Biomedical Engineering Reference
In-Depth Information
implantation in ectopic (sub-cutaneous or intra-muscular) and orthotopic (calvaria) sites al-
low in vivo evaluation of biocompatibility, biodegradability, osseointegration, osteoconductivity,
osteoinductive and osteogenic potential. On the contrary preclinical evaluations rely on animal
models simulating the clinical situation in which the BRM will be used. Because the main
application of BRM in orthopaedic surgery is bone loss replacement, the most commonly used
designs are surgically induced bone defects that are known to progress to nonunion if not
replaced. The notion of a critical size defect (CSD) was firstly described by Schmitz as “the
smallest intraosseous wound that does not heal by bone formation during the lifetime of the
animal”. 2 Hollinger et al further defined a CSD as “a defect which has less than 10% of bony
regeneration occurring within the lifetime of the animal”. 3 The CSD must be created under
conditions of optimal mechanical stability in order to guarantee that nonunion results exclu-
sively from bone loss. Periosteum should also be resected because leaving the periosteum intact
when performing resection of the bone enhances bone healing.
Experimental design and associated effects must not only be correlated in the laboratory
animal but also in human surgical applications. Animal anatomy, bone healing and remodel-
ling specifications, as well as immunological and genetic status, condition model relevance.
Anatomical Features
Specific anatomical characteristics may condition the feasibility of surgical procedures in
preclinical tests. For example, mandibular defects, currently used in maxillofacial experimental
surgery to evaluate BRM, are challenging to perform in rodents and rabbits as mouth opening
is very limited in these species. BRM stability is also difficult to obtain in such very small
defects. 3 Bones shapes and sizes also condition surgical technical feasibility. Rodents and rab-
bits have small-sized long bones, with thin and fragile cortices, thus requiring delicate surgical
technique and custom-made implants for bone fixation. 4,5 Cats, dogs, sheep and pigs have
larger bones, allowing the use of surgical techniques and implants designed for humans.
Lastly, the type of bony tissue in which the material is tested will be different depending on
the future applications of the BRM: calvarias (i.e., membranous bone) will be preferred if the
material is to be used in cranioplasties while metaphyseal extremities (i.e., trabecular bone) or
diaphysis (i.e., cortical bone) will be preferred if the material is to be used for filling defects or
segmental loss in long bones.
Bone Healing and Remodelling Characteristics
Bone healing and remodelling characteristics in the laboratory animal depend on many
variables amongst which some are species or age dependent. Bone blood supply and mechani-
cal loading also affect healing.
Order along the phylogenetic scale inversely correlates with the rate of bone repair: bone
healing capacity is higher in rodents and rabbits than in other species. 2 The type and rate of
bone remodelling also differ amongst species. Whereas large animal (rabbits, cats, dogs, pigs,
and nonhuman primates (NHP)) show Haversian type remodelling in cortical bone, rodents
do not. 6 Cortical bone remodelling in rabbits is also twice as fast as in dogs and three times as
fast as in humans. 7 These features must be taken into account as they may affect material
resorption: natural coral resorption is for example slower in sheep than in pigs. 8 Results in
rodents and rabbits must therefore be considered with caution and validated in other species
higher on the phylogenetic scale before attempting extrapolation to humans.
Immature animals have higher bone healing capacity and regeneration compared with adults.
The magnitude of a critical size defect is therefore inversely related to the age of the animal and
bone substitutes must be evaluated in adult animals in which closed epiphyseal plates are docu-
mented with radiographs. 9 Mice and rats remain exceptions to that rule as bone growth is
constant throughout life in these species. 6
Local blood flow and mechanical loading should be critically assessed when studying aug-
menting bone healing procedures. Kusumuto 10 has recently noted the importance of blood
supply in promoting heterotopic osteoinduction by rhBMP-2. Skeletal unloading in weight
 
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