BiofabricationPub Date : 2025-05-27DOI: 10.1088/1758-5090/add9d2
Mengyuan Li, Jiaming Ge, Jingwen Yao, Yuanhao Zhang, Lin Ma, Zheng Li, Xiangli Han, Ming Liu, Fei Tian, Jing Zhao
{"title":"Multifunctional nanoplatform based on polyethylene glycol-folic acid modified UiO-66 (Zr) as drug delivery platform for enhanced therapy of cancer.","authors":"Mengyuan Li, Jiaming Ge, Jingwen Yao, Yuanhao Zhang, Lin Ma, Zheng Li, Xiangli Han, Ming Liu, Fei Tian, Jing Zhao","doi":"10.1088/1758-5090/add9d2","DOIUrl":"10.1088/1758-5090/add9d2","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck. Due to low bioavailability and passive targetability of anticancer drugs show great limitations in cancer therapy, the treatment of OSCC faces major challenges. Folic acid (FA) targeting can deliver anticancer drugs efficiently into the tumor environment, further enhance the anti-cancer efficacy. Herein, the nanoplatform based on UiO-66 that encapsulated with an effective FA targeting ligands and the pH-responsive polyethylene glycol (PEG) layer for the targeted delivery of berberine (Ber) is constructed for fighting against OSCC. The FA modification and controlled pH-responsiveness enable the targeted delivery of UiO-66/PEG-FA, which promotes the release of Ber and increases the cumulative intracellular Ber concentration, which both promote consumption of glutathione (GSH) and induced generation of reactive oxygen species (ROS), further stimulate the secretion of inflammatory factors (TNF-<i>α</i>and IL-1<i>β</i>). A comprehensive evaluation of<i>in vitro</i>and<i>in vivo</i>experiments show that UiO-66@Ber/PEG-FA promote autophagy and apoptosis of tumor cells by regulating the expression of Beclin-1, ATG13, BAX and Bcl-2, and effectively inhibit tumor growth. Overall, UiO-66@Ber/PEG-FA exhibit superior pH-responsiveness and targeted therapeutic efficiencies<i>in vitro</i>and vivo, it can serve as an approach for OSCC therapy.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-23DOI: 10.1088/1758-5090/add627
Léa Pourchet, Laura Casado-Medina, Yvonne Richaud-Patin, Karine Tadevosyan, Alba Morillas-García, Edgar Lorenzo, Ioannis Lazis, Antoni Ventura, Jagoda Litowczenko, Jordi Guiu, Angel Raya
{"title":"3D bioprinting of human iPSC-derived cardiac constructs with microvascular network support for improved graft survival<i>in vivo</i>.","authors":"Léa Pourchet, Laura Casado-Medina, Yvonne Richaud-Patin, Karine Tadevosyan, Alba Morillas-García, Edgar Lorenzo, Ioannis Lazis, Antoni Ventura, Jagoda Litowczenko, Jordi Guiu, Angel Raya","doi":"10.1088/1758-5090/add627","DOIUrl":"10.1088/1758-5090/add627","url":null,"abstract":"<p><p>Cardiac tissue engineering is a rapidly growing field that holds great promise for the development of new therapies for heart disease. While significant progress has been made in the field over the past two decades, engineering functional myocardium of clinically relevant size and thickness remains an unmet challenge. A major roadblock in this respect is the current difficulty in incorporating efficient vascularization into engineered constructs. One potential solution involves the use of microvascular fragments from adipose tissue, which have demonstrated encouraging results in improving vascularization and graft survival following transplantation. However, this method lacks precise control over the vascular architecture within the constructs. Here, we set out to investigate the use of 3D bioprinting for the fabrication of human cardiac tissue constructs composed of human induced pluripotent stem cell derivatives, while allowing for the precise control of the distribution and density of microvessel fragments within the bioprinted constructs. We carefully selected and optimized bioink compositions based on their printability, biocompatibility, and construct stability. Following transplantation into immunodeficient mice, 3D bioprinted cardiac constructs containing microvessel fragments exhibited rapid and efficient vascularization, resulting in prolonged graft survival. Overall, our studies underscore the advantages of employing engineering design and self-assembly across different scales to address current limitations of tissue engineering, and highlight the usefulness of 3D bioprinting in this context.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-22DOI: 10.1088/1758-5090/add49e
Minghui Shi, Peer Fischer, Kai Melde
{"title":"Acoustic holographic assembly of cell-dense tissue constructs.","authors":"Minghui Shi, Peer Fischer, Kai Melde","doi":"10.1088/1758-5090/add49e","DOIUrl":"10.1088/1758-5090/add49e","url":null,"abstract":"<p><p>Tissue engineering aims to develop tissue constructs as models or substitutes for native tissues. For organ-level biological studies and regenerative medicine applications, it is essential to fabricate tissue constructs with physiologically relevant cell densities (on the order of 10 million to 1 billion cells·ml<sup>-1</sup>), large size (centimeter scale and larger), and a controllable geometry to guide tissue maturation. State-of-the-art biofabrication methods, however, struggle to simultaneously meet all of these demands. The recently proposed acoustic holographic assembly (AHA) method shows promise, as it is compatible with culture media and enables the contactless, label-free, and volumetric assembly of biological cells in a predefined geometry within few minutes. Here we present an AHA biofabrication scheme designated for fabricating cell-dense, centimeter-scale, and arbitrarily-shaped tissue constructs using a compact benchtop instrument compatible with a biolab environment. We demonstrate the assembly of C2C12 myoblasts in gelatin methacryloyl (GelMA) into large and asymmetric branch-shaped constructs, which are rapidly formed with an average cell density of 40 million cells·ml<sup>-1</sup>and a local density of up to 260 million cells·ml<sup>-1</sup>. Featuring a high viability of 90.5 ± 4.3%, the assembled cell constructs are observed to grow within the GelMA hydrogel under perfusion over five days. Further, we show how AHA can-in a single step-assemble cells into layered and three-dimensional geometries inside standard cell culture labware. It can therefore help obtain engineered tissue constructs with structural and functional characteristics seen in more complex native tissues.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-22DOI: 10.1088/1758-5090/addc41
Parisa Samadi, Mohsen Sheykhhasan, Ilham Omer, Asad Ullah, Ahmed Zarea, Victoria Toomajian, Muhammad Umar Aslam Khan, Derya Ertas, Lamont R Jones, Albert M Levin, Anwarul Hasan, Christopher H Contag, Yavuz Nuri Ertas, Nureddin Ashammakhi
{"title":"Regeneration of cartilage defects using engineered extracellular vesicles.","authors":"Parisa Samadi, Mohsen Sheykhhasan, Ilham Omer, Asad Ullah, Ahmed Zarea, Victoria Toomajian, Muhammad Umar Aslam Khan, Derya Ertas, Lamont R Jones, Albert M Levin, Anwarul Hasan, Christopher H Contag, Yavuz Nuri Ertas, Nureddin Ashammakhi","doi":"10.1088/1758-5090/addc41","DOIUrl":"https://doi.org/10.1088/1758-5090/addc41","url":null,"abstract":"<p><p>In recent years, the number of adults with diagnosed cartilage defects has increased significantly, and various modes of treatment have been sought. However, traditional cartilage repair strategies have been proven inefficient, with limited success. Recently, regenerative treatment options have become more routinely used for specific indications, but they still have major limitations. Cell-derived extracellular vesicles (EVs) are becoming increasingly attractive for regenerative purposes because they provide several regenerative factors. In addition, they can be engineered to function as delivery agents for proteins, nucleic acids, and other molecules. Recently, EVs were explored for cartilage tissue engineering, with varying results. Unlike other cell-based therapies, this approach will lead to the avoidance of problems associated with immunogenic reactions against allogenic cells and easier approval of the therapy by regulatory bodies, which is expected to stimulate wider clinical application. Because of its broad interest and importance, this review was developed to discuss published works, their outcomes, and limitations and outline future research directions.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genetically modified cell membrane proteins in tissue engineering and regenerative medicine.","authors":"Yilin Bao, Yue Hu, Mengxuan Hao, Qinmeng Zhang, Guoli Yang, Zhiwei Jiang","doi":"10.1088/1758-5090/add625","DOIUrl":"10.1088/1758-5090/add625","url":null,"abstract":"<p><p>Genetically modified cell membrane proteins can effectively regulate cell proliferation and differentiation, while also integrating novel biomaterials. As a promising biomedical tool, this technology has broad applications in tissue engineering and regenerative medicine. Both viral and non-viral gene transfection methods have been employed to create genetically modified cell membrane proteins. Numerous studies have demonstrated the significant efficacy of genetically modified cell membrane proteins in promoting bone regeneration, treating cardiovascular diseases, aiding lung injury recovery, advancing immunotherapy, and in applications involving engineered cell membrane sheets and cell spheroids. However, this technology faces several limitations, including biosafety and ethical concerns associated with genetic modification. This article summarizes recent advances in genetically modified cell membrane proteins, detailing their preparation, applications, limitations, and future directions.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-16DOI: 10.1088/1758-5090/add37f
Caleb D Vogt, Joseph R Broomhead, Kyle Y Kunisaki, Johanna Margaret Teegarden, Kallie L Frett, Kyleigh Q Pacello, Anthony H Vitale, Angela Panoskaltsis-Mortari
{"title":"Efficient wet-spinning of pre-aligned microtissues for 3D bioprinting complex tissue alignment.","authors":"Caleb D Vogt, Joseph R Broomhead, Kyle Y Kunisaki, Johanna Margaret Teegarden, Kallie L Frett, Kyleigh Q Pacello, Anthony H Vitale, Angela Panoskaltsis-Mortari","doi":"10.1088/1758-5090/add37f","DOIUrl":"10.1088/1758-5090/add37f","url":null,"abstract":"<p><p>Engineering functional smooth muscle tissues requires precise control of cellular alignment, particularly in complex anatomical regions such as the gastroesophageal junction (GEJ). We present a scalable wet-spinning approach for generating pre-aligned microtissues (PAMs) from immortalized human esophageal smooth muscle cells embedded in a collagen-alginate core-shell fiber. After maturation, fibers were sectioned into uniform PAMs with preserved alignment and high cell viability. Immunofluorescence and gene expression analyses confirmed the expression of key contractile markers. PAMs were incorporated into a gelatin-methacryloyl bioink and 3D bioprinted to demonstrate alignment along the extrusion path. This method does not require specialized culture platforms and enables efficient production of aligned microtissues for bioprinting. It offers a promising strategy for fabricating anisotropic tissues and may facilitate the reconstruction of complex muscle structures such as the GEJ.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-14DOI: 10.1088/1758-5090/add49f
Chao Zhang, Ze Fu, Qinghua Liu, Xu Guo, Zhao Li, Wei Song, Yi Kong, Jinpeng Du, Yanlin Su, Bingyang Yu, Yue Kong, Feng Tian, Xiaobing Fu, Xiaohui Du, Sha Huang
{"title":"Bioprinted M2 macrophage-derived extracellular vesicle mimics attenuate foreign body reaction and enhance vascularized tissue regeneration.","authors":"Chao Zhang, Ze Fu, Qinghua Liu, Xu Guo, Zhao Li, Wei Song, Yi Kong, Jinpeng Du, Yanlin Su, Bingyang Yu, Yue Kong, Feng Tian, Xiaobing Fu, Xiaohui Du, Sha Huang","doi":"10.1088/1758-5090/add49f","DOIUrl":"https://doi.org/10.1088/1758-5090/add49f","url":null,"abstract":"<p><p>Foreign body reaction (FBR) and insufficient vascularization greatly hinder the integration of 3D-bioprinted tissue substitutes with host tissues. Previous studies have shown that these problems are exacerbated by the stiffness of the 3D-bioprinted constructions, which is highly associated with the abnormal polarization of macrophages. Therefore, we developed an engineering strategy using membrane extrusion to prepare macrophage-derived extracellular vesicle mimics (EVMs). The EVMs derived from M1 and M2 macrophages (M1-EVMs and M2-EVMs) were rich in functional proteins. In the 2D environment, M1-EVMs promoted the fibrotic phenotype of fibroblasts, vascularization, and the M1 polarization of macrophages. In contrast, M2-EVMs effectively avoided the fibrotic trend, showed stronger angiogenic capabilities, and prevented excessive M1 polarization, demonstrating their potential to inhibit FBR and promote neovascularization. After bioprinting the EVMs loaded by gelatin-alginate bioink, the basic physical properties of the bioink were not significantly affected, and the biological functions of EVMs remain stable, indicating their potential as bioink additives. In the subcutaneous implantation model, unlike the FBR-aggravating effects of M1-EVMs, 3D-bioprinted M2-EVMs successfully reduced the immune response, prevented fibrous capsule formation, and increased vascular density. When applied to skin wound treatment, 3D-bioprinted M2-EVMs not only inhibited inflammatory levels but also exhibited pleiotropic pro-regenerative effects, effectively promoting vascularization, re-epithelialization, and appendage regeneration. As an innovative additive for bioinks, M2-EVMs present a promising approach to enhance the survival of bioengineered tissues and can further serve as a targeted drug loading system, promoting the development of regenerative medicine and improving clinical outcomes.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":"17 3","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-14DOI: 10.1088/1758-5090/add210
Harshita Sharma, Woochan Kim, Sejong Oh, Dream Kim, Shinyull Lee, Sangbae Park, Jooseon Oh, Sunho Park, Jangho Kim
{"title":"Ultra-tiny-scale technology for engineering human ear therapeutics.","authors":"Harshita Sharma, Woochan Kim, Sejong Oh, Dream Kim, Shinyull Lee, Sangbae Park, Jooseon Oh, Sunho Park, Jangho Kim","doi":"10.1088/1758-5090/add210","DOIUrl":"https://doi.org/10.1088/1758-5090/add210","url":null,"abstract":"<p><p>Ultra-tiny-scale technology representing engineered micro- and nano-scale materials has gained considerable attention for a wide range of applications, including hearing restoration. The advent of hearing loss and its recovery has been the topic of intense discussion since many decades. Although conventional treatments partially support hearing recovery, they present certain limitations such as subsequent immune response and donor site morbidity leading to even worsened sensory disturbances. Microscale- and nanoscale-based approaches such as tissue engineering, nanoparticle-assisted drug delivery systems, and micro/nanofabrication-aided auditory stimulations have been shown to play an efficient role in recovery from hearing disorders. In particular, the introduction of different biomaterials and biopolymers (natural and synthetic) with influential topographical cues and excellent biocompatibility has been found to conveniently bypass previous challenges posed by rigid human ear structures and provided a new path for improved and advanced hearing-recovery approaches. This review is focused on the development of micro/nanoengineering-based hearing recovery therapeutics and their significant impact on the future of hearing research. It discusses the physiological functions associated with the human ear and the mechanism underlying distinct hearing loss disorders as well as highlights various engineered ultra-tiny-scale-assisted strategies for developing advanced hearing therapeutics. Finally, we deliberate on commercialization aspect and future perspectives of implementing micro/nanotechnologies for hearing restoration platforms.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":"17 3","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-05-13DOI: 10.1088/1758-5090/add20f
Maj-Britt Buchholz, Paulina Nunez Bernal, Nils Bessler, Camille Bonhomme, Riccardo Levato, Anne Rios
{"title":"Development of a bioreactor and volumetric bioprinting protocol to enable perfused culture of biofabricated human epithelial mammary ducts and endothelial constructs.","authors":"Maj-Britt Buchholz, Paulina Nunez Bernal, Nils Bessler, Camille Bonhomme, Riccardo Levato, Anne Rios","doi":"10.1088/1758-5090/add20f","DOIUrl":"https://doi.org/10.1088/1758-5090/add20f","url":null,"abstract":"<p><p>Tissue function depends on the 3D spatial organization of cells, extracellular matrix components, as well as dynamic nutrient gradients and mechanical forces. Advances in biofabrication technologies have enabled the creation of increasingly sophisticated tissue models, but achieving native-like tissue maturation post-fabrication remains a challenge. The development of bioreactors and microfluidic systems capable of introducing dynamic culture platforms and controlled mechanical and biochemical stimulation for biofabricated tissue analogues is therefore imperative to address this. In this technical note, we introduce a multi-step pipeline to fabricate, seed and perfuse geometrically complex hydrogel constructs with quality control protocols through the computational analysis of confocal multispectral 3D imaging data for each step of the process. Employing ultra-fast volumetric bioprinting, chips with tunable channel architectures were fabricated. Furthermore, an autoclavable and transparent perfusion bioreactor inspired by open-source designs was developed to enable controlled, long-term perfusion (up to 28 days) and real-time monitoring of cell behavior. As proof-of-concept, employing this pipeline, we fabricated a human mammary ductal model and an endothelialized vessel on-a-chip, demonstrating the compatibility of the platform with epithelial and endothelial cell lines, and investigated the effect of dynamic culture on tissue-specific cell organization. Dynamic perfusion underlined the influence of mechanical stimulation on cell organization and maturation. Various chip architectures, capable of recapitulating tissue-specific features (<i>i.e.</i>lobules) were printed, enabling the mono- and co-culture of human mammary epithelial and endothelial cells. Our pipeline, with the accompanying protocols and analysis scripts presented here, provide the potential to be applied for the dynamic culture of a wide range of tissues.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":"17 3","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiofabricationPub Date : 2025-04-28DOI: 10.1088/1758-5090/adcd9f
Sabrina Schoenborn, Mingyang Yuan, Cody A Fell, Chuanhai Liu, David F Fletcher, Selene Priola, Hon Fai Chan, Mia Woodruff, Zhiyong Li, Yi-Chin Toh, Mark C Allenby
{"title":"Simulating big mechanically-active culture systems (BigMACS) using paired biomechanics-histology FEA modelling to derive mechanobiology design relationships.","authors":"Sabrina Schoenborn, Mingyang Yuan, Cody A Fell, Chuanhai Liu, David F Fletcher, Selene Priola, Hon Fai Chan, Mia Woodruff, Zhiyong Li, Yi-Chin Toh, Mark C Allenby","doi":"10.1088/1758-5090/adcd9f","DOIUrl":"https://doi.org/10.1088/1758-5090/adcd9f","url":null,"abstract":"<p><p>Big mechanically-active culture systems (BigMACS) are promising to stimulate, control, and pattern cell and tissue behaviours with less soluble factor requirements. However, it remains challenging to predict if and how distributed mechanical forces impact single-cell behaviours to pattern tissue. In this study, we introduce a tissue-scale finite element analysis framework able to correlate sub-cellular quantitative histology with centimetre-scale biomechanics. Our framework is relevant to diverse BigMACS, including media perfusion, tensile-stress, magnetic, and pneumatic tissue culture platforms. We apply our framework to understand how the design and operation of a multi-axial soft robotic bioreactor can spatially control mesenchymal stem cell (MSC) proliferation, orientation, differentiation to smooth muscle, and extracellular vascular matrix deposition. We find MSC proliferation and matrix deposition to positively correlate with mechanical stimulation but cannot be locally patterned by soft robot mechanical stimulation within a centimetre scale tissue. In contrast, local stress distribution was able to locally pattern MSC orientation and differentiation to smooth muscle phenotypes, where MSCs aligned perpendicular to principal stress direction and expressed increased α-SMA with increasing 3D Von Mises Stresses from 0 to 15 kPa. Altogether, our new biomechanical-histological simulation framework is a promising technique to derive the future mechanical design equations to control cell behaviours and engineer patterned tissue.</p>","PeriodicalId":8964,"journal":{"name":"Biofabrication","volume":"17 3","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}