced an engineered scaffold-free tendon tissue (ESFTT) in vitro and investigated its potentials for neo-tendon formation and promoting tendon healing in vivo. The ESFTT, produced via tendon-derived stem cells (TDSCs) by treatment of connective tissue growth factor (CTGF) and ascorbic acid in vitro, was characterized by histology, qRT-PCR and immunohistochemistry methods. After ESFTT implanted into the nude mouse, the in vivo fluorescence imaging, histology and immunohistochemistry examinations showed neo-tendon formation. In a rat patellar tendon window injury model, the histology, immunohistochemistry and biomechanical testing data indicated ESFTT could significantly promote tendon healing. In conclusion, this is a proof-of-concept study demonstrating that ESFTT could be a potentially new approach for tendon repair and regeneration.
Article
Full-text available
Rotator cuff tendon pathology is thought to account for 30-70 % of all shoulder pain. For cases that have failed conservative treatment, surgical re-attachment of the tendon to the bone with a non-absorbable suture is a common option. However, the failure rate of these repairs is high, estimated at up to 75 %. Studies have shown that in late disease stages the tendon itself is extremely degenerate, with reduced cell numbers and poor matrix organisation. Thus, it has been suggested that adding biological factors such as platelet rich plasma (PRP) and mesenchymal stem cells could improve healing. However, the articular capsule of the glenohumeral joint and the subacromial bursa are large spaces, and injecting beneficial factors into these sites does not ensure localisation to the area of tendon damage. Thus, the aim of this study was to develop a biocompatible patch for improving the healing rates of rotator cuff repairs. The patch will create a confinement around the repair area and will be used to guide injections to the vicinity of the surgical repair. Here, we characterised and tested a preliminary prototype of the patch utilising in vitro tools and primary tendon-derived cells, showing exceptional biocompatibility despite rapid degradation, improved cell attachment and that cells could migrate across the patch towards a chemo-attractant. Finally, we showed the feasibility of detecting the patch using ultrasound and injecting liquid into the confinement ex vivo. There is a potential for using this scaffold in the surgical repair of interfaces such as the tendon insertion in the rotator cuff, in conjunction with beneficial factors.
Article
This study was designed to investigate the effects of tarantula cubensis (TC) on the superficial digital flexor tendon (SDFT) rupture after surgical anastomosis, on day 84-postinjury (DPI) in rabbits. Forty white New Zealand, mature, male rabbits were randomly and evenly divided into treated and control groups. After tenotomy and primary repair, the injured legs were immobilized for 2 weeks. TC was injected subcutaneously over the lesion on 3, 7, and 10 DPI. The control animals received subcutaneous injections of normal saline similarly. Animal's weight, tendon diameter, clinical status, radiographic and ultrasonographic evaluations were recorded at weekly intervals. The animals were euthanized on 84 DPI and the injured tendons and their normal contralaterals were evaluated for histopathologic, histomorphometric, ultrastructural, biomechanical, and percentage dry weight parameters. Treatment significantly improved the clinical performance, cell, collagen and tissue maturation, tissue alignment and remodeling, ultimate strength, stiffness, maximum stress, and dry weight content and decreased the tendon diameter, inflammation, adhesions and degeneration of the injured treated tendons compared to the injured control ones. The present findings showed that TC is effective on sharp ruptured SDFT in rabbits and it could be one of the novel therapeutic options in clinical trial studies.
Article
Distinct from tissue engineering, which focuses primarily on the repair of tissues, regenerative engineering focuses on the regeneration of tissues: creating living, functional tissue that has the ability to replace organs that are dysfunctional. The challenge of working in an area like regenerative engineering lies, in part, in the breadth of information required to truly appreciate and begin to think about this field. Regenerative Engineering introduces the field through the presentation of fundamental concepts of cell biology, stem cell science, materials science, and cell-material interactions. It also focuses on specific organ and tissue types and presents up-to-date examples of ongoing work, often in the context of a specific clinical need. Regenerative medicine focuses on the biological aspects of tissue regeneration via stem cells, factors, and cytokines, while tissue engineering focuses on the integration of materials science and life sciences. This book integrates these two areas, presenting each concept in the framework of regenerative engineering. Features: • Covers a number of cutting-edge topics related to regenerative medicine and tissue engineering • Includes an introductory chapter on materials science • Features a number of the contributors who are world-class researchers, one of whom is Dr. Anthony Atala, whose work dealing with organ regenerative engineering was featured on Sixty Minutes • Incorporates problem-based learning throughout the text, which is not hypothetical but based on actual biological, engineering, or clinical scenarios Combining science, engineering and medicine, Regenerative Engineering incorporates all of the essential elements needed for further advancement in this field. The book explores the development and examination of vital organs and tissue types and addresses concerns as it relates to the regenerative engineering of various organ tissues, vascular tissues, bone, ligament, neural tissue, and the interfaces between tissues.
Article
The diameter of collagen fibrils in connective tissues, such as tendons and ligaments is known to decrease upon injury or with age, leading to inferior biomechanical properties and poor healing capacity. This study tests the hypotheses that scaffold fiber diameter modulates the response of human tendon fibroblasts, and that diameter-dependent cell responses are analogous to those seen in healthy versus healing tissues. Particularly, the effect of the fiber diameter (320 nm, 680 nm, and 1.80 μm) on scaffold properties and the response of human tendon fibroblasts were determined over 4 weeks of culture. It was observed that scaffold mechanical properties, cell proliferation, matrix production, and differentiation were regulated by changes in the fiber diameter. More specifically, a higher cell number, total collagen, and proteoglycan production were found on the nanofiber scaffolds, while microfibers promoted the expression of phenotypic markers of tendon fibroblasts, such as collagen I, III, V, and tenomodulin. It is possible that the nanofiber scaffolds of this study resemble the matrix in a state of injury, stimulating the cells for matrix deposition as part of the repair process, while microfibers represent the healthy matrix with micron-sized collagen bundles, thereby inducing cells to maintain the fibroblastic phenotype. The results of this study demonstrate that controlling the scaffold fiber diameter is critical in the design of scaffolds for functional and guided connective tissue repair, and provide new insights into the role of matrix parameters in guiding soft tissue healing.
Article
We review the available evidence for regeneration of adult organs of very diverse nature and examine the applicability of simple rules that can be used to summarize these treatments. In the field of regenerative medicine no widely accepted paradigm is currently available that can guide formulation of new theories on the mechanism of regeneration in adults and open new directions for improved regeneration outcomes. The four rules have emerged from multiyear quantitative studies with skin and peripheral nerve regeneration using scaffold libraries based on a simple, well-defined collagen scaffold. These largely quantitative rules distinguish sharply between spontaneously regenerative and nonregenerative tissues, select the two reactants that are required for regeneration, recognize the essential modification of the wound healing process that must be realized prior to regeneration, and identify three structural features of scaffolds that are required for regenerative activity. The combined evidence points at certain requirements for the structure of a collagen scaffold with regenerative activity. An active scaffold emerges as a temporarily insoluble collagen surface, equipped with sufficient ligands for integrins of contractile cells, that inhibits wound contraction while also serving as a topographic template for new stroma synthesis. The four rules, based on studies with just two organs (skin and peripheral nerves), are now viewed in the context of ongoing studies using scaffolds based on decellularized matrices, which are mostly based on collagen. Decellularized matrices have been used during the past few years to regenerate, in whole or in part, the urethra, the abdominal wall, the Achilles tendon, the bladder, the trachea and other organs in several animal models and occasionally in humans. Although these acellular matrices are distinctly different from simple collagen scaffolds, and the methods used by the investigators are still evolving, the results obtained are shown to be broadly consistent with the predictions of the four rules. Future use or adaptations of these largely quantitative rules could account more satisfactorily for problems, such as imperfect function of regenerated organs, that are currently encountered by researchers. It could also further the explanation of the mechanism of regeneration at the cellular and molecular level.
Article
In order to investigate cell-based tendon regeneration, a tendon rupture was simulated by utilizing a critical full-size model in female rat achilles tendons. For bridging the defect, polyglycol acid (PGA) and collagen type I scaffolds were used and fixed with a frame suture to ensure postoperatively a functional continuity. Scaffolds were seeded with mesenchymal stem cells (MSC) or tenocytes derived from male animals, while control groups were left without cells. After a healing period of 16 weeks, biomechanical, PCR, histologic, and electron microscopic analyses of the regenerates were performed. Genomic PCR for male-specific gene was used to detect transplanted cells in the regenerates. After 16 weeks, central ossification and tendon-like tissue in the superficial tendon layers were observed in all study groups. Biomechanical test showed that samples loaded with tenocytes had significantly better failure strength/cross-section ratio (P < 0.01) compared to MSC and the control groups whereas maximum failure strength was similar in all groups. Thus, we concluded that the application of tenocytes improves the outcome in this model concerning the grade of ossification and the mechanical properties in comparison to the use of MSC or just scaffold materials.
Article
Efforts to develop engineered tendons and ligaments have focused on the use of a biomaterial scaffold and a stem cell source. However, the ideal scaffold microenvironment to promote stem cell differentiation and development of organized extracellular matrix is unknown. Through electrospinning, fibre scaffolds can be designed with tailorable architectures to mimic the intended tissue. In this study, the effects of fibre diameter and orientation were examined by electrospinning thin mats, consisting of small (< 1 µm), medium (1-2 µm) or large (> 2 µm) diameter fibres with either random or aligned fibre orientation. C3H10T1/2 model stem cells were cultured on the six different electrospun mats, as well as smooth spin-coated films, and the morphology, growth and expression of tendon/ligament genes were evaluated. The results demonstrated that fibre diameter affects cellular behaviour more significantly than fibre alignment. Initially, cell density was greater on the small fibre diameter mats, but similar cell densities were found on all mats after an additional week in culture. After 2 weeks, gene expression of collagen 1α1 and decorin was increased on all mats compared to films. Expression of the tendon/ligament transcription factor scleraxis was suppressed on all electrospun mats relative to spin-coated films, but expression on the large-diameter fibre mats was consistently greater than on the medium-diameter fibre mats. These results suggest that larger-diameter fibres (e.g. > 2 µm) may be more suitable for in vitro development of a tendon/ligament tissue. Copyright © 2012 John Wiley & Sons, Ltd.