The treatment of large cranial defects may be greatly improved by the development of precisely formed bone tissue engineering scaffolds. Such scaffolds could be constructed by using UV laser stereolithography to photocrosslink a linear, biodegradable polymer into a three-dimensional implant. We have previously presented a method to photocrosslink the biodegradable polyester, poly(propylene fumarate) (PPF). To ensure the safety and effectiveness of this technique, the soft and hard tissue response to photocrosslinked PPF scaffolds of different pore morphologies was investigated. Four classes of photocrosslinked PPF scaffolds, constructed with differing porosities (57-75%) and pore sizes (300-500 or 600-800 microm), were implanted both subcutaneously and in 6.3-mm-diameter cranial defects in a rabbit model. The rabbits were sacrificed at 2 and 8 weeks, and the implants were analyzed by light microscopy, histological scoring analysis, and histomorphometric analysis. Results showed the PPF scaffolds elicit a mild tissue response in both soft and hard tissues. Inflammatory cells, vascularization, and connective tissue were observed at 2 weeks; a decrease in inflammatory cell density and a more organized connective tissue were observed at 8 weeks. Scaffold porosity and scaffold pore size were not found to significantly affect the observed tissue response. Evidence of scaffold surface degradation was noted both by histology and histomorphometric analysis. Bone ingrowth in PPF scaffolds implanted into cranial defects was <3% of the defect area. The results indicate that photocrosslinked PPF scaffolds are biocompatible in both soft and hard tissues and thus may be an attractive platform for bone tissue engineering.

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This study determined the bone growth into pretreated poly(propylene fumarate) (PPF) scaffolds implanted into a subcritical size, rabbit cranial defect. PPF scaffolds were constructed by using a photocrosslinking-porogen leaching technique. These scaffolds were then either prewetted (PPF-Pw), treated with RF glow-discharge (PPF-Gd), coated with fibronectin (PPF-Fn), or coated with rhTGF-beta1 (PPF-TGF-beta1). One of each scaffold type was then placed into the cranium of nine rabbits. The rabbits were sacrificed after 8 weeks, and the scaffolds were retrieved for histological analysis. The most bone formation was present in the PPF-TGF-beta1 implants; the newly formed bone had a trabecular appearance together with bone marrow-like tissue. Little or no bone formation was observed in implants without rhTGF-beta1. These histological findings were confirmed by image analysis. Bone surface area, bone area percentage, pore fill percentage, and pore area percentage were significantly higher in the rhTGF-beta1-coated implants than in the noncoated implants. No statistical difference was seen between the PPF-Fn, PPF-Pw, or PPF-Gd scaffolds for these parameters. Quadruple fluorochrome labeling showed that in PPF-TGF-beta1 implants bone formation mainly started in the interior of a pore and proceeded toward the scaffold. We conclude that (a) PPF-TGF-beta1 scaffolds can indeed adequately induce bone formation in porous PPF, and (b) PPF scaffolds prepared by the photocrosslinking-porogen leaching technique are good candidates for the creation of bone graft substitutes.

The osteoconductive properties of porous titanium (Ti) fiber mesh with or without a calcium phosphate (Ca-P) coating and osteoinductive properties of noncoated Ti fiber mesh loaded with recombinant human Transforming Growth Factor beta-1 (rhTGF-beta1) were investigated in a rabbit non-critical size cranial defect model. Nine Ca-P-coated and 18 non-coated porous titanium implants, half of them loaded with rhTGF-beta1, were bilaterally placed in the cranium of 18 New Zealand White rabbits. At 8 weeks postoperative, the rabbits were sacrificed and the skulls with the implants were retrieved. Histological analysis demonstrated that in the TGF-beta1-loaded implants, bone had been formed throughout the implant, up to its center, whereas in the non-loaded implants only partial ingrowth of bone was observed. Bone formation had a trabecular appearance together with bone marrow-like tissue. No difference in ingrowth could be observed between the non-TGF-beta1-loaded non-coated implants and the Ca-P-coated ones. All histological findings were confirmed by image analysis: 97% ingrowth was seen in the rhTGF-beta1-loaded implants, while only 57% and 54% ingrowth was observed in the non-loaded Ca-P-coated and non-coated implants, respectively. Bone surface area and bone fill were significantly higher in the rhTGF-beta1-loaded implants (1.37 mm2 and 36%, respectively) than in the non-loaded implants (0.57 mm2 and 26%). No statistical difference was found for any parameter between the Ca-P-coated and noncoated implants. Quadruple fluorochrome labeling showed that in the Ti and Ti-CaP implants mainly bone guidance had occurred from the former defect edge, while in the Ti-TGF-beta1 implants bone formation had mainly started in the center of a pore and proceeded in a centrifugal manner. Our results show that: (1) the combination of Timesh with TGF-beta1 can induce orthotopic bone formation; (2) Ti-fiber mesh has good osteoconductive properties; (3) a thin Ca-P coating, as applied in this study, does not seem to further enhance the bone-conducting properties of a titanium scaffold material.