Biomedical Engineering Reference
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in high concentrations during early fracture repair processes, but levels off in later stages,
eliciting specific responses resulting from these concentration changes. For instance, in
the early stages of repair, TGF-β1 promotes division of fibroblasts, osteoblast recruitment,
and differentiation, whereas in later stages, it promotes osteoclastogenesis. Therefore, a
temporally graded administration of TGF-β1 would enhance the repair and regeneration
process. Similarly, BMP2 promotes chemotaxis and cell proliferation at low concentrations
and cell differentiation and bone formation at high concentrations (Allori, Sailon, and
Warren 2008). Likewise, a pulsatile delivery of BMP2 may be optimal for tissue regenera-
tion strategies.
Coprecipitation can tailor the administration of growth factors and bioactive molecules
to control their release kinetics and the rate of tissue regeneration. For example, rat bone
marrow cells cultured on titanium alloys coated with biomimetically precipitated BLM
and BMP-2 showed a significant increase in bone formation compared to adsorption
(Hunter and Goldberg 1994). This method of growth factor incorporation into the min-
eral matrix allowed for a sustained release over a period of 5 weeks as compared to the
1-week burst release of adsorbed growth factor that only produced a sporadic osteogenic
response. Although the same amount of BMP-2 was used for both methods, BMP incorpo-
rated via coprecipitation showed more of a sustained osteogenic response (Liu, de Groot,
and Hunziker 2004). Similarly, insulin-like growth factor-1 (IGF-1) coprecipitated with
BLM on PLGA scaffolds showed a sustained and linearly increasing release profile over a
30-day period (Jayasuriya and Shah 2008).
A complex biological response such as tissue regeneration is a result of the coordi-
nated cellular events involving the sequential secretion of multiple growth factors.
Coprecipitation and surface immobilization could be used to customize and mimic these
coordinated events. For example, TGF-β1 also regulates gene expression of other growth
factors such as VEGF. In a rat mandibular orthotopic model, TGF-β and VEGF mRNA
transcription increased 2.5-fold only 3 h after surgery and TGF-β and VEGF expression
increased 3-fold compared to baseline levels for 4 weeks after wound healing commenced
(Allori, Sailon, and Warren 2008). Incorporation of multiple growth factors into a single
construct has the potential to enhance bioactivity. For example, the delivery of TGF-β and
BMP-2 delivery from alginate gels resulted in greater bone tissue formation after 6 weeks,
but no significant changes were observed even 22 weeks after implantation when they
were administered alone (Simmons et al. 2004).
Coprecipitation provides the flexibility to tailor release profiles since the concentra-
tions of different growth factors could be graded separately through the thickness of
the coating. A similar coordinated response can be achieved by coupling coprecipita-
tion of proteins with surface immobilization methods; the adsorbed molecule could be
released in a burst profile and the coprecipitated molecule could be delivered in a sus-
tained fashion.
Coprecipitation of DNA and Mineral
DNA coprecipitation allows the incorporation of nucleic acids into the biomimetically pre-
cipitated mineral layer at physiological conditions (Figure 1.6). Similar to growth factors,
coprecipitation with mineral can be used to control the spatial distribution of DNA through
the thickness of the coating. As the mineral layer degrades in physiological conditions,
DNA will be released in a spatially and temporally controlled manner. Coprecipitation
of mineral also improves the stiffness of soft substrate surfaces, which improves cellular
uptake of DNA (Kong et al. 2005).
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