Esophageal cancer is a prevalent disease in Iran. Esophagus is a tubular-shaped organ that connects the mouth and throat to the stomach. Treatment of the esophagus disorders is usually performed with substitution surgeries. However, the success rate of these surgeries is approximately 30 %-40 %. Today, the tissue engineering methods deal novel solutions for treatment of the esophageal diseases with natural and synthetic scaffolds and prostheses. such structures should have appropriate mechanical properties to adapt with forces exerted by food bolus. In this study, a novel biodegradable multi-layer esophageal prosthesis has been produced using the natural and synthetic fibers and nanofibers. It was assumed that each element in multi-layered structure contribute to different mechanical aspects of multi-layer esophageal prosthesis. The tubular knitted silk fabric (substrate of the prosthesis) was used to mimic the muscular layer of the esophagus. The muscular layer function is to strengthen the esophageal wall against the exerted pressure from food bolus. The silk yarn was selected to knit the tubular fabrics due to its remarkable elasticity (35%), mechanical properties (up to 4.8 GPa) and good long-term biological features. The PU nanofiber was also chosen to mimic the thin elastic tissues in lamina propria and thin elastic fibers in muscularis mucosae (submucosa) layers of the esophagus. The inner layer also consists of polytetrafluoroethylene (PTFE) nanofibers to prevent from liquid leakage into the prosthesis. There is also a thin layer of polyurethane nanofibrous layer to fix the PTFE nanofibers on the multi-layer structure. Optimization process has been performed in two steps. At first, twenty different tubular structures of knitted silk fabrics were produced and mechanical properties were measured in both directions. The mechanical properties were optimized using artificial neural network (ANN) and genetic algorithm (GA) and optimum knitted structure was produced as a substrate for coating with PU nanofibers. In second step, twenty different samples were produced by electrospinning the PU nanofibers at different process conditions (collector speed, feeding rate) on optimized structure of the knitted fabric. Finally, the elastic properties of the bi-layered tubular structures were measured and optimized by ANN and GA methods. The optimized bi-layered structure was then coated with PTFE/PVA nanofibers of 527 nm diameter. Mechanical properties including the ultimate stress and strain, the elastic modulus at 40% strain and structure behavior after 50 cycles of loading-unloading were measured. In addition, the physical properties including the dynamic contact angle and degradation behavior of multi-layer prosthesis were also investigated. Results presented that the optimized multi-layer structure of the esophageal prosthesis had proper mechanical properties similar to esophagus. The dynamic contact angle was measured as 140 degrees that represents a highly hydrophobe structure. Therefore, the developed prosthesis can prevent from leakage of liquids into the structure. Most of esophagus disorders are caused by gastroesophageal reflux disease (acidic, pH=2) and bile flow upward into the esophagus (basic, pH=8). Such acidic and basic conditions can affect the degradation of any implemented prosthesis and shall be considered in degradation studies. Therefore, three different degradation environments were investigated for esophageal prosthesis. Results showed a slow rate of degradation in basic and phosphate buffer saline solutions. But, acidic condition represented a vigorous degradation of silk knitted structure up to 90%. It can be said that the developed prosthesis also can be used as a scaffold for cell adhesion, growth and proliferation during the regeneration of new tissue and implementation time. MTS assay was also performed to investigate the cytotoxicity of applied materials using the mesenchymal stem cells. Results indicated that mesenchymal cells have kept their viability during a period of 7 days. It can be concluded that this structure can be used as a substitute in esophagus disorders. A novel rheological model was also proposed for the tubular knitted structures. Twenty different structures of tubular silk weft knitted fabrics were produced and their mechanical properties were measured in longitudinal and circumferential directions under constant rate of elongation (CRE). Twelve samples were used to study the performance of seven rheological models to investigate the mechanical behavior of the tubular knitted structures. Results showed that rheological model of a nonlinear spring (that follows the power rule) in parallel with a Newtonian dashpot, can properly describe the mechanical behavior of the tubular fabrics under loading.