ClinicalTrials.gov identifier: NCT02388919.

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N ovel startup companies often face not only risk, but also unforeseeable uncertainty (the inability to recognize and articulate all relevant variables affecting performance). The literature recognizes that established risk planning methods are very powerful when the nature of risks is well understood, but that they are insufficient for managing unforeseeable uncertainty. For this case, two fundamental approaches have been identified: trial-and-error learning, or actively searching for information and repeatedly changing the goals and course of action as new information emerges, and selectionism, or pursuing several approaches in parallel to see ex post what works best. Based on a sample of 58 startups in Shanghai, we test predictions from prior literature on the circumstances under which selectionism or trial-and-error learning leads to higher performance. We find that the best approach depends on a combination of uncertainty and complexity of the startup: risk planning is sufficient when both are low; trial-and-error learning promises the highest potential when unforeseeable uncertainty is high, and selectionism is preferred when both unforeseeable uncertainty and complexity are high, provided that the choice of the best trial can be delayed until its true market performance can be assessed.

Composites of bone marrow-derived osteoblasts (BMOs) and porous ceramics have been widely used as a bone graft model for bone tissue engineering. Perfusion culture has potential utility for many cell types in three-dimensional (3D) culture. Our hypothesis was that perfusion of medium would increase the cell viability and biosynthetic activity of BMOs in porous ceramic materials, which would be revealed by increased levels of alkaline phosphate (ALP) activity and osteocalcin (OCN) and enhanced bone formation in vivo. For testing in vitro, BMO/beta-tricalcium phosphate composites were cultured in a perfusion container (Minucells and Minutissue, Bad Abbach, Germany) with fresh medium delivered at a rate of 2 mL/h by a peristaltic pump. The ALP activity and OCN content of composites were measured at the end of 1, 2, 3, and 4 weeks of subculture. For testing in vivo, after subculturing for 2 weeks, the composites were subcutaneously implanted into syngeneic rats. These implants were harvested 4 or 8 weeks later. The samples then underwent a biochemical analysis of ALP activity and OCN content and were observed by light microscopy. The levels of ALP activity and OCN in the composites were significantly higher in the perfusion group than in the control group (p < 0.01), both in vitro and in vivo. Histomorphometric analysis of the hematoxylin- and eosin-stained sections revealed a higher average ratio of bone to pore in BMO/beta-TCP composites of the perfusion group after implantation: 47.64 +/- 6.16 for the perfusion group and 26.22 +/- 4.84 for control at 4 weeks (n = 6, p < 0.01); 67.97 +/- 3.58 for the perfusion group and 47.39 +/- 4.10 for control at 8 weeks (n = 6, p < 0.05). These results show that the application of a perfusion culture system during the subculture of BMOs in a porous ceramic scaffold is beneficial to their osteogenesis. After differentiation culture in vitro with the perfusion culture system, the activity of the osteoblastic cells and the consequent bone formation in vivo were significantly enhanced. These results suggest that the perfusion culture system is a valuable and convenient tool for applications in tissue engineering, especially in the generation of artificial bone tissue.

Bilayered porous scaffolds have recently attracted interest because of their considerable promise for repairing osteochondral defects. However, determination of optimal pore size in bilayered porous scaffolds remains an important issue. This study investigated the in vivo effects of pore size in bilayered scaffolds using a rabbit model of osteochondral defects. We fabricated five types of integrated bilayered poly(lactide-co-glycolide) (PLGA) scaffolds with different pore sizes in the chondral and osseous layers (50-100 µm, 100-200 µm, 200-300 µm, and 300-450 µm). A subset of bilayered scaffolds seeded with or without allogenic bone marrow mesenchymal stem cells (BMSCs) was implanted in rabbit osteochondral defects. All of the cell/scaffold composite constructs supported the simultaneous regeneration of articular cartilage and subchondral bone, but the best results were observed in cell-seeded PLGA scaffolds with 100-200 µm pores in the chondral layer and 300-450 µm pores in the osseous layer. Our study supports the concept that the effects of pore size on osteochondral repair should be taken into consideration during scaffold design for tissue engineering.

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