Background: Bone morphogenetic proteins (BMPs)
are biologically active molecules capable of eliciting new bone
formation. In combination with biomaterials, these proteins can
be used in a clinical setting as bone-graft substitutes to promote
bone repair. Collagen from animal sources has previously been the preferred
carrier material in animal experiments. More recently, synthetic
biodegradable polymers have been tested as a delivery vehicle for
osteoinductive agents. In earlier studies performed in our laboratory,
it was found that the polylactic acid homopolymers (PLA650) and
poly-d,l-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200)
are viscous liquids that can be used as BMP delivery systems.
Methods: To obtain new PLA-PEG polymers that exhibit greater
plasticity, the molecular sizes of PLA and PEG segments in the copolymer
chains were increased. Plastic PLA-PEG polymers with various molecular
sizes and PLA/PEG ratios were synthesized, mixed with recombinant
human (rh) BMP-2, and implanted into the dorsal muscles of mice
for 3 weeks to evaluate their capacity to elicit new bone formation.
To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200
polymer, these two polymers were combined with rhBMP-2, implanted,
and harvested after 3 weeks. Bone mineral content (BMC), bone area,
and bone mineral density (BMD) of the ectopic new bone were measured
by means of single energy X-ray absorptiometry (SXA).
Results: All of the PLA6,500-PEG3,000 implants with
10 or 20 g of rhBMP-2 showed new bone formation. In contrast, little
or no bone formation was seen in other plastic PLA-PEG implants
with rhBMP-2. Control implants that lacked rhBMP-2 did not show new
bone formation. Radiographic and histologic examinations showed
that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks
after implantation had normal bone characteristics with hematopoietic
marrow and osseous trabeculae. SXA analysis showed that the values
for bone mineral content (BMC), bone area, and bone mineral density
(BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000
polymers with rhBMP-2 were significantly higher than those obtained
with the liquid PLA650-PEG200 polymers (p < 0.001 for each
of the three values).
Conclusions: These results indicate that the PLA6,500-PEG3000 block
copolymer with plastic properties works effectively as a BMP delivery
system. These data suggest that the total molecular size and ratio
of PLA size to PEG size is an essential factor in determining the
efficacy of a BMP delivery system. After implantation, it is possible
that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids
and become swollen, resulting in bone formation that exceeded the
size of the original implants. This expansion characteristic is
a potentially beneficial property, given the intended practical
application of the polymer in the repair of bone defects.
Clinical Relevance:
New synthetic biodegradable delivery systems will play an important
role in the clinical applications of rhBMPs in which local formation
of bone via an osteoinductive graft material is needed. Further
pre-clinical and clinical work is necessary to establish the safety
of these implants before they are adopted for widespread clinical
use.