ProcessModelling - Process-oriented maturation model of biohybrid heart valves during bioreactor conditioning

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Tissue-engineered heart valves (TEHV) are a promising approach in the area of heart valve replacement. So-called biohybrid implants consist of a textile scaffold providing mechanical strength covered with patient-own cells embedded in a hydrogel, which are able to regenerate and adapt their surroundings. The maturation process of such artificial heart valves is performed in a bioreactor, in which the heart valve is perfused by a pulsating flow of culture media. This process involves complex dynamics, which depend not only on external stimuli acting on the heart valve, but also on the individual growth parameters of the tissue-forming cells used. Thus, the longterm research goal is the robust and adaptive control of the individual maturation process for the production of biocompatible and resilient implants. For such a control scheme, the underlying dynamics of the maturation process must be known. In phase I of this project, we identified the key relationships between input, state, and output variables of the process that describe tissue maturation. Based on this, we developed a mathematical model of tissue maturation. The model contains the evolution of the cell number as well as the development of the extracellular matrix represented by the proteins collagen and elastin, as they are crucial for the architecture and mechanical characteristics of heart valve leaflets. For the model validation, a bioreactor setup for automated and thus reproducible and comparable maturation experiments was established including multiphoton endoscopic microscopy for non-destructive and longitudinal tissue observation. Multiple experiments were performed to gain process knowledge and validate our model. In PAK phase-II, the focus will move from open-loop control of the maturation process of TEHV towards closed-loop control. Based on the insights about tissue maturation control gained in phase I, the bioreactor setup will be expanded with additional control concepts (WP1). For the online observation of the state variables, two-photon endoscopy image acquisition and data analysis routines will be implemented (WP2). Building on the results of phase I regarding our mathematical model of the maturation process, the newly developed bioreactor, implementation of two-photon endoscopy, and the image-based analysis of maturation, we will establish a model-based control scheme for the process (WP3). These improvements will be closely related to maturation experiments, iteratively testing the system and collecting data for process validation (WP4). With this project, we acquire an explicit understanding of closed-loop maturation control of aortic TEHV, leading towards a robust production of these implants while considering the high degree of heart valve individuality. The insights gained in this project are also transferrable to other biohybrid constructs such as tissue engineered vascular grafts and patches, as well as other non-cardiovascular tissue engineered implants.