CAREER: Reaction-Diffusion Modeling of Growth Factor Exposure Profiles in Tissue Engineering

Growth factors are a class of potent growth-stimulating hormones that have become ubiquitous in tissue engineering applications. A growing trend in the field is the utilization of biomaterial scaffolds that aim to achieve controlled delivery of growth factors to cells during tissue regeneration. However, the resulting growth factor concentration profiles to which cells are ultimately exposed to during delivery can be difficult to predict because they are influenced by a complex array of biochemical interactions in the tissue between growth factors and scaffold material, extracellular matrix (ECM) constituents, and cell receptors. The primary research goal of this Faculty Early Career Development (CAREER) program project is to develop a new approach for assessment and optimization of emerging growth factor delivery scaffolds. The project utilizes computational models to predict cell exposure profiles of administered growth factors for different biomaterial scaffold designs. The project tests the hypothesis that scaffolds that are predicted to achieve optimal growth factor exposure profiles to cells will yield improved tissue regeneration outcomes. The successful completion of this research project can lead to a paradigm shift in the field of growth factor delivery, whereby scaffolds can be designed and evaluated based on computational model predictions. Further, this project develops educational activities to introduce K-12 students to fundamental concepts of molecular transport and the field of tissue engineering. The project also develops undergraduate training and lab-based graduate coursework to train the next generation of tissue engineers in growth factor transport phenomena. The primary research goal is examined through a cartilage tissue engineering model system consisting of the delivery of transforming growth factor beta (TGF-beta) to chondrocyte-seeded constructs. TGF-beta is delivered via slow release from scaffold-conjugated heparin affinity domains. Reaction-diffusion models are developed to predict the spatiotemporal distribution of free TGF-beta in constructs for different scaffold design parameters, varied by factors of heparin concentration, heparin affinity, and TGF-beta loaded dose. Models account for the salient chemical reactions that act on TGF-beta in the construct extracellular milieu, including reversible binding/release to scaffold affinity domains, binding to cell deposited ECM, and cell-mediated internalization. Models further incorporate non-linear chemical reaction kinetics, using a Brunauer–Emmett–Teller (BET) multilayer absorption model to account for TGF-beta aggregation at binding sites and Michaelis-Menten kinetics to account for saturating rates of cell-internalization. Through model predictions, the project tests the hypothesis that scaffolds that promote optimal exposure doses of TGF-beta to chondrocytes will yield constructs that better recapitulate the composition, structure, and functional properties of native hyaline cartilage, marked by native matched mechanical properties, while mitigating features detrimental to hyaline cartilage tissue function (type-I collagen, cell hypertrophy, and chondrocyte clustering). This hypothesis is tested for multiple donors of relevant cell populations (chondrocytes, mesenchymal stem cells, and induced pluripotent stem cell-derived chondrocytes), which elicit variable rates of chemical reactions upon TGF-beta and possess variable TGF-beta dosing requirements. The successful completion of this research project will support the future use of model-optimized scaffold designs to improve tissue regeneration outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.