Development of a suitable biological scaffold is an essential pre-requisite for functional development of organ including blood vessel. Biological scaffold prepared by conventional means using physical or chemical agent have been shown to cause damage to the extracellular matrix architecture as well as produce immune response subsequent to scaffold implantation/engraftment. During the current study, taking advantage of different host tissue environment (subcutaneous vs omentum), acellular scaffold was prepared using a syngeneic vs allogeneic model of scaffold implantation (in vivo decellularization) and compared with a chemically decellularized scaffold. By means of molecular, proteomics and histologic techniques, we confirmed that site specific advantages exist in modulating the ECM as well as regulating the immune response (macrophage and T-cells) to produce an acellular scaffold without the need for immunosuppressants. The current approach opens up the possibility for creation of tailor made scaffold for further use in the clinics with a possibility for long term acceptability without adverse reactions in the host and a further possibility to build functional organs following cell engraftment.