Barbieri Thesis - BioMedical Materials program (BMM)

Chapter 2 – The role of gels in instructive putties
2.1. Introduction
There is a worldwide increasing population with likely more bone injuries due to age
and accidents. Consequently, the number of annual bone graft procedures is steadily
growing and is leading to the search of improved grafting techniques. [258] Due to the
many disadvantages of the gold standard autologous bone grafting (i.e. additional
surgical procedure, pain and limited availability), there is a need for developing
alternative (synthetic) bone graft materials that can stimulate bone healing.
Commercially available bone growth factors such as rhBMP–2 have a strong
osteoinductive potential but can result in undesired ectopic bone growth, [259] and
complications with its use in spinal surgery have been reported, [408] making them sub–
optimal to replace autografts in the long term. Inorganic, synthetic materials such as
polymers and calcium phosphate ceramics on the other hand, generally do not have
bone–inducing potential and can therefore only be used to repair small bone defects
in an osteoconductive fashion.
In the past two decades, calcium phosphate ceramics with micro–structured
surface have been reported to have the unique ability to induce bone growth when
intramuscularly implanted in large animals (e.g. dog, sheep and goat) without addition
of (osteogenic) factors or cells. [217, 220, 225, 226, 236, 260–263] Although the process
underlying bone induction by these materials has not yet been fully elucidated,
surface micro– and nano–structural features such as grain and micro–pore size have
been shown to play a crucial role. [86] When micro–structured hydroxyapatite (HA) was
implanted in the muscle of dogs, it induced ectopic bone formation. On the contrary,
HA lacking such surface micro–structure was not able to trigger osteoinduction [236, 237]
Similar results were shown in studies comparing HA and biphasic calcium phosphate
(BCP) ceramics with various micro–porosity. [228] It has furthermore been shown that
micro–structured, osteoinductive calcium phosphate ceramics are superior to non–
osteoinductive calcium phosphate ceramics for the repair of critical sized bone
defects (e.g. 17 mm diameter in goats). [86, 238] Recently, it has even been shown that
these materials are a promising synthetic alternative to autologous bone grafting. [86]
Since most calcium phosphate ceramics are prepared in block or particular form,
their handling properties are not optimal. Placing individual particles in bone voids
may lead to incomplete filling of irregularly shaped defect or granule dispersion and
loss during surgery. To overcome these issues, calcium phosphate–based cements
have been developed as alternatives [264–266] but inherent drawbacks include unstable
flowability, which is dependent on the setting time, [267] lack of micro– and macro–
porosity to allow angiogenesis and tissue ingrowth, [268] slow cement resorption [266] and
they are not osteoinductive. [269] These disadvantages might be surmounted by
developing injectable pastes or putties where a binder or gel with proper rheological
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