In silico-guided hypothesis generation for design and cultivation of tissue-engineered biohybrid implants

Biohybrid implants, in which scaffolds provide mechanical reinforcement for tissue-engineered heart valves, vascular grafts, and related constructs, represent a promising strategy in regenerative medicine. Their mid- to long-term performance, however, is critically governed by the growth and remodeling (G&R) of biological constituents, a process poorly understood and difficult to control in the design phase. We present a computational mechanics framework coupling anisotropic textile scaffold mechanics with a homeostatic-surface G&R model, tailored for tissue-engineering applications. Biochemically informed collagen evolution equations are introduced to account for the influence of culturing medium constituents, overcoming the pseudo-time limitations of prior approaches. The results suggest that, in specific scenarios, G&R can counteract predefined scaffold anisotropy: collagen density and orientation evolve toward a mechanical equilibrium for the investigated scaffold designs, consistent with the failure of biomimetic scaffolds to sustain native-like behavior in long-term in vivo studies. For tissue-engineered vascular grafts, the model suggests that the experimentally observed reorientation of collagen fibers toward the axial direction may arise from the dominance of contractile stresses over pressure-induced hoop stress during cultivation, and predicts that dynamic luminal pressure loading and scaffold compliance are potential levers for recovering native-like fiber architecture. Global sensitivity analysis indicates that G&R parameters progressively displace scaffold properties as dominant drivers of mechanical response, identifying homeostatic stress, growth relaxation time, and the collagen densification threshold as the quantities most critical for experimental calibration. These model predictions offer valuable information on the relevant quantities that require experimental investigation to establish a quantitative basis for rational design of scaffold architectures and cultivation protocols for tissue-engineered implants.