Biomaterials are indispensable for tissue engineering, which plays a pivotal role in the skeletal tissue repair. However, biomaterials currently used such as animal extracts and chemically synthesized polymers display unsatisfactory bioactivity and safety. In recent years, modular protein engineering-based (MPE) biomaterials composed of polypeptides produced by molecular cloning and protein synthesis have greatly developed due to their lower batch-to-batch variation, avoidance of possible pathogens and, most importantly, sequence-tunable property. In this review, we first briefly describe the properties of different MPE biomaterials classified by the structural domains of polypeptides, and techniques to engineer the polypeptide sequence and synthesize MPE biomaterials at will. Then, we focus on the application of bio-designed MPE biomaterials in skeletal tissue engineering. Different structural domains of polypeptides are used individually or covalently fused with different bioactive motifs to generate a variety of MPE biomaterials. The sequence (protein modules) of MPE biomaterials would determine and guide their cytocompatibility, their effects on cell fate and ECM formation, the mechanical properties and functions during the in vivo skeletal tissue repair. Moreover, we propose several bio-design strategies and potential directions to develop MPE biomaterials for better performing skeletal tissue engineering and to achieve fast skeletal tissue regeneration. Combinations of material science and protein engineering would provide solutions to the obstacles in regenerative medicine. This article provides a board review of skeletal tissue engineering in a polypeptide sequence-guided way by using MPE biomaterials.
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