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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.

SUBMITTER: Cheng A

PROVIDER: S-EPMC6383700 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Cheng Albert A Krishnan Laxminarayanan L Tran Lisa L Stevens Hazel Y HY Xia Boao B Lee Nari N Williams Joseph K JK Gibson Greg G Guldberg Robert E RE

JBMR plus 20180716 2

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 adv ...[more]

PMID: 30828685

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Project description:Bone morphogenetic protein-2 (BMP-2) is an osteoinductive growth factor used clinically to induce bone regeneration and fusion. Some complications associated with BMP-2 treatment have been attributed to rapid release of BMP-2 from conventional collagen scaffolds, motivating the development of tunable sustained-release strategies. We incorporated BMP-2-binding heparin microparticles (HMPs) into a hydrogel scaffold to improve spatiotemporal control of BMP-2 delivery to large bone defects. HMPs pre-loaded with BMP-2 were mixed into alginate hydrogels and compared to hydrogels containing BMP-2 alone. BMP-2 release from scaffolds in vitro, BMP-2 retention within injury sites in vivo, and bone regeneration in a critically sized femoral defect were evaluated. Compared to hydrogel delivery alone, BMP-2-loaded HMPs reduced BMP-2 release in vitro and increased early BMP-2 retention in the bone defect. BMP-2-loaded HMPs induced bone formation at both ectopic and orthotopic sites; however, the volume of induced bone was lower for defects treated with BMP-2-loaded HMPs compared to hydrogel delivery. To better understand the effect of HMPs on BMP-2 release kinetics, a computational model was developed to predict BMP-2 release from constructs in vivo. The model suggested that HMPs limited BMP-2 release into surrounding tissues, and that changing the HMP density could modulate BMP-2 release. Taken together, these experimental and computational results suggest the importance of achieving a balance of BMP-2 retention within the bone defect and BMP-2 release into surrounding soft tissues. HMP delivery of BMP-2 may provide a method of tuning BMP-2 release in vivo that can be further investigated to improve current methods of bone regeneration.Statement of significanceThe development of effective biomaterials for sustained protein delivery is a crucial component of tissue engineering strategies. However, in most applications, including bone repair, the optimal balance between protein presentation in the injury site and protein release into the surrounding tissues is unknown. Herein, we introduced heparin microparticles (HMPs) into a tissue engineered construct to increase in vivo retention of bone morphogenetic protein-2 (BMP-2) and enhance healing in femoral defects. Although HMPs induced bone regeneration, no increase in bone volume was observed, leading to further experimental and computational analysis of the effect of HMP-BMP-2 interactions on protein retention and release. Ultimately, this work provides insight into designing tunable protein-material interactions and their implications for controlling BMP-2 delivery.

Dataset Information

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

Publications

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

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