首页 > 最新文献

Bioengineering & Translational Medicine最新文献

英文 中文
Micro Trojan horses: Engineering extracellular vesicles crossing biological barriers for drug delivery 微型特洛伊木马:穿越生物屏障的细胞外囊泡工程,用于药物输送
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-11 DOI: 10.1002/btm2.10623
Bin Zeng, Ying Li, Jiang Xia, Yin Xiao, Nawaz Khan, Bin Jiang, Yujie Liang, Li Duan

The biological barriers of the body, such as the blood–brain, placental, intestinal, skin, and air-blood, protect against invading viruses and bacteria while providing necessary physical support. However, these barriers also hinder the delivery of drugs to target tissues, reducing their therapeutic efficacy. Extracellular vesicles (EVs), nanostructures with a diameter ranging from 30 nm to 10 μm secreted by cells, offer a potential solution to this challenge. These natural vesicles can effectively pass through various biological barriers, facilitating intercellular communication. As a result, artificially engineered EVs that mimic or are superior to the natural ones have emerged as a promising drug delivery vehicle, capable of delivering drugs to almost any body part to treat various diseases. This review first provides an overview of the formation and cross-species uptake of natural EVs from different organisms, including animals, plants, and bacteria. Later, it explores the current clinical applications, perspectives, and challenges associated with using engineered EVs as a drug delivery platform. Finally, it aims to inspire further research to help bioengineered EVs effectively cross biological barriers to treat diseases.

人体的生物屏障,如血脑屏障、胎盘屏障、肠屏障、皮肤屏障和气血屏障,可抵御病毒和细菌的入侵,同时提供必要的物理支持。然而,这些屏障也阻碍了药物向目标组织的输送,降低了药物的疗效。细胞外囊泡(EVs)是细胞分泌的直径在 30 纳米到 10 微米之间的纳米结构,为解决这一难题提供了潜在的解决方案。这些天然囊泡能有效穿过各种生物屏障,促进细胞间的交流。因此,模仿天然囊泡或优于天然囊泡的人工工程囊泡已成为一种前景广阔的药物输送载体,几乎能将药物输送到身体的任何部位以治疗各种疾病。本综述首先概述了不同生物体(包括动物、植物和细菌)天然 EVs 的形成和跨物种吸收。随后,它探讨了目前将工程EVs作为药物输送平台的临床应用、前景和相关挑战。最后,它旨在启发进一步的研究,帮助生物工程EVs有效跨越生物屏障治疗疾病。
{"title":"Micro Trojan horses: Engineering extracellular vesicles crossing biological barriers for drug delivery","authors":"Bin Zeng,&nbsp;Ying Li,&nbsp;Jiang Xia,&nbsp;Yin Xiao,&nbsp;Nawaz Khan,&nbsp;Bin Jiang,&nbsp;Yujie Liang,&nbsp;Li Duan","doi":"10.1002/btm2.10623","DOIUrl":"10.1002/btm2.10623","url":null,"abstract":"<p>The biological barriers of the body, such as the blood–brain, placental, intestinal, skin, and air-blood, protect against invading viruses and bacteria while providing necessary physical support. However, these barriers also hinder the delivery of drugs to target tissues, reducing their therapeutic efficacy. Extracellular vesicles (EVs), nanostructures with a diameter ranging from 30 nm to 10 μm secreted by cells, offer a potential solution to this challenge. These natural vesicles can effectively pass through various biological barriers, facilitating intercellular communication. As a result, artificially engineered EVs that mimic or are superior to the natural ones have emerged as a promising drug delivery vehicle, capable of delivering drugs to almost any body part to treat various diseases. This review first provides an overview of the formation and cross-species uptake of natural EVs from different organisms, including animals, plants, and bacteria. Later, it explores the current clinical applications, perspectives, and challenges associated with using engineered EVs as a drug delivery platform. Finally, it aims to inspire further research to help bioengineered EVs effectively cross biological barriers to treat diseases.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10623","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139431687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ultrasound molecular imaging for early detection of acute renal ischemia–reperfusion injury 超声分子成像用于早期检测急性肾缺血再灌注损伤
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-01-03 DOI: 10.1002/btm2.10638
Ling Ren, Yuzhuo Zhao, Tiantian Wang, Yan Tong, Ping Zhao, Fang Nie, Yukun Luo, Lianhua Zhu

Background

Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti-vascular cell adhesion molecule-1(VCAM-1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response.

Methods

TM carrying VCAM-1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia–reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty-six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham-operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated.

Results

TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM-1 molecule expressed by tumor necrosis factor-alpha (TNF-α)-treated HUVECs. In the renal IRI-AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p < 0.05). Normalized intensity difference (NID) of TM at different reperfusion time was all higher than that of blank microbubbles (BM) and the Sham group (p < 0.05). Ultrasound molecular imaging of TM could detect AKI early before commonly used renal function markers, histopathological biomarkers, and BM imaging. AUC of TM was negatively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), and Cystatin C (Cys-C) levels, and NID of TM was linearly correlated with VCAM-1, TNF-α, and interleukin-6 (IL-6) expression (p < 0.05).

Conclusions

Ultrasound molecular imaging based on TM carrying VCAM-1 polypeptide can accurately evaluate the changes in renal microcirculatory perfusion and inflammatory response, which might be a promising modality for early diagnosis of AKI.

微循环灌注障碍和炎症反应是急性肾损伤(AKI)的关键环节。我们的目标是构建抗血管细胞粘附分子-1(VCAM-1)靶向微气泡(TM)来监测肾脏微循环灌注和炎症反应。
{"title":"Ultrasound molecular imaging for early detection of acute renal ischemia–reperfusion injury","authors":"Ling Ren,&nbsp;Yuzhuo Zhao,&nbsp;Tiantian Wang,&nbsp;Yan Tong,&nbsp;Ping Zhao,&nbsp;Fang Nie,&nbsp;Yukun Luo,&nbsp;Lianhua Zhu","doi":"10.1002/btm2.10638","DOIUrl":"10.1002/btm2.10638","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti-vascular cell adhesion molecule-1(VCAM-1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>TM carrying VCAM-1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia–reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty-six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham-operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM-1 molecule expressed by tumor necrosis factor-alpha (TNF-α)-treated HUVECs. In the renal IRI-AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (<i>p</i> &lt; 0.05). Normalized intensity difference (NID) of TM at different reperfusion time was all higher than that of blank microbubbles (BM) and the Sham group (<i>p</i> &lt; 0.05). Ultrasound molecular imaging of TM could detect AKI early before commonly used renal function markers, histopathological biomarkers, and BM imaging. AUC of TM was negatively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), and Cystatin C (Cys-C) levels, and NID of TM was linearly correlated with VCAM-1, TNF-α, and interleukin-6 (IL-6) expression (<i>p</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Ultrasound molecular imaging based on TM carrying VCAM-1 polypeptide can accurately evaluate the changes in renal microcirculatory perfusion and inflammatory response, which might be a promising modality for early diagnosis of AKI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139110487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An AI-assisted integrated, scalable, single-cell phenomic-transcriptomic platform to elucidate intratumor heterogeneity against immune response 人工智能辅助的集成、可扩展的单细胞表观-转录组学平台,用于阐明肿瘤内异质性对免疫反应的影响
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-02 DOI: 10.1002/btm2.10628
Christopher P. Tostado, Lucas Xian Da Ong, Joel Jia Wei Heng, Carlo Miccolis, Shumei Chia, Justine Jia Wen Seow, Yi-Chin Toh, Ramanuj DasGupta

We present a novel framework combining single-cell phenotypic data with single-cell transcriptomic analysis to identify factors underpinning heterogeneity in antitumor immune response. We developed a pairwise, tumor-immune discretized interaction assay between natural killer (NK-92MI) cells and patient-derived head and neck squamous cell carcinoma (HNSCC) cell lines on a microfluidic cell-trapping platform. Furthermore we generated a deep-learning computer vision algorithm that is capable of automating the acquisition and analysis of a large, live-cell imaging data set (>1 million) of paired tumor-immune interactions spanning a time course of 24 h across multiple HNSCC lines (n = 10). Finally, we combined the response data measured by Kaplan–Meier survival analysis against NK-mediated killing with downstream single-cell transcriptomic analysis to interrogate molecular signatures associated with NK-effector response. As proof-of-concept for the proposed framework, we efficiently identified MHC class I-driven cytotoxic resistance as a key mechanism for immune evasion in nonresponders, while enhanced expression of cell adhesion molecules was found to be correlated with sensitivity against NK-mediated cytotoxicity. We conclude that this integrated, data-driven phenotypic approach holds tremendous promise in advancing the rapid identification of new mechanisms and therapeutic targets related to immune evasion and response.

我们提出了一个结合单细胞表型数据和单细胞转录组分析的新框架,以确定抗肿瘤免疫反应异质性的基础因素。我们在微流控细胞捕获平台上开发了自然杀伤(NK-92MI)细胞与患者来源的头颈部鳞状细胞癌(HNSCC)细胞系之间的成对、肿瘤免疫离散化相互作用测定。此外,我们还生成了一种深度学习计算机视觉算法,该算法能够自动获取和分析大型活细胞成像数据集(>100 万),这些数据集记录了多个 HNSCC 细胞系(n = 10)在 24 小时内肿瘤与免疫相互作用的配对情况。最后,我们将通过 Kaplan-Meier 生存分析测得的 NK 介导杀伤反应数据与下游单细胞转录组分析相结合,研究与 NK 效应相关的分子特征。作为拟议框架的概念验证,我们有效地确定了 MHC I 类驱动的细胞毒性抵抗是无应答者免疫逃避的关键机制,同时发现细胞粘附分子表达的增强与对 NK 介导的细胞毒性的敏感性相关。我们的结论是,这种数据驱动的综合表型方法在推动快速识别与免疫逃避和反应相关的新机制和治疗靶点方面前景广阔。
{"title":"An AI-assisted integrated, scalable, single-cell phenomic-transcriptomic platform to elucidate intratumor heterogeneity against immune response","authors":"Christopher P. Tostado,&nbsp;Lucas Xian Da Ong,&nbsp;Joel Jia Wei Heng,&nbsp;Carlo Miccolis,&nbsp;Shumei Chia,&nbsp;Justine Jia Wen Seow,&nbsp;Yi-Chin Toh,&nbsp;Ramanuj DasGupta","doi":"10.1002/btm2.10628","DOIUrl":"10.1002/btm2.10628","url":null,"abstract":"<p>We present a novel framework combining single-cell phenotypic data with single-cell transcriptomic analysis to identify factors underpinning heterogeneity in antitumor immune response. We developed a pairwise, tumor-immune discretized interaction assay between natural killer (NK-92MI) cells and patient-derived head and neck squamous cell carcinoma (HNSCC) cell lines on a microfluidic cell-trapping platform. Furthermore we generated a deep-learning computer vision algorithm that is capable of automating the acquisition and analysis of a large, live-cell imaging data set (&gt;1 million) of paired tumor-immune interactions spanning a time course of 24 h across multiple HNSCC lines (<i>n</i> = 10). Finally, we combined the response data measured by Kaplan–Meier survival analysis against NK-mediated killing with downstream single-cell transcriptomic analysis to interrogate molecular signatures associated with NK-effector response. As proof-of-concept for the proposed framework, we efficiently identified MHC class I-driven cytotoxic resistance as a key mechanism for immune evasion in nonresponders, while enhanced expression of cell adhesion molecules was found to be correlated with sensitivity against NK-mediated cytotoxicity. We conclude that this integrated, data-driven phenotypic approach holds tremendous promise in advancing the rapid identification of new mechanisms and therapeutic targets related to immune evasion and response.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10628","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139389698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Feasibility of engineered Bacillus subtilis for use as a microbiome-based topical drug delivery platform 将工程枯草芽孢杆菌用作微生物局部给药平台的可行性
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-01-02 DOI: 10.1002/btm2.10645
Veronica A. Montgomery, Amy J. Wood-Yang, Mark P. Styczynski, Mark R. Prausnitz

Non-adherence to medication is a major challenge in healthcare that results in worsened treatment outcomes for patients. Reducing the frequency of required administrations could improve adherence but is challenging for topical drug delivery due to the generally short residence time of topical formulations on the skin. In this study, we sought to determine the feasibility of developing a microbiome-based, long-acting, topical delivery platform using Bacillus subtilis for drug production and delivery on the skin, which was assessed using green fluorescent protein as a model heterologous protein for delivery. We developed a computational model of bacteria population dynamics on the skin and used its qualitative predictions to guide experimental design choices. Using an ex vivo pig skin model and a human skin tissue culture model, we saw persistence of delivered bacteria for multiple days and observed little evidence of cytotoxicity to human keratinocyte cells in vitro. Finally, using an in vivo mouse model, we found that the delivered bacteria persisted on the skin for at least 1 day during every-other-day application and did not appear to present safety concerns. Taken together, our results support the feasibility of using engineered B. subtilis for topical drug delivery.

不坚持用药是医疗保健领域的一大挑战,会导致患者的治疗效果恶化。减少用药次数可以提高用药依从性,但由于外用制剂在皮肤上的停留时间通常较短,因此对于外用给药来说具有挑战性。在本研究中,我们试图确定利用枯草芽孢杆菌开发一种基于微生物组的长效局部给药平台的可行性,以绿色荧光蛋白作为给药的异源蛋白模型。我们开发了皮肤上细菌种群动态的计算模型,并利用其定性预测来指导实验设计选择。通过使用猪体外皮肤模型和人体皮肤组织培养模型,我们发现递送的细菌可持续存在多天,并且在体外几乎没有观察到对人体角质细胞产生细胞毒性的证据。最后,通过使用体内小鼠模型,我们发现在隔天一次的施用过程中,递送的细菌在皮肤上至少能持续存在 1 天,似乎不存在安全问题。综上所述,我们的研究结果支持使用工程化枯草杆菌进行局部给药的可行性。
{"title":"Feasibility of engineered Bacillus subtilis for use as a microbiome-based topical drug delivery platform","authors":"Veronica A. Montgomery,&nbsp;Amy J. Wood-Yang,&nbsp;Mark P. Styczynski,&nbsp;Mark R. Prausnitz","doi":"10.1002/btm2.10645","DOIUrl":"10.1002/btm2.10645","url":null,"abstract":"<p>Non-adherence to medication is a major challenge in healthcare that results in worsened treatment outcomes for patients. Reducing the frequency of required administrations could improve adherence but is challenging for topical drug delivery due to the generally short residence time of topical formulations on the skin. In this study, we sought to determine the feasibility of developing a microbiome-based, long-acting, topical delivery platform using <i>Bacillus subtilis</i> for drug production and delivery on the skin, which was assessed using green fluorescent protein as a model heterologous protein for delivery. We developed a computational model of bacteria population dynamics on the skin and used its qualitative predictions to guide experimental design choices. Using an <i>ex vivo</i> pig skin model and a human skin tissue culture model, we saw persistence of delivered bacteria for multiple days and observed little evidence of cytotoxicity to human keratinocyte cells <i>in vitro</i>. Finally, using an in vivo mouse model, we found that the delivered bacteria persisted on the skin for at least 1 day during every-other-day application and did not appear to present safety concerns. Taken together, our results support the feasibility of using engineered <i>B. subtilis</i> for topical drug delivery.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139076851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Growth factors and growth factor gene therapies for treating chronic wounds 用于治疗慢性伤口的生长因子和生长因子基因疗法
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-28 DOI: 10.1002/btm2.10642
James A. Mullin, Erfan Rahmani, Kristi L. Kiick, Millicent O. Sullivan

Chronic wounds are an unmet clinical need affecting millions of patients globally, and current standards of care fail to consistently promote complete wound closure and prevent recurrence. Disruptions in growth factor signaling, a hallmark of chronic wounds, have led researchers to pursue growth factor therapies as potential supplements to standards of care. Initial studies delivering growth factors in protein form showed promise, with a few formulations reaching clinical trials and one obtaining clinical approval. However, protein-form growth factors are limited by instability and off-target effects. Gene therapy offers an alternative approach to deliver growth factors to the chronic wound environment, but safety concerns surrounding gene therapy as well as efficacy challenges in the gene delivery process have prevented clinical translation. Current growth factor delivery and gene therapy approaches have primarily used single growth factor formulations, but recent efforts have aimed to develop multi-growth factor approaches that are better suited to address growth factor insufficiencies in the chronic wound environment, and these strategies have demonstrated improved efficacy in preclinical studies. This review provides an overview of chronic wound healing, emphasizing the need and potential for growth factor therapies. It includes a summary of current standards of care, recent advances in growth factor, cell-based, and gene therapy approaches, and future perspectives for multi-growth factor therapeutics.

慢性伤口是一项尚未得到满足的临床需求,影响着全球数百万患者,而目前的护理标准无法持续促进伤口完全闭合并防止复发。生长因子信号转导紊乱是慢性伤口的一大特征,这促使研究人员将生长因子疗法作为治疗标准的潜在补充。最初的研究显示,以蛋白质形式提供生长因子大有可为,一些制剂已进入临床试验阶段,其中一种制剂还获得了临床批准。然而,蛋白形式的生长因子受到不稳定性和脱靶效应的限制。基因疗法为向慢性伤口环境输送生长因子提供了另一种方法,但基因疗法的安全性问题以及基因输送过程中的疗效挑战阻碍了临床转化。目前的生长因子输送和基因治疗方法主要使用单一生长因子制剂,但最近的努力旨在开发更适合解决慢性伤口环境中生长因子不足问题的多生长因子方法,这些策略已在临床前研究中证明了更好的疗效。本综述概述了慢性伤口愈合,强调了生长因子疗法的必要性和潜力。文章概述了目前的治疗标准,生长因子、细胞和基因治疗方法的最新进展,以及多种生长因子疗法的未来前景。
{"title":"Growth factors and growth factor gene therapies for treating chronic wounds","authors":"James A. Mullin,&nbsp;Erfan Rahmani,&nbsp;Kristi L. Kiick,&nbsp;Millicent O. Sullivan","doi":"10.1002/btm2.10642","DOIUrl":"10.1002/btm2.10642","url":null,"abstract":"<p>Chronic wounds are an unmet clinical need affecting millions of patients globally, and current standards of care fail to consistently promote complete wound closure and prevent recurrence. Disruptions in growth factor signaling, a hallmark of chronic wounds, have led researchers to pursue growth factor therapies as potential supplements to standards of care. Initial studies delivering growth factors in protein form showed promise, with a few formulations reaching clinical trials and one obtaining clinical approval. However, protein-form growth factors are limited by instability and off-target effects. Gene therapy offers an alternative approach to deliver growth factors to the chronic wound environment, but safety concerns surrounding gene therapy as well as efficacy challenges in the gene delivery process have prevented clinical translation. Current growth factor delivery and gene therapy approaches have primarily used single growth factor formulations, but recent efforts have aimed to develop multi-growth factor approaches that are better suited to address growth factor insufficiencies in the chronic wound environment, and these strategies have demonstrated improved efficacy in preclinical studies. This review provides an overview of chronic wound healing, emphasizing the need and potential for growth factor therapies. It includes a summary of current standards of care, recent advances in growth factor, cell-based, and gene therapy approaches, and future perspectives for multi-growth factor therapeutics.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10642","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139051018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Trafficking through the blood–brain barrier is directed by core and outer surface components of layer-by-layer nanoparticles 逐层纳米粒子的核心和外表面成分引导血脑屏障的迁移
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-12-28 DOI: 10.1002/btm2.10636
Nicholas G. Lamson, Andrew J. Pickering, Jeffrey Wyckoff, Priya Ganesh, Elizabeth A. Calle, Joelle P. Straehla, Paula T. Hammond

Drug-carrying nanoparticles are a promising strategy to deliver therapeutics into the brain, but their translation requires better characterization of interactions between nanomaterials and endothelial cells of the blood–brain barrier (BBB). Here, we use a library of 18 layer-by-layer electrostatically assembled nanoparticles (NPs) to independently assess the impact of NP core and surface materials on in vitro uptake, transport, and intracellular trafficking in brain endothelial cells. We demonstrate that NP core stiffness determines the magnitude of transport, while surface chemistry directs intracellular trafficking. Finally, we demonstrate that these factors similarly dictate in vivo BBB transport using intravital imaging through cranial windows in mice. We identify that hyaluronic acid surface chemistry increases transport across the BBB in vivo, and flow conditions are necessary to replicate this finding in vitro. Taken together, these findings highlight the importance of assay geometry, cell biology, and fluid flow in developing nanocarriers for delivery to the brain.

载药纳米粒子是向大脑输送治疗药物的一种很有前景的策略,但要将其转化为药物,需要更好地描述纳米材料与血脑屏障(BBB)内皮细胞之间的相互作用。在这里,我们利用 18 种逐层静电组装的纳米粒子(NPs)库,独立评估了 NP 核心和表面材料对体外吸收、运输和脑内皮细胞胞内贩运的影响。我们证明,NP 核心硬度决定了运输量的大小,而表面化学物质则引导着细胞内的运输。最后,我们通过对小鼠颅窗的体内成像证明,这些因素同样决定着体内 BBB 的运输。我们发现透明质酸表面化学成分能增加体内通过 BBB 的转运,而在体外复制这一发现需要流动条件。总之,这些发现突出表明了在开发向大脑输送纳米载体的过程中,检测几何形状、细胞生物学和流体流动的重要性。
{"title":"Trafficking through the blood–brain barrier is directed by core and outer surface components of layer-by-layer nanoparticles","authors":"Nicholas G. Lamson,&nbsp;Andrew J. Pickering,&nbsp;Jeffrey Wyckoff,&nbsp;Priya Ganesh,&nbsp;Elizabeth A. Calle,&nbsp;Joelle P. Straehla,&nbsp;Paula T. Hammond","doi":"10.1002/btm2.10636","DOIUrl":"10.1002/btm2.10636","url":null,"abstract":"<p>Drug-carrying nanoparticles are a promising strategy to deliver therapeutics into the brain, but their translation requires better characterization of interactions between nanomaterials and endothelial cells of the blood–brain barrier (BBB). Here, we use a library of 18 layer-by-layer electrostatically assembled nanoparticles (NPs) to independently assess the impact of NP core and surface materials on in vitro uptake, transport, and intracellular trafficking in brain endothelial cells. We demonstrate that NP core stiffness determines the magnitude of transport, while surface chemistry directs intracellular trafficking. Finally, we demonstrate that these factors similarly dictate in vivo BBB transport using intravital imaging through cranial windows in mice. We identify that hyaluronic acid surface chemistry increases transport across the BBB in vivo, and flow conditions are necessary to replicate this finding in vitro. Taken together, these findings highlight the importance of assay geometry, cell biology, and fluid flow in developing nanocarriers for delivery to the brain.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139061235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differential sensitivity to hypoxia enables shape-based classification of sickle cell disease and trait blood samples at point of care 对缺氧的不同敏感性可在护理点对镰状细胞疾病和特质血液样本进行基于形状的分类
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2023-12-27 DOI: 10.1002/btm2.10643
Claudy D'Costa, Oshin Sharma, Riddha Manna, Minakshi Singh, Samrat Singh, Srushti Singh, Anish Mahto, Pratiksha Govil, Sampath Satti, Ninad Mehendale, Yazdi Italia, Debjani Paul

Red blood cells (RBCs) become sickle-shaped and stiff under hypoxia as a consequence of hemoglobin (Hb) polymerization in sickle cell anemia. Distinguishing between sickle cell disease and trait is crucial during the diagnosis of sickle cell disease. While genetic analysis or high-performance liquid chromatography (HPLC) can accurately differentiate between these two genotypes, these tests are unsuitable for field use. Here, we report a novel microscopy-based diagnostic test called ShapeDx™ to distinguish between disease and trait blood in less than 1 h. This is achieved by mixing an unknown blood sample with low and high concentrations of a chemical oxygen scavenger and thereby subjecting the blood to slow and fast hypoxia, respectively. The different rates of Hb polymerization resulting from slow and fast hypoxia lead to two distinct RBC shape distributions in the same blood sample, which allows us to identify it as healthy, trait, or disease. The controlled hypoxic environment necessary for differential Hb polymerization is generated using an imaging microchamber, which also reduces the sickling time of trait blood from several hours to just 30 min. In a single-blinded proof-of-concept study conducted on a small cohort of clinical samples, the results of the ShapeDx™ test were 100% concordant with HPLC results. Additionally, our field studies have demonstrated that ShapeDx™ is the first reported microscopy test capable of distinguishing between sickle cell disease and trait samples in resource-limited settings with the same accuracy as a gold standard test.

由于镰状细胞贫血症中血红蛋白(Hb)聚合的结果,红细胞(RBC)在缺氧情况下会变成镰状且僵硬。在诊断镰状细胞病的过程中,区分镰状细胞病和遗传性镰状细胞病至关重要。虽然基因分析或高效液相色谱法(HPLC)可以准确区分这两种基因型,但这些检测方法不适合现场使用。在这里,我们报告了一种名为 ShapeDx™ 的基于显微镜的新型诊断测试,该测试可在 1 小时内区分疾病和特异性血液,其方法是将未知血液样本与低浓度和高浓度的化学氧清除剂混合,从而使血液分别处于慢缺氧和快缺氧状态。缓慢缺氧和快速缺氧导致 Hb 聚合速度不同,从而在同一血液样本中形成两种不同的红细胞形状分布,这使我们能够将其识别为健康、特质或疾病。差异 Hb 聚合所需的可控缺氧环境是通过成像微室产生的,它还能将特质血液的镰状时间从数小时缩短到 30 分钟。在对一小批临床样本进行的单盲概念验证研究中,ShapeDx™ 检测结果与 HPLC 结果的一致性达到 100%。此外,我们的现场研究还表明,ShapeDx™ 是首个报道的显微镜检测方法,能够在资源有限的环境中区分镰状细胞疾病和特质样本,其准确性与金标准检测方法相同。
{"title":"Differential sensitivity to hypoxia enables shape-based classification of sickle cell disease and trait blood samples at point of care","authors":"Claudy D'Costa,&nbsp;Oshin Sharma,&nbsp;Riddha Manna,&nbsp;Minakshi Singh,&nbsp;Samrat Singh,&nbsp;Srushti Singh,&nbsp;Anish Mahto,&nbsp;Pratiksha Govil,&nbsp;Sampath Satti,&nbsp;Ninad Mehendale,&nbsp;Yazdi Italia,&nbsp;Debjani Paul","doi":"10.1002/btm2.10643","DOIUrl":"10.1002/btm2.10643","url":null,"abstract":"<p>Red blood cells (RBCs) become sickle-shaped and stiff under hypoxia as a consequence of hemoglobin (Hb) polymerization in sickle cell anemia. Distinguishing between sickle cell disease and trait is crucial during the diagnosis of sickle cell disease. While genetic analysis or high-performance liquid chromatography (HPLC) can accurately differentiate between these two genotypes, these tests are unsuitable for field use. Here, we report a novel microscopy-based diagnostic test called ShapeDx™ to distinguish between disease and trait blood in less than 1 h. This is achieved by mixing an unknown blood sample with low and high concentrations of a chemical oxygen scavenger and thereby subjecting the blood to slow and fast hypoxia, respectively. The different rates of Hb polymerization resulting from slow and fast hypoxia lead to two distinct RBC shape distributions in the same blood sample, which allows us to identify it as healthy, trait, or disease. The controlled hypoxic environment necessary for differential Hb polymerization is generated using an imaging microchamber, which also reduces the sickling time of trait blood from several hours to just 30 min. In a single-blinded proof-of-concept study conducted on a small cohort of clinical samples, the results of the ShapeDx™ test were 100% concordant with HPLC results. Additionally, our field studies have demonstrated that ShapeDx™ is the first reported microscopy test capable of distinguishing between sickle cell disease and trait samples in resource-limited settings with the same accuracy as a gold standard test.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2023-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10643","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139051012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair 许旺细胞集结成球体后获得修复表型,在促进周围神经修复方面显示出更强的体内治疗潜力
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-26 DOI: 10.1002/btm2.10635
Shih-Heng Chen, Hsin-Wen Wang, Pei-Ching Yang, Shih-Shien Chen, Chia-Hsin Ho, Pei-Ching Yang, Ying-Chi Kao, Shao-Wen Liu, Han Chiu, Yu-Jie Lin, Er-Yuan Chuang, Jen-Huang Huang, Huang-Kai Kao, Chieh-Cheng Huang

The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three-dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c-Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid-derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC-based transplantation approaches for promoting peripheral nerve regeneration.

损伤后周围神经再生的预后仍不理想。虽然移植外源性许旺细胞(SCs)被认为是促进神经修复的一种很有前景的治疗方法,但这种策略在实践中一直受到SC来源有限和移植后细胞保留率不足的阻碍。在本研究中,为了应对这些挑战,我们先将 SC 聚合成球,然后再输送到受伤的大鼠坐骨神经中。我们发现,SCs 的三维聚集诱导其获得修复表型,表现为 c-Jun 表达/激活水平的提高和髓鞘蛋白表达的降低。此外,我们的体外实验结果表明,SC球状体衍生的分泌组在促进背根神经节神经元的神经元生长、增强内源性SC的增殖和迁移以及招募巨噬细胞方面具有卓越的潜力。此外,将 SC 球体移植到坐骨神经横断后的大鼠体内,可有效提高伤后神经结构恢复率和运动功能恢复率,证明了 SC 球体的治疗潜力。总之,预组装的SC球体移植在提高细胞输送效率和治疗效果方面具有巨大潜力,从而改进了基于SC的移植方法,促进了周围神经再生。
{"title":"Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair","authors":"Shih-Heng Chen,&nbsp;Hsin-Wen Wang,&nbsp;Pei-Ching Yang,&nbsp;Shih-Shien Chen,&nbsp;Chia-Hsin Ho,&nbsp;Pei-Ching Yang,&nbsp;Ying-Chi Kao,&nbsp;Shao-Wen Liu,&nbsp;Han Chiu,&nbsp;Yu-Jie Lin,&nbsp;Er-Yuan Chuang,&nbsp;Jen-Huang Huang,&nbsp;Huang-Kai Kao,&nbsp;Chieh-Cheng Huang","doi":"10.1002/btm2.10635","DOIUrl":"10.1002/btm2.10635","url":null,"abstract":"<p>The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three-dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c-Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid-derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC-based transplantation approaches for promoting peripheral nerve regeneration.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139051014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Photothermal Prussian blue nanoparticles generate potent multi-targeted tumor-specific T cells as an adoptive cell therapy 光热普鲁士蓝纳米粒子可产生强效多靶点肿瘤特异性 T 细胞,作为一种采用性细胞疗法
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-22 DOI: 10.1002/btm2.10639
Elizabeth E. Sweeney, Palak Sekhri, Nethaji Muniraj, Jie Chen, Sally Feng, Joshua Terao, Samantha J. Chin, Danielle E. Schmidt, Catherine M. Bollard, Conrad Russell Y. Cruz, Rohan Fernandes

Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP-PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP-PTT could be used ex vivo to generate tumor-specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP-PTT. We observed that PBNP-PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co-culture with U87 cells, consistent with tumor-specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP-PTT-derived T cells effectively reduced U87 tumor growth and generated long-term survival in >80% of tumor-bearing mice by Day 100, compared to 0% of mice treated with PBS, non-specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and acute monocytic leukemia (THP-1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor-specific cytolytic function relative to controls, demonstrating the versatility of PBNP-PTT in generating tumor-specific T cells for ATCT.

基于普鲁士蓝纳米粒子的光热疗法(PBNP-PTT)是一种能激发抗肿瘤免疫反应的有效肿瘤治疗方法。由于普鲁士蓝纳米粒子能增强内源性免疫反应,我们最近证明了普鲁士蓝纳米粒子可用于体外产生针对胶质母细胞瘤(GBM)细胞系的肿瘤特异性 T 细胞,作为一种领养 T 细胞疗法(ATCT)。在本研究中,我们进一步开发了这一前景广阔的 T 细胞开发平台。首先,我们评估了使用 PBNP-PTT 生成的 T 细胞的表型和功能。我们观察到,PBNP-PTT 促进了来自健康供体 PBMC 的 CD8+ T 细胞扩增,这些细胞分泌 IFNγ 和 TNFα,并在与靶 U87 细胞接触时上调 CD107a,这表明特异性抗肿瘤 T 细胞活化和脱颗粒。此外,CD8+效应和效应记忆T细胞群在与U87细胞共培养后显著扩大,这与肿瘤特异性效应反应一致。在体内正位植入的 U87 GBM 肿瘤中,PBNP-PTT 衍生的 T 细胞能有效减少 U87 肿瘤的生长,并使 80% 的肿瘤小鼠在第 100 天时长期存活,而用 PBS、非特异性 T 细胞或由裂解的 U87 细胞扩增的 T 细胞治疗的小鼠则只有 0%,这表明该 ATCT 平台的抗肿瘤功效得到了增强。最后,我们通过生成靶向髓母细胞瘤(D556)、乳腺癌(MDA-MB-231)、神经母细胞瘤(SH-SY5Y)和急性单核细胞白血病(THP-1)细胞系的 T 细胞,测试了这种方法的通用性。与对照组相比,产生的T细胞分泌IFNγ并发挥更强的肿瘤特异性细胞溶解功能,这证明了PBNP-PTT在为ATCT生成肿瘤特异性T细胞方面的多功能性。
{"title":"Photothermal Prussian blue nanoparticles generate potent multi-targeted tumor-specific T cells as an adoptive cell therapy","authors":"Elizabeth E. Sweeney,&nbsp;Palak Sekhri,&nbsp;Nethaji Muniraj,&nbsp;Jie Chen,&nbsp;Sally Feng,&nbsp;Joshua Terao,&nbsp;Samantha J. Chin,&nbsp;Danielle E. Schmidt,&nbsp;Catherine M. Bollard,&nbsp;Conrad Russell Y. Cruz,&nbsp;Rohan Fernandes","doi":"10.1002/btm2.10639","DOIUrl":"10.1002/btm2.10639","url":null,"abstract":"<p>Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP-PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP-PTT could be used ex vivo to generate tumor-specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP-PTT. We observed that PBNP-PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co-culture with U87 cells, consistent with tumor-specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP-PTT-derived T cells effectively reduced U87 tumor growth and generated long-term survival in &gt;80% of tumor-bearing mice by Day 100, compared to 0% of mice treated with PBS, non-specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and acute monocytic leukemia (THP-1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor-specific cytolytic function relative to controls, demonstrating the versatility of PBNP-PTT in generating tumor-specific T cells for ATCT.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138943480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: Insights from in vitro and in vivo models 成纤维细胞和内皮细胞的相互作用推动了肥厚性疤痕的形成:体外和体内模型的启示
IF 7.4 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-20 DOI: 10.1002/btm2.10630
Yaxin Tan, Mengde Zhang, Yi Kong, Fanliang Zhang, Yuzhen Wang, Yuyan Huang, Wei Song, Zhao Li, Linhao Hou, Liting Liang, Xu Guo, Qinghua Liu, Yu Feng, Chao Zhang, Xiaobing Fu, Sha Huang

Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-β. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-β, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.

肥厚性疤痕的形成受成纤维细胞和内皮细胞之间错综复杂的相互作用的影响。在本研究中,我们利用体外和体内模型研究了这种关系。临床观察发现,病理疤痕部位有明显的形态变化和血管增加。利用 OCTA、免疫组织化学和免疫荧光技术进行的进一步分析证实,血管生成参与了疤痕的形成。我们的间接共培养系统证明,内皮细胞通过分泌细胞因子(包括血管内皮生长因子、血管内皮生长因子、bFGF 和 TGF-β)促进成纤维细胞的增殖和迁移。此外,悬浮共培养多细胞球体模型揭示了与细胞外基质重塑、细胞行为、炎症反应和促血管生成活性相关的分子水平变化。此外,KEGG 通路分析确定了 TGF-β、IL-17、Wnt、Notch、PI3K-Akt 和 MAPK 通路参与调节成纤维细胞的活性。这些发现强调了成纤维细胞-内皮细胞串扰在疤痕形成中的关键作用,并为治疗干预提供了潜在靶点。了解这种相互作用的分子机制有望开发出治疗组织损伤和疾病的创新方法。
{"title":"Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: Insights from in vitro and in vivo models","authors":"Yaxin Tan,&nbsp;Mengde Zhang,&nbsp;Yi Kong,&nbsp;Fanliang Zhang,&nbsp;Yuzhen Wang,&nbsp;Yuyan Huang,&nbsp;Wei Song,&nbsp;Zhao Li,&nbsp;Linhao Hou,&nbsp;Liting Liang,&nbsp;Xu Guo,&nbsp;Qinghua Liu,&nbsp;Yu Feng,&nbsp;Chao Zhang,&nbsp;Xiaobing Fu,&nbsp;Sha Huang","doi":"10.1002/btm2.10630","DOIUrl":"10.1002/btm2.10630","url":null,"abstract":"<p>Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-β. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-β, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10630","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Bioengineering & Translational Medicine
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1