Harnessing the Bio-Instructive Placental Extracellular Matrix: Structural Properties, Decellularization, and Applications in Regenerative Medicine

The persistent shortage of donor organs and the inherent drawbacks of autologous grafts highlight the urgent need for advanced biomaterial scaffolds in regenerative medicine. Synthetic polymers and animal-derived matrices offer structural support, yet they frequently lack the biological complexity of native tissue or carry translational liabilities—xenogeneic antigens, pathogen transmission risk, and batch variability. This review positions the human placenta as a compelling, ethically sourced, and abundant reservoir for fully human, xeno-free biomaterials. We examine the placenta’s distinct anatomical compartments and their rich complement of extracellular matrix (ECM) proteins, growth factors, and bioactive cytokines. These components confer potent pro-angiogenic, anti-inflammatory, antimicrobial, and immunomodulatory properties, enabling precise direction of cellular behavior and tissue regeneration. We systematically assess recent advances in decellularization and the processing strategies required to preserve these bioactivities while eliminating immunogenic material. By integrating current tissue engineering applications with the regulatory and ethical frameworks shaping clinical translation, we argue that placenta-derived matrices are uniquely positioned to transcend the limitations of conventional scaffolds and serve as a robust platform for future regenerative therapies.