Transport of transforming growth factor-beta in native and engineered articular cartilage
Embargo Date
2026-03-07
OA Version
Citation
Abstract
Transforming growth factor-β (TGF-β) is a highly specialized, potent signaling molecule that is paramount for the growth and development of musculoskeletal connective tissues (e.g., articular cartilage, meniscus, tendon, intervertebral disk). The roles and applications of TGF-β in connective tissue biomedicine are expansive, including as endogenous signaling agents to coordinate native tissue development, as pharmacological therapeutics to treat degenerative pathology, and as growth-stimulating supplements in regenerative medicine. The regulation of TGF-β in musculoskeletal connective tissues is a particularly complex process due to their unique avascular nature and dense extracellular matrices (ECMs). As such, TGF-β is required to transport large distances to reach their cell targets while undergoing an array of chemical reactions (ECM binding, molecular activation, cell internalization, enzymatic degradation) in the extracellular domain. The impact of these reactions can be substantial and can ultimately impact the functional roles of TGF-β in tissue systems. For example, 1) reaction-induced TGF-β gradients can regulate tissue development and homeostasis, and 2) reactions can be exploited to control TGF-β delivery in therapeutic applications.
This thesis explores a highly innovative research direction through the development of novel TGF-β transport models that account for chemical reactions in native and engineered connective tissues. We examine the utility of reaction-diffusion modeling by exploring its predictive capability in a wide range of tissue systems: 1) the native regulation of TGF-β in the synovial joint by analyzing functional role of spatial TGF-β activity, and 2) the delivery of TGF-β in cartilage tissue engineering and in patient specific regenerative medicine platforms. Together, these objectives aim to demonstrate that reaction-diffusion frameworks can provide novel insights into the contribution of TGF-β regulation in synovial joint and can advance novel optimizations of TGF-β delivery in translational tissue engineering/pharmacological platforms.
Finally, this work advances the use of the nondimensional Damkohler number as an innovative tool to estimate biomolecule concentration gradients within engineered tissues. Here we demonstrate the efficacy of Damkohler number analysis in predicting the steady-state distribution of biomolecules in tissue-engineered cartilage. This analytical approach enables parametric analysis of concentration gradients of different classes of growth-stimulating biomolecules. This technique might guide the development of novel tissue engineering cultivation systems to optimize growth-stimulating biomolecule delivery, leading to control of engineered tissue composition and mechanics to improve their performance after clinical implantation.
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Attribution 4.0 International