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Author Notes:

Robert E. Guldberg, 315 Ferst Drive, Georgia Institute of Technology, Atlanta, GA 30332-0363 USA, robert.guldberg@me.gatech.edu.

The authors acknowledge Ashley Allen, Brett Klosterhoff, David Reece, Marissa Ruehle, Giuliana Salazar-Noratto, Sanjay Sridaran, and Brennan Torstrick for their assistance with surgeries.


Research Funding:

BMP-2 was provided by Pfizer Inc.

This work was supported by funding from the National Institutes of Health (R01 AR062006 to TCM); and the Armed Forces Institute of Regenerative Medicine (Award W81XWH-14-2-0003 to REG).

The U.S. Army Medical Research Acquisition Activity is the awarding and administering acquisition office.

MHH was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) post-graduate scholarship; and Philanthropic Educational Organization (PEO) Scholar Award.

CC was supported by the Petit Undergraduate Research Scholars Program at Georgia Tech.


  • Science & Technology
  • Technology
  • Engineering, Biomedical
  • Materials Science, Biomaterials
  • Engineering
  • Materials Science

Enhanced in vivo retention of low dose BMP-2 via heparin microparticle delivery does not accelerate bone healing in a critically sized femoral defect


Journal Title:

Acta Biomaterialia


Volume 59


, Pages 21-32

Type of Work:

Article | Post-print: After Peer Review


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 Significance The 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.

Copyright information:

© 2017 Acta Materialia Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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