Samenvatting
Fracture repair is a complex and multifactorial process, which involves a well-programmed
series of cellular and molecular events that result in a combination of intramembranous and
endochondral bone formation. The vast majority of fractures is treated successfully. They heal
through ‘secondary healing’, a sequence of tissue differentiation processes, from initial
haematoma, to connective tissues, and via cartilage to bone. However, the process can fail and
this results in delayed healing or non-union, which occur in 5-10% of all cases. A better
understanding of this process would enable the development of more accurate and rational
strategies for fracture treatment and accelerating healing. Impaired healing has been associated
with a variety of factors, related to the biological and mechanical environments. The local
mechanical environment can induce fracture healing or alter its biological pathway by
directing the cell and tissue differentiation pathways. The mechanical environment is usually
described by global mechanical factors, such as gap size and interfragmentary movement. The
relationship between global mechanical factors and the local stresses and strains that influence
cell differentiation can be calculated using computational models.
In this thesis, mechano-regulation algorithms are used to predict the influence of mechanical
stimuli on tissue differentiation during bone healing. These models used can assist in
unraveling the basic principles of cell and tissue differentiation, optimization of implant
design, and investigation of treatments for non-union and other pathologies. However, this can
only be accomplished after the models have been suitably validated. The aim of this thesis is
to corroborate mechanoregulatory models, by comparing existing models with well
characterized experimental data, identify shortcomings and develop new computational
models of bone healing. The underlying hypothesis throughout this work is that the cells act as
sensors of mechanical stimuli during bone healing. This directs their differentiation
accordingly. Moreover, the cells respond to mechanical loading by proliferation,
differentiation or apoptosis, as well as by synthesis or removal of extracellular matrix.
In the first part of this work, both well-established and new potential mechano-regulation
algorithms were implemented into the same computational model and their capacities to
predict the general tissue distributions in normal fracture healing under cyclic axial load were
compared. Several algorithms, based on different biophysical stimuli, were equally well able
to predict normal fracture healing processes (Chapter 3). To corroborate the algorithms, they
were compared with extensive in vivo experimental bone healing data. Healing under two
distinctly different mechanical conditions was compared: axial compression or torsional
rotation. None of the established algorithms properly predicted the spatial and temporal tissue
distributions observed experimentally, for both loading modes and time points. Specific
inadequacies with each model were identified. One algorithm, based on deviatoric strain and
fluid flow, predicted the experimental results the best (Chapter 4). This algorithm was then
employed in further studies of bone regeneration. By including volumetric growth of
individual tissue types, it was shown to correctly predict experimentally observed spatial and
temporal tissue distributions during distraction osteogenesis, as well as known perturbations
due to changes in distraction rate and frequency (Chapter 5).
In the second part of this work, a novel ‘mechanistic model’ of cellular activity in bone
healing was developed, in which the limitations of previous models were addressed. The
formulation included mechanical modulation of cell phenotype and skeletal tissue-type
specific activities and rates. This model was shown to correctly predict the normal fracture
healing processes, as well as delayed and non-union due to excessive loading, and also the
effects of some specific biological perturbations and pathological situations. For example,
alterations due to periosteal stripping or impaired cartilage remodeling (endochondral
ossification) compared well with experimental observations (Chapter 6). The model requires
extensive parametric data as input, which was gathered, as far as possible, from literature.
Since many of the parameter magnitudes are not well established, a factorial analysis was
conducted using ‘design of experiments’ methods and Taguchi orthogonal arrays. A few
cellular parameters were thereby identified as key factors in the process of bone healing.
These were related to bone formation, and cartilage production and degradation, which
corresponded to those processes that have been suggested to be crucial biological steps in
bone healing. Bone healing was found to be sensitive to parameters related to fibrous tissue
and cartilage formation. These parameters had optimum values, indicating that some amounts
of soft tissue production are beneficial, but too little or too much may be detrimental to the
healing process (Chapter 7).
The final part of this work focused on the remodeling phase of bone healing. Long bone postfracture
remodeling in mice femora was characterized, including a new phenomenon
described as ‘dual cortex formation’. The effect of mechanical loading modes on fracturecallus
remodeling was evaluated using a bone remodeling algorithm, and it was shown that the
distinct remodeling behavior observed in mice, compared to larger mammals, could be
explained by a difference in major mechanical loading mode (Chapter 8).
In summary, this work has further established the potential of mechanobiological
computational models in developing our knowledge of cell and tissue differentiation processes
during bone healing in general, and fracture healing and distraction osteogenesis in particular.
The studies presented in this thesis have led to the development of more mechanistic models
of cell and tissue differentiation and validation approaches have been described. These models
can further assist in screening for potential treatment protocols of pathophysiological bone
healing.
Originele taal-2 | Engels |
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Kwalificatie | Doctor in de Filosofie |
Toekennende instantie |
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Begeleider(s)/adviseur |
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Datum van toekenning | 26 nov. 2007 |
Plaats van publicatie | Eindhoven |
Uitgever | |
Gedrukte ISBN's | 978-90-386-1146-4 |
DOI's | |
Status | Gepubliceerd - 2007 |