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Upon breaking supersaturation, crystals form and the concentration of the solute decreases to its thermodynamic solubility. Soon after the discovery of the prion phenomena, it was recognized that prion disease transmission and propagation share some similarities with the process of crystallization. Subsequent studies exploring the structural and functional association between amyloid fibrils and amyloidoses solidified this paradigm. However, recent studies have not necessarily focused on supersaturation, possibly because of marked advancements in structural studies clarifying the atomic structures of amyloid fibrils. On the other hand, there is increasing evidence that supersaturation plays a critical role in the formation of amyloid fibrils and the onset of amyloidosis. Here, we review the recent evidence that supersaturation plays a role in linking unfolding\/folding and amyloid fibril formation. We also introduce the HANABI (HANdai Amyloid Burst Inducer) system, which enables high-throughput analysis of amyloid fibril formation by the ultrasonication-triggered breakdown of supersaturation. In addition to structural studies, studies based on solubility and supersaturation are essential both to developing a comprehensive understanding of amyloid fibrils and their roles in amyloidosis, and to developing therapeutic strategies.<\/jats:p>","DOI":"10.3390\/molecules27144588","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T05:37:53Z","timestamp":1658209073000},"page":"4588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Supersaturation-Dependent Formation of Amyloid Fibrils"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1221-1270","authenticated-orcid":false,"given":"Yuji","family":"Goto","sequence":"first","affiliation":[{"name":"Global Center for Medical Engineering and Informatics, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9707-035X","authenticated-orcid":false,"given":"Masahiro","family":"Noji","sequence":"additional","affiliation":[{"name":"Graduate School of Human and Environmental Studies, Kyoto University, Kyoto Sakyo-ku, Kyoto 606-8316, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kichitaro","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Global Center for Medical Engineering and Informatics, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Global Center for Medical Engineering and Informatics, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1146\/annurev.physchem.47.1.171","article-title":"Protein crystallization","volume":"47","author":"Durbin","year":"1996","journal-title":"Annu. 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