Acta Biomaterialia最新文献

{"title":"Simultaneous measurement of tensile and shear elasticity and anisotropy in human skeletal muscle tissue using steered ultrasound shear waves","authors":"Ricardo J. Andrade ,&nbsp;Apolline Racapé ,&nbsp;Mar Hernández-Secorún ,&nbsp;Ha-Hien-Phuong Ngo ,&nbsp;Alice Lemoine ,&nbsp;Nicolas Etaix ,&nbsp;Thomas Frappart ,&nbsp;Christophe Fraschini ,&nbsp;Jean-Luc Gennisson ,&nbsp;Antoine Nordez","doi":"10.1016/j.actbio.2025.05.010","DOIUrl":"10.1016/j.actbio.2025.05.010","url":null,"abstract":"<div><div>Load-bearing skeletal muscle tissues are reinforced by intricate networks of protein fibers aligned in preferential orientations, imparting direction-dependent mechanical properties (anisotropy). Characterizing this anisotropy <em>in vivo</em> is essential for understanding both normal and pathological muscle function, as well as structural integrity. However, current noninvasive techniques are limited in their ability to accurately measure the mechanical properties of anisotropic tissues such as skeletal muscle. Here, we used an innovative angle-resolved ultrasound elastography method, recently developed by our team, to simultaneously quantify tensile and shear elasticity and anisotropy, enabling comprehensive assessment of muscle biomechanics. We fully characterized the mechanical properties of the <em>biceps brachii</em> in fourteen healthy young adults under passive and active axial loadings, revealing distinct shear and tensile mechanical behaviors both along and across muscle fibers. Notably, tensile and shear moduli along the main fiber orientation were found to be uncoupled, while cross-muscle fiber measurements exhibited a consistent modulus ratio of 3.4 ± 0.2, regardless of axial loading conditions or intensities. These findings highlight the anisotropic nature of skeletal muscle and provide valuable insights into its <em>in vivo</em> mechanical behavior. Both shear and tensile anisotropy increased with muscle axial physiological loading, indicating that our method is sensitive to changes in anisotropic tissue mechanics. Lastly, we demonstrated that angle-resolved ultrasound shear wave elastography provides direct estimates of shear and tensile properties, offering significant promise for clinical applications, including neuromuscular disease diagnostics and monitoring, biomechanical modeling for predicting tissue responses to loading and therapies, and tissue engineering.</div></div><div><h3>Statement of significance</h3><div><strong>:</strong> Conventional ultrasound shear wave elastography techniques overlook the anisotropy of skeletal muscles, leading to incomplete tissue mechanical characterization. In this study, we leveraged an innovative angle-resolved elastography method to assess tensile and shear elasticity, along with their anisotropic factors, of human muscle <em>in vivo</em>. For the first time, we reveal the intricate relationships between tensile and shear elasticities during active and passive physiological loading. This technique enhances our understanding of muscle mechanics and has promising clinical implications for muscle health and neuromuscular disease management, where tissue structural and mechanical properties are often altered. Additionally, it could help in developing constitutive models for muscle tissue and contribute to the design of tissue-engineered materials.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 217-229"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shape-adaptive, deformable and adhesive hydrogels enable stable closure of long incision wounds","authors":"Xiaojun Zeng ,&nbsp;Wenguang Dou ,&nbsp;Shuzhuang Zhu ,&nbsp;Ye Zhu ,&nbsp;Weijun Ji ,&nbsp;Mingxue Sun ,&nbsp;Jin Zhao ,&nbsp;Xubo Yuan ,&nbsp;Hongliang Liu ,&nbsp;Yansheng Li ,&nbsp;Yonglin Gao ,&nbsp;Sidi Li","doi":"10.1016/j.actbio.2025.04.045","DOIUrl":"10.1016/j.actbio.2025.04.045","url":null,"abstract":"<div><div>Effective closure of long incision wounds is crucial in clinical practice but remains challenging for existing bioadhesives due to the deformations of the long incisions. Herein, we propose a concept of shape-adaptive adhesion and achieve it by designing a class of shape-adaptive, deformable adhesive hydrogels (DAHs) for long incision wound closure. The design strategy is facile yet universally applicable, which involves aldehyde polysaccharides as adhesive primers and microgel-type gelators as building blocks. We demonstrate that the microgel-type gelators are responsible for the integration of a deformable matrix in situ, and aldehyde polysaccharides enhance the adhesive performance of the matrix at cost of a little deformability. Optimization of the flexibility of DAH network is effective in balancing the adhesive and deformable properties, thus developing DAHs featured with the adaptability to irregular shapes, robust adhesive properties, and appropriate deformability. As a result, DAHs achieve shape-adaptive adhesion by effectively bonding the long incision and deforming with it without failure. In vivo results clearly show that DAHs stably close the 4 cm-long incision wounds on the backs and the more dynamic incisions on the napes of rats. The shape-adaptive adhesion achieved by DAHs may provide an alternative way for long incision wound treatment.</div></div><div><h3>Statement of significance</h3><div>Bioadhesive is emerging as an effective tool in clinical wound treatment. However, the closure of severe long incision wounds by currently available bioadhesives is still challenging. In this work, we proposed a concept of shape-adaptive adhesion and accordingly developed a bioadhesive building strategy for long incision wound closure. The strategy is universally applicable, which involves aldehyde polysaccharide as an adhesive primer and microgel-type gelators as building blocks. The results showed that the strategy is effective in developing bioadhesives (DAHs) that simultaneously possess shape-adaptive properties, robust adhesive properties and appropriate deformability, thus overcoming the limitations of most existing bioadhesives. With these features, DAHs successfully achieved shape-adaptive adhesion and stable closure of long incision wounds, providing an effective way for wound treatment.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 74-89"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Invasive phenotypes of triple-negative breast cancer-associated fibroblasts are mechanosensitive, AhR-dependent and correlate with disease state","authors":"Gabrielle Brewer ,&nbsp;Paul Savage ,&nbsp;Anne-Marie Fortier ,&nbsp;Hong Zhao ,&nbsp;Alain Pacis ,&nbsp;Yu-Chang Wang ,&nbsp;Dongmei Zuo ,&nbsp;Monyse de Nobrega ,&nbsp;Annika Pedersen ,&nbsp;Camille Cassel de Camps ,&nbsp;Margarita Souleimanova ,&nbsp;Valentina Muñoz Ramos ,&nbsp;Jiannis Ragoussis ,&nbsp;Morag Park ,&nbsp;Christopher Moraes","doi":"10.1016/j.actbio.2025.04.061","DOIUrl":"10.1016/j.actbio.2025.04.061","url":null,"abstract":"<div><div>Cancer associated fibroblasts (CAFs) play a critically important role in facilitating tumour cell invasion during metastasis. They also modulate local biophysical features of the tumour microenvironment through the formation of fibrotic foci, which have been correlated with breast cancer aggression. However, the impact of the evolving three-dimensional biophysical tumour microenvironment on CAF function remains undefined. Here, by isolating CAFs from primary human triple-negative breast cancer tissue at the time of surgery, we find that their ability to remodel the local microenvironment and invade into a three-dimensional matrix correlates with disease state. We then engineered culture models to systematically deconstruct and recreate mechanical tissue features of early breast cancer fibrotic foci; and demonstrate that invasion is mechanically-activated only in CAFs from patients with no detectable pre-existing metastases, but is independent of mechanical cues in CAFs isolated from patients with later-stage axillary lymph node metastases. By comparing the differential transcriptional response of these cells to microenvironmental tissue stiffness, we identify the aryl hydrocarbon receptor (AhR) as being significantly upregulated in invasive sub-populations of both mechanically-activated and mechanically-insensitive CAFs. Increasing AhR expression in CAFs induced invasion, while suppressing AhR significantly reduced invasion in both mechanically-activated and mechanically-insensitive CAF populations, even on stiffnesses that recapitulate late-stage disease. This work therefore uses mechanobiological analyses to identify AhR as a mediator of CAF invasion, providing a potential stratification marker to identify those patients who might respond to future mechanics-based prophylactic therapies, and provides a targetable mechanism to limit CAF-associated metastatic disease progression in triple-negative breast cancer patients.</div></div><div><h3>Statement of Significance</h3><div>By designing a mechanically-tunable tissue-engineered model of fibroblastic foci, and using this to culture patient-derived cancer-associated fibroblasts, we demonstrate that these cells are differentially mechanosensitive, depending on disease stage of the patient. While comparing transcriptomic profiles of patient-derived cells produces too many pathways to screen, identifying the pathways activated by local tissue mechanics that were common across each patient allowed us to identify a specific target to limit fibroblast invasion. This broad discovery strategy may be useful across a variety of biomaterials-based tissue engineered models; and these specific findings suggest (1) a strategy to identify patients who might respond to CAF- or matrix-targeting therapies, and (2) a specific actionable target to limit CAF-associated metastatic disease progression.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 202-216"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming by chemo-gene co-delivery nanoparticles for chemo-immunotherapy in head and neck squamous cell carcinoma","authors":"Wenqing Zou ,&nbsp;Bingyue Huo ,&nbsp;Yaqin Tu ,&nbsp;Yuhe Zhu ,&nbsp;Yuwei Hu ,&nbsp;Qianru Li ,&nbsp;Xuan Yu ,&nbsp;Bo Liu ,&nbsp;Wei Tang ,&nbsp;Songwei Tan ,&nbsp;Hongjun Xiao","doi":"10.1016/j.actbio.2025.04.031","DOIUrl":"10.1016/j.actbio.2025.04.031","url":null,"abstract":"<div><div>The therapeutic effects of platinum-based drugs are closely linked to the dysregulation of tumor metabolic-immune microenvironment, particularly aberrant lactate accumulation. Herein, we engineered multifunctional nanoparticles (PPPt^IV NPs) through electrostatic self-assembly of poly(β-amino ester) to co-encapsulate a cisplatin prodrug (Pt^IV) and CRISPR/Cas9-PKM2 plasmids. Mechanistically, PPPt^IV NPs efficiently entered cells via endocytosis, followed by escape from lysosomal degradation and cargo release. The reduction of Pt^IV prodrug to active Pt^II via GSH depletion induced DNA damage and ROS upregulation, thereby triggering apoptosis. Concurrently, CRISPR/Cas9-mediated PKM2 knockdown suppressed the Warburg effect, resulting in reduced lactate production and downregulated expression of HIF-1α and PD-L1. These alterations drove immune microenvironment remodeling through enhanced dendritic cell maturation, polarized M1 macrophages, and altered cytokine profiles (characterized by upregulation of IFN-γ, TNF-α, and IL-12 alongside suppression of IL-10), ultimately activating T cell-mediated antitumor immunity. Compared to conventional cisplatin, PPPt^IV NPs demonstrated superior efficacy against both primary and recurrent tumors while reducing nephrotoxicity through synergistic chemo-immunotherapeutic effects, offering a valuable strategy for HNSCC treatment.</div></div><div><h3>Statement of significance</h3><div>This study engineered an innovative nanoplatform (PPPt^IV) that synergistically integrates a Pt^IV prodrug with a CRISPR/Cas9-PKM2 plasmid for treating head and neck squamous cell carcinoma. By simultaneously enhancing DNA damage and reversing lactate-mediated immunosuppression, PPPt^IV nanoplatform achieved chemo-immunotherapy that showed greater suppression of primary and recurrent tumors with reduced renal toxicity compared to cisplatin. This nanotechnology-driven strategy provides valuable insights into the combination of platinum-based drugs with immunometabolic interventions.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 361-373"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantum sensing to monitor changes in free radical generation by intracellular vesicles of polarized macrophages","authors":"Aldona Mzyk ,&nbsp;Claudia Reyes-San-Martin ,&nbsp;Yasemin Doğan ,&nbsp;Willem Woudstra ,&nbsp;Yue Zhang ,&nbsp;Ezgi Yilmaz ,&nbsp;Reinier Bron ,&nbsp;Willy de Haan-Visser ,&nbsp;Kirstine Berg-Sorensen ,&nbsp;Romana Schirhagl","doi":"10.1016/j.actbio.2025.04.024","DOIUrl":"10.1016/j.actbio.2025.04.024","url":null,"abstract":"<div><div>Macrophages are immune cells crucial in clearing our tissues from bacteria, viruses, dying cells, cell debris and other waste products. They also regulate inflammation by differentiating from non-activated (M0) cells into macrophages that initiate inflammation (pro-inflammatory macrophages, M1), or resolve inflammation (anti-inflammatory macrophages, M2). One of their key functions is to ingest pathogens within vesicles where they are degraded. The production of free radical (FR) plays an important role in this degradation process but also in macrophage differentiation and signaling. Here we used diamond-based quantum sensing to track free radical changes in vesicles with nanoscale resolution. We further followed the oxidative stress status, through free radical measurement during the macrophage activation process. We found that the three macrophage subtypes differed significantly in free radical generation in their vesicles. Additionally, we showed that the FR generation evolves over time in the different subtypes. We observed a 50 % increase in radical production in M0 after 24 h compared to the T1 values measured after 4 h of cell culture, a decrease in M1 and constant radical levels in M2 macrophages.</div></div><div><h3>Statement of significance</h3><div>Here we use quantum sensing for the first time to investigate the role that free radicals play in immune cells when they differentiate to fulfill their functions in the immune system. We were able to measure free radical generation specifically in vesicles while the macrophages differentiated.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 315-323"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","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 ,&nbsp;Rui Li ,&nbsp;Shiyang Jin ,&nbsp;Yuhang Tian ,&nbsp;Chunyue Wang ,&nbsp;Yucao Sun ,&nbsp;Zhifei Dai ,&nbsp;Wen Cheng","doi":"10.1016/j.actbio.2025.05.029","DOIUrl":"10.1016/j.actbio.2025.05.029","url":null,"abstract":"<div><div>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⁺ <em>T</em> 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.</div></div><div><h3>Statement of significance</h3><div>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⁺ <em>T</em> 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.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 387-397"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RGD peptide hydrogel downregulates mechanosignal YAP to inhibit postoperative scarring","authors":"Yao Lv ,&nbsp;Licheng Liang ,&nbsp;Mian Qin ,&nbsp;Ru-Ping Jiang ,&nbsp;Fei-Fei Zong ,&nbsp;Xia Wu ,&nbsp;Kai-Li Wu ,&nbsp;Liang Liang","doi":"10.1016/j.actbio.2025.04.059","DOIUrl":"10.1016/j.actbio.2025.04.059","url":null,"abstract":"<div><div>Objective: Glaucoma filtration failure may result from an overabundance of human Tenon's capsule fibroblasts (HTFs) forming a filtration tract scar. Conversely, the Yes-associated protein (YAP), a transcriptional activator of the Hippo signaling pathway, is a crucial matrix stiffness regulator of matrix production and fibroblast activation. With superior biocompatibility and biodegradability, RGD peptide hydrogels imitate the structure of real tissues' extracellular matrix (ECM). The purpose of this research was to determine whether down-regulating YAP expression via RGD peptide hydrogels may prevent HTFs activation and ECM protein secretion. Transforming growth factor-β2 (TGF-β2) was used to induce the activation of HTFs in a cellular model of scarring following glaucoma filtration surgery. Utilizing SD rats, a murine model of subconjunctival injury was established. The shape of collagen fibers was observed through Masson staining, and the expression of YAP and α-smooth muscle actin (α-SMA) was identified through immunohistochemistry. RGD peptide hydrogel was discovered to have anti-scarring properties in a mouse eye injury model, as well as the ability to lessen HTFs activation, YAP expression, cytosolic nucleus accumulation, and the expression of connective tissue growth factor (CTGF) and ECM proteins. The best concentration was found to be 1.0 weight percent among them. This concentration not only makes it easier to inject a drug subconjunctivally <em>in vivo</em> and maintain the filtration vesicle space in the conjunctiva, but it also inhibits the activation of fibroblasts into myofibroblasts and down-regulates the expression of the Hippo-YAP signaling pathway in Tenon's capsule fibroblasts.</div></div><div><h3>Statement of significance</h3><div>1. The homogenous reticular three-dimensional nanostructure that made up the interior structure of the 1.0 weight percent gel had good drug delivery characteristics for long-lasting controlled drug release.</div><div>2. RGD peptide hydrogel had a certain matrix hardness, which could mimic the normal connective tissue hardness under the conjunctiva.</div><div>3. RGD peptide hydrogels could prevented the development of rat conjunctival fibrosis.</div><div>4. RGD peptide hydrogel could inhibit the expression of YAP and its target gene CTGF, as well as α-SMA, ECM proteins in HTFs.</div><div>5. RGD peptide hydrogel has good biocompatibility, biodegradability, and stable mechanical properties, and can also be used as a promising carrier for the controlled release of drugs.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 132-141"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the osteosarcoma microenvironment: Multiscale analysis of structural and mineral heterogeneity","authors":"Francesca Rossi ,&nbsp;Martyna Malgorzata Rydzyk ,&nbsp;Luisa Barba ,&nbsp;Emil Malucelli ,&nbsp;Maria Elisabetta Federica Palamà ,&nbsp;Chiara Gentili ,&nbsp;Maddalena Mastrogiacomo ,&nbsp;Alessia Cedola ,&nbsp;Lucia Mancini ,&nbsp;Murielle Salomé ,&nbsp;Hiram Castillo-Michel ,&nbsp;Davide Maria Donati ,&nbsp;Marco Gambarotti ,&nbsp;Enrico Lucarelli ,&nbsp;Michela Fratini ,&nbsp;Stefano Iotti","doi":"10.1016/j.actbio.2025.04.057","DOIUrl":"10.1016/j.actbio.2025.04.057","url":null,"abstract":"<div><div>Osteosarcoma (OS) is a malignant and heterogeneous disease that typically originates in the long bones of children and adolescents. It is characterized by the presence of immature cells having an aggressive phenotype and rapid uncontrolled proliferation. OS progression induces significant molecular and cellular changes locally within the bone, resulting in the development of an abnormal tumor microenvironment (TME). The OS TME plays a crucial role in tumor progression and development, however, the precise effects of OS on bone structure and mineralization still remain poorly understood. In this study, we examined the OS TME by analyzing samples from osteoblastic, parosteal, and periosteal osteosarcomas. Employing advanced synchrotron-based X-ray techniques, we performed a multiscale analysis to evaluate the structural and mineral complexity of tumor-affected bone. Our results revealed marked morphological differences among the osteosarcoma subtypes, while confirming that biomineralization remains active through the production of hydroxyapatite (HA). X-ray diffraction identified two distinct hydroxyapatite crystalline phases across all samples, suggesting a critical behavior of minerals in bone. Additionally, we observed that the bone mineral structure in periosteal and parosteal osteosarcomas exhibited crystal deformations along the c-axis, whereas the osteoblastic osteosarcoma displayed a mineral profile comparable to control bone. Micro-X-ray absorption near-edge spectroscopy revealed the occurrence of a dysregulated biomineralization in the parosteal and periosteal subtypes, marked by the presence of calcium compounds different from HA, in contrast to the mature mineral state found in the osteoblastic variant. These findings highlight the complexity of osteosarcoma repercussion on bone tissue, offering new insights into the interactions within the OS TME.</div></div><div><h3>Statement of Significance</h3><div>This study investigates the tumor microenvironment (TME) of osteosarcoma (OS), a rare and aggressive bone cancer mainly affecting children and adolescents. Using advanced synchrotron-based X-ray techniques, we analyzed structural and mineral alterations in bone from three OS subtypes: osteoblastic, parosteal, and periosteal. The results reveal distinct subtype-specific differences in bone mineralization and crystallinity, highlighting the heterogeneity of OS and the pivotal role of its microenvironment in driving disease progression. This research contributes to our understanding of OS pathophysiology and provides foundation for future studies aimed at developing targeted therapies and improving diagnostic approaches.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 193-201"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biodegradable Zn-Li-Mn alloy to achieve optimal strength and ductility for bone implants","authors":"Danni Shen ,&nbsp;Yahong Li ,&nbsp;Jiahui Shi ,&nbsp;Ting Zhang ,&nbsp;Jing-Jun Nie ,&nbsp;Dafu Chen ,&nbsp;Dandan Xia ,&nbsp;Yufeng Zheng","doi":"10.1016/j.actbio.2025.04.056","DOIUrl":"10.1016/j.actbio.2025.04.056","url":null,"abstract":"<div><div>Biodegradable zinc-based metals have received attention due to their strength, biodegradability, and desirable biocompatibility. However, the trade-off between strength and ductility has limited their use. Here, we designed a biodegradable Zn-Li-Mn ternary alloy with superior strength and ductility. The ultimate tensile strength (UTS) of Zn-0.4Li-xMn (<em>x</em> = 0.1, 0.4, and 0.8) alloys reached 438.74–469.96 MPa, similar to pure Ti, with elongation reaching 41.52%–54.91%, surpassing other Zn-Li-based alloys. We investigated the biodegradation behavior and osteogenic effects of the Zn-Li-Mn alloys both <em>in vitro</em> and <em>in vivo</em>. Immersion tests demonstrated that the alloys exhibited a more uniform degradation morphology with significantly less release of Zn²⁺ ion compared to pure Zn. Cytocompatibility, hemocompatibility, and histological analyses demonstrated their biosafety. In addition, Zn-Li-Mn alloy extracts significantly enhanced osteogenesis of human bone marrow-derived mesenchymal stem cells (hBMSCs), manifesting higher alkaline phosphatase activity, increased biomineralization, and elevated osteogenic gene expression. Zn-0.4Li-0.8Mn alloy showed the highest osteogenic activity <em>in vitro</em>. When implanted in rat femoral condyles, it demonstrated improved <em>in vivo</em> bone regeneration effects, exhibiting enhanced osteointegration. Transcriptomic analysis revealed that Zn²⁺, Mn²⁺, and Li⁺ ions released from Zn-Li-Mn alloy collectively activated the MAPK-ERK and Wnt/β-catenin signaling pathways, prompting osteogenic differentiation. These findings demonstrate the high potential of the Zn-0.4Li-0.8Mn alloy for bone implants.</div></div><div><h3>Statement of Significance</h3><div>1. Biodegradable Zn-Li-Mn ternary alloy with superior mechanical strength and excellent ductility were designed. 2. Enhanced osteointegration were observed in Zn-0.4Li-0.8Mn implants <em>in vivo</em>. 3. Transcriptomic analysis revealed that the Zn²⁺, Mn²⁺, and Li⁺ released from Zn-0.4Li-0.8Mn collectively activated the MAPK-ERK and Wnt/β-catenin signaling pathways, enhancing osteogenesis.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 483-499"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterising epi-perineurial barrier function by microscale techniques including a miniaturised Ussing chamber","authors":"SM Krug ,&nbsp;IM Lee ,&nbsp;L Knobe ,&nbsp;B Hartmannsberger ,&nbsp;MS Atalla ,&nbsp;HL Rittner ,&nbsp;M Fromm","doi":"10.1016/j.actbio.2025.04.043","DOIUrl":"10.1016/j.actbio.2025.04.043","url":null,"abstract":"<div><div>Barriers of peripheral nerves, like the sciatic nerve, are complex structures, consisting of the inner endoneurial capillary barriers and the outer epi‑ and perineurial layers. The latter two, collectively also known as epi‑perineurium (EPN), are necessary for maintenance of the nerve homeostasis. However, the involvement of the EPN in altered nerve conduction in neuropathy is not well-understood. To date, reliable data on barrier properties and ion permeabilities have been limited by the difficulty of accessing the barrier experimentally. For analysing the EPN of rat sciatic nerves, we developed a preparation technique and a miniaturised (area 0.6 mm²), though edge damage-free, Ussing chamber. Electrophysiological characterisation included measurement of transepiperineurial resistance, differentiation of para- and transcellular contributions to this by two-path impedance spectroscopy and determination of permeabilities for flux markers and for ions by dilution and bi-ionic potential measurements.We found the EPN being definable as tight and responsive to changes in the gradients between the endoneurial and the extra-nerval compartment. In a rat model of bortezomib (Bortezomib)-induced polyneuropathy, we demonstrate the EPN to be impaired with a specific increase in potassium permeability, which normalises with the recovery of the animals.In conclusion, we present an advanced, dependable method to analyse the EPN, which can be extended to other microscale epi‑ or endothelia. Functionally, we demonstrate with this technique that the EPN forms a crucial and specific barrier to maintain ion gradients within the sciatic nerve.</div></div><div><h3>Statement of significance</h3><div>We developed a miniaturized Ussing chamber allowing precise electrophysiological analysis of microscale barrier tissues, avoiding edge damage and experimental interferences. Using this, we characterized the epi‑perineurium (EPN) barrier of sciatic nerves, demonstrating it to be a tight and responsive barrier, essential for maintaining ion balance within that nerve. In a neuropathy model, we identified impaired potassium permeability during hyperalgesia, which normalized with recovery. Beyond the EPN, this method is broadly applicable to other previously inaccessible microscale barriers, enabling advanced studies of barrier (patho)physiology. Our work bridges biomaterial development and tissue barrier research, providing detailed insights into ion and solute transport, and may be used to study regulatory mechanisms and the subsequent development of potential therapeutic strategies such as targeted drug delivery across these barrier tissues.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"199 ","pages":"Pages 290-300"},"PeriodicalIF":9.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}