Pub Date : 2024-11-06DOI: 10.1016/j.biomaterials.2024.122949
Zhao-Wei Zhu , Ge Li , Guang-Geng Wu , Yu-Jing Zhang , Yu-Rong Bai , Bi-Qin Lai , Ying Ding , Xiang Zeng , Yuan-Huan Ma , Shu Liu , Rui Wang , Jing-Hua Liang , Yang-Bin Xu , Bo He , Yuan-Shan Zeng
Peripheral nerve injury (PNI) involving the loss of sensory and movement functions is challenging to repair. Although the gold standard of PNI repair is still the use of autologous nerve grafts, the destruction of the donor side is inevitable. In the present study, peripheral nerve tissueoids (PNTs) composed of a Schwann cell (SC)-based neurotrophin-3 (NT-3) delivery system and a decellularized optic nerve (DON) with naturally oriented channels were engineered to investigate the mechanism of PNTs in nerve regeneration. Proteomic analysis and mRNA sequencing revealed that PNTs have the advantage of promoting nerve regeneration by the three mechanisms of chemotaxis, adhesion and intrinsic mobilisation. The results demonstrated that a local NT-3-enriched pool was constructed by laminin γ3 (LAMC3) in PNTs, creating a niche for the colonization of TrkC-positive SCs, attraction of axons to the defect/graft area, and remyelination. In addition, LAMC3 in PNTs can rapidly promote axon adhesion through integrin aVβ6 and can precisely guide long projecting axons to target tissues. Furthermore, the interactions among the NT-3/TrkC, LAMC3/integrin aVβ6 and the scaffold synergistically activate the PI3K-AKT signalling pathway in damaged neurons, further stimulating the intrinsic regenerative drive within the neurons to ultimately achieve the rapid reinnervation and the improvement of sensory and movement functions in the hindlimb.
{"title":"Transplantation of peripheral nerve tissueoid based on a decellularized optic nerve scaffold to restore rat hindlimb sensory and movement functions","authors":"Zhao-Wei Zhu , Ge Li , Guang-Geng Wu , Yu-Jing Zhang , Yu-Rong Bai , Bi-Qin Lai , Ying Ding , Xiang Zeng , Yuan-Huan Ma , Shu Liu , Rui Wang , Jing-Hua Liang , Yang-Bin Xu , Bo He , Yuan-Shan Zeng","doi":"10.1016/j.biomaterials.2024.122949","DOIUrl":"10.1016/j.biomaterials.2024.122949","url":null,"abstract":"<div><div>Peripheral nerve injury (PNI) involving the loss of sensory and movement functions is challenging to repair. Although the gold standard of PNI repair is still the use of autologous nerve grafts, the destruction of the donor side is inevitable. In the present study, peripheral nerve tissueoids (PNTs) composed of a Schwann cell (SC)-based neurotrophin-3 (NT-3) delivery system and a decellularized optic nerve (DON) with naturally oriented channels were engineered to investigate the mechanism of PNTs in nerve regeneration. Proteomic analysis and mRNA sequencing revealed that PNTs have the advantage of promoting nerve regeneration by the three mechanisms of chemotaxis, adhesion and intrinsic mobilisation. The results demonstrated that a local NT-3-enriched pool was constructed by laminin γ3 (LAMC3) in PNTs, creating a niche for the colonization of TrkC-positive SCs, attraction of axons to the defect/graft area, and remyelination. In addition, LAMC3 in PNTs can rapidly promote axon adhesion through integrin aVβ6 and can precisely guide long projecting axons to target tissues. Furthermore, the interactions among the NT-3/TrkC, LAMC3/integrin aVβ6 and the scaffold synergistically activate the PI3K-AKT signalling pathway in damaged neurons, further stimulating the intrinsic regenerative drive within the neurons to ultimately achieve the rapid reinnervation and the improvement of sensory and movement functions in the hindlimb.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122949"},"PeriodicalIF":12.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613394","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}
Pub Date : 2024-11-06DOI: 10.1016/j.biomaterials.2024.122947
Shuang Chen, Wenshuang Wang, Lanlin Shen, Haofan Liu, Jing Luo, Yushuang Ren, Susu Cui, Yixin Ye, Gang Shi, Fuyi Cheng, Xiaolan Su, Lei Dai, Maling Gou, Hongxin Deng
Transplantation of insulin-secreting cells provides a promising method for re-establishing the autonomous blood glucose control ability of type 1 diabetes (T1D) patients, but the low survival of the transplanted cells hinder the therapeutic efficacy. In this study, we 3D-printed an encapsulation system containing β-like cells and microvascular fragments (MVF), to create a retrivable microdevice with vascularized islets in vivo for T1D therapy. The functional β-like cells were differentiated from the urine epithelial cell-derived induced pluripotent stem cells (UiPSCs). Single-cell RNA sequencing provided an integrative study and macroscopic developmental analyses of the entire process of differentiation, which revealed the developmental trajectory of differentiation in vitro follows the developmental pattern of embryonic pancreas in vivo. The MVF were isolated from the epididymal fat pad. The microdevice with a groove structure were rapidly fabricated by the digital light processing (DLP)-3D printing technology. The β-like cells and MVF were uniformly distributed in the device. After subcutaneous transplantation into C57BL/6 mice, the microdevice have less collagen accumulation and low immune cell infiltration. Moreover, the microdevice encapsulated vascularized islets reduced hyperglycemia in 33 % of the treated mice for up to 100 days without immunosuppressants, and the humanized C-peptide was also detected in the serum of the mice. In summary, we described the microdevice-protected vascularized islets for long-term treatment of T1D, with high safety and potential clinical transformative value, and may therefore provide a translatable solution to advance the research progress of β cell replacement therapy for T1D.
{"title":"A 3D-printed microdevice encapsulates vascularized islets composed of iPSC-derived β-like cells and microvascular fragments for type 1 diabetes treatment","authors":"Shuang Chen, Wenshuang Wang, Lanlin Shen, Haofan Liu, Jing Luo, Yushuang Ren, Susu Cui, Yixin Ye, Gang Shi, Fuyi Cheng, Xiaolan Su, Lei Dai, Maling Gou, Hongxin Deng","doi":"10.1016/j.biomaterials.2024.122947","DOIUrl":"10.1016/j.biomaterials.2024.122947","url":null,"abstract":"<div><div>Transplantation of insulin-secreting cells provides a promising method for re-establishing the autonomous blood glucose control ability of type 1 diabetes (T1D) patients, but the low survival of the transplanted cells hinder the therapeutic efficacy. In this study, we 3D-printed an encapsulation system containing β-like cells and microvascular fragments (MVF), to create a retrivable microdevice with vascularized islets in vivo for T1D therapy. The functional β-like cells were differentiated from the urine epithelial cell-derived induced pluripotent stem cells (UiPSCs). Single-cell RNA sequencing provided an integrative study and macroscopic developmental analyses of the entire process of differentiation, which revealed the developmental trajectory of differentiation in vitro follows the developmental pattern of embryonic pancreas in vivo. The MVF were isolated from the epididymal fat pad. The microdevice with a groove structure were rapidly fabricated by the digital light processing (DLP)-3D printing technology. The β-like cells and MVF were uniformly distributed in the device. After subcutaneous transplantation into C57BL/6 mice, the microdevice have less collagen accumulation and low immune cell infiltration. Moreover, the microdevice encapsulated vascularized islets reduced hyperglycemia in 33 % of the treated mice for up to 100 days without immunosuppressants, and the humanized C-peptide was also detected in the serum of the mice. In summary, we described the microdevice-protected vascularized islets for long-term treatment of T1D, with high safety and potential clinical transformative value, and may therefore provide a translatable solution to advance the research progress of β cell replacement therapy for T1D.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122947"},"PeriodicalIF":12.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637983","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}
Pub Date : 2024-11-05DOI: 10.1016/j.biomaterials.2024.122945
Bichun Zhao , Chao Wang , Manqiang Sun , Xiaocao Ma , Quan Zeng , Jiafei Xi , Junnian Zhou , Xuetao Pei , Yali Jia , Wen Yue
Neuroinflammation triggered by activated microglia leads to neuronal damage and, to a certain extent, neurodegeneration. Human umbilical cord mesenchymal stem cells (UC-MSCs) have good immunomodulatory and neuroprotective effects as well as therapeutic potential for neuroinflammation-related diseases. However, the complex microenvironment created by neuroinflammation poses a challenge to transplanted UC-MSCs. The emerging biomimetic microniche (BN)-based culture technology provides new opportunities to optimize the preparation of UC-MSCs; but the fundamental changes in the characteristics of UC-MSCs based on BN remain unclear, and more reliable preclinical data are needed to support their ability to regulate inflammation. Here, we systematically studied the cellular properties and inflammation regulatory capacity of UC-MSCs in conventional static planar culture (SP-UCMSCs) and suspension culture based on BN (BN-UCMSCs). In vitro, compared with SP-UCMSCs, BN-UCMSCs not only maintained the fundamental characteristics of MSCs, but also significantly enhanced cell proliferation, adhesion, and migration capabilities, etc; notably, the paracrine function and anti-inflammatory capacity of BN-UCMSCs were also enhanced. We further established a murine model of acute brain inflammation and demonstrated that the expression level of pro-inflammatory cytokines in hippocampal and cortical tissues of the BN-UCMSCs group was significantly decreased compared with that in the SP-UCMSCs group. Subsequent transcriptomic analysis of hippocampal and cortical tissues revealed that BN-UCMSCs had the advantage of significantly reducing the expression of pro-inflammatory cytokines through the TLR4-Myd88-NF-κB axis, which was further validated at the gene and protein levels. Taken together, these data strongly indicated that BN-UCMSCs exerts excellent regulatory effects on acute brain inflammation through advantageous properties.
{"title":"UC-MSCs based on biomimetic microniche exert excellent regulatory effects on acute brain inflammation through advantageous properties","authors":"Bichun Zhao , Chao Wang , Manqiang Sun , Xiaocao Ma , Quan Zeng , Jiafei Xi , Junnian Zhou , Xuetao Pei , Yali Jia , Wen Yue","doi":"10.1016/j.biomaterials.2024.122945","DOIUrl":"10.1016/j.biomaterials.2024.122945","url":null,"abstract":"<div><div>Neuroinflammation triggered by activated microglia leads to neuronal damage and, to a certain extent, neurodegeneration. Human umbilical cord mesenchymal stem cells (UC-MSCs) have good immunomodulatory and neuroprotective effects as well as therapeutic potential for neuroinflammation-related diseases. However, the complex microenvironment created by neuroinflammation poses a challenge to transplanted UC-MSCs. The emerging biomimetic microniche (BN)-based culture technology provides new opportunities to optimize the preparation of UC-MSCs; but the fundamental changes in the characteristics of UC-MSCs based on BN remain unclear, and more reliable preclinical data are needed to support their ability to regulate inflammation. Here, we systematically studied the cellular properties and inflammation regulatory capacity of UC-MSCs in conventional static planar culture (SP-UCMSCs) and suspension culture based on BN (BN-UCMSCs). <em>In vitro</em>, compared with SP-UCMSCs, BN-UCMSCs not only maintained the fundamental characteristics of MSCs, but also significantly enhanced cell proliferation, adhesion, and migration capabilities, etc; notably, the paracrine function and anti-inflammatory capacity of BN-UCMSCs were also enhanced. We further established a murine model of acute brain inflammation and demonstrated that the expression level of pro-inflammatory cytokines in hippocampal and cortical tissues of the BN-UCMSCs group was significantly decreased compared with that in the SP-UCMSCs group. Subsequent transcriptomic analysis of hippocampal and cortical tissues revealed that BN-UCMSCs had the advantage of significantly reducing the expression of pro-inflammatory cytokines through the TLR4-Myd88-NF-κB axis, which was further validated at the gene and protein levels. Taken together, these data strongly indicated that BN-UCMSCs exerts excellent regulatory effects on acute brain inflammation through advantageous properties.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122945"},"PeriodicalIF":12.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613395","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}
Pub Date : 2024-11-05DOI: 10.1016/j.biomaterials.2024.122946
Chao Pan , Shujuan Yu , Caixia Li , Juntao Li , Peng Sun , Yan Guo , Ting Li , Dongshu Wang , Kangfeng Wang , Yufei Lyu , Xiankai Liu , Xiang Li , Jun Wu , Li Zhu , Hengliang Wang
Modular self-assembling nanoparticle vaccines, represent a cutting-edge approach in immunology with the potential to revolutionize vaccine design and efficacy. Although many innovative efficient modular self-assembling nanoparticles have been designed for vaccination, the immune activation characteristics underlying such strong protection remain poorly understood, limiting the further expansion of such nanocarrier. Here, we prepared a novel modular nanovaccine, which self-assembled via a pentamer cholera toxin B subunit (CTB) domain and an unnatural trimer domain, presenting S. Paratyphi A O-polysaccharide antigen, and investigated its rapid immune activation mechanism. The nanovaccine efficiently targets draining lymph nodes and antigen-presenting cells, facilitating co-localization with Golgi and endoplasmic reticulum. In addition, dendritic cells, macrophages, B cells, and neutrophils potentially participate in antigen presentation, unveiling a dynamic change of the vaccines in lymph nodes. Single-cell RNA sequencing at early stage and iN vivo/iN vitro experiments reveal its potent humoral immune response capabilities and protection effects. This nanoparticle outperforms traditional CTB carriers in eliciting robust prophylactic effects in various infection models. This work not only provides a promising and efficient candidate vaccine, but also promotes the design and application of the new type of self-assembled nanoparticle, offering a safe and promising vaccination strategy for infection diseases.
模块化自组装纳米粒子疫苗是免疫学的前沿方法，有可能彻底改变疫苗的设计和功效。尽管已经设计出了许多创新的高效模块化自组装纳米颗粒用于疫苗接种，但人们对这种强保护性所依赖的免疫激活特性仍然知之甚少，从而限制了这种纳米载体的进一步推广。在此，我们制备了一种新型模块化纳米疫苗，它通过五聚体霍乱毒素 B 亚基（CTB）结构域和非天然三聚体结构域自组装，呈现副伤寒甲型流感杆菌 O 型多糖抗原，并研究了其快速免疫激活机制。该纳米疫苗可有效靶向引流淋巴结和抗原递呈细胞，促进与高尔基体和内质网的共定位。此外，树突状细胞、巨噬细胞、B 细胞和中性粒细胞也可能参与抗原呈递，从而揭示了疫苗在淋巴结中的动态变化。早期的单细胞 RNA 测序和体内/体外实验揭示了其强大的体液免疫反应能力和保护效果。在各种感染模型中，这种纳米粒子在激发强大的预防效果方面优于传统的 CTB 载体。这项工作不仅提供了一种有前景的高效候选疫苗，而且促进了新型自组装纳米粒子的设计和应用，为感染性疾病提供了一种安全、有前景的疫苗接种策略。
{"title":"Rapid and efficient immune response induced by a designed modular cholera toxin B subunit (CTB)-based self-assembling nanoparticle","authors":"Chao Pan , Shujuan Yu , Caixia Li , Juntao Li , Peng Sun , Yan Guo , Ting Li , Dongshu Wang , Kangfeng Wang , Yufei Lyu , Xiankai Liu , Xiang Li , Jun Wu , Li Zhu , Hengliang Wang","doi":"10.1016/j.biomaterials.2024.122946","DOIUrl":"10.1016/j.biomaterials.2024.122946","url":null,"abstract":"<div><div>Modular self-assembling nanoparticle vaccines, represent a cutting-edge approach in immunology with the potential to revolutionize vaccine design and efficacy. Although many innovative efficient modular self-assembling nanoparticles have been designed for vaccination, the immune activation characteristics underlying such strong protection remain poorly understood, limiting the further expansion of such nanocarrier. Here, we prepared a novel modular nanovaccine, which self-assembled via a pentamer cholera toxin B subunit (CTB) domain and an unnatural trimer domain, presenting <em>S.</em> Paratyphi A O-polysaccharide antigen, and investigated its rapid immune activation mechanism. The nanovaccine efficiently targets draining lymph nodes and antigen-presenting cells, facilitating co-localization with Golgi and endoplasmic reticulum. In addition, dendritic cells, macrophages, B cells, and neutrophils potentially participate in antigen presentation, unveiling a dynamic change of the vaccines in lymph nodes. Single-cell RNA sequencing at early stage and <em>i</em>N <em>vivo</em>/<em>i</em>N <em>vitro</em> experiments reveal its potent humoral immune response capabilities and protection effects. This nanoparticle outperforms traditional CTB carriers in eliciting robust prophylactic effects in various infection models. This work not only provides a promising and efficient candidate vaccine, but also promotes the design and application of the new type of self-assembled nanoparticle, offering a safe and promising vaccination strategy for infection diseases.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122946"},"PeriodicalIF":12.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602178","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}
Pub Date : 2024-11-02DOI: 10.1016/j.biomaterials.2024.122943
Guoquan Wu , Tianyu Su , Peng Zhou , Rongze Tang , Xu Zhu , Jin Wang , Minghao Chao , Liying Fan , Hanrong Yan , Peng Ye , Dehong Yu , Fenglei Gao , Hongliang Chen
Nanomedicines for immune modulation have made advancements in the treatment of rheumatoid arthritis (RA). However, due to aberrations in patients' immune systems, inducing antigen-specific immune tolerance while halting disease progression remains a significant challenge. Here, we develop a highly targeted multifunctional nanocomplex, termed M2Exo@CuS-CitP-Rapa (M2CPR), with the aim of selectively inhibiting inflammatory immune reactions while promoting immune tolerance towards specific antigens. M2CPR specifically targets inflammatory tissues in RA, delivering CuS NPs, CitP, Rapa, and endogenous anti-inflammatory factors, thereby ameliorating the inflammatory joint microenvironment. CuS NPs induce Cuproptosis of activated T cells, whose fragments are engulfed by resident or recruited macrophages, resulting in abundant production of TGF-β. TGF-β acts synergistically with Rapa to induce the iDCs into tDCs. tDCs present CitP to Naive T cells, promoting Tregs differentiation. Tregs, in turn, produce more TGF-β, inducing tDCs differentiation, thereby establishing a cycle of immune tolerance. Through in vitro and in vivo experiments, we validate that M2CPR can induce robust and durable antigen-specific immune tolerance, offering a new paradigm for RA therapy.
用于免疫调节的纳米药物在治疗类风湿性关节炎（RA）方面取得了进展。然而，由于患者免疫系统的畸变，在诱导抗原特异性免疫耐受的同时阻止疾病进展仍是一项重大挑战。在这里，我们开发了一种高度靶向性的多功能纳米复合物，称为 M2Exo@CuS-CitP-Rapa（M2CPR），旨在选择性地抑制炎症性免疫反应，同时促进对特定抗原的免疫耐受。M2CPR 专门针对 RA 中的炎症组织，输送 CuS NPs、CitP、Rapa 和内源性抗炎因子，从而改善炎性关节微环境。CuS NPs 能诱导活化的 T 细胞发生杯突分裂，其碎片被常驻或招募的巨噬细胞吞噬，从而产生大量的 TGF-β。TGF-β 与 Rapa 协同作用，将 iDCs 诱导为 tDCs。Tregs反过来会产生更多的TGF-β，诱导tDCs分化，从而建立免疫耐受循环。通过体外和体内实验，我们验证了 M2CPR 可以诱导稳健持久的抗原特异性免疫耐受，为 RA 治疗提供了一种新的范例。
{"title":"Engineering M2 macrophage-derived exosomes modulate activated T cell cuproptosis to promote immune tolerance in rheumatoid arthritis","authors":"Guoquan Wu , Tianyu Su , Peng Zhou , Rongze Tang , Xu Zhu , Jin Wang , Minghao Chao , Liying Fan , Hanrong Yan , Peng Ye , Dehong Yu , Fenglei Gao , Hongliang Chen","doi":"10.1016/j.biomaterials.2024.122943","DOIUrl":"10.1016/j.biomaterials.2024.122943","url":null,"abstract":"<div><div>Nanomedicines for immune modulation have made advancements in the treatment of rheumatoid arthritis (RA). However, due to aberrations in patients' immune systems, inducing antigen-specific immune tolerance while halting disease progression remains a significant challenge. Here, we develop a highly targeted multifunctional nanocomplex, termed M2Exo@CuS-CitP-Rapa (M2CPR), with the aim of selectively inhibiting inflammatory immune reactions while promoting immune tolerance towards specific antigens. M2CPR specifically targets inflammatory tissues in RA, delivering CuS NPs, CitP, Rapa, and endogenous anti-inflammatory factors, thereby ameliorating the inflammatory joint microenvironment. CuS NPs induce Cuproptosis of activated T cells, whose fragments are engulfed by resident or recruited macrophages, resulting in abundant production of TGF-β. TGF-β acts synergistically with Rapa to induce the iDCs into tDCs. tDCs present CitP to Naive T cells, promoting Tregs differentiation. Tregs, in turn, produce more TGF-β, inducing tDCs differentiation, thereby establishing a cycle of immune tolerance. Through in vitro and in vivo experiments, we validate that M2CPR can induce robust and durable antigen-specific immune tolerance, offering a new paradigm for RA therapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122943"},"PeriodicalIF":12.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602157","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}
Pub Date : 2024-11-02DOI: 10.1016/j.biomaterials.2024.122944
Guichun Zeng , Xiayi Liang , Yuan Ling , Xiaoqi Zhu , Qin Wang , Zelun Li , Junjie Liu , Xiaobo Wang , Guanhua Qiu , Kangning Yan , Duo Wang , Jie Chen
Radiofrequency ablation (RFA) therapy for hepatocellular carcinoma (HCC) suffers from incomplete ablation with tumor remnants, recurrence, and metastasis. To capture these matters, a calcium-based thermosensitizer (CBT) was constructed, which can swell the thermal ablation treatment. DMXAA was encapsulated within CaCO3 nanoparticles and surface-modified using PEG. DMXAA @CBTNps emanates continuous cavitation to enhance the RFA effect, lower RFA power, and shorten the RFA time by responding to the acidic tumor microenvironment and releasing carbon dioxide bubbles. Ca2+ deposition to form calcification instigates the calcium death of the tumor and strengthens the thermal conductivity, wherein CBT fortifies the immunogenic cell death (ICD) of RFA. The vascular disruptor DMXAA is administered to the tumor site to impair the blood and nutrient supply to the tumor tissue. Calcium carbonate nanoparticles generate persistent carbon dioxide bubbles within the acidic microenvironment, leading to a sustained cavitation effect that enhances magneto-thermal conversion. This synergistic approach facilitates tumor vascular occlusion, thereby improving thermal ablation therapy. This strategy is different from previous thermal ablation treatments in that the CBT-released product Ca2+, the continuous cavitation effect of CO2, and the vascular disrupting agent can accelerate the conversion of energy from electromagnetic energy to thermal energy and reduce the heat loss, which significantly amplifies the effect of thermal ablation treatment of HCC and intensifies ICD. Therefore, this research provides a promising avenue and therapeutic platform for clinical liver cancer treatment.
{"title":"Tumor vascular occlusion by calcium-based thermosensitizer provokes continuous cavitation effect and thermal energy transition efficiency of radiofrequency ablation therapy","authors":"Guichun Zeng , Xiayi Liang , Yuan Ling , Xiaoqi Zhu , Qin Wang , Zelun Li , Junjie Liu , Xiaobo Wang , Guanhua Qiu , Kangning Yan , Duo Wang , Jie Chen","doi":"10.1016/j.biomaterials.2024.122944","DOIUrl":"10.1016/j.biomaterials.2024.122944","url":null,"abstract":"<div><div>Radiofrequency ablation (RFA) therapy for hepatocellular carcinoma (HCC) suffers from incomplete ablation with tumor remnants, recurrence, and metastasis. To capture these matters, a calcium-based thermosensitizer (CBT) was constructed, which can swell the thermal ablation treatment. DMXAA was encapsulated within CaCO<sub>3</sub> nanoparticles and surface-modified using PEG. DMXAA @CBTNps emanates continuous cavitation to enhance the RFA effect, lower RFA power, and shorten the RFA time by responding to the acidic tumor microenvironment and releasing carbon dioxide bubbles. Ca<sup>2+</sup> deposition to form calcification instigates the calcium death of the tumor and strengthens the thermal conductivity, wherein CBT fortifies the immunogenic cell death (ICD) of RFA. The vascular disruptor DMXAA is administered to the tumor site to impair the blood and nutrient supply to the tumor tissue. Calcium carbonate nanoparticles generate persistent carbon dioxide bubbles within the acidic microenvironment, leading to a sustained cavitation effect that enhances magneto-thermal conversion. This synergistic approach facilitates tumor vascular occlusion, thereby improving thermal ablation therapy. This strategy is different from previous thermal ablation treatments in that the CBT-released product Ca<sup>2+</sup>, the continuous cavitation effect of CO<sub>2</sub>, and the vascular disrupting agent can accelerate the conversion of energy from electromagnetic energy to thermal energy and reduce the heat loss, which significantly amplifies the effect of thermal ablation treatment of HCC and intensifies ICD. Therefore, this research provides a promising avenue and therapeutic platform for clinical liver cancer treatment.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122944"},"PeriodicalIF":12.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577889","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}
Pub Date : 2024-11-01DOI: 10.1016/j.biomaterials.2024.122942
Yuan Feng , Jinlin Chen , Xiao Wang , Chao Long , Wenbo Wang , Jingjing Lin , Yuanyuan He , Yanchao Wang , Feng Luo , Zhen Li , Jiehua Li , Hong Tan
Cell metabolism, as the key driver of inflammation, revascularization and even subsequent tissue regeneration, is controlled by and also conversely influenced by signal transduction. Incorporation of cell metabolism into tissue engineering research holds immense potential for in-situ treatment repair and further understanding of the host-biomaterial cues in body response. In this study, an anti-inflammatory waterborne polyurethane scaffold incorporated with poly-l-lactic acid (PLLA) block was served to repair nerve injuries (LAx-WPU). Lactate was released through the degradation of LAx-WPU scaffolds, and the content increased with the addition of PLLA block over the degradation times. Thenceforth, the production of adenosine triphosphate (ATP) in primary neurons and neuronal axon growth were achieved by taking up lactate through monocarboxylate transporters (MCT2) for energy metabolism under glucose-free environment treated with LAx-WPU degradation solution. After LAx-WPU was implanted to repair brain nerve defects in rats, filamentous neurons elongation, rapid vascularization, and nerve tissue regeneration were realized up to 28 days with the positive expression of microtubule-associated protein (MAP2), β-tubulin (Tuj1), and platelet endothelial cell adhesion molecule (CD31) in the scaffolds. Results highlighted that the LAx-WPU scaffolds up-regulated not only the ATP-ADP-AMP purine metabolism compounds to mainly bridge neuroactive ligand-receptor interaction genes, cAMP pathway genes, and calcium pathway genes for neurocytes but also the ATP-GMP purine metabolism to angiogenesis in Gene Ontology (GO) analysis. Further analysis in reverse showed axonal regeneration is restrained by the inhibition of MCT2, proving LAx-WPU promoted nerve repair depended on lactate for energy. Therefore, LAx-WPU scaffolds construct an expected way to modulate the metabolic microenvironment for inducing nerve regeneration by intrinsic biomaterial metabolism cues without any bioactive factors.
{"title":"Reprogramming metabolic microenvironment for nerve regeneration via waterborne polylactic acid-polyurethane copolymer scaffolds","authors":"Yuan Feng , Jinlin Chen , Xiao Wang , Chao Long , Wenbo Wang , Jingjing Lin , Yuanyuan He , Yanchao Wang , Feng Luo , Zhen Li , Jiehua Li , Hong Tan","doi":"10.1016/j.biomaterials.2024.122942","DOIUrl":"10.1016/j.biomaterials.2024.122942","url":null,"abstract":"<div><div>Cell metabolism, as the key driver of inflammation, revascularization and even subsequent tissue regeneration, is controlled by and also conversely influenced by signal transduction. Incorporation of cell metabolism into tissue engineering research holds immense potential for in-situ treatment repair and further understanding of the host-biomaterial cues in body response. In this study, an anti-inflammatory waterborne polyurethane scaffold incorporated with poly-<span>l</span>-lactic acid (PLLA) block was served to repair nerve injuries (LAx-WPU). Lactate was released through the degradation of LAx-WPU scaffolds, and the content increased with the addition of PLLA block over the degradation times. Thenceforth, the production of adenosine triphosphate (ATP) in primary neurons and neuronal axon growth were achieved by taking up lactate through monocarboxylate transporters (MCT2) for energy metabolism under glucose-free environment treated with LAx-WPU degradation solution. After LAx-WPU was implanted to repair brain nerve defects in rats, filamentous neurons elongation, rapid vascularization, and nerve tissue regeneration were realized up to 28 days with the positive expression of microtubule-associated protein (MAP2), β-tubulin (Tuj1), and platelet endothelial cell adhesion molecule (CD31) in the scaffolds. Results highlighted that the LAx-WPU scaffolds up-regulated not only the ATP-ADP-AMP purine metabolism compounds to mainly bridge neuroactive ligand-receptor interaction genes, cAMP pathway genes, and calcium pathway genes for neurocytes but also the ATP-GMP purine metabolism to angiogenesis in Gene Ontology (GO) analysis. Further analysis in reverse showed axonal regeneration is restrained by the inhibition of MCT2, proving LAx-WPU promoted nerve repair depended on lactate for energy. Therefore, LAx-WPU scaffolds construct an expected way to modulate the metabolic microenvironment for inducing nerve regeneration by intrinsic biomaterial metabolism cues without any bioactive factors.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122942"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602182","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}
Pub Date : 2024-11-01DOI: 10.1016/j.biomaterials.2024.122941
Grace H. Chen , Kee-Chin Sia , Shao-Wen Liu , Ying-Chi Kao , Pei-Ching Yang , Chia-Hsin Ho , Shih-Chen Huang , Peng-Ying Lee , Min-Zong Liang , Linyi Chen , Chieh-Cheng Huang
Traumatic brain injury (TBI) presents substantial clinical challenges, as existing treatments are unable to reverse damage or effectively promote brain tissue regeneration. Although implantable biomaterials have been proposed to support tissue repair by mitigating the adverse microenvironment in injured brains, many fail to replicate the complex composition and architecture of the native extracellular matrix (ECM), resulting in only limited therapeutic outcomes. This study introduces an innovative approach by developing a mesenchymal stem cell (MSC) spheroid-derived three-dimensional (3D) decellularized ECM (dECM) that is enriched with the MSC-derived matrisome and secretome, offering a promising solution for TBI treatment and brain tissue regeneration. Proteomic and cytokine array analyses revealed that 3D dECM retained a diverse array of MSC spheroid-derived matrisome proteins and secretome components, which are crucial for replicating the complexity of native ECM and the therapeutic capabilities of MSCs. These molecules were found to underlie the observed effects of 3D dECM on immunomodulation, proneuritogenesis, and proangiogenesis in our in vitro functional assays. Implantation of 3D dECM into TBI model mice effectively mitigated postinjury tissue damage and promoted brain repair, as evidenced by a reduced brain lesion volume, decreased cell apoptosis, alleviated neuroinflammation, reduced glial scar formation, and increased of neuroblast recruitment to the lesion site. These outcomes culminated in improved motor function recovery in animals, highlighting the multifaceted therapeutic potential of 3D dECM for TBI. In summary, our study elucidates the transformative potential of MSC spheroid-derived bioactive 3D dECM as an implantable biomaterial for effectively mitigating post-TBI neurological damage, paving the way for its broader therapeutic application.
{"title":"Implantation of MSC spheroid-derived 3D decellularized ECM enriched with the MSC secretome ameliorates traumatic brain injury and promotes brain repair","authors":"Grace H. Chen , Kee-Chin Sia , Shao-Wen Liu , Ying-Chi Kao , Pei-Ching Yang , Chia-Hsin Ho , Shih-Chen Huang , Peng-Ying Lee , Min-Zong Liang , Linyi Chen , Chieh-Cheng Huang","doi":"10.1016/j.biomaterials.2024.122941","DOIUrl":"10.1016/j.biomaterials.2024.122941","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) presents substantial clinical challenges, as existing treatments are unable to reverse damage or effectively promote brain tissue regeneration. Although implantable biomaterials have been proposed to support tissue repair by mitigating the adverse microenvironment in injured brains, many fail to replicate the complex composition and architecture of the native extracellular matrix (ECM), resulting in only limited therapeutic outcomes. This study introduces an innovative approach by developing a mesenchymal stem cell (MSC) spheroid-derived three-dimensional (3D) decellularized ECM (dECM) that is enriched with the MSC-derived matrisome and secretome, offering a promising solution for TBI treatment and brain tissue regeneration. Proteomic and cytokine array analyses revealed that 3D dECM retained a diverse array of MSC spheroid-derived matrisome proteins and secretome components, which are crucial for replicating the complexity of native ECM and the therapeutic capabilities of MSCs. These molecules were found to underlie the observed effects of 3D dECM on immunomodulation, proneuritogenesis, and proangiogenesis in our <em>in vitro</em> functional assays. Implantation of 3D dECM into TBI model mice effectively mitigated postinjury tissue damage and promoted brain repair, as evidenced by a reduced brain lesion volume, decreased cell apoptosis, alleviated neuroinflammation, reduced glial scar formation, and increased of neuroblast recruitment to the lesion site. These outcomes culminated in improved motor function recovery in animals, highlighting the multifaceted therapeutic potential of 3D dECM for TBI. In summary, our study elucidates the transformative potential of MSC spheroid-derived bioactive 3D dECM as an implantable biomaterial for effectively mitigating post-TBI neurological damage, paving the way for its broader therapeutic application.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122941"},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602159","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}
Pub Date : 2024-10-30DOI: 10.1016/j.biomaterials.2024.122923
Yuxiang Liang , Jian Meng , Zhaowei Yu , Yuqian Guo , Xiao Zhang , Yujia Yan , Shaobo Du , Shanshan Jin , Jing Li , Hailan Yang , Xiaozheng Zhang , Zhizhen Liu , Liping Li , Jun Xie
Intrauterine adhesion (IUA) presents a significant challenge in gynecology, characterized by excessive fibrosis and compromised reproductive function, leading to severe infertility. Although biocompatible hydrogels integrated with stem cells offer a promising approach for IUA therapy, clinical applications remain limited. Recent studies have highlighted the role of ferroptosis and reactive oxygen species (ROS) in IUA pathogenesis, yet strategies targeting ferroptosis through antioxidant stress are underexplored. This study investigates the therapeutic effects and mechanisms of a Ru-Single-Atom Nanozyme (Ru-SAN) incorporated into chitosan hydrogel for treating IUA. Ru-SAN, which mimics the enzyme activities of catalase, superoxide dismutase, and glutathione peroxidase, effectively clears excess ROS and shows promise in treating oxidative stress-induced diseases. The results demonstrate the superior antioxidative capabilities of Ru-SAN, significantly suppressing the ROS-ferroptosis cycle at the injury site. This creates a favorable microenvironment for post-injury repair by inhibiting inflammation, enhancing mesenchymal-to-epithelial transformation, promoting angiogenesis, and polarizing M2 macrophages. Importantly, it mitigates adverse repair outcomes from inflammation and excessive collagen fiber deposition, ultimately restoring uterine glandular structures and thickness, thereby achieving the ultimate goal of restoring fertility and live birth rates. In conclusion, our study delineates a pioneering therapeutic approach leveraging the antioxidant properties of Ru-SAN to target ferroptosis, thereby offering an efficacious treatment for IUA.
{"title":"Ru single-atom nanozymes targeting ROS-ferroptosis pathways for enhanced endometrial regeneration in intrauterine adhesion therapy","authors":"Yuxiang Liang , Jian Meng , Zhaowei Yu , Yuqian Guo , Xiao Zhang , Yujia Yan , Shaobo Du , Shanshan Jin , Jing Li , Hailan Yang , Xiaozheng Zhang , Zhizhen Liu , Liping Li , Jun Xie","doi":"10.1016/j.biomaterials.2024.122923","DOIUrl":"10.1016/j.biomaterials.2024.122923","url":null,"abstract":"<div><div>Intrauterine adhesion (IUA) presents a significant challenge in gynecology, characterized by excessive fibrosis and compromised reproductive function, leading to severe infertility. Although biocompatible hydrogels integrated with stem cells offer a promising approach for IUA therapy, clinical applications remain limited. Recent studies have highlighted the role of ferroptosis and reactive oxygen species (ROS) in IUA pathogenesis, yet strategies targeting ferroptosis through antioxidant stress are underexplored. This study investigates the therapeutic effects and mechanisms of a Ru-Single-Atom Nanozyme (Ru-SAN) incorporated into chitosan hydrogel for treating IUA. Ru-SAN, which mimics the enzyme activities of catalase, superoxide dismutase, and glutathione peroxidase, effectively clears excess ROS and shows promise in treating oxidative stress-induced diseases. The results demonstrate the superior antioxidative capabilities of Ru-SAN, significantly suppressing the ROS-ferroptosis cycle at the injury site. This creates a favorable microenvironment for post-injury repair by inhibiting inflammation, enhancing mesenchymal-to-epithelial transformation, promoting angiogenesis, and polarizing M2 macrophages. Importantly, it mitigates adverse repair outcomes from inflammation and excessive collagen fiber deposition, ultimately restoring uterine glandular structures and thickness, thereby achieving the ultimate goal of restoring fertility and live birth rates. In conclusion, our study delineates a pioneering therapeutic approach leveraging the antioxidant properties of Ru-SAN to target ferroptosis, thereby offering an efficacious treatment for IUA.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122923"},"PeriodicalIF":12.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566709","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}
Pub Date : 2024-10-30DOI: 10.1016/j.biomaterials.2024.122934
Min Han , Shiying Zhou , Zunde Liao , Chen Zishan , Xiangting Yi , Chuanbin Wu , Dongmei Zhang , Yao He , Kam W. Leong , Yiling Zhong
Immunotherapy has transformed cancer treatment, but its efficacy is often limited by the immunosuppressive characteristics of the tumor microenvironment (TME), which are predominantly influenced by the metabolism of cancer cells. Among these metabolic pathways, the indoleamine 2,3-dioxygenase (IDO) pathway is particularly crucial, as it significantly contributes to TME suppression and influences immune cell activity. Additionally, inducing immunogenic cell death (ICD) in tumor cells can reverse the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy. Herein, we develop CGDMRR, a novel bimetallic peroxide-based nanodrug based on copper-cerium peroxide nanoparticles. These nanotherapeutics are engineered to mitigate tumor hypoxia and deliver therapeutics such as 1-methyltryptophan (1MT), glucose oxidase (GOx), and doxorubicin (Dox) in a targeted manner. The design aims to alleviate tumor hypoxia, reduce the immunosuppressive effects of the IDO pathway, and promote ICD. CGDMRR effectively inhibits the growth of 4T1 tumors and elicits antitumor immune responses by leveraging immunometabolic interventions and therapies that induce ICD. Furthermore, when CGDMRR is combined with a clinically certified anti-PD-L1 antibody, its efficacy in inhibiting tumor growth is enhanced. This improved efficacy extends beyond unilateral tumor models, also affecting bilateral tumors and lung metastases, due to the activation of systemic antitumor immunity. This study underscores CGDMRR's potential to augment the efficacy of PD-L1 blockade in breast cancer immunotherapy.
{"title":"Bimetallic peroxide-based nanotherapeutics for immunometabolic intervention and induction of immunogenic cell death to augment cancer immunotherapy","authors":"Min Han , Shiying Zhou , Zunde Liao , Chen Zishan , Xiangting Yi , Chuanbin Wu , Dongmei Zhang , Yao He , Kam W. Leong , Yiling Zhong","doi":"10.1016/j.biomaterials.2024.122934","DOIUrl":"10.1016/j.biomaterials.2024.122934","url":null,"abstract":"<div><div>Immunotherapy has transformed cancer treatment, but its efficacy is often limited by the immunosuppressive characteristics of the tumor microenvironment (TME), which are predominantly influenced by the metabolism of cancer cells. Among these metabolic pathways, the indoleamine 2,3-dioxygenase (IDO) pathway is particularly crucial, as it significantly contributes to TME suppression and influences immune cell activity. Additionally, inducing immunogenic cell death (ICD) in tumor cells can reverse the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy. Herein, we develop CGDMRR, a novel bimetallic peroxide-based nanodrug based on copper-cerium peroxide nanoparticles. These nanotherapeutics are engineered to mitigate tumor hypoxia and deliver therapeutics such as 1-methyltryptophan (1MT), glucose oxidase (GOx), and doxorubicin (Dox) in a targeted manner. The design aims to alleviate tumor hypoxia, reduce the immunosuppressive effects of the IDO pathway, and promote ICD. CGDMRR effectively inhibits the growth of 4T1 tumors and elicits antitumor immune responses by leveraging immunometabolic interventions and therapies that induce ICD. Furthermore, when CGDMRR is combined with a clinically certified anti-PD-L1 antibody, its efficacy in inhibiting tumor growth is enhanced. This improved efficacy extends beyond unilateral tumor models, also affecting bilateral tumors and lung metastases, due to the activation of systemic antitumor immunity. This study underscores CGDMRR's potential to augment the efficacy of PD-L1 blockade in breast cancer immunotherapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122934"},"PeriodicalIF":12.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602154","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}
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