ACS Biomaterials Science & Engineering最新文献

{"title":"Bioinspired Microneedles for Multifunctional Theranostics: Design Principles, Fabrication Strategies, and Translational Barriers","authors":"Inel Mesbahi,&nbsp;Heng An,&nbsp;Yongqiang Wen,&nbsp;Guojie Wang","doi":"10.1021/acsbiomaterials.6c00874","DOIUrl":"10.1021/acsbiomaterials.6c00874","url":null,"abstract":"<p>Bioinspired microneedles (MNs) are rapidly evolving into advanced, minimally invasive platforms for transdermal drug delivery and diagnostics, driven by the growing demand for multifunctional, patient-centric theranostic systems. However, the integration of multiple therapeutic and diagnostic modalities within a single MN architecture remains a significant challenge owing to the conflicting requirements of mechanical penetration, anchoring stability, biofluid transport, and long-term functional reliability. Bioinspiration offers a coherent, transformative framework for addressing these bottlenecks by translating structural, interfacial, and adaptive strategies evolved in natural systems into engineered designs. This review systematically examines biomimetic MN architectures that enable optimized skin access, asymmetric tissue anchoring, and efficient biofluidic transport, highlighting how these features provide the structural requirements for multifunctional operation. Recent advances in fabrication technologies, including high-resolution additive manufacturing, magnetic and dynamic field-assisted assembly, and four-dimensional printing, are discussed as key enablers for implementing complex bioinspired geometries and spatially programmed functionalities. Complementary material selection strategies, encompassing high-performance polymers, hydrogels, biocomposites, and stimuli-responsive materials, are analyzed for their roles in preserving mechanical fidelity, enabling dynamic adhesion, and supporting active therapeutic and diagnostic functions. Building on these foundations, we critically review multifunctional theranostic MN platforms integrating synergistic drug delivery, embedded biosensing, and autonomous functional sequencing, alongside key translational considerations such as insertion reliability, dosing fidelity, and multicomponent stability. Collectively, this review positions bioinspired multifunctional MN patches as a promising pathway toward robust, adaptive, and clinically viable transdermal theranostic systems.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5250–5275"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928496","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":"Decoding Cytoskeletal Mechanobiology with Tunable Microenvironments","authors":"Rupesh Kandel,&nbsp;Md. Amzadul Hoque Chowdhury,&nbsp;Jacqueline Robinson,&nbsp;Dana N. Reinemann","doi":"10.1021/acsbiomaterials.6c00339","DOIUrl":"10.1021/acsbiomaterials.6c00339","url":null,"abstract":"<p>Mechanical cues from the cellular microenvironment are key regulators of cytoskeletal organization, force generation, and mechanotransduction, yet defining how specific mechanical inputs control distinct cytoskeletal processes remains an ongoing challenge. Mechanically tunable microenvironments have become essential tools for addressing this problem by enabling systematic variation of substrate stiffness, viscoelasticity, and interfacial mechanics under well-controlled conditions. In this review, we survey major classes of tunable platforms used to study cytoskeletal dynamics, including biologically derived matrices, synthetic hydrogels, micropatterned and nanotopographic substrates, and polymeric thin films, highlighting how each approach affords unique insight into cytoskeletal regulation. Beyond material composition, these platforms reveal key mechanistic principles: they allow separation of protrusion, contractility, and adhesion processes; uncover how mechanical coupling drives alignment and polarity; and identify stiffness thresholds that govern force transmission. Control over interface mechanics also enables selective engagement of cytoskeletal modules that are otherwise inseparable on rigid substrates. We conclude by discussing current limitations and emerging opportunities for integrating tunable microenvironments with quantitative measurements of force generation and cytoskeletal organization, advancing a more predictive understanding of how cells sense, transmit, and respond to mechanical information.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5108–5124"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928574","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":"Advances in Marine Biomineralized Materials in Bone Repair and Regeneration","authors":"Bixuan Cao,&nbsp;Shiyi Guo,&nbsp;Jiaming Cui,&nbsp;Miaoyang Liang,&nbsp;Leisheng Zhang,&nbsp;Qiang Ren,&nbsp;Chao Wei,&nbsp;Rende Ning,&nbsp;Bin Zhang,&nbsp;Qibao Wang,&nbsp;Mingzhi Song","doi":"10.1021/acsbiomaterials.6c00447","DOIUrl":"10.1021/acsbiomaterials.6c00447","url":null,"abstract":"<p>Marine biomineralized materials (MBMs), derived from organisms such as corals, mollusks, cuttlefish, sponges, and fish, represent a promising class of natural resources for bone tissue engineering due to their structural similarity to human bone, excellent biocompatibility, and bioactive properties. The composition, hierarchical architecture, biomineralization mechanisms, and species-specific characteristics of MBMs collectively determine their physicochemical properties and regenerative potential. The porous framework of coral bone, the “brick-and-mortar” structure of nacre, the multi-chambered design of cuttlebone, and the concentric lamellae of sponge spicules provide mechanical strength, facilitate vascularization, and support osteogenesis. Furthermore, bioactive proteins and ions inherent in MBMs further may promote osteoinduction and angiogenesis. Despite their potential, challenges related to resource sustainability, mechanical compatibility, and clinical scalability remain. By enhancing the functionality and applicability of MBMs, designing strategies for the preparation of emerging materials has become a major research highlight including 3D printing, biomimetic synthesis, and composite fabrication. MBMs represent a diverse class of biomineralized resources with significant application value in bone repair and regeneration. This review presents the transition of MBMs from passive bone grafts to active, intelligent regenerative systems, offering innovative solutions for the treatment of bone defects while aligning with ecological and economic sustainability.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5125–5144"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149078983","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":"Supercritical Carbon Dioxide-Peracetic Acid Treatment Inactivates Low-Level Bacterial Inocula in Collagen Analogue-Phosphorylcholine Hydrogels while Preserving Functional Properties","authors":"Hamid Goodarzi,&nbsp;Mohammad Mirazul Islam,&nbsp;Mostafa Zamani-Roudbaraki,&nbsp;Solange Muhayimana,&nbsp;Sophie Lerouge,&nbsp;Dick J. Sjöström,&nbsp;Rakibul Islam,&nbsp;Amrita Saha,&nbsp;Per H. Nilsson,&nbsp;Emilio I. Alarcon,&nbsp;Marie-Claude Robert,&nbsp;Christos Boutopoulos,&nbsp;May Griffith","doi":"10.1021/acsbiomaterials.6c00519","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.6c00519","url":null,"abstract":"<p>Terminal sterilization of hydrogels is challenging because their high-water-content, chemical structures, and cell-friendly properties are often altered by conventional sterilization methods. Hydrogel implants comprising collagen-like peptide (CLP), polyethylene glycol (PEG), and poly (2-methacryloyloxyethyl phosphorylcholine) (MPC) showed promise in promoting corneal regeneration in preclinical animal studies. However, before these CLP-PEG-MPC implants can be used clinically, they must be sterilized effectively to ensure patient safety. Here, we evaluated supercritical carbon dioxide (scCO₂) with peracetic acid (PAA) as a potential sterilization technique for hydrogels. CLP-PEG-MPC was treated with scCO₂ containing PAA and compared against 15 kGy of electron beam irradiation (E-beam) and chloroform (CF) sterilization. Several samples were spiked with 200 colony-forming units (CFU) of either <em>Pseudomonas aeruginosa</em> or <em><em>Staphylococcus aureus</em></em> prior to sterilization to compare the bactericidal efficacy of the three sterilization methods. Only scCO₂-PAA effectively inactivated all the inoculated bioburden. Non-spiked hydrogels were also sterilized and then compared for complement activation, changes to their physical and mechanical properties, and biocompatibility. Optical clarity was unchanged regardless of sterilization mode. scCO₂-PAA did not alter the mechanical properties of the hydrogels but resulted in a modest lowering of corneal epithelial cell proliferation, while E-beamed hydrogels showed reduced mechanical strength. In conclusion, newer scCO₂-PAA terminal sterilization preserves the functional properties of soft hydrogels, such as CLP-PEG-MPC, including transparency, which is needed for corneal implants.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5541–5549"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152987","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":"Synergistic Tuning of Pore Architecture and Mechanical Properties in a Biomimetic COL-HA-PVA Hydrogel Directs BMSC Chondrogenesis for Osteochondral Regeneration","authors":"Peng Chen,&nbsp;Wei Lu,&nbsp;Haoyi Wang,&nbsp;Tianhua Liu,&nbsp;Qihong Jiang,&nbsp;Lingchen Yang,&nbsp;Yihe Hu","doi":"10.1021/acsbiomaterials.6c00857","DOIUrl":"10.1021/acsbiomaterials.6c00857","url":null,"abstract":"<p>Engineering hydrogels that simultaneously provide interconnected porosity for cell infiltration while delivering appropriate mechanical cues to direct stem cell fate remains a critical challenge in cartilage tissue engineering. Herein, we report a biomimetic COL-HA-PVA hydrogel scaffold with systematically tunable pore sizes (1.2, 1.4, and 1.6 mm) and concomitant mechanical properties, enabling the co-regulation of the structural and biomechanical microenvironment. The 1.2 mm scaffold exhibited the lowest and most stable compressive modulus across the physiologically relevant strain range, providing a compliant mechanical microenvironment that promoted BMSC chondrogenesis, coupled with enhanced surface hydrophilicity due to collagen functionalization. In vitro, this optimized pore architecture significantly promoted goat bone marrow mesenchymal stem cell (gBMSC) adhesion, spreading, and sustained proliferation over 14 days. More importantly, the 1.2 mm scaffold directed robust chondrogenic differentiation, as evidenced by markedly increased expression of the genes and proteins SOX9, COL-II, and aggrecan relative to larger-pore counterparts. Mechanistically, the scaffold activated the integrin β1–FAK–RhoA/ROCK mechanotransduction axis to enhance SOX9-mediated transcription while suppressing osteogenic markers RUNX2 and COL-I. In a caprine model of full-thickness osteochondral defects, the BMSC-laden 1.2 mm scaffold achieved seamless integration with host tissue, progressive subchondral bone regeneration, and formation of proteoglycan-rich hyaline-like cartilage, as confirmed by micro-CT, histological staining, and GAG quantification. This work demonstrates that synergistic tuning of pore architecture and mechanical properties represents a powerful design strategy for directing stem cell-based cartilage regeneration, offering mechanistic insights into scaffold-guided cell fate determination.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5426–5442"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910222","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":"Correction to “Design and Performance Analysis of a Bionic Radially Gradient Irregular Bone Scaffold”","authors":"Qingyu Xu,&nbsp;Jizhe Hai,&nbsp;Jie Chen","doi":"10.1021/acsbiomaterials.6c01652","DOIUrl":"10.1021/acsbiomaterials.6c01652","url":null,"abstract":"","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5722–5722"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917715","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":"Fabrication and Characterization of Melt-Electrowritten Hierarchical PCL Scaffolds for Conjunctival Tissue Engineering","authors":"Wahaj Ul Haq,&nbsp;Camilla Mussoni,&nbsp;Zhi Liang,&nbsp;Muhammad Aslam,&nbsp;Raoul Verma-Fuehring,&nbsp;Franziska Seifert,&nbsp;Martina Wiesler,&nbsp;Philipp Stahlhut,&nbsp;Jürgen Groll,&nbsp;Jost Hillenkamp,&nbsp;Taufiq Ahmad,&nbsp;Malik Salman Haider","doi":"10.1021/acsbiomaterials.6c00996","DOIUrl":"10.1021/acsbiomaterials.6c00996","url":null,"abstract":"<p>Conjunctival tissue loss resulting from trauma, inflammatory diseases, or surgical interventions remains a major clinical challenge and highlights the need for reliable tissue substitutes. Additionally, advanced three-dimensional <em>in vitro</em> systems are required for studying conjunctival biology, evaluating therapeutics, and supporting the principles of the 3Rs. This study aimed to develop a hierarchically structured melt-electro-written (MEW) poly(ε-caprolactone) (PCL) scaffold as a platform for generating bilayered conjunctival constructs. The scaffold comprised a dense apical network to support epithelial attachment and a porous basal region to facilitate fibroblast infiltration and extracellular matrix formation. To enhance cell–material interactions, scaffolds were functionalized with a polydopamine coating. Morphology, surface modification, and mechanical properties were characterized by scanning electron microscopy, Raman spectroscopy, and tensile testing. Human conjunctival fibroblasts and epithelial cells were sequentially seeded to establish a bilayered model, followed by immunocytochemical evaluation. MEW enabled reproducible fabrication of thin scaffolds with defined apical and basal pore architectures. Compared with a conventional nonhierarchical box-pattern scaffold, the hierarchical design increased ultimate tensile stress from 0.32 to 0.83 MPa, reaching the mean value measured for fresh porcine conjunctiva, while producing little change in Young’s modulus. PDA functionalization enhanced cellular attachment, spreading, and scaffold colonization. Sequential seeding generated a bilayer-like construct within seven days, characterized by preferential fibroblast integration within the porous basal region and formation of a CK13-positive epithelial layer predominantly localized to the dense apical surface. In conclusion, the developed scaffold supports the generation of bi-layered conjunctival constructs and represents a promising platform for conjunctival tissue engineering and standardized ocular surface models for advanced <em>in vitro</em> research.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5646–5661"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872307","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":"Bioengineered Vascular Grafts for Hemodialysis Access: Design Requirements, Clinical Evidence, and Translational Barriers","authors":"Suqi Rui,&nbsp;Junjie Chen,&nbsp;Lei Tian","doi":"10.1021/acsbiomaterials.6c00469","DOIUrl":"10.1021/acsbiomaterials.6c00469","url":null,"abstract":"<p>Autogenous arteriovenous fistulas (AVFs) remain the preferred hemodialysis access when suitable vessels and sufficient maturation time are available, but high nonmaturation rates, catheter dependence, and increasing multimorbidity in end-stage kidney disease (ESKD) have intensified the need for reliable alternative conduits. Conventional expanded polytetrafluoroethylene (ePTFE) grafts provide an immediately available surgical option, yet their chemically inert surfaces are not intrinsically blood-compatible and remain susceptible to thrombosis, infection, compliance mismatch, and venous neointimal hyperplasia. This critical review evaluates bioengineered vascular grafts as candidate solutions for hemodialysis access, emphasizing how material design, tissue-engineered scaffolds, and localized therapeutic delivery must be matched to dialysis-specific requirements, including puncture sealing, suture retention, infection resistance, endothelialization, and high-flow durability. Early clinical experience with endogenous tissue restoration grafts, human acellular vessels, and scaffold-free autologous tissue-engineered grafts provides encouraging signals, but current evidence remains limited by small cohorts, single-arm designs, incomplete comparative data, and uncertain long-term performance under repeated cannulation. We also examine major translational barriers, including the “uremic mismatch” between healthy animal models and the inflammatory, calcified, hypercoagulable, and immunologically impaired ESKD milieu. Finally, immunomodulatory scaffolds, 4D-printed structures, and biosensing graft concepts are discussed as experimental research directions rather than established clinical solutions. A patient-centered, ESKD Life-Plan-informed strategy may ultimately align graft selection with vessel quality, life expectancy, dialysis trajectory, and acceptable intervention burden.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5145–5158"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917700","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":"Tailored Microrobotic Approaches for Tissue Engineering","authors":"Anal Kishore Singh,&nbsp;Rui L. Reis,&nbsp;Subhas C. Kundu,&nbsp;Chinmaya Mahapatra","doi":"10.1021/acsbiomaterials.6c00562","DOIUrl":"10.1021/acsbiomaterials.6c00562","url":null,"abstract":"<p>Microrobotics, while emerging as a promising technological platform for tissue engineering and regenerative medicine, is also enabling minimally invasive manipulation, localized stimulation, targeted delivery, and controlled organization of cells and biomaterials within complex tissue-based environments. This review examines the fundamental principles governing the design and operation of microrobotic systems, with particular emphasis on magnetic, acoustic, optical, and biohybrid actuation strategies. The influence of microrobot geometry, material composition, fabrication approach, biocompatibility, collective behavior, and interactions with viscoelastic biological media is discussed in relation to their functional performance. The review further evaluates the operational roles of microrobots in mechanotransduction, cellular stimulation, delivery of therapeutic molecules, cell transport and assembly, biosensing, and spatial organization of tissue-engineered constructs. Their usage in musculoskeletal, cardiovascular, and neural tissue engineering, as well as in organoid manipulation and disease modeling, is critically examined. Specific attention is given to magnetically actuated microrobots because of their fuel-free operation, precise external control, compatibility with medical imaging, and potential for multifunctional therapeutic interventions. Even after substantial progress, clinical translation remains constrained by challenges associated with scalable fabrication, propulsion and navigation in heterogeneous physiological environments, long-term biocompatibility, biodegradation, retrieval, imaging, biosafety, and standardized performance assessment. Emerging opportunities that involve stimuli-responsive disassembly, biohybrid architectures, microrobot swarms, real-time imaging, and artificial-intelligence-assisted navigation may help address these limitations. Overall, this review outlines the current capabilities, translational barriers, and future research priorities required to advance microrobotic systems from experimental platforms toward clinically relevant tools for tissue regeneration and repair.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5159–5190"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014870","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":"Matrix Stiffness Regulates Mechanotransduction and Vascular Network Formation of hiPSC-Derived Endothelial Progenitors Encapsulated in 3D Hydrogels","authors":"Jiwan Han,&nbsp;Kathleen Halwachs,&nbsp;Toni West,&nbsp;Bryce Larsen,&nbsp;Michael S. Sacks,&nbsp;Adrianne M. Rosales,&nbsp;Janet Zoldan","doi":"10.1021/acsbiomaterials.6c00563","DOIUrl":"10.1021/acsbiomaterials.6c00563","url":null,"abstract":"<p>Matrix mechanics are central to vasculogenesis, yet stiffness is often confounded with ligand density or degradability in common hydrogel platforms. Here, we use norbornene-modified hyaluronic acid (NorHA) hydrogels to independently tune stiffness within a sub-kilopascal range (190–884 Pa) relevant to embryonic vascular development and assess how stiffness regulates self-assembly of human iPSC-derived endothelial progenitors (hiPSC-EPs) into vascular networks, focusing on temporal dynamics of cellular mechanotransduction and contractility, leading to matrix displacement. EPs in intermediate-stiffness hydrogels (∼551 Pa) displayed the highest cell volume and surface area, increased nuclear Yes-associated protein (YAP), and elevated upstream phosphorylated focal adhesion kinase (pFAK), consistent with enhanced mechanotransduction signaling. However, despite high vinculin and pFAK expression, cells at this stiffness condition failed to form a robust, interconnected plexus. In contrast, the most compliant hydrogels (∼190 Pa) supported the most interconnected plexus assembly despite lower nuclear YAP, vinculin, and pFAK expression. ROCK inhibition reduced nuclear YAP, vinculin, and pFAK, confirming tension-dependent regulation, but did not rescue vasculogenesis at 551 Pa and instead impaired network formation at 190 Pa. Importantly, 3D traction microscopy revealed that hiPSC-EPs displayed the highest matrix displacement at this lowest storage modulus, suggesting that cell-generated traction forces and matrix deformability synergistically facilitate vascular morphogenesis. These results suggest that the plexus formation is promoted by matrix compliance that permits matrix displacement, rather than by elevated YAP-mediated mechanotransduction alone. Together, these findings establish a mechanically tunable framework to guide the design of next-generation hydrogels for therapeutic vascular regeneration.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 10","pages":"5566–5582"},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035702","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}