The Effects of Age and Dose on Gene Expression and Segmental Bone Defect Repair After BMP‐2 Delivery

Abstract

Age is a well‐known influential factor in bone healing, with younger patients generally healing bone fractures more rapidly and suffering fewer complications compared with older patients. Yet the impact age has on the response to current bone healing treatments, such as delivery of bone morphogenetic protein 2 (BMP‐2), remains poorly characterized. It remains unclear how or if therapeutic dosing of BMP‐2 should be modified to account for age‐related differences in order to minimize potential adverse effects and consequently improve patient bone‐healing outcomes. For this study, we sought to address this issue by using a preclinical critically sized segmental bone defect model in rats to investigate age‐related differences in bone repair after delivery of BMP‐2 in a collagen sponge, the current clinical standard. Femoral defects were created in young (7‐week‐old) and adult (8‐month‐old) rats, and healing was assessed using gene expression analyses, longitudinal radiography, ex vivo micro‐computed tomography (µCT), as well as torsional testing. We found that young rats demonstrated elevated expression of genes related to osteogenesis, chondrogenesis, and matrix remodeling at the early 1‐week time point compared with adult rats. These early gene expression differences may have impacted long‐term healing as the regenerated bones of young rats exhibited higher bone mineral densities compared with those of adult rats after 12 weeks. Furthermore, the young rats demonstrated significantly more bone formation and increased mechanical strength when BMP‐2 dose was increased from 1 µg to 10 µg, a finding not observed in adult rats. Overall, these results indicate there are age‐related differences in BMP‐2‐mediated bone regeneration, including relative dose sensitivity, suggesting that age is an important consideration when implementing a BMP‐2 treatment strategy. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

BMP-2 Modified Electrospun Scaffold for Acetabular Labral Reconstruction Promotes Collagen Fiber Regeneration in a Porcine Model

“…Age and BMP-2 dose are closely related to osteogenic differentiation and gene expression. 2 Studies have shown that BMP-2 can induce chondrogenic differentiation, osteogenic differentiation, and endochondral bone formation in the same system. 20 The results of scanning electron microscopy showed that there were fibrous structures in the implants.…”

Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression

“…While it is likely that higher doses would result in improved bridging rates, increasing BMP‐2 dose also increases the risk for complications, such as heterotopic ossification and excessive inflammation. In fact, we have observed some of these adverse effects in previous studies that delivered 10 and 30 µg BMP‐2 to the rat segmental defect . Based on historical experience, the 5 µg dose utilized in this study was chosen as the ideal minimum dose for healing in rats with low risk of complications.…”

“…Torsional testing to failure was performed as previously described . Femurs were excised at 12 weeks post‐surgery, wrapped in PBS‐soaked gauze, and stored at −20°C until testing could be performed.…”

BMP-2 Delivery through Liposomes in Bone Regeneration

“…Biocompatibility is one of the most important features of the carriers. Natural compounds, i.e., collagen [74], gelatin [75], fibrin and fibronectin [76], chitosan [77], hyaluronic acid [78]; synthetic polymers, i.e., poly(lactic acid) [79], poly(glycolic acid) [80], poly(lactic-co-glycolic acid) [81]; or inorganic materials, i.e., hydroxyapatite (HA) [82,83], tricalcium phosphate (TCP) [84], and combinations of them are used for slow delivery.…”