Acta Biomaterialia最新文献

{"title":"Ionic medicine: Exploiting metallic ions to stimulate skeletal muscle tissue regeneration","authors":"Hsuan-Heng Lu ,&nbsp;Duygu Ege ,&nbsp;Sahar Salehi ,&nbsp;Aldo R. Boccaccini","doi":"10.1016/j.actbio.2024.10.033","DOIUrl":"10.1016/j.actbio.2024.10.033","url":null,"abstract":"<div><div>The regeneration of healthy and functional skeletal muscle at sites of injuries and defects remains a challenge. Mimicking the natural environment surrounding skeletal muscle cells and the application of electrical and mechanical stimuli are approaches being investigated to promote muscle tissue regeneration. Likewise, chemical stimulation with therapeutic (biologically active) ions is an emerging attractive alternative in the tissue engineering and regenerative medicine fields, specifically to trigger myoblast proliferation, myogenic differentiation, myofiber formation, and ultimately to promote new muscle tissue growth. The present review covers the specialized literature focusing on the biochemical stimulation of muscle tissue repair by applying inorganic ions (bioinorganics). Extracting information from the literature, different ions and their potential influence as chemical cues on skeletal muscle regeneration are discussed. It is revealed that different ions and their varied doses have an individual effect at different stages of muscle cellular development. The dose-dependent effects of ions, as well as applications of ions alone and in combination with biomaterials, are also summarized. Some ions, such as boron, silicon, magnesium, selenium and zinc, are reported to exhibit a beneficial effect on skeletal muscle cells in carefully controlled doses, while the effects of other ions such as iron and copper appear to be contradictory. In addition, calcium is an essential regulatory ion for the differentiation of myoblasts. On the other hand, some ions such as phosphate have been shown to inhibit muscle cell behavior. This review thus provides a complete overview of the application of ionic stimulation for skeletal muscle tissue engineering applications, highlighting the importance of inorganic ions as an attractive alternative to the application of small molecules and growth factors to stimulate muscle tissue repair.</div></div><div><h3>Statement of significance</h3><div>Ionic medicine (IM) is emerging as a promising and attractive approach in the field of tissue engineering, including muscle tissue regeneration. IM is based on the delivery of biologically active ions to injury sites, acting as stimulants for the repair process. This method offers a potentially simpler and more affordable alternative to conventional biomolecule-based regulators such as growth factors. Different biologically active ions, depending on their specific doping concentrations, can have varying effects on cellular development, which could be either beneficial or inhibitory. This literature review covers the field of IM in muscle regeneration with focus on the impact of various ions on skeletal muscle regeneration. The paper is thus a critical summary for guiding future research in ionic-related regenerative medicine, highlighting the potential and challenges of this approach for muscle regeneration.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 1-23"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514419","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":"Dual-activity nanozyme as an oxygen pump to alleviate tumor hypoxia and enhance photodynamic/ NIR-II photothermal therapy for sniping oral squamous cell carcinoma","authors":"Xingchen Li ,&nbsp;Ming Hao ,&nbsp;Annan Liu ,&nbsp;Lei Li ,&nbsp;Maja D. Nešić ,&nbsp;Bai Yang ,&nbsp;Weiwei Liu ,&nbsp;Quan Lin","doi":"10.1016/j.actbio.2024.10.018","DOIUrl":"10.1016/j.actbio.2024.10.018","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck region, and its treatment is limited by hypoxia and inadequate oxygen supply. Continuous oxygen delivery combined with photodynamic therapy (PDT) is the key to addressing this issue. Here, a dual-enzyme activity sea urchin-like Au@Pt-Ce6-HN-1 nanoplatform was designed to serve as an \"oxygen pump\" to alleviate tumor hypoxia for synergistic photodynamic/photothermal therapy (PTT). In this design, the photosensitizer chlorin e6 (Ce6) is covalently linked to the Au@Pt nanozyme for PDT treatment. The Au@Pt nanozyme exhibits catalase-like activity, continuously decomposing H₂O₂ in the tumor microenvironment to enhance O₂ levels, thereby achieving efficient PDT. Furthermore, Au@Pt can perform PTT and increase oxygen levels under NIR-II light to further promote PDT. The Au@Pt nanozyme also exhibits peroxidase-like activity, generating ·OH for chemodynamic therapy (CDT). Additionally, HN-1 guides the direction of \"sniping\" OSCC, and its high specificity benefits Au@Pt-Ce6-HN-1 at the tumor site. Au@Pt-Ce6-HN-1 exhibits bright fluorescence (FL), strong CT signal, and photothermal imaging capabilities, laying the foundation for subsequent guided PDT/PTT. This nanoplatform, which combines advantages such as continuous oxygen production, tumor targeting, and multimodal imaging, is expected to provide valuable insights into the treatment of OSCC.</div></div><div><h3>Statement of significance</h3><div>Accurate clinical diagnosis and treatment of OSCC are challenging. We report a dual-enzyme activity sea urchin-like Au@Pt-Ce6-HN-1 nanoplatform, serving as an \"oxygen pump\" to guide photodynamic therapy (PDT) and photothermal therapy (PTT) for OSCC. This nanoplatform targets OSCC for preoperative CT diagnosis and offers fluorescence visualization for surgical navigation, demonstrating potential in clinical cancer detection and surgery guidance. This innovative approach addresses OSCC hypoxia and enhances treatment efficacy through continuous oxygen production, tumor targeting, and multimodal imaging, significantly improving patient outcomes in OSCC treatment.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 476-487"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482759","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":"Modeling tumor-immune interactions using hybrid spheroids and microfluidic platforms for studying tumor-associated macrophage polarization in melanoma","authors":"Junki Seo ,&nbsp;Giheon Ha ,&nbsp;Geonho Lee ,&nbsp;Rohollah Nasiri ,&nbsp;Junmin Lee","doi":"10.1016/j.actbio.2024.10.036","DOIUrl":"10.1016/j.actbio.2024.10.036","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs), as key components of tumor microenvironment (TME), exhibit phenotypic plasticity in response to environmental cues, causing polarization into either pro-inflammatory M1 phenotypes or immunosuppressive M2 phenotypes. Although TAM has been widely studied for its crucial involvement in the initiation, progression, metastasis, and immune regulation of cancer cells, there have been limited attempts to understand how the metastatic potentials of cancer cells influence TAM polarization within TME. Here, we developed a miniaturized TME model using a 3D hybrid system composed of murine melanoma cells and macrophages, aiming to investigate interactions between cancer cells exhibiting various metastatic potentials and macrophages within TME. The increase in spheroid size within this model was associated with a reduction in cancer cell viability. Examining macrophage surface marker expression and cytokine secretion indicated the development of diverse TMEs influenced by both spheroid size and the metastatic potential of cancer cells. Furthermore, a high-throughput microfluidic platform equipped with trapping systems and hybrid spheroids was employed to simulate the tumor-immune system of complex TMEs and for comparative analysis with traditional 3D culture models. This study provides insight into TAM polarization in melanoma with different heterogeneities by modeling cancer-immune systems, which can be potentially employed for immune-oncology research, drug screening, and personalized therapy.</div></div><div><h3>Statement of significance</h3><div>This study presents the development of a 3D hybrid spheroid system designed to model tumor-immune interactions, providing a detailed analysis of how melanoma cell metastatic potential influences tumor-associated macrophage (TAM) polarization. By utilizing a microfluidic platform, we are able to replicate and investigate the complex tumor-immune system of the tumor microenvironments (TMEs) under continuous flow conditions. Our model holds significant potential for high-throughput drug screening and personalized medicine applications, offering a versatile tool for advancing cancer research and treatment strategies.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 233-246"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514433","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":"An ultrasound-activated piezoelectric sonosensitizer enhances mitochondrial depolarization for effective treatment of orthotopic glioma","authors":"Xiaoyu Huang ,&nbsp;Lu Gao ,&nbsp;Wei Ge ,&nbsp;Shuxian Li ,&nbsp;Yi Liu ,&nbsp;Xiaoyun Fan ,&nbsp;Shengxian Tu ,&nbsp;Fu Wang","doi":"10.1016/j.actbio.2024.10.051","DOIUrl":"10.1016/j.actbio.2024.10.051","url":null,"abstract":"<div><div>Despite the significant advancements in piezoelectric materials for sonodynamic therapy (SDT), the suppression of orthotopic glioma remains challenging, primarily due to the unclear mechanism and the restriction of blood-brain barrier (BBB). Herein, we proposed that layered piezoelectric SrBi₂Ta₂O₉ nanoparticles (SBTO NPs) could effectively depolarize the mitochondrial membrane potential (ΔΨ_m) of glioma cells under ultrasound (US) exposure. The US-induced band bending in SBTO NPs enhanced redox ability, promoting an increase in reactive oxygen species (ROS) generation. The in vitro results proved that SBTO NPs selectively accumulated in mitochondria under US and induced apoptosis in a mitochondrial depolarization manner mediated by the generation of ROS and free charges. Furthermore, SBTO NPs could cross the BBB and then accumulate in gliomas through US/microbubbles (MBs) procedure and protein-mediated transport. The therapeutic effect of piezoelectric SBTO NPs mediated SDT was proved in the orthotopic glioma mouse model. As validated by the histopathological observation and the long-term evaluation, the good biocompatibility and biosafety of SBTO NPs make it possible for deep tumor therapy, and worthy for further preclinical study.</div></div><div><h3>Statement of significance</h3><div>Employing piezoelectric sonosensitizers for sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, the unclear mechanism and blood-brain barrier (BBB) limit the effectiveness of SDT in glioma. Herein, we developed piezoelectric SrBi₂Ta₂O₉ nanoparticles (SBTO NPs) with a built-in electric field for glioma treatment and explored the underlying therapeutic mechanism. Notably, SBTO NPs selectively accumulated in mitochondria under ultrasound (US) and induced apoptosis in a mitochondrial depolarization manner, which is mediated by the generation of reactive oxygen species (ROS) and free charges. In an orthotopic glioma mouse model, SBTO NPs were delivered into the glioma through US/microbubbles and transferrin-mediated transport pathways, inhibiting tumor growth. This work provides a new paradigm for the treatment of orthotopic glioma and other tumor types.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 435-446"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607592","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":"Synergizing autophagic cell death and oxaliplatin-induced immunogenic death by a self-delivery micelle for enhanced tumor immunotherapy","authors":"Tao Deng ,&nbsp;Dong Chen ,&nbsp;Fang Chen ,&nbsp;Chaoqun Xu ,&nbsp;Qiang Zhang ,&nbsp;Min Li ,&nbsp;Yashi Wang ,&nbsp;Zhidi He ,&nbsp;Man Li ,&nbsp;Qin He","doi":"10.1016/j.actbio.2024.10.025","DOIUrl":"10.1016/j.actbio.2024.10.025","url":null,"abstract":"<div><div>Chemotherapy has become an emerging strategy to activate cytotoxic T cell responses by inducing immunogenic cell death (ICD), but the level of antitumor immunity induced by chemotherapeutic agents, such as oxaliplatin (OXA), is limited due to inadequate tumor antigen presentation and T cell activation. Inducing autophagic cell death (ACD) promotes the release of tumor antigen and the recruitment of dendritic cells, therefore strengthening antitumor immune responses. Here we simultaneously activate ICD and ACD with tumor targeting micelle to achieve enhanced antitumor chemo-immunotherapy. A self-delivery micelle is formulated by conjugating OXA prodrug with tocopherol succinate (TOS) as a hydrophobic segment and further encapsulates autophagy activator SMER28 to afford TOPR/SMER28, which specifically targets αvβ3 on tumor cells with c(RGDfK). Upon cellular internalization, OXA is released from the prodrug in response to the high concentration of reduced glutathione (GSH) in tumor cells, triggering ICD and releasing associated molecular patterns (DAMPs) signaling molecules to stimulate immunity. Meanwhile, SMER28 over-activates autophagy to induce autophagic cell death, which further leads to the maturation of dendritic cells and ultimately activates anti-tumor immune response. In the 4T1 tumor-bearing mice, the combination of OXA and SMER28 effectively inhibits tumor growth and activates antitumor immune responses. The tumor targeted micelle releases OXA and SMER28 in an on-demand profile and strengthens tumor chemo-immunotherapy by synergizing ICD and ACD, providing an alternative for antitumor immunotherapy.</div></div><div><h3>Statement of significance</h3><div>Chemotherapy induces immunogenic cell death (ICD) to activate anti-tumor immunity. However, the efficacy is limited by low levels of antigen presentation and T cell activation. To strengthen the antitumor immune responses induced by ICD, we first combine autophagic cell death (ACD) with ICD by formulating a glutathione-responsive oxaliplatin prodrug micelle co-encapsulating the autophagy activator SMER28. The activated autophagic level by SMER28 enhances the release of antigen and the recruitment of APCs, and ultimately bolsters T cell-mediated antitumor immune responses. We provide a potential strategy to amplify antitumor immune effects by combining autophagy activation with chemotherapy.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 548-559"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482779","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":"Machine learning reveals correlations between brain age and mechanics","authors":"Mayra Hoppstädter ,&nbsp;Kevin Linka ,&nbsp;Ellen Kuhl ,&nbsp;Marion Schmicke ,&nbsp;Markus Böl","doi":"10.1016/j.actbio.2024.10.003","DOIUrl":"10.1016/j.actbio.2024.10.003","url":null,"abstract":"<div><div>Our brain undergoes significant micro- and macroscopic changes throughout its life cycle. It is therefore crucial to understand the effect of aging on the mechanical properties of the brain in order to develop accurate personalized simulations and diagnostic tools. Here we systematically probed the mechanical behavior of <span><math><mrow><mi>n</mi><mo>=</mo><mn>439</mn></mrow></math></span> brain tissue samples in tension and compression, in different anatomical regions, for different axon orientations, across five age groups. We used Bayesian statistics to characterize the relation between brain age and mechanical properties and quantify uncertainties. Our results, based on our experimental data and material parameters for the isotropic Ogden and the anisotropic Gasser-Ogden-Holzapfel models, reveal a non-linear relationship between age and mechanics across the life cycle of the porcine brain. Both tensile and compressive shear moduli reached peak values ranging from 0.4–1.0 kPa in tension to 0.16–0.32 kPa in compression at three years of age. Anisotropy was most pronounced at six months, and then decreased. These results represent an important step in understanding age-dependent changes in the mechanical properties of brain tissue and provide the scientific basis for more accurate and realistic computational brain simulations.</div></div><div><h3>Statement of significance</h3><div>In this paper, we investigate the age-dependent mechanical properties of brain tissue based on different deformation modes, anatomical regions, and axon orientations. Hierarchical Bayesian modeling was used to identify isotropic and anisotropic material parameters. The study reveals a nonlinear relationship between shear modulus, degree of anisotropy, and tension-compression asymmetry over the life cycle of the brain. By demonstrating the non-linearity of these relationships, the study fills a significant knowledge gap in current research. This work is a fundamental step in accurately characterizing the complex relationship between brain aging and mechanical properties.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 362-378"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568333","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":"NIR-activated Janus nanomotors with promoted tumor permeability for synergistic photo-immunotherapy","authors":"Yingying Zhang ,&nbsp;Yujuan Xing ,&nbsp;Hong Zhou ,&nbsp;Enhui Ma ,&nbsp;Wenbei Xu ,&nbsp;Xinran Zhang ,&nbsp;Canran Jiang ,&nbsp;Shuo Ye ,&nbsp;Yanjia Deng ,&nbsp;Hong Wang ,&nbsp;Jingjing Li ,&nbsp;Shaohui Zheng","doi":"10.1016/j.actbio.2024.10.040","DOIUrl":"10.1016/j.actbio.2024.10.040","url":null,"abstract":"<div><div>Nanoparticle-based photo-immunotherapy has become an attractive strategy to eliminate tumors and activate host immune responses. However, the therapeutic efficacy is heavily restricted by low tumoral penetration and immunosuppressive tumor microenvironment (TME). Herein, near infrared laser (NIR)-propelled Janus nanomotors were presented for deep tumoral penetration, photothermal tumor ablation and photothermal-triggered augmented immunotherapy. The Janus nanomotors (AuNR/PMO@CPG) were constructed with gold nanorods (AuNR) and periodic mesoporous organo-silica nanospheres (PMO), followed by loading of immune adjuvant (CPG ODNs). Under NIR irradiation, the nanomotors exhibited superior photothermal effect, which produced active motion with a speed of 19.3 µm/s for deep tumor penetration and accumulation <em>in vivo</em>. Moreover, the good photothermal heating also benefited effective photothermal ablation to trigger immunogenic cell death (ICD). Subsequently, the ICD effect promoted the release of tumor-associated antigens (TAAs) and damage associated molecular patterns (DAMPs), and further generated abundant tumor vaccines <em>in situ</em> for reprograming the immunosuppressive TME in combination with CPG ODNs to inhibit tumor growth. As a result, a notable <em>in vivo</em> synergistic therapeutic effect was realized on CT26-bearing mice by combining photothermal therapy-induced ICD with modulation of immunosuppressive TME. Thus, we believe that the synthesized nanomotors can provide a new inspect to boost photothermal therapy-induced ICD in tumor immunotherapy.</div></div><div><h3>Statement of Significance</h3><div>Nanoparticle-based synergistic photo-immunotherapy has become a popular strategy to eliminate tumors and activate host immune responses. However, the therapeutic efficacy is heavily restricted by low tumoral penetration and immunosuppressive tumor microenvironment (TME). In this work, near infrared laser (NIR)-propelled Janus nanomotors were presented for deep tumoral penetration, photothermal tumor ablation and photothermal-triggered augmented immunotherapy. Under NIR irradiation, the nanomotors exhibited a superior photothermal effect, which produced active motion for deep tumor penetration and accumulation <em>in vivo</em>. Moreover, good photothermal heating also facilitated effective photothermal ablation to trigger immunogenic cell death (ICD), which promoted the release of tumor-associated antigens and damage-associated molecular patterns (DAMPs), and further generated abundant tumor vaccines <em>in situ</em> for reprograming the immunosuppressive TME to inhibit tumor growth.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 463-475"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568334","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 data-driven microstructure-based model for predicting circumferential behavior and failure in degenerated human annulus fibrosus","authors":"Abderrahman Tamoud ,&nbsp;Fahmi Zaïri ,&nbsp;Fahed Zaïri","doi":"10.1016/j.actbio.2024.10.028","DOIUrl":"10.1016/j.actbio.2024.10.028","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The degeneration of the intervertebral disc annulus fibrosus poses significant challenges in understanding and predicting its mechanical behavior. In this article, we present a novel approach, enriched with detailed insights into microstructure and degeneration progression, to accurately predict the mechanics of the degenerated human annulus. Central to this framework is a fully three-dimensional continuum-based model that integrates hydration state and multiscale structural features, including proteoglycan macromolecules and interpenetrating collagen fibrillar networks across various hierarchical levels within the multi-layered lamellar/inter-lamellar soft tissue, capable of sustaining deformation-induced damage. To ensure accurate and comprehensive predictions of the degenerated annulus mechanical behavior, we establish a data-driven correlation between disc degeneration grade and individual age, which influences the composition and mechanical integrity of annulus constituents while accounting for regional variations. The methodology includes a thorough identification of age- and grade-related evolutions of model inputs, followed by a detailed quantitative evaluation of the model predictive capabilities, with a focus on circumferential behavior and failure. The model successfully replicates experimental data, accurately capturing stiffness, transverse response (Poisson's ratio), and ultimate properties across different annulus regions, while also accommodating the modulation of the age/grade relationship. The reduction rates between normal and severe degeneration align reasonably well with experimental data, with the inner region exhibiting the largest decrease in stiffness (34.63 %) and no significant change observed in the outer region. Failure stress drops considerably in both regions (49.86 % in the inner and 45.33 % in the outer), while failure strain decreases by 36.39 % in the outer and 24.74 % in the inner. Our findings demonstrate that the proposed framework significantly enhances the predictive accuracy of annulus mechanics across a spectrum of degeneration levels, from normal to severely degenerated states. This approach promises improved predictive accuracy, deeper insights into disc health and injury risk, and a robust foundation for further research on the impact of degeneration on disc integrity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Statement of significance&lt;/h3&gt;&lt;div&gt;Understanding and predicting the mechanical behavior of degenerated human annulus fibrosus remains a significant challenge due to the complex interplay of structural, biochemical, and age-related factors. This study presents a microstructure-based approach to address this challenge by integrating hydration state, detailed structural features across hierarchical scales, and deformation-induced damage and failure, alongside age-related changes and degeneration grade factors. This approach enables accurate simulations of annulus mechanics across regions, with model results tho","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 379-397"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482753","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":"Bioengineering strategy to promote CNS nerve growth and regeneration via chronic glutamate signaling","authors":"Karen Chang ,&nbsp;Jhih-Guang Wu ,&nbsp;Tien-Li Ma ,&nbsp;Sheng-Hao Hsu ,&nbsp;Kin-Sang Cho ,&nbsp;Zicheng Yu ,&nbsp;Anton Lennikov ,&nbsp;Ajay Ashok ,&nbsp;Aishwarya Rajagopalan ,&nbsp;Min-Huey Chen ,&nbsp;Wei-Fang Su ,&nbsp;Tor Paaske Utheim ,&nbsp;Dong Feng Chen","doi":"10.1016/j.actbio.2024.10.023","DOIUrl":"10.1016/j.actbio.2024.10.023","url":null,"abstract":"<div><div>Being part of the mature mammalian central nervous system, impairments of the retina and optic nerves caused by trauma or diseases often cannot be restored. Progressive degeneration of retinal ganglion cells (RGCs) in glaucoma and other optic neuropathies gradually leads to permanent vision loss, which currently has no cure. The purpose of this study is to develop a biocompatible scaffold to support RGC survival and guide axon growth, facilitating optic nerve repair and regeneration. We here report that electrical stimulation (ES) significantly promoted neurite outgrowth and elongation from primary RGCs, mediated through glutamate receptor signaling. To mimic prolonged glutamate stimulation and facilitate sustained nerve growth, we fabricated biocompatible poly-γ-benzyl-L-glutamate (PBG) scaffolds for controlled glutamate release. These PBG scaffolds supported RGC survival and robust long-distance nerve growth in both retinal explants and isolated RGC cultures. In contrast, control polycaprolactone (PCL) scaffolds with similar physical structures showed little benefits on RGC survival or nerve growth. Moreover, PBG scaffolds promoted the differentiation and neurite outgrowth from embryonic stem cell-derived RGC progenitors. The aligned PBG scaffold drove directed nerve elongation along the fiber alignment. Transplantation of PBG-coated biocompatible conduits induced robust optic nerve regeneration in adult mice following nerve transection. Together, the findings present the exciting possibility of driving optic nerve regeneration and RGC progenitor cell differentiation by imitating ES or glutamate signaling. PBG presents a permissive biomaterial in supporting robust and directed axon growth with promising clinical applications in the future.</div></div><div><h3>Statement of Significance</h3><div>We here reported compelling findings that demonstrate the potent regenerative effects of a bioengineered scaffold incorporating poly-γ-benzyl-L-glutamate (PBG) on the optic nerve. Retinal ganglion cell (RGC) axons, which form the optic nerve, are incapable of regenerating in adulthood, posing a significant hurdle in restoring vision for patients with optic nerve diseases or injuries. Built upon the finding that electrical stimulation promotes RGC axonal growth through glutamate signaling, we developed PBG scaffolds to provide sustained glutamate stimulation and showed their exceptional effects on driving directed axonal elongation in cultured RGCs and neural progenitors, as well as supporting robust optic nerve regeneration after transection <em>in vivo</em>. The findings hold great promise for reversing vision loss in patients with optic nerve conditions.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 165-177"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482756","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":"Structural determinants of tendon multiscale mechanics and their sensitivity to mechanical stimulation during development in an embryonic chick model","authors":"Benjamin E. Peterson ,&nbsp;Maria L. Canonicco Castro ,&nbsp;Helen O. McCarthy ,&nbsp;Niamh Buckley ,&nbsp;Nicholas Dunne ,&nbsp;Rebecca A. Rolfe ,&nbsp;Paula Murphy ,&nbsp;Spencer E. Szczesny","doi":"10.1016/j.actbio.2024.10.011","DOIUrl":"10.1016/j.actbio.2024.10.011","url":null,"abstract":"<div><div>There is an abrupt increase in the multiscale mechanical properties and load-bearing capabilities of tendon during development. While prior work has identified numerous changes that occur within the collagenous structure during this developmental period, the primary structural elements that give rise to this abrupt increase in mechanical functionality, and their mechanobiological sensitivity, remain unclear. To address this knowledge gap, we used a shear lag model along with ultrastructural imaging, biochemical/thermodynamic assays, and multiscale mechanical testing to investigate the dynamic structure-function relationships during late-stage embryonic chick development and to establish their sensitivity to mechanical stimulation. Mechanical testing and modeling suggested that the rapid increase in multiscale mechanics can be explained by increases in fibril length, intrafibrillar crosslinking, and fibril area fraction. To partially test this, we inhibited collagen crosslinking during development and observed a drastic reduction in multiscale mechanical behavior that was explained by a reduction in both fibril modulus and length. Using muscle paralysis to investigate mechanosensitivity, we observed a significantly impaired multiscale mechanical response despite minimal changes in fibril diameter and fibril area fraction. Additionally, the shear lag model found a trend toward lower fibril lengths with paralysis and experimental data found decreased crosslinking and fibril modulus values following flaccid paralysis. Together, these data suggest that both intrafibrillar crosslink formation and fibril elongation are critical to the formation of load-bearing capabilities in tenogenesis and are sensitive to mechanical loading. These findings provide critical insights into the biological and structural mechanisms that give rise to tensile load-bearing soft tissue.</div></div><div><h3>Statement of Significance</h3><div>Despite prior work investigating the structural and mechanical changes that occur during tendon development, there has not been a comprehensive analysis of how these simultaneous changes in structure and function are connected. In this study, we performed a comprehensive battery of mechanical and structural assessments of embryonic chick tendons and input these data into a shear lag model to estimate the individual importance of each structural change to the tendon mechanical properties. Additionally, we inhibited muscle activity in the embryos to evaluate the impact of mechanical stimulation on these evolving structure-function relationships during tendon development. These data provide insight into the primary structural elements that produce the tensile load-bearing capabilities of tendon, which will inform efforts to produce tissue engineered tendon replacements.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 303-316"},"PeriodicalIF":9.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482777","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}