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Inherited Platelet Disorders affect \u2248 3 million individuals worldwide and are characterized by defects in platelet formation or function. A critical challenge in the identification of these diseases lies in the absence of models that facilitate the study of hematopoiesis ex vivo. Here, a silk fibroin\u2010based bioink is developed and designed for 3D bioprinting. This bioink replicates a soft and biomimetic environment, enabling the controlled differentiation of HSPCs into platelets. The formulation consisting of silk fibroin, gelatin, and alginate is fine\u2010tuned to obtain a viscoelastic, shear\u2010thinning, thixotropic bioink with the remarkable ability to rapidly recover after bioprinting and provide structural integrity and mechanical stability over long\u2010term culture. Optical transparency allowed for high\u2010resolution imaging of platelet generation, while the incorporation of enzymatic sensors allowed quantitative analysis of glycolytic metabolism during differentiation that is represented through measurable color changes. Bioprinting patient samples revealed a decrease in metabolic activity and platelet production in Inherited Platelet Disorders. These discoveries are instrumental in establishing reference ranges for classification and automating the assessment of treatment responses. This model has far\u2010reaching implications for application in the research of blood\u2010related diseases, prioritizing drug development strategies, and tailoring personalized therapies.<\/jats:p>","DOI":"10.1002\/advs.202308276","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:41:38Z","timestamp":1711068098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Bioprinting Soft 3D Models of Hematopoiesis using Natural Silk Fibroin\u2010Based Bioink Efficiently Supports Platelet Differentiation"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-2008","authenticated-orcid":false,"given":"Christian Andrea","family":"Di Buduo","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Lunghi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volodymyr","family":"Kuzmenko","sequence":"additional","affiliation":[{"name":"CELLINK Bioprinting AB  Gothenburg 41276 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1435-9298","authenticated-orcid":false,"given":"Pierre\u2010Alexandre","family":"Laurent","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9533-4593","authenticated-orcid":false,"given":"Giulia","family":"Della Rosa","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0822-0342","authenticated-orcid":false,"given":"Claudia","family":"Del Fante","sequence":"additional","affiliation":[{"name":"Immunohaematology and Transfusion Service I.R.C.C.S. Policlinico S. Matteo Foundation  Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian Edward","family":"Dalle Nogare","sequence":"additional","affiliation":[{"name":"Human Technopole  Milan 20157 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8499-5812","authenticated-orcid":false,"given":"Florian","family":"Jug","sequence":"additional","affiliation":[{"name":"Human Technopole  Milan 20157 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Perotti","sequence":"additional","affiliation":[{"name":"Immunohaematology and Transfusion Service I.R.C.C.S. Policlinico S. 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