(5ap) Theoretical and Experimental Approaches to Study Vascularization in Sintered Microsphere Based Scaffolds for Bone Repair

Tissue engineered bone graft alternatives hold the promise to eliminate the need for autografts and allografts and avoid problems associated with them such as limited supply, donor site morbidity, possible immunorejection and transmission of pathogens. However, the success of osseous healing in-vivo using engineered tissue replacements depends on the feasibility of angiogenesis (formation of new capillaries from preexisting blood vessels) within the structure. Extensive studies on the process of angiogenesis have led to identification of genes, proteins and cells which play critical roles and are currently under investigation for the promotion of therapeutic angiogenesis. Nevertheless, in order to understand and engineer vascular ingrowth in biomaterials, there is a vital need for an integrative tool that incorporates the parameters which govern growth factor transport and parameters which regulate cell behavior.

My PhD thesis is aimed at exploring the relevant underlying mechanisms responsible for successful promotion of blood vessel growth into porous bone scaffolds utilizing growth factors through a close cooperation between experimentation and mathematical modeling.

Model and Simulations:

We are developing a discrete probabilistic mathematical model of cell migration in 3D porous biomaterials. A particular application of this model is to simulate angiogenesis within implants where the specific goal is to understand the simultaneous effects of the following parameters on the extent of vascular infiltration:

• The porous microstructure (mean pore size, porosity, internal surface area)

• Molecular transport of growth factors such as VEGF (optimal release rate, method of release, release duration)

• Cell response to growth factors (chemotaxis and chemokinesis)

Such a model that bridges the gap between the mechanism of cellular migration and environmental and biochemical cues, will help in design of novel biomaterials for tissue engineering applications.

Experimental Studies:

Our laboratory has employed PLGA microspheres to develop a 3D porous bioresorbable scaffolds with a biomimetic pore structure similar to the structure of human trabecular bone. These scaffolds have demonstrated a high degree of osteoconductivity and a degradation rate that can be matched to cell proliferation and new bone tissue growth. With the hypothesis that delivering an angiogenic growth factor in a localized and sustained manner would accelerate blood vessel formation, we employ two approaches to incorporate VEGF within the scaffolds:

• Protein Delivery:

We incorporate vascular endothelial growth factor (VEGF) into PLGA scaffolds via local adsorption on the surface of sintered microspheres and evaluate its ability to stimulate endothelial cells proliferation (in vitro).

Following subcutaneous implantation in severe combined immune deficient (SCID) mouse, we assess the effect of the pore size, porosity and VEGF adsorption on the extent of vessel ingrowth and morphology using histological techniques (in vivo).

• Gene Therapy:

We transfect adipose tissue derived stromal cells using adenovirus with cDNA encoding VEGF and we evaluate the ability of released VEGF on endothelial cells proliferation. (in vitro).

In a subcutaneous SCID mouse model, we determine the potential of transfected adipose tissue derived stromal cells seeded on the scaffolds to induce vascular neogenesis (in vivo).

Future Directions:

• Understanding cell-material interaction on biomimetic materials for tissue engineering applications. This work will be complemented by developing novel mathematical models to quantify cellular responses and statistical methods to characterize the distributions of these responses.

• Exploring methods for spatial and temporal control of combined multiple cell (such as endothelial and osteoblasts) and drug (such as VEGF and BMPs) delivery systems in tissue engineered scaffolds for bone repair.

• Studying the plasticity of stem cells toward endothelial lineage: applications in biomaterial vascularization.

Journal publications

E. Jabbarzadeh, C. F. Abrams, ?Strategies to enhance capillary formation inside biomaterials: A computational study,? Tissue engineering, (Submitted, 2006).

E. Jabbarzadeh and C. F. Abrams, ?Simulation of chemotaxis and random motility in 2D random porous domains,? Bull. Math. Biol., (Submitted, 2006).

E. Jabbarzadeh and C. F. Abrams, ?Chemotaxis and random motility in unsteady chemoattractant fields: A computational study,? J. Theor. Biol. 235: 221-23, (2005).

E. Jabbarzadeh and C. F. Abrams, ?Fundamental limits on the efficacy of intercellular communication by diffusion,? J. Phys. Soc. Japan 74(4):1139-1141, (2005).