N. Saito et al., Biodegradable poly-D,L-lactic acid-polyethylene glycol block copolymers asa BMP delivery system for inducing bone, J BONE-AM V, 83A, 2001, pp. S92-S98
Citations number
30
Categorie Soggetti
Ortopedics, Rehabilitation & Sport Medicine","da verificare
Background: Bone morphogenetic proteins (BMPs) are biologically active mole
cules capable of eliciting new bone formation. In combination with biomater
ials, these proteins can be used in a clinical setting as bone-graft substi
tutes to promote bone repair. Collagen from animal sources has previously b
een the preferred carrier material in animal experiments. More recently, sy
nthetic biodegradable polymers have been tested as a delivery vehicle for o
steoinductive agents. In earlier studies performed in our laboratory, it wa
s found that the polylactic acid homopolymers (PLA650) and poly-D,L-lactic
acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liqui
ds that can be used as BMP delivery systems.
Methods: To obtain new PLA-PEG polymers that exhibit greater plasticity, th
e molecular sizes of PLA and PEG segments in the copolymer chains were incr
eased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ra
tios were synthesized, mixed with recombinant human (rh) BMP-2, and implant
ed into the dorsal muscles of mice for 3 weeks to evaluate their capacity t
o elicit new bone formation. To compare the plastic PLA-PEG polymer with th
e liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP
-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bon
e area, and bone mineral density (BMD) of the ectopic new bone were measure
d by means of single energy X-ray absorptiometry (SXA).
Results: All of the PLA6,500-PEG3,000 implants with 10 or 20 mug of rhBMP-2
showed new bone formation. In contrast, little or no bone formation was se
en in other plastic PLA-PEG implants with rhBMP-2. Control implants that la
cked rhBMP-2 did not show new bone formation. Radiographic and histologic e
xaminations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvest
ed 3 weeks after implantation had normal bone characteristics with hematopo
ietic marrow and osseous trabeculae. SXA analysis showed that the values fo
r 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 PLA65
0-PEG200 polymers (p < 0.001 for each of the three values).
Conclusions: These results indicate that the PLA6,500-PEG3000 block copolym
er with plastic properties works effectively as a BMP delivery system. Thes
e data suggest that the total molecular size and ratio of PLA size to PEG s
ize is an essential factor in determining the efficacy of a BMP delivery sy
stem. After implantation, it is possible that the PLA6,500-PEG3,000 pellets
might have absorbed tissue fluids and become swollen, resulting in bone fo
rmation that exceeded the size of the original implants. This expansion cha
racteristic is a potentially beneficial property, given the intended practi
cal application of the polymer in the repair of bone defects.
Conclusions: These results indicate that the PLA6,500-PEG3000 block copolym
er with plastic properties works effectively as a BMP delivery system. Thes
e data suggest that the total molecular size and ratio of PLA size to PEG s
ize is an essential factor in determining the efficacy of a BMP delivery sy
stem. After implantation, it is possible that the PLA6,500-PEG3,000 pellets
might have absorbed tissue fluids and become swollen, resulting in bone fo
rmation that exceeded the size of the original implants. This expansion cha
racteristic is a potentially beneficial property, given the intended practi
cal 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 for
mation of bone via an osteoinductive graft material is needed. Further pre-
clinical and clinical work is necessary to establish the safety of these im
plants before they are adopted for widespread clinical use.