Purpose <p>Advancements in additive manufacturing technology have facilitated the use of cellular lattice structures for orthopedic implants. Gradient porosity can enhance the biomechanical performance of cementless implants by improving fixation and reducing aseptic loosening. Previous studies designing gradient cellular implants have been often limited to unidirectional graded structures. This study aimed at conceptual design of bidirectional graded lattice structures for the tibial stem of total knee replacement (TKR), to enhance osteogenic response and periprosthetic bone remodeling.</p> Methods <p>A multi-objective optimization problem was addressed using the design of experiment approach to find the optimal gradient parameters. Three finite element models, including a preoperative, an early postoperative, and a late postoperative model of the TKR, were developed to predict the osseointegration and remodeling behaviors, based on a computational mechanobiology framework.</p> Results <p>Five optimal graded lattice structures were obtained, each hypothetically appropriate for a specific group of patients. A low porosity (20% density) axially graded structure was predicted to induce a strong osteogenic response, as needed for over-aged patients with weak osteoblast activity. Also, a high porosity (10% density) radially graded structure was predicted to lead to a low bone resorption, as required for young adults demanding long implant lifespan. The overall optimal structure made of bidirectional gradient (27% radial and 73% axial) with high porosity (10% density) was predicted to enhance the bone remodeling with minimal change in osteogenic response. SEM examination of the graded gyroid specimens, fabricated by selective laser melting, revealed small fabrication errors compared to the average lattice dimensions.</p> Conclusion <p>Computational and experimental results were promising and provided supportive evidence for the beneficial impact of bidirectional graded tibial stems and their manufacturability.</p>