Acta Biomaterialia最新文献

{"title":"Self-assembled aptamer nanoparticles for enhanced recognition and anticancer therapy through a lysosome-independent pathway","authors":"Fangfang Xia ,&nbsp;Qiao Duan ,&nbsp;Qing Zhang ,&nbsp;Wenqi Feng ,&nbsp;Ding Ding ,&nbsp;Ding-Kun Ji ,&nbsp;Xiang Wang ,&nbsp;Weihong Tan","doi":"10.1016/j.actbio.2025.01.037","DOIUrl":"10.1016/j.actbio.2025.01.037","url":null,"abstract":"<div><div>Aptamers and aptamer-drug conjugates (ApDCs) have shown some success as targeted therapies in cancer theranostics. However, their stability in complex media and their capacity to evade lysosomal breakdown still need improvement. To address these challenges, we herein developed a one-step self-assembly strategy to improve the stability of aptamers or ApDCs, while simultaneously enhancing their delivery performance and therapeutic efficiency through a lysosome-independent pathway. This strategy involves the formation of stable complexes between disulfide monomer and aptamers (Sgc8) or ApDCs (Gem-Sgc8). Self-assembled Sgc8 NPs resisted nuclease degradation for up to 24 h, whereas the aptamer alone degraded within just 3 h. These self-assembled Sgc8 NPs, as well as Gem-Sgc8 NPs, demonstrated enhanced binding capabilities compared to Sgc8 aptamers or Gem-Sgc8 alone. Furthermore, lysosome-independent cellular uptake was significantly improved, which in turn increased the therapeutic efficacy of Gem-Sgc8 NPs by 2.5 times compared to Gem-Sgc8 alone. <em>In vivo</em> results demonstrated that Gem-Sgc8 NPs can effectively suppress the growth of tumors. The same self-assembly strategy was successfully applied to other aptamers, such as MJ5C and cMET, showing the generalizability of our method, Overall, this aptamer self-assembly strategy not only overcomes the limitations associated with instability and lysosomal degradation but also demonstrates its broad applicability, highlighting its potential as a promising avenue for advancing targeted cancer theranostics.</div></div><div><h3>Statement of significance</h3><div>We developed a one-step self-assembly strategy to improve the stability of aptamers or ApDCs and enhance their drug therapeutic efficiency through a lysosome-independent pathway. The stability of self-assembled Sgc8 nanoparticles (NPs) was significantly improved. The resulting Sgc8 NPs or GEM-Sgc8 NPs exhibited enhanced binding ability compared to Sgc8 aptamers or GEM-Sgc8 alone, and they also facilitated lysosome-independent cellular uptake, resulting in a 2.5-fold increase in therapeutic efficacy of GEM-Sgc8-NPs. The same self-assembly strategy was successfully applied to other aptamers, such as MJ5C and cMET, showing the generalizability of our method.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"194 ","pages":"Pages 364-372"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043882","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":"Biomineralized and metallized small extracellular vesicles encapsulated in hydrogels for mitochondrial-targeted synergistic tumor therapy","authors":"Qi Zhang ,&nbsp;Ruo-Fei Ma ,&nbsp;Si-Wen Chen ,&nbsp;Ke Cao ,&nbsp;Yue Wang ,&nbsp;Zhang-Run Xu","doi":"10.1016/j.actbio.2025.01.041","DOIUrl":"10.1016/j.actbio.2025.01.041","url":null,"abstract":"<div><div>Targeted organelle therapy is a promising therapeutic method for significantly regulating the tumor microenvironment, yet it often lacks effective strategies for leveraging synergistic enhancement effect. Engineered small extracellular vesicles (sEVs) are expected to address this challenge due to their notable advantages in drug delivery, extended circulation time, and intercellular information transmission. Herein, we prepare sEVs with pH and photothermal dual-responsiveness, which are encapsulated with hydrogels for a quadruple-efficient synergistic therapy. M₁-phenotype macrophages-derived sEVs, which carry cytokines that inhibit tumor progression, were separately encapsulated with calcium phosphates (CaPs) and Au@Pt nanoparticles (Au@Pt NPs), endowing them with pH and photothermal dual-responsiveness. Subsequently, they were assembled into sEV-Au@Pt NPs/CaPs nanohybrids, and functionalized with mitochondria-targeting peptides. Within tumor cells, mitochondrial targeting enhances Ca²⁺ accumulation, resulting in mitochondrial homeostasis imbalance. The release of Pt²⁺ causes nuclear damage and exacerbates mitochondrial dysfunction. Furthermore, under laser irradiation, the sEV-Au@Pt NPs absorb light, generating hyperthermia that promotes the release of Ca²⁺ and Pt²⁺ from the hydrogel and cytokines from the sEVs, thereby achieving a quadruple-efficient synergistic therapy. The hydrogel effectively prolongs the retention time of nanohybrids, aiding in the prevention of tumor recurrence. These nanohybrids exhibit favorable mitochondrial targeting ability, with a Pearson's co-localization coefficient of 0.877. In experimental trials, tumor growth was significantly inhibited after only five treatments, with the tumor volume reduced to 0.16-fold that of the control group. This strategy presents a potential tailored platform for engineered sEVs in mitochondrial-targeted therapy and holds great promise for advancing organelle-targeted therapeutic strategies.</div></div><div><h3>Statement of significance</h3><div>Engineering small extracellular vesicles (sEVs) can significantly enhance the synergistic effects of organelle-targeted therapy, thereby improving therapeutic efficacy and reducing side effects. However, their full development is still pending. In this study, we present a promising strategy that involves engineering sEVs with pH and photothermal dual-responsiveness through biomineralization and metallization, enabling quadruple synergistic tumor therapy. Our study demonstrates the remarkable synergistic effects of mitochondrial homeostasis imbalance caused by Ca²⁺ bursts and nuclear damage due to Pt²⁺ release. After five treatments, the tumor volume in the experimental group was reduced to 0.16-fold that of the control group. This strategy holds great promise for the design of engineered sEVs as organelle-targeted therapeutic systems.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"194 ","pages":"Pages 428-441"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054646","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":"Enhanced nasal-to-brain drug delivery by multivalent bioadhesive nanoparticle clusters for cerebral ischemic reperfusion injury protection","authors":"Yizhen Jia ,&nbsp;Xiaohan Kong ,&nbsp;Rui Li ,&nbsp;Han Wang ,&nbsp;Chujie Li ,&nbsp;Shihong Cheng ,&nbsp;Wei Duan ,&nbsp;Yan Xiao ,&nbsp;Yang Mai ,&nbsp;Wenbin Deng ,&nbsp;Yang Liu","doi":"10.1016/j.actbio.2025.01.036","DOIUrl":"10.1016/j.actbio.2025.01.036","url":null,"abstract":"<div><div>Following cerebral ischemia, reperfusion injury can worsen ischemia-induced functional, metabolic disturbances, and pathological damage upon blood flow restoration, potentially leading to irreversible harm. Yet, there's a dearth of advanced, localized drug delivery systems ensuring active pharmaceutical ingredient (API) efficacy in cerebral protection during ischemia-reperfusion. This study introduces a multivalent bioadhesive nanoparticle-cluster, merging bioadhesive nanoparticles (BNPs) with dendritic polyamidoamine (PAMAM), enhancing nose-to-brain delivery and brain protection efficacy against cerebral ischemia-reperfusion injuries (CIRI). The BNPs-PAMAM cluster exhibits superior adhesion within the rat nasal cavity, prolonged retention, enabling sustained drug release, cerebral transportation, and accumulation, resulting in enhanced intracerebral pharmacokinetic profile. Intranasal administration circumvents systemic delivery challenges, ensuring CIRI protection drugs reach ischemic areas pre-reperfusion, overcoming thrombus-related delays. Administering BNPs-PAMAM loaded with dexmedetomidine (DEX) pre-reperfusion effectively prevents neuron apoptosis by α2-adrenoceptor activation, modulating the ischemic microenvironment, exerting triple neuroprotective effects against cerebral reperfusion injury. Importantly, only therapeutic DEX releases and accumulates in the nasal cavity, averting brain nanomaterial toxicity, promising for repeat administrations. This study presents a translational platform for nasal-to-brain drug delivery in CNS disease treatment.</div></div><div><h3>Statement of Significance</h3><div><strong>Innovative Drug Delivery System:</strong> This study introduces a multivalent bioadhesive nanoparticle-cluster (BNPs-PAMAM) to enhance nasal-to-brain drug delivery for cerebral ischemia-reperfusion injury (CIRI) treatment.</div><div><strong>Enhanced Retention and Efficacy:</strong> The BNPs-PAMAM system significantly improves drug retention in the nasal cavity and ensures sustained release, thereby enhancing the therapeutic efficacy of the neuroprotective agent dexmedetomidine (DEX).</div><div><strong>Blood-Brain Barrier Circumvention:</strong> By leveraging intranasal administration, the system bypasses the blood-brain barrier, delivering DEX directly to ischemic brain regions before reperfusion and minimizing systemic side effects.</div><div><strong>Triple Neuroprotective Effects for CIRI protection:</strong> DEX delivered via BNPs-PAMAM effectively reduces oxidative stress and inflammation while enhancing mitochondrial autophagy, providing comprehensive protection against neuronal damage.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"194 ","pages":"Pages 411-427"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054655","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":"Lung-targeted delivery of PTEN mRNA combined with anti-PD-1-mediated immunotherapy for In Situ lung cancer treatment","authors":"Yue Hu,&nbsp;Xi He,&nbsp;Ping Chen,&nbsp;Xiao-Li Tian,&nbsp;Rong Wang,&nbsp;Xiangrong Song,&nbsp;Xiao-Qi Yu,&nbsp;Ji Zhang","doi":"10.1016/j.actbio.2025.01.040","DOIUrl":"10.1016/j.actbio.2025.01.040","url":null,"abstract":"<div><div>mRNA-based protein replacement therapy has become one of the most widely applied forms of mRNA therapy, with lipid nanoparticles (LNPs) being extensively studied as efficient delivery platforms for mRNA. However, existing LNPs tend to accumulate in the liver or kidneys after intravenous injection, highlighting the need to develop vectors capable of targeting specific organs. In this study, we synthesized a small library of ionizable lipids and identified <strong>PPz-2R₁</strong> as a promising candidate, exhibiting lung-targeting capabilities, high mRNA transfection efficiency, and good stability through structure-activity relationship studies. In an <em>in situ</em> lung cancer model with PTEN deletion, precise delivery of PTEN mRNA to the lungs restored the cancer-suppressing function of the PTEN protein and successfully alleviated the immunosuppressive tumor microenvironment in the lungs by modulating immune cell activity and cytokine levels. Additionally, the upregulation of PD-L1 expression at the tumor site was triggered. Building on this, <em>in vivo</em> treatment with PTEN mRNA combined with anti-PD-1 therapy was tested in tumor-bearing mice. The results demonstrated that the combined treatment strategy effectively overcame immune escape, promoted T cell infiltration, improved survival rates over 60 days, and significantly inhibited tumor growth. Furthermore, the combination treatment was more effective than either therapy alone. This study presents an effective and practical strategy for the targeted treatment of lung diseases and relevant combination therapies.</div></div><div><h3>Statement of significance</h3><div>Lipid nanoparticles (LNPs) have been extensively studied as efficient delivery vectors for mRNA. However, it remains essential to develop vectors that can specifically target distinct organs. In this study, we designed and synthesized a series of piperazine-containing ionizable lipids and their analogues, which were initially explored as lung-targeting vectors for PTEN mRNA delivery. Through screening in both <em>in vitro</em> and <em>in vivo</em> experiments, we found that the leading LNPs-assisted PTEN mRNA-mediated protein supplementation therapy effectively downregulated Treg expression and activated immune cells, thereby reversing the immunosuppressive tumor microenvironment in a mouse model of lung cancer. Furthermore, when combined with anti-PD-1-mediated immunotherapy, the combination therapy exhibited the strongest tumor growth inhibition. This approach offers a novel strategy for the targeted treatment of lung diseases and associated combination therapies.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"194 ","pages":"Pages 442-454"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061730","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":"Development of self-healing hydrogels to support choroidal endothelial cell transplantation for the treatment of early age related macular degeneration","authors":"Narendra G. Pandala ,&nbsp;Ian C. Han ,&nbsp;Lauryn J. Renze ,&nbsp;Hailey J. Steffen ,&nbsp;Emily E. Meyering ,&nbsp;Edwin M. Stone ,&nbsp;Kelly Mulfaul ,&nbsp;Robert F. Mullins ,&nbsp;Budd A. Tucker","doi":"10.1016/j.actbio.2024.12.052","DOIUrl":"10.1016/j.actbio.2024.12.052","url":null,"abstract":"<div><div>In retinal diseases such as age-related macular degeneration (AMD) and choroideremia, a key pathophysiologic step is loss of endothelial cells of the choriocapillaris. Repopulation of choroidal vasculature early in the disease process may halt disease progression. Prior studies have shown that injection of donor cells in suspension results in significant cellular efflux and poor cell survival. As such, the goal of this study was to develop a hydrogel system designed to support choroidal endothelial cell transplantation. A library of hydrogels was synthesized using laminin (i.e., LN111, LN121, and LN421), carboxy methyl chitosan, and oxidized dextran via reversible Schiff base chemistry. Each of the developed self-healing hydrogels was readily injectable into the suprachoroidal space, with ideal gelation, mechanical, and degradation properties. While all hydrogels were found to be compatible with choroidal endothelial cell survival in vitro, only LN111 and LN121 gels were well-tolerated in vivo. To determine if hydrogel mediated cell delivery enhances donor cell retention and survival in vivo, iPSC-derived choroidal endothelial cell laden hydrogels were injected into the suprachoroidal space of an immunocompromised choroidal cell injury rat model. Significantly more donor cells were retained and survived in eyes that received cell laden hydrogels versus contralateral hydrogel free controls. Furthermore, donor cells positive for human nuclear antigen were identified in the choroid of hydrogel eyes only. These findings pave the way for future cell replacement studies in large animal models of choroidal cell dropout focused on evaluating functional integration of donor cells within decellularized vascular tubes.</div></div><div><h3>Statement of significance</h3><div>Age related macular degeneration (AMD) is a leading cause of untreatable blindness in the industrial world. A key pathologic step in AMD is loss of the choriocapillaris endothelial cells, which provide vascular support to the overlying retina. Choroidal cell replacement early in disease may prevent retinal cell death and subsequent vision loss. In this study, we present a strategy for repopulating the choriocapillaris using choroidal endothelial cell laden hydrogels. Specifically, we demonstrate the synthesis and characterization of 3 different laminin-based hydrogel systems. LN111 and LN121 hydrogels were found to have excellent biocompatibility both in vitro and in vivo. Hydrogel mediated delivery of iPSC-derived choroidal endothelial cells enhanced donor cell retention and survival, paving the way for functional large animal studies.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"194 ","pages":"Pages 98-108"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878931","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":"Bioimpedance measurements of fibrotic and acutely injured lung tissues","authors":"Mohammad Mir ,&nbsp;Jiawen Chen ,&nbsp;Aneri Patel ,&nbsp;Meghan R. Pinezich ,&nbsp;Maria R. Hudock ,&nbsp;Alexander Yoon ,&nbsp;Mohamed Diane ,&nbsp;John O'Neill ,&nbsp;Matthew Bacchetta ,&nbsp;Gordana Vunjak-Novakovic ,&nbsp;Jinho Kim","doi":"10.1016/j.actbio.2025.01.039","DOIUrl":"10.1016/j.actbio.2025.01.039","url":null,"abstract":"<div><div>In injured and diseased tissues, changes in molecular and cellular compositions, as well as tissue architecture, lead to alterations in both physiological and physical characteristics. Notably, the electrical properties of tissues, which can be characterized as bioelectrical impedance (bioimpedance), are closely linked to the health and pathological conditions of the tissues. This highlights the significant role of quantitatively characterizing these electrical properties in improving the accuracy and speed of diagnosis and prognosis. In this study, we investigate how diseases, injuries, and physical conditions can affect the electrical properties of lung tissues, using both rat and human lung tissue samples. Results showed that rat lung and trachea tissues exhibit a frequency-dependent behavior to alternating current (AC) across the frequency range of 0.1–300 kHz. The bioimpedance of the lung tissue increased with the level of aeration of the lung, which was manipulated by altering alveolar pressure (PALV: 1–15 cmH2O; bioimpedance level: 1.2–2.8 kΩ; AC frequency: 2 kHz). This increase is mainly because air is electrically nonconductive. The bioimpedance of rat lungs injured via intratracheal aspiration of hydrochloric acid (HCl; volume: 1 mL; AC frequency: 2 kHz) decreased by at least 82 % compared to that of healthy control lungs due to accumulation of fluids inside the airspace of the injured lungs. Moreover, using decellularized lung tissues, we determined the contributions of cellular components and tissue extracellular matrix (ECM) on the electrical characteristics of the lung tissues. Specifically, we observed a considerable increase in bioimpedance in fibrotic human lung tissues due to excessive ECM deposition (healthy: 70.8 Ω ± 10.2 Ω, fibrotic: 132.1 Ω ± 15.8 Ω, frequency: 2 kHz). Overall, the findings of this study can enhance our understanding of the correlation between electrical properties and pathological lung conditions, thereby improving diagnostic and prognostic capabilities and aiding in the treatment of lung diseases and injuries.</div></div><div><h3>Statement of significance</h3><div>The bioelectrical properties of tissue are closely linked to both its physiological and physical characteristics. This underscores the importance of quantitatively characterizing these properties to improve the accuracy and speed of diagnosis and prognosis. In this study, we investigate how the bioelectrical properties of lung tissues are affected by different physical states and pathological conditions using rat and human lung tissues. As the burden of lung diseases continues to increase, our findings can contribute to improved treatment outcomes by enabling accurate and rapid assessment of lung tissue conditions.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"194 ","pages":"Pages 270-287"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054633","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":"The ultrastructure of the starfish skeleton is correlated with mechanical stress","authors":"Raman,&nbsp;Susanna Labisch,&nbsp;Jan-Henning Dirks","doi":"10.1016/j.actbio.2024.12.032","DOIUrl":"10.1016/j.actbio.2024.12.032","url":null,"abstract":"<div><div>Echinoderms and vertebrates both possess mesodermal endoskeletons. In vertebrates, the response to mechanical loads and the capacity to remodel the ultrastructure of the skeletal system are fundamental attributes of their endoskeleton. To determine whether these characteristics are also inherent in Echinoderms, we conducted a comprehensive biomechanical and morphological study on the endoskeleton of <em>Asterias rubens</em>, a representative model organism for Echinoderm skeletons. Our analysis involved high-resolution X-ray CT scans of entire individual ossicles, covering the full stereom distribution along with the attached muscles. Leveraging this data, we conducted finite element analysis to explore the correlation between mechanical loads acting on an ossicle and its corresponding stereom structure. To understand the effects of localized stress concentration, we examined stereom regions subjected to high mechanical stress and compared them to areas with lower mechanical stress. Our results show that the stereom microstructure, both in terms of thickness and orientation, corresponds closely to the mechanical loading experienced by the ossicles. Additionally, by comparing the stereom structures of ossicles in various developmental stages, we assessed the general remodeling capacity of these ossicles. Our findings suggest that the ability to adapt to mechanical loads is a common feature of mesoderm endoskeletons within the Deuterostomia taxonomic group. However, the material remodelling may be a specific trait unique to vertebrate endoskeletons.</div></div><div><h3>Statement of Significance</h3><div>This study shows a correlation between the ultrastructure and the mechanical stress in the starfish endoskeleton, suggesting that this fundamental structure-function relationship may be an ancestral feature of not only vertebrate endoskeletons. However, unlike vertebrate skeletons, not all starfish ossicles remodel in response to changing stress, indicating a potential divergence in skeletal adaptation mechanisms. Our methodological approach combines morphometrics and finite element modeling and thus provides a powerful tool to investigate biomechanics in complex skeletal structures.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"193 ","pages":"Pages 279-290"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the mechanics of networked type II collagen: Experiments, constitutive modeling, and validation","authors":"Phoebe Szarek ,&nbsp;David M. Pierce","doi":"10.1016/j.actbio.2024.12.043","DOIUrl":"10.1016/j.actbio.2024.12.043","url":null,"abstract":"<div><div>In this study we investigate the mechanics of type II collagen fibrils, an essential structural component in many load-bearing tissues including cartilage. Although type II collagen plays a crucial role in maintaining tissue integrity, the stress–stretch and failure response of type II collagen fibrils in tension is not established in the current mechanics literature. To address this knowledge gap, we conducted tensile tests on isolated collagen networks from articular cartilage and established a validated constitutive model for type II collagen fibril. We identified two distinct failure mechanisms: one without softening before failure and another with pronounced softening. Our findings reveal that network morphology significantly influences the bulk mechanical response, providing a framework for modeling the complex behavior of collagen fibrils in both healthy and diseased tissues. The validated model enhances the accuracy of finite element models used in analyses of soft tissues and may deepen our understanding of the mechanical progression of diseases like osteoarthritis. Our results offer valuable insights into the mechanics of type II collagen, with implications for improving computational models and for guiding future studies in tissue regeneration and disease treatment.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"193 ","pages":"Pages 267-278"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960191","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":"A bacteria-responsive nanoplatform with biofilm dispersion and ROS scavenging for the healing of infected diabetic wounds","authors":"Yin Zheng ,&nbsp;Mingyue Wang ,&nbsp;Xinge Zhang ,&nbsp;Zhongming Wu ,&nbsp;Ling Gao","doi":"10.1016/j.actbio.2024.12.042","DOIUrl":"10.1016/j.actbio.2024.12.042","url":null,"abstract":"<div><div>Delayed wound healing in patients with diabetes remains a major health challenge worldwide. Uncontrolled bacterial infection leads to excessive production of reactive oxygen species (ROS) and persistent inflammatory responses, which seriously hinder conventional physiological healing processes after injury. Biofilms, as protective barriers for bacteria, pose a critical obstacle to effective bacterial eradication. Herein, an innovative therapeutic nanoplatform with <em>in situ</em> antibacterial and antioxidant properties is developed for enhancing infected diabetic wound healing. The enrichment of phenylboronic acid (PBA) moieties on the nanoplatform enhances biofilm penetration, actively anchors and aggregates the enclosed bacteria through the \"multivalent effect\", with an anchoring efficiency as high as 80 %. Additionally, glycine moieties on the nanoplatform ensure spatial extensibility by charge repulsion, enabling targeted antibiotic release around bacteria. This precise antibacterial effect increases the bactericidal activities of the nanoplatform against <em>S. aureus</em> or <em>P. aeruginosa</em> by 25 % and 22 % respectively, effectively eliminating the bacteria and dispersing the biofilms. Furthermore, 3,4-dihydropyrimidin-2(1H)-one (DHPM) moieties act as ROS scavengers that alleviate oxidative stress and inflammatory responses, promoting tissue repair progression into the proliferative phase characterized by increased extracellular matrix deposition, angiogenesis, and granulation tissue formation, ultimately accelerating diabetic wound healing. Overall, this work presents an innovative bacterial response strategy for achieving <em>in situ</em> antibacterial and antioxidant effects in infected tissues and provides a promising therapeutic approach for treating infected diabetic wounds.</div></div><div><h3>Statement of significance</h3><div>Infected diabetic wound management remains a major world health issue. Severe bacterial infection leads to excessive oxidative stress and persistent inflammatory response, which seriously hinders the wound healing process. As a protective barrier for bacteria, biofilms are a key obstacle to effective bacterial clearance. This study provides a bacteria-responsive nanoplatform for the healing of infected diabetic wounds. The nanoplatform not only exhibits improved biofilm penetration but also actively anchors the enclosed bacteria and enables targeted antibiotic release to disperse the biofilm. The DHPM moieties of the nanoplatform act as ROS scavengers which could alleviate inflammatory responses, promote tissue repair progression into the proliferative phase, and ultimately accelerate diabetic wound repair.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"193 ","pages":"Pages 545-558"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878926","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":"A GSH-responsive oxidative stress nanoamplifier for self-augmented chemo/chemodynamic therapy to reverse cisplatin resistance","authors":"Yanjuan Huang ,&nbsp;Meng Xia ,&nbsp;Congjun Xu ,&nbsp;Zijun Lin ,&nbsp;Meixu Chen ,&nbsp;Xianmin Shi ,&nbsp;Yaqing Ding ,&nbsp;Yan Xiao ,&nbsp;Chunshun Zhao","doi":"10.1016/j.actbio.2024.12.041","DOIUrl":"10.1016/j.actbio.2024.12.041","url":null,"abstract":"<div><div>Drug resistance and off-target toxicity of cisplatin (CDDP) pose significant challenges in effectively treating non-small cell lung cancer (NSCLC). Recently, chemodynamic therapy (CDT), an emerging reactive oxygen species (ROS)-mediated tumor-specific therapeutic modality, has shown great potential in sensitizing multidrug resistance tumor cells. Herein, a glutathione (GSH)-responsive Pt(IV) prodrug-based oxidative stress nanoamplifier (CuBSO@Pt_C16) was developed for effective chemo/chemodynamic therapy to reverse CDDP resistance in NSCLC. CuBSO@Pt_C16, a lipid-coated nanoagent, was constructed by coordinating Cu²⁺ with l-buthioninesulfoximine (BSO) as the core framework, and Pt(IV) prodrug (Pt_C16) was concurrently loaded on the outer lipid bilayer. With appropriate particle size (∼35 nm) and good physiological stability, CuBSO@Pt_C16 efficiently accumulated at tumor tissue. Under high intracellular GSH levels, Pt_C16 was reduced to generate cytotoxic CDDP that induced cell-killing and boosted intracellular H₂O₂ levels, and the CuBSO core was disassembled to release Cu ions and BSO simultaneously. The released BSO could efficiently reduce the intracellular GSH content to weaken its detoxification effect on CDDP, leading to more Pt-DNA adduct formation and more severe DNA damage. Meanwhile, Cu ions catalyzed the intracellular elevated H₂O₂ into highly lethal •OH through Fenton-like reactions, and the reduction of GSH weakened the •OH elimination, which jointly amplified the intracellular oxidative stress levels, finally achieving enhanced chemo/chemodynamic therapeutic effect and reversing CDDP resistance in NSCLC. Therefore, this work offers an inspirational idea for effectively treating drug-resistant cancers.</div></div><div><h3>Statement of significance</h3><div>Cisplatin (CDDP) faces challenges in treating non-small cell lung cancer (NSCLC) due to drug resistance and off-target toxicity. Herein, a GSH-responsive nanoreactor (CuBSO@Pt_C16) was developed for effective chemo/chemodynamic therapy to address CDDP resistance. CuBSO@Pt_C16 could efficiently traffic to tumor site and response to high GSH levels in tumor cells to release CDDP, Cu ions and buthioninesulfoximine (BSO) simultaneously. CDDP could induce DNA damage and boost intracellular H₂O₂ levels, which then served as the substrate of Cu to induce •OH generation through Fenton-like reactions. Meanwhile, the released BSO efficiently reduced the intracellular GSH content to weaken its detoxification effect on CDDP and the elimination of the •OH, leading to amplified intracellular oxidative stress and more severe damage to induce cell death.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"193 ","pages":"Pages 440-454"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873573","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}