Is it possible to 3D bioprint load-bearing bone implants? A critical review.

Rehabilitative capabilities of any tissue engineered scaffold rely primarily on the triad of (i) biomechanical properties such as mechanical properties and architecture, (ii) chemical behavior such as regulation of cytokine expression, and (iii) cellular response modulation (including their recruitment and differentiation). The closer the implant can mimic the native tissue, the better it can rehabilitate the damage therein. Among the available fabrication techniques, only 3D bioprinting (3DBP) can satisfactorily replicate the inherent heterogeneity of the host tissue. However, 3DBP scaffolds typically suffer from poor mechanical properties, thereby, driving the increased research interest in development of load-bearing 3DBP orthopedic scaffolds in recent years. Typically, these scaffolds involve multi-material 3D printing, comprising of at-least one bioink and a load-bearing ink; such that mechanical and biological requirements of the biomaterials are decoupled. Ensuring high cellular survivability and good mechanical properties are of key concerns in all these studies. 3DBP of such scaffolds is in early developmental stages, and research data from only a handful of preliminary animal studies are available, owing to limitations in print-capabilities and restrictive materials library. This article presents a topically focused review of the state-of-the-art, while highlighting aspects like available 3DBP techniques; biomaterials' printability; mechanical and degradation behavior; and their overall bone-tissue rehabilitative efficacy. This collection amalgamates and critically analyses the research aimed at 3DBP of load-bearing scaffolds for fulfilling demands of personalized-medicine. We highlight the recent-advances in 3DBP techniques employing thermoplastics and phosphate-cements for load-bearing applications. Finally, we provide an outlook for possible future perspectives of 3DBP for load-bearing orthopedic applications. Overall, the article creates ample foundation for future research, as it gathers the latest and ongoing research that scientists could utilize.

Mechanistic basis for Sgo1-mediated centromere localization and function of the CPC.

Centromere association of the chromosomal passenger complex (CPC; Borealin-Survivin-INCENP-Aurora B) and Sgo1 is crucial for chromosome biorientation, a process essential for error-free chromosome segregation. Phosphorylated histone H3 Thr3 (H3T3ph; directly recognized by Survivin) and histone H2A Thr120 (H2AT120ph; indirectly recognized via Sgo1), together with CPC's intrinsic nucleosome-binding ability, facilitate CPC centromere recruitment. However, the molecular basis for CPC-Sgo1 binding and how their physical interaction influences CPC centromere localization are lacking. Here, using an integrative structure-function approach, we show that the "histone H3-like" Sgo1 N-terminal tail-Survivin BIR domain interaction acts as a hotspot essential for CPC-Sgo1 assembly, while downstream Sgo1 residues and Borealin contribute for high-affinity binding. Disrupting Sgo1-Survivin interaction abolished CPC-Sgo1 assembly and perturbed CPC centromere localization and function. Our findings reveal that Sgo1 and H3T3ph use the same surface on Survivin to bind CPC. Hence, it is likely that these interactions take place in a spatiotemporally restricted manner, providing a rationale for the Sgo1-mediated "kinetochore-proximal" CPC centromere pool.

A highly conserved pocket on PP2A-B56 is required for hSgo1 binding and cohesion protection during mitosis.

The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human hSgo1 to the PP2A-B56 phosphatase through a coiled-coil (CC) region mediates cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A-B56-hSgo1 complex, revealing unanticipated aspects of complex formation and function. We establish that a highly conserved pocket on the B56 regulatory subunit is required for hSgo1 binding and cohesion protection during mitosis in human somatic cells. Consistent with this, we show that hSgo1 blocks the binding of PP2A-B56 substrates containing a canonical B56 binding motif. We find that PP2A-B56 bound to hSgo1 dephosphorylates Cdk1 sites on hSgo1 itself to modulate cohesin interactions. Collectively our work provides important insight into cohesion protection during mitosis.