Many clinical situations in musculoskeletal care require a bone reconstruction strategy. Novel orthopaedic biomaterials that effect guided bone growth into biodegradable polymeric composite scaffolds are candidates to address such requirements, and the goal that has motivated the development of these materials is the eventual elimination of autograft bone harvest for transplantation into skeletal regeneration sites. For the past decade, our laboratory has done extensive work on the synthesis and characterization of in situ polymerizable materials, in vitro evaluation of cell-biomaterial interactions, and in vivo assessment of scaffold function in small animal models. This proposal focuses on the translation of our bone tissue engineering work toward initial human use via three integrated aims.
In Aim 1, we will encapsulate vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) into two hydrogel porogens that have different degradation rates, designed to generate two sequential pore systems in the self-crosslinking poly(propylene fumarate)-co- poly(caprolactone) (PPF-co-PCL) composite biomaterial scaffold. This dual porosity generation will affect dual, sequential delivery of angiogenic and osteoinductive factors to provide an initial vascular network that will support the subsequent osteogenic process.
In Aim 2, we will determine the in vivo effect of PPF-co-PCL composite scaffolds on bone formation in a rabbit posterolateral spine fusion model. We will evaluate both injectable and preformed scaffold strategies in this model. The injectable strategy involves injection of a polymerizing scaffold formulation into a bony defect to form a composite biomaterial. The preformed strategy utilizes solid freeform fabrication to manufacture a composite biomaterial implant that has a specified size, shape, and internal microarchitecture. The design goal for this composite biomaterial implant is to fabricate a three-dimensional scaffold that directs the bone regeneration process and provides mechanical support to the reconstructed region during polymer degradation and new bone formation.
In Aim 3, we will assess the bone regeneration performance of PPF-co-PCL composite scaffolds in a large animal model of a clinically relevant human surgical procedure as a translational step toward initial human use. We have selected an anterior- posterior sheep spine reconstruction, consisting of both a posterolateral intertransverse process fusion and an anterior skeletal gap (discectomy/vertebrectomy) reconstruction, utilizing our injectable and preformed scaffold strategies to accomplish this goal.

Public Health Relevance

The novel biodegradable polymeric composite scaffolds to be developed in this project will offer new treatment options for skeletal defects of various size and shape. The biomaterial will provide biological reconstruction of the defect site by inducing bone formation following either implantation of preformed scaffolds or injection of in situ polymerizable formulations. These two application modalities offer distinct advantages. The preformed scaffolds allow precise control over scaffold geometry and internal architecture, while the injectable scaffolds utilize minimally invasive surgical techniques that can lead to shortened hospital stay and faster recovery for patients. The degradable nature of the biomaterial will not require implant retrieval, saving them time, expense, and inconvenience.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB003060-08
Application #
8440796
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Hunziker, Rosemarie
Project Start
2003-09-30
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$393,715
Indirect Cost
$144,054
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Fang, Zhong; Giambini, Hugo; Zeng, Heng et al. (2014) Biomechanical evaluation of an injectable and biodegradable copolymer P(PF-co-CL) in a cadaveric vertebral body defect model. Tissue Eng Part A 20:1096-102
Dadsetan, Mahrokh; Taylor, K Efua; Yong, Chun et al. (2013) Controlled release of doxorubicin from pH-responsive microgels. Acta Biomater 9:5438-46
Kim, Jinku; Sharma, Aditi; Runge, Brett et al. (2012) Osteoblast growth and bone-healing response to three-dimensional poly(?-caprolactone fumarate) scaffolds. J Tissue Eng Regen Med 6:404-13
Dadsetan, Mahrokh; Giuliani, Melissa; Wanivenhaus, Florian et al. (2012) Incorporation of phosphate group modulates bone cell attachment and differentiation on oligo(polyethylene glycol) fumarate hydrogel. Acta Biomater 8:1430-9
Dadsetan, Mahrokh; Pumberger, Matthias; Casper, Michelle E et al. (2011) The effects of fixed electrical charge on chondrocyte behavior. Acta Biomater 7:2080-90
Kim, Jinku; Dadsetan, Mahrokh; Ameenuddin, Syed et al. (2010) In vivo biodegradation and biocompatibility of PEG/sebacic acid-based hydrogels using a cage implant system. J Biomed Mater Res A 95:191-7
Lee, Kee-Won; Wang, Shanfeng; Dadsetan, Mahrokh et al. (2010) Enhanced cell ingrowth and proliferation through three-dimensional nanocomposite scaffolds with controlled pore structures. Biomacromolecules 11:682-9
Dadsetan, Mahrokh; Liu, Zen; Pumberger, Matthias et al. (2010) A stimuli-responsive hydrogel for doxorubicin delivery. Biomaterials 31:8051-62
Kim, Jinku; Yaszemski, Michael J; Lu, Lichun (2009) Development of biodegradable and injectable macromers based on poly(ethylene glycol) and diacid monomers. J Biomed Mater Res A 90:1010-20
Kempen, Diederik H R; Kruyt, Moyo C; Lu, Lichun et al. (2009) Effect of autologous bone marrow stromal cell seeding and bone morphogenetic protein-2 delivery on ectopic bone formation in a microsphere/poly(propylene fumarate) composite. Tissue Eng Part A 15:587-94

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