Biomedical Engineering Reference
In-Depth Information
Another component of the pathway, again common with bone adaptation, is nitric oxide.
This mediator has been shown to be present in the cascade of indirect repair, suppression of
this messenger molecule being inhibitory to the repair process. 20 Additionally this mediate has
been shown to be most prevalent in the early stages of repair 19 with specific isoforms occurring
in association with progression though the early tissue types. 84 Thus the interaction of the
different isoforms with time in the repair process could have implications for modulating the
progress of the repair process using inhibitors or stimulators at specific times after injury. 83
Despite the identification of these potential transduction pathways further work is required
to identify the critical time related interactions and thus optimise conditions in specific frac-
tures for a maximal rate of restoration of mechanical integrity.
The Process of Bone Repair as an in Vivo Tissue Regeneration
Scenario and Implications for Tissue Engineering
Interestingly, the fracture repair process seen in indirect or endochondral repair involves the
formation de novo within the adult osseous skeleton of the entire range of connective tissues,
from blood in the immediate post-fracture period forming the fracture haematoma, through
fibrous and cartilaginous connective tissues to lamellar bone. Additionally the endochondral
element of the repair process resembles a repeat of embryological bone development. This
indicates the potential for the body to regenerate connective tissues given the appropriate me-
chanical and biological signals. Thus a delayed or nonunion is a complication for fracture
healing but an in vivo bioreactor to generate nonosseous connective tissues.
In hypertrophic nonunions hyaline cartilage is formed on a bone surface, this biological
response could provide a biological solution to resurfacing degenerate joints. Theoretical mod-
els of tissue formation in fracture healing have been proposed based upon the influence of
stress and strain in relation to tissue differentiation. Claes and Heigele (1999) 16 developed a
model that suggests influences that might indicate the conditions inducing specific tissue dif-
ferentiation from mesenchymal stem cells in the process of bone repair. This model suggests
that low values of strain and hydrostatic pressure induce intra-membranous bone formation,
whereas high values of hydrostatic stress with low strains induce cartilage and high hydrostatic
stress with high strains leads to fibrocartilage. This work built on previous modelling of both
bone development and bone healing that indicated a potential to control tissue formation
solely by imposed mechanical environment and thus set the scene for the role of mechanobiology
in skeletal tissue engineering. 4,6,7
As has been discussed above the application of specific regimens of inter-fragmentary move-
ment can lead to enhancement or inhibition of the progression of bony union. Some regimens
will induce formation and persistence of nonosseus tissues. In addition the size of an osteotomy
gap will also influence the progression of healing and large gaps form a “critical size defect” that
inhibits bone union resulting in a persistence of fibrous fibro-cartilaginous or cartilaginous
tissue. The interaction of biological and mechanical signals in engineering differentiation of
specific connective tissues requires a mechanically defined model, the use of rodent species
allowing biological techniques to be used that can identify the associated molecular mecha-
nisms, 37 With such a model where mechanical conditions can be determined to some extent,
the effects of biological cues can be examined under more controlled conditions.
The models that have been proposed in relation to the mechanobiology of bone formation
and connective tissue differentiation in bone healing need to be cross referenced to the emerg-
ing field of tissue engineering.
An understanding of the mechanical and biological interactions in bone repair contributes
to the requirements to engineer skeletal tissues both using bioreactors in vitro and manipula-
tion of tissues in vivo. Additionally these mechanisms can be applied to improve osseointegration
of current synthetic skeletal prostheses.
Fracture healing should be viewed not only as a clinical challenge but also as one of the most
fascinating tissue repair and regeneration processes in the body.
 
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