A novel biodegradable delivery system for bone morphogenetic protein-2.
BACKGROUND
The efficacy of recombinant growth factors in vivo is highly dependent on the delivery vehicle. The authors investigated the osteoinductive effects of recombinant human bone morphogenetic proteins (BMP)-2 implanted together with a complex of heparin and chitosan.


METHODS
Sixty rats were used. Three different carriers in gel formulation (type I collagen, heparin/type I collagen, and heparin/chitosan) were mixed with either 0, 10, or 50 microg of BMP-2, making the number of groups nine. The gels were injected into the quadriceps muscles of both legs in 45 rats (n = 10 per group). Freeze-dried formulations of the carriers were also tested with the same amounts of BMP-2 using 15 rats (n = 5 per group). Four weeks after implantation, the quality and amount of newly formed bone were assessed.


RESULTS
Chitosan was shown to protect the heparinase-mediated degradation of heparin in vitro. The osteoinductive effects of BMP-2 in combination with heparin/chitosan were superior as compared with BMP-2 implanted together with type I collagen. Interestingly, the heparin/chitosan complex induced a small amount of bone also without BMP-2 added. The heparin/chitosan was completely absorbed after 4 weeks as determined by histologic evaluation, and a normal active bone formation was present. The freeze-dried formulations of the carriers demonstrated similar osteoinductive effects as the gels.


CONCLUSIONS
An osteoinductive formula for clinical use is needed for general bone reconstruction. Heparin in complex with chitosan has the ability to stabilize or activate the growth factor in vivo and induce the generation of new bone in good yields.
Stockholm and Gothenburg, Sweden From the Stockholm Craniofacial Centre, Department of Reconstructive Plastic Surgery, Karolinska University Hospital and Karolinska Institute; Center for Bone Research, Sahlgrenska Academy; and ExThera, Karolinska Institute.
Thomas
T
Engstrand
Riikka
R
Veltheim
Claes
C
Arnander
Ann-Charlott
AC
Docherty-Skogh
Anders
A
Westermark
Claes
C
Ohlsson
Lars
L
Adolfsson
Olle
O
Larm
D020341:Absorbable Implants; D000818:Animals; D001672:Biocompatible Materials; D001707:Biopsy, Needle; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D048271:Chitosan / Q000494:pharmacology*; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006493:Heparin / Q000494:pharmacology*; D007150:Immunohistochemistry; D020007:Implants, Experimental; D008297:Male; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C525718:BMP2 protein, human; D001672:Biocompatible Materials; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D016212:Transforming Growth Factor beta; D006493:Heparin; D048271:Chitosan