Vascularization remains the principle obstacle that impedes the translation of most bone tissue engineered constructs to clinical practice. Pre-vascularization of large constructs has great potential to improve functional vasculature throughout the scaffold to rapidly facilitate integration with the surrounding tissue and circumvent necrosis in the core of the scaffold. In our previous studies, we have developed microengineered gels to co- culture human endothelial progenitor cells (hEPCs) and human mesenchymal stem cells (hMSCs) to engineer microvasculature, but observed limited anastomotic potential. We have also developed a number of approaches in which engineered hydrogels can be assembled into graded tissue scaffolds to generate vascularized constructs, and determined the need to protect structural integrity of microvasculature using mechanically-robust scaffolds. A major remaining challenge in our work is that despite the initial remodeling of the cells into functioning microvessels, efficient integration to major vessels has not been observed. The main premise of this renewal proposal is that by incorporating a perfusable vessel graft that connects the microvasculature of the engineered construct to large host vessels, we will be able to address this challenging issue. In this renewal project, we propose to engineer a bone scaffold that integrates microvasculature with a surgically-anastomizable large vessel graft to heal critical size segmental bone defects. This construct will be developed in vitr such that the microvascular capillaries in gels connect with the large vessel graft and subsequently to the host vessel in vivo. Our hypothesis is this construct can substantially improve on the integration to the host tissue by restoring blood supply immediately after transplantation. To test our hypothesis, our team comprised of experts in tissue engineering, biomaterials, microengineering, and orthopedics proposes the following aims:
Aim 1. Develop components for fabrication of surgically-anastomizable pre- vascularized bone construct.
Aim 2. Engineer and characterize surgically-anastomizable pre-vascularized bone construct in vitro.
Aim 3. Evaluate the efficiency of surgically-anastomizable pre-vascularized bone construct in repair of critical size segmental bone defects. The completion of this work will be a paradigm shift and a landmark achievement in efforts to clinical treatments for bone critical size defects.

Public Health Relevance

Vascularization remains a strategic challenge that prevents the translation of most bone tissue engineered constructs to clinical practice such as treatment of large bone defects. The success of the novel bone grafts that integrates microvasculature with large vessel graft will aid to translate pre-vascularized large constructs into clinical environments and significantly improve the existing methods for integrating pre-vascularized, engineered grafts, a long standing problem in regenerative medicine and bone tissue engineering. The completion of this work will be a paradigm shift and a landmark achievement in efforts to clinical treatments for bone critical size defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR057837-05
Application #
8762300
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2009-12-01
Project End
2019-07-31
Budget Start
2014-08-21
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$602,506
Indirect Cost
$148,508
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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