Acta biomaterialia最新文献

{"title":"Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence.","authors":"Aiyana G Fortin, Nada Naguib, Erica J Secor, Heidi L Reesink, Ulrich B Wiesner, Lawrence J Bonassar","doi":"10.1016/j.actbio.2025.05.031","DOIUrl":"https://doi.org/10.1016/j.actbio.2025.05.031","url":null,"abstract":"<p><p>Development of non-surgical disease-modifying interventions for knee osteoarthritis (OA) remains a persistent challenge despite decades of efforts. Therapeutic transport to cartilage in synovial joints is hindered by the dense, negatively charged cartilage matrix, and further challenged by rapid synovial fluid clearance within hours to days. In this study, we investigated ultrasmall (d_h = 6 nm) fluorescent core-shell silica nanoparticles (Cornell Prime Dots, or C' Dots), which have received FDA-investigational new drug (IND) approval for multiple human clinical trials in oncology, as cartilage-penetrating delivery vehicles for applications in knee OA. Across multiple length and time scales, we examined the relationship between C' Dot tissue and cellular transport kinetics and whole joint clearance. In vitro, C' Dots penetrated cartilage explants within 30 minutes (D ∼ 2 µm²/s). C' Dots were internalized by chondrocytes within 24 hours and were retained in vesicular structures for up to 5 days. In vivo, C' Dot clearance following intra-articular knee injection was well described by two distinct time constants (τ₁ ∼ 18 hours, τ₂ ∼ 3 weeks), consistent with mechanisms of synovial- and tissue-mediated clearance. C' Dot clearance rates were not affected by surgically-induced cruciate ligament transection. Notably, C' Dots remained in the knee longer than 3 months after a single injection and were localized to cartilage, meniscus, ligaments, and synovium. Collectively, these results illustrate the potential of C' Dots for long-term delivery of conjugated therapeutics in the knee. STATEMENT OF SIGNIFICANCE: Dummy.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microfluidic-assisted engineering of hydrogels with microscale complexity.","authors":"Yuehong Li, Danyang Huang, Yuting Zhang, Yun Xiao, Xingdong Zhang","doi":"10.1016/j.actbio.2025.05.023","DOIUrl":"10.1016/j.actbio.2025.05.023","url":null,"abstract":"<p><p>Hydrogels have emerged as a promising 3D cell culture scaffold owing to their structural similarity to the extracellular matrix (ECM) and their tunable physicochemical properties. Recent advances in microfluidic technology have enabled the fabrication of hydrogels into precisely controlled microspheres and microfibers, which serve as modular units for scalable 3D tissue assembly. Furthermore, advances in 3D bioprinting have allowed facile and precise spatial engineering of these hydrogel-based structures into complex architectures. When integrated with microfluidics, these systems facilitate microscale heterogeneity, dynamic shear flow, and gradient generation-critical features for advancing organoids and organ-on-a-chip systems. In this review, we will discuss (1) microfluidic strategies for the preparation of hydrogel microspheres and microfibers, (2) the integration of microfluidics with 3D bioprinting technologies, and (3) their transformative applications in organoids and organ-on-a-chip systems. STATEMENT OF SIGNIFICANCE: Microfluidic-assisted preparation and assembly of hydrogel microspheres and microfibers have enabled unprecedented precision in size, morphology and compositional control. The diverse configurations of these hydrogel modules offer the opportunities to generate 3D constructs with microscale complexity-recapitulating critical features of native tissues such as compartmentalized microenvironments, cellular gradients, and vascular networks. In this review, we discuss the fundamental microfluidic principles governing the generation of hydrogel microspheres (0D) and microfibers (1D), their hierarchical assembly into 3D constructs, and their integration with 3D bioprinting platforms to generate and culture organoids and organ-on-a-chip systems. The synergistic integration of microfluidics and bioprinting overcomes longstanding limitations of conventional 3D culture, such as static microenvironments and poor spatial resolution. Advances in microfluidic design offer tunable hydrogel biophysical and biochemical properties that regulate cell behaviors dynamically. Looking forward, the growing mastery of these principles paves the way for next-generation organoids and organ-on-a-chip systems with improved cellular heterogeneity, integrated vasculature, and multicellular crosstalk, closing the gap between in vitro models and human pathophysiology.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted nanosensitizer-augmented sono-immunotherapy with STING agonist to remodel the immune microenvironment in hepatocellular carcinoma.","authors":"Huajing Yang, Rui Li, Shiyang Jin, Yuhang Tian, Chunyue Wang, Yucao Sun, Zhifei Dai, Wen Cheng","doi":"10.1016/j.actbio.2025.05.029","DOIUrl":"10.1016/j.actbio.2025.05.029","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most common primary malignant disease of the liver. Although immunotherapy offers new opportunities for treating advanced HCC, its therapeutic effect is still limited by the immunosuppressive tumor microenvironment (TME). Herein, a nanosensitizer RGD@Ce6@MSA-2@Liposome (RCM-Lip) is synthesized to specifically initiate the HCC tumor immune microenvironment through sonodynamic therapy (SDT)-triggered immunogenic cell death (ICD) and MSA-2-activated cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. RCM-Lip consists of a sonosensitizer (Chlorin e6, Ce6) with a STING agonist (MSA-2) and a tumor targeting peptide RGD inserted on the outer liposome surface. Under ultrasound irradiation, RCM-Lip generates reactive oxygen species that induce cytotoxicity and apoptosis of tumor cells. Meanwhile, tumor antigens released by apoptosis are taken up by dendritic cells (DCs), while STING is activated in the DCs by MSA-2. Moreover, DC maturation is stimulated, further enhancing the systematic anti-tumor immune responses. Sono-immunotherapy mediated by RCM-Lip promotes DCs maturation and tumor infiltration of CD8⁺T cells, increasing inflammatory cytokine secretion. Consequently, the immunologically \"cold\" TME of HCC is successfully turned into a \"hot\" one, leading to a significant tumor suppression effect with good bio-safety. These results suggest a promising method for precise tumor targeting and synergistic cancer sono-immunotherapy. STATEMENT OF SIGNIFICANCE: Our study addressed the therapeutic dilemma of hepatocellular carcinoma (HCC) as an immunological \"cold\" tumor by the synergistic application of sonodynamic therapy (SDT) and STING agonist. The cGAS-STING signaling pathway plays a pivotal role in innate immunity against cancer, but the clinical application of STING agonists were hampered by inflammatory responses due to off-target activation. Our innovative solution introduces RGD-targeted peptide to encapsulate sonosensitizer and STING agonist, strengthening therapeutic effects and reducing systemic toxicity. The targeted sono-immunotherapy promoted DCs maturation and tumor infiltration of CD8⁺T cells, producing intense tumor-killing effect on mice model with good bio-safety. As a result, the immunological \"cold\" tumor microenvironment of HCC is successfully turned into a \"hot\" one.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissolving microneedles for nucleic acid delivery: A systematic search, review, and data synthesis.","authors":"Carmen I Tobos, Kim A Woodrow","doi":"10.1016/j.actbio.2025.05.025","DOIUrl":"10.1016/j.actbio.2025.05.025","url":null,"abstract":"<p><p>Dissolving microneedles deliver many classes of nucleic acids, overcoming susceptibility to enzymatic cleavage and poor intracellular delivery. Understanding the impact of microneedle formulation on nucleic acid therapeutic efficacy is critical for clinical translation. Here, we performed a systematic search to identify preclinical dissolving microneedle studies that deliver nucleic acid therapeutics including aptamers, DNA enzymes, mRNA, miRNA, plasmid DNA, recombinant viral vectors, and siRNA. This review quantitatively synthesizes preclinical data to identify correlations between microneedle form and function. Factors such as polymer molecular weight and incorporation of a nucleic acid carrier strongly influence mechanical and biological properties, while other design parameters allow for more flexibility. Altogether, 83 % of studies show equivalent or superior efficacy to existing nucleic acid administration routes including topical, subcutaneous, and intramuscular administration. Data especially supports the use of dissolving microneedles for viral and cancer vaccine applications, with a growing body of work exploring their utility for gene silencing. Nonetheless, several knowledge gaps remain. Emerging nucleic acid carrier chemistries that retain efficacy with improved toxicity profiles will define the next generation of formulations. Plasmid DNA and viral vectors show excellent long-term stability in dissolving microneedles, but further characterization is needed for long RNA transcripts. Finally, future work could explore the potential for non-dermal administration routes, as well as co-delivery of nucleic acids with small molecules to leverage synergistic effects. STATEMENT OF SIGNIFICANCE: This review comprehensively, critically, and quantitatively synthesizes preclinical dissolving microneedles for nucleic acid delivery. This approach identifies empirically supported correlations between microneedle form and function, highlighting evidence-based best practices and remaining challenges. The form-function relationships identified in this review will be valuable to those within the immediate microneedle field, as well as more broadly to audiences interested in nucleic acid therapeutics, drug delivery systems, microfabrication, and delivery strategies for low resource settings.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative polarization microscopy as a potential tool for quantification of mechanical stresses within 3D matrices.","authors":"Reza Alavi, Olivier Chancy, Benjamin Trudel, Louise Dewit, Carole Luthold, Léo Piquet, Abdolhamid Akbarzadeh, Michèle Desjardins, Solange Landreville, François Bordeleau","doi":"10.1016/j.actbio.2025.04.052","DOIUrl":"https://doi.org/10.1016/j.actbio.2025.04.052","url":null,"abstract":"<p><p>3D mechanical stresses within tissues/extracellular matrices (ECMs) play a significant role in pathological and physiological processes, making their quantification a necessary step to understand the mechanobiological phenomena. Unfortunately, it is rather challenging to quantify these 3D mechanical stresses due to the highly nonlinear and heterogeneous nature of the fibrous matrix. A number of techniques have been developed to address this challenge, including 3D traction force microscopy (TFM), micropillar devices or microparticle-based force sensors; yet, these techniques come with certain drawbacks. Here, we are presenting quantitative polarization microscopy (QPOL) as a non-invasive and label-free technique to quantify mechanical stresses in 3D matrix without a necessity to assume a matrix material model. Taking collagen as a birefringent material, we demonstrated the correlation between the retardance signals obtained by QPOL and the mechanical parameters associated with the 3D collagen hydrogel, i.e. applied external forces and maximum shear stresses. Using cantilever-collagen systems wherein cantilevers applied external loads on the collagen hydrogel, we showed that the retardance signal within loaded collagen positively correlated with the applied load. Also, the retardance signal values within the collagen hydrogel correlated with the maximum shear stress values derived from computational finite element (FE) models. Finally, we obtained the retardance signals around the spheroids of different contractility levels embedded in collagen hydrogel, and the retardance distribution around the spheroids reflected the stress distribution and applied force. This study provides the framework to use QPOL as a tool for quantification of mechanical stresses within 3D ECM. STATEMENT OF SIGNIFICANCE: Mechanical stresses within the 3D extracellular matrix play an important role during physiological and pathological processes. Quantification of such 3D forces is paramount to our understanding of such phenomena and potentially developing therapeutic interventions based on mechanobiological status of the disease. The existing approaches to quantify these 3D mechanical stresses face certain drawbacks such as high computational cost or introduce discontinuities and alteration within the natural 3D microenvironment of the cells. Here, we provide the framework to use quantitative polarization microscopy (QPOL) as an optical-based, non-invasive and computationally efficient technique to quantify the 3D mechanical stresses within the 3D matrix.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuning energy transport in helical protein nanotubes through side-chain modifications.","authors":"Jiayue Hu, Md Mohaiminul Islam, Jinlong He, Lin Zhang, Ling Liu","doi":"10.1016/j.actbio.2025.05.020","DOIUrl":"10.1016/j.actbio.2025.05.020","url":null,"abstract":"<p><p>Fibrous proteins are widely used as materials due to their biocompatibility, flexibility, and mechanical properties. With advancements in bioelectronics and flexible materials, there is increasing demand for biocompatible materials with tunable thermal conductivity. Understanding the mechanisms of thermal transport in proteins can facilitate the design of biomaterials with tailored thermal properties. In this study, we use non-equilibrium molecular dynamics (NEMD) to investigate how side-chain mass affects thermal transport in α-helix proteins. We analyze four representative residues - glycine (G), alanine (A), leucine (L), and phenylalanine (F) - and demonstrate that variations in side-chain mass significantly influence thermal conductivity. Results show that heavier side chains hinder heat transport, while lighter side chains enhance it. Phonon analysis reveals that side-chain mass primarily affects the properties of low-frequency acoustic and semi-optical phonons, which are critical for energy transfer. These findings provide insights into the design of protein-based biomaterials with customized thermal properties, offering potential applications in bioelectronics, medical devices, and sustainable materials. STATEMENT OF SIGNIFICANCE: This research explores how side chains in α-helix proteins influence their thermal conductivity through the application of molecular dynamics simulations. By analyzing four types of amino acids with differing side-chain masses, the study demonstrates that lighter side chains enhance heat transport, whereas heavier ones diminish it. This work establishes a direct correlation between protein structural features and their thermal properties, providing the groundwork that could enable the engineering of biomaterials with tailored heat conduction capabilities. The findings have implications for applications in bioelectronics, medical devices, and sustainable materials, where precise thermal management is essential, rendering this research highly relevant to scientists and engineers focused on advancing biocompatible materials with specific thermal characteristics.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomaterial-Driven 3D Scaffolds for Immune Cell Expansion toward Personalized Immunotherapy.","authors":"Antonio Minopoli, Giordano Perini, Lishan Cui, Valentina Palmieri, Marco De Spirito, Massimiliano Papi","doi":"10.1016/j.actbio.2025.05.027","DOIUrl":"https://doi.org/10.1016/j.actbio.2025.05.027","url":null,"abstract":"<p><p>Immunotherapy has emerged as a transformative medical approach in recent years, providing novel treatments for cancer eradication, autoimmune disorders, and infectious diseases. Fundamental to the success of therapy is the enrichment of the immune cell population, particularly T cells, natural killer cells, and dendritic cells. However, achieving a robust and long-term proliferation of immune cells is still challenging both in vivo and ex vivo. In vivo expansion leverages the patient's natural microenvironment and regulatory mechanisms through therapeutic interventions like immune checkpoint inhibitors, cytokine therapy, and targeted antibodies. This approach fosters long-term immune memory and sustained protection. In contrast, ex vivo expansion involves isolation, manipulation, and expansion of the immune cells under controlled conditions before reinfusion, allowing for precise control over the process and generating potent immune cell populations. Hydrogels, due to their tunable biomechanical properties, high biocompatibility, and ability to mimic the extracellular matrix, provide an ideal platform for both in vivo and ex vivo immune cell expansion. For instance, hydrogel-based scaffolds or beads can facilitate a controlled and efficient expansion of immune cells ex vivo, whereas injectable and implantable hydrogels can provide innovative solutions for enhancing immune cell activity within the patient supporting prolonged immune cell activity. This review aims to elucidate the importance of hydrogel-based strategies in immune cell expansion, advancing the development of effective, personalized immunotherapies to improve patient outcomes. STATEMENT OF SIGNIFICANCE: This review highlights the transformative potential of hydrogel-based 3D scaffolds in advancing personalized immunotherapy. By integrating in vivo and ex vivo strategies, hydrogels provide an innovative platform to enhance immune cell expansion, addressing critical challenges in immunotherapy. The discussion emphasizes the unique biomechanical and biochemical tunability of hydrogels, enabling precise mimicry of the extracellular matrix to support T cell proliferation, activation, and memory formation. These advances offer scalable, cost-effective solutions for producing high-quality immune cells, contributing to more effective cancer treatments, autoimmune disease management, and infectious disease control. By bridging materials science and immunology, this work underscores the pivotal role of hydrogels in shaping the future of immune-based therapies.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging the microstructure of the arterial wall - ex vivo to in vivo potential.","authors":"B Tornifoglio, C Hughes, F Digeronimo, Y Guendouz, R D Johnston, C Lally","doi":"10.1016/j.actbio.2025.05.022","DOIUrl":"10.1016/j.actbio.2025.05.022","url":null,"abstract":"<p><p>Microstructural imaging enables researchers to visualise changes in the arterial wall, allowing for (i) a deeper understanding of the role of specific components in arterial mechanics, (ii) the observation of cellular responses, (iii) insights into pathological alterations in tissue microstructure, and/or (iv) advancements in tissue engineering aimed at replicating healthy native tissue. In this prospective review, we present various imaging modalities spanning from ex vivo to in vivo applications within arterial tissue. The pros, cons, and sensitivities of these modalities are highlighted. By consolidating the latest advancements in microstructural imaging of arterial tissue, the authors aim for this paper to serve as a guide for researchers designing experiments at various stages. Furthermore, the integration of non-invasive, non-destructive imaging techniques into studies provides an additional layer of microstructural information, enhancing scientific findings, improving our understanding of disease, and potentially enabling earlier or more effective diagnostic capabilities. STATEMENT OF SIGNIFICANCE: Imaging the specific microstructural components of the arterial wall provides critical insights into vascular biology, mechanics, and pathology. It enables the visualisation of key structural components and their roles in arterial function, supports the analysis of cell-matrix interactions, and reveals microarchitectural changes associated with disease progression. This level of specificity also informs the design of biomimetic materials and scaffolds in tissue engineering, facilitating the replication of native arterial properties. By synthesising recent developments in microstructural imaging techniques, this paper serves as a reference for investigators designing experiments across a range of vascular research applications. Moreover, the incorporation of non-invasive, non-destructive imaging methods offers a means to acquire detailed microstructural data without compromising tissue integrity. This enhances the interpretability and translational potential of findings, deepens our understanding of vascular disease mechanisms, and may ultimately contribute to the development of earlier and more precise diagnostic approaches.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of PDMS culture on stem cell differentiation towards definitive endoderm and hepatocytes.","authors":"Christopher T Clark, Yao Wang, Devin C Johnson, Seohyun C Lee, Quinton Smith","doi":"10.1016/j.actbio.2025.05.017","DOIUrl":"10.1016/j.actbio.2025.05.017","url":null,"abstract":"<p><p>The generation of human induced pluripotent stem cell (hiPSC) derivatives for regenerative medicine applications holds tremendous promise in treating various disorders. One critical target includes liver disease, in which the primary curative treatment is a cellular transplant aimed to restore the lost function of hepatocytes. In an effort to improve the differentiation of hiPSC-derived liver tissue, we manipulated the mechanical conditions of endoderm specification through directed perturbation of the cytoskeleton and through 2D substrate culture on viscoelastic materials. Through a combination of qRT-PCR, immunofluorescence staining, and functional assays, we found that mechanical cues can bias endoderm specification in an actomyosin and Yes-associated protein (YAP) dependent manner, unveiling new insights into mechanotransduction in germ layer specification and downstream maturation toward parenchymal cells. STATEMENT OF SIGNIFICANCE: The translational potential of using human induced pluripotent stem cell (hiPSC) derived hepatocytes to therapeutically improve impaired liver function holds great clinical promise. However, challenges remain in efficiently differentiating functional hepatocytes with mature marker expression. In an effort to improve the differentiation efficiency of hepatocytes, the role of early mechanosensing mechanisms was investigated in the specification of hiPSCs to definitive endoderm progenitor populations. Through a combination of cytoskeletal modulation, control of mechanoresponsive, yes-associated protein expression, and culture on physiologically compliant PDMS substrates, we found that soft environments not only improve progenitor specification but also impact the downstream functionality of differentiated hepatocytes. These results contribute to the collective appreciation that mechanical cues are critical in developmental processes.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suspension bioprinted whole intervertebral disc analogues enable regional stiffness- and hypoxia-regulated matrix secretion by primary human nucleus pulposus and annulus fibrosus cells.","authors":"Matthew J Kibble, Miguel J S Ferreira, Yusuf H Usta, Guus G H van den Akker, Samuel R Moxon, Pauline Baird, Judith A Hoyland, Marco A N Domingos, Stephen M Richardson","doi":"10.1016/j.actbio.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.actbio.2025.05.015","url":null,"abstract":"<p><p>Intervertebral disc (IVD) degeneration is a leading cause of back pain, and while studies have revealed the roles resident nucleus pulposus (NP) and annulus fibrosus (AF) cells play in degeneration, tissue-engineered IVD models are needed to better investigate the mechanisms underpinning these cell-driven changes. This study therefore integrated suspension baths with bioprinting to create four multi-material, whole IVD analogues and investigated the combined effect of reduced oxygen tension and increased regional matrix stiffness on disc cell phenotype since these factors correlate with IVD degeneration. Primary NP and AF cells were seeded into alginate-collagen hydrogels and bioprinted into biphasic IVD structures. The nascent area, intensity, and integrated density of pro-collagen type I, collagen type VI, aggrecan, and hyaluronic acid were quantified using immunofluorescence staining in each region. Stiffness-mediated collagen and glycosaminoglycan production was observed in the AF, and increased stiffness downregulated collagen type VI in the AF but upregulated it in NP. Oxygen tension impacted proteoglycan production, with hypoxia increasing aggrecan and hyaluronic acid in both regions. This work represents a step towards the automated biofabrication of whole IVD analogues and expands the state-of-the-art in suspension bioprinting using regionally specific matrix cues. The findings provide important insights into two key microenvironmental factors driving IVD degeneration. STATEMENT OF SIGNIFICANCE: This manuscript outlines an original application of suspended layer additive manufacturing to biofabricate novel, biphasic intervertebral disc analogues containing patient-derived primary human cells. Significantly, the bioprinted models demonstrated biological function and were used to assess the effect of stiffness and oxygen concentration on regional matrix production using a range of internationally-recognized phenotypic intervertebral disc cell markers. The study therefore furthers the state-of-the-art in suspended bioprinting using regionally specific matrix cues and paves the way for future bioprinted disc models that can serve as biosimulators capable of generating insights into key mechanisms governing tissue development, homeostasis, and degeneration.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}