Repair of large cranial defects by hBMP‐2 expressing bone marrow stromal cells: Comparison between alginate and collagen type I systems

Abstract

Despite a wide range of available sources for bone repair, significant limitations persist. To bioengineer bone, we have previously transferred adenovirus-mediated human BMP-2 gene into autologous bone marrow stromal cells (MSC). We have successfully repaired large, full thickness, cranial defects using this approach. We report now the effectiveness of various hydrogels as the scaffold for this type of bone regeneration, comparing specifically alginate with Type I collagen. Cultured MSC of miniature swine were infected with BMP-2 or beta-gal adenovirus 7 days before implantation. These cells were mixed with alginate, ultrapure alginate, alginate-RGD, or type I collagen to fabricate the MSC/biomaterial constructs. The results of cranial bone regeneration were assessed by gross examination, histology, 3D CT, and biomechanical tests at 6 weeks and 3 months after implantation. We found that the BMP-2 MSC/collagen type I construct, but not the beta-gal control, effectively achieved nearly complete repair of the cranial defects. No bone regeneration was observed with the other hydrogels. Biomechanical testing showed that the new bone strength was very close and only slightly inferior to that of normal cranial bone. Controlling for the integration of stem cells and ex vivo gene transfer, the alginate scaffolds has a significant negative impact on the success of the construct. Our study demonstrates better bone regeneration by collagen type I over alginate. This may have therapeutic implications for tissue engineered bone repair.

A comparison of bone regeneration with human mesenchymal stem cells and muscle-derived stem cells and the critical role of BMP

“…Many different scaffolds have been used for promoting the osteogenesis of bone marrow MSCs in vivo, including collagen type I, alginate hydrogel [10, 11], gelatin beads [12], hydroxyapatite [13, 14], small intestine submucosa, and akermanite bioceramics [15, 16]. In the current study, we utilized fibrin sealant, which is the natural product of blood clot formation and is completely bio-resorbable.…”

Growth factor regulation of proliferation and survival of multipotential stromal cells

“…While BMP-2, BMP-4, BMP-6, and BMP-7 induce MSCs to form osteoblasts, BMP-2 has the greatest impact on differentiation [35]. MSCs overexpressing BMP-2 and implanted with the extracellular matrix protein collagen I as a hydrogel system increase proliferation of MSC differentiation into bone, and this model has been used to study cranial closures in swine [36,37]. Another member of the same family, BMP-3, increases MSC proliferation threefold [38].…”

Collagen Three-Dimensional Hydrogel Matrix Carrying Basic Fibroblast Growth Factor for the Cultivation of Mesenchymal Stem Cells and Osteogenic Differentiation

“…34,35 The transforming growth factor b superfamily member, bone morphogenetic protein 2 (BMP2), directly promotes induction of an osteogenic differentiation 36,37 by upregulating markers of mature osteoblasts such as type I collagen (Col I), osteocalcin (OCN), and alkaline phosphatase (ALP) activity. 38,39 Recently, collagen hydrogels containing MSCs overexpressing recombinant BMP2 have proven very effective at repairing full-thickness cranial defects in a miniature pig model, 40 and a direct comparison of bFGF versus BMP2 suggested also that bFGF is a potent growth factor to promote osteogenesis. Therefore, in this study we report the effects of bFGF on osteogenic differentiation of MSCs in collagen hydrogels to exploit 3D culture conditions, which better represents the natural in vivo tissue environment.…”