Ankit Kumar, Ranganath Maringanti, Tanmay Mathur, Jun‐ichi Abe, Nhat‐Tu Le, Yiwei Xiao, Guangyu Wang, Anahita Mojiri, John P. Cooke, Abhishek Jain
The US Food and Drug Administration (FDA) Modernization Act 3.0, and the announcement of an National Institutes of Health (NIH)‐wide Office of Research Innovation, Validation, and Application has increased funding for, and encouraged development of, human avatars for disease modeling and drug discovery. This pivotal change has sparked excitement among engineers, scientists, and industry stakeholders to utilize microphysiological systems—also known as organ‐chips—as viable alternative platforms that may be alternatives to animal models in replicating human pathophysiology. The promise of such systems is that they will be more predictive of clinical responses to novel therapeutic interventions. Furthermore, such systems lend themselves to relatively more patient‐specific approaches. These human chips might support precision medicine by predicting response to drugs and therapies—in early clinical trial phases or perhaps even at the bedside. However, for vascular avatars to be useful in preclinical drug development or in clinical trial refinement, several technical, scientific, and educational barriers remain to be addressed. This review highlights the current advancements, potential, and challenges in leveraging vessel‐chip technologies to accelerate vascular medicine and drug discovery, raising the prospect of more rapid FDA investigational new drug approvals and efficient clinical trials.
{"title":"Investigational New Drug ‐enabling studies in a human vessel‐chip: Are we there yet?","authors":"Ankit Kumar, Ranganath Maringanti, Tanmay Mathur, Jun‐ichi Abe, Nhat‐Tu Le, Yiwei Xiao, Guangyu Wang, Anahita Mojiri, John P. Cooke, Abhishek Jain","doi":"10.1002/btm2.70129","DOIUrl":"https://doi.org/10.1002/btm2.70129","url":null,"abstract":"The US Food and Drug Administration (FDA) Modernization Act 3.0, and the announcement of an National Institutes of Health (NIH)‐wide Office of Research Innovation, Validation, and Application has increased funding for, and encouraged development of, human avatars for disease modeling and drug discovery. This pivotal change has sparked excitement among engineers, scientists, and industry stakeholders to utilize microphysiological systems—also known as organ‐chips—as viable alternative platforms that may be alternatives to animal models in replicating human pathophysiology. The promise of such systems is that they will be more predictive of clinical responses to novel therapeutic interventions. Furthermore, such systems lend themselves to relatively more patient‐specific approaches. These human chips might support precision medicine by predicting response to drugs and therapies—in early clinical trial phases or perhaps even at the bedside. However, for vascular avatars to be useful in preclinical drug development or in clinical trial refinement, several technical, scientific, and educational barriers remain to be addressed. This review highlights the current advancements, potential, and challenges in leveraging vessel‐chip technologies to accelerate vascular medicine and drug discovery, raising the prospect of more rapid FDA investigational new drug approvals and efficient clinical trials.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"27 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Burak Kahveci, Elifsu Polatli, Ali Eren Evranos, Hüseyin Güner, Gökhan Karakülah, Yalin Bastanlar, Sinan Güven
Human‐induced pluripotent stem cells (iPSCs) offer transformative potential for biomedical research, with iPSC‐derived organoids providing more physiologically relevant models than traditional 2D cell cultures. Among these, brain organoids (BO) are particularly valuable for drug screening, disease modeling, and investigations into molecular pathways. Accurate representation of brain morphology is critical, as more complex organoid structures better mimic the human brain. Deep learning (DL) and machine learning (ML) approaches have become integral to analyzing organoid morphology, yet tools for comprehensive, time‐resolved assessments are scarce. Here, we introduce BrAIn , a DL‐based application for analyzing the developmental progression of BOs. BrAIn tracks their evolution from embryoid bodies (EBs) and quantifies parameters including area, Feret diameter, perimeter, roundness, and circularity. It also classifies budding and abnormal morphologies of 3D organoids and detects monolayer neural rosette structures, key features of neuronal differentiation. Designed with accessibility in mind, BrAIn provides a no‐code interface, enabling researchers of all technical backgrounds to conduct advanced morphological analyses with ease. Our study demonstrates the application of BrAIn to evaluate the effects of different growth conditions—static, orbital shaker, and microfluidic chip‐based—on BO development. Orbital shaker cultures resulted in the largest organoids, while chip‐based systems achieved more homogeneous growth. Both conditions produced organoids with greater morphological complexity compared to static culture. BrAIn emerges as a robust, user‐friendly tool to quantify BO development and explore how versatile growth conditions influence their morphology and maturation.
{"title":"BrAIn : A comprehensive artificial intelligence‐based morphology analysis system for brain organoids and neuroscience","authors":"Burak Kahveci, Elifsu Polatli, Ali Eren Evranos, Hüseyin Güner, Gökhan Karakülah, Yalin Bastanlar, Sinan Güven","doi":"10.1002/btm2.70123","DOIUrl":"https://doi.org/10.1002/btm2.70123","url":null,"abstract":"Human‐induced pluripotent stem cells (iPSCs) offer transformative potential for biomedical research, with iPSC‐derived organoids providing more physiologically relevant models than traditional 2D cell cultures. Among these, brain organoids (BO) are particularly valuable for drug screening, disease modeling, and investigations into molecular pathways. Accurate representation of brain morphology is critical, as more complex organoid structures better mimic the human brain. Deep learning (DL) and machine learning (ML) approaches have become integral to analyzing organoid morphology, yet tools for comprehensive, time‐resolved assessments are scarce. Here, we introduce <jats:italic>BrAIn</jats:italic> , a DL‐based application for analyzing the developmental progression of BOs. BrAIn tracks their evolution from embryoid bodies (EBs) and quantifies parameters including area, Feret diameter, perimeter, roundness, and circularity. It also classifies budding and abnormal morphologies of 3D organoids and detects monolayer neural rosette structures, key features of neuronal differentiation. Designed with accessibility in mind, BrAIn provides a no‐code interface, enabling researchers of all technical backgrounds to conduct advanced morphological analyses with ease. Our study demonstrates the application of BrAIn to evaluate the effects of different growth conditions—static, orbital shaker, and microfluidic chip‐based—on BO development. Orbital shaker cultures resulted in the largest organoids, while chip‐based systems achieved more homogeneous growth. Both conditions produced organoids with greater morphological complexity compared to static culture. BrAIn emerges as a robust, user‐friendly tool to quantify BO development and explore how versatile growth conditions influence their morphology and maturation.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"19 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarah S. Nasr, Yahya Cheema, Alexa Stern, Owen Tabah, Stephanie Poore, Gregg A. Duncan
For genetic therapies to have their intended benefit, delivery systems must be designed which reach disease‐affected organs with high efficiency. To accomplish this, gene delivery systems must overcome multiple intra‐ and extracellular barriers to avoid rapid clearance from the body and/or significant accumulation in off‐target sites which can lead to undesired side effects (e.g., genotoxicity, immunogenicity). This requires an in‐depth knowledge of biomolecular and biophysical interactions at the nano–bio interface to engineer gene vectors which preferentially access specific organs such as the liver, spleen, and brain after systemic administration. In this review, we will discuss the strategies employed to engineer genetic therapies which selectively target organs of interest after systemic administration. We focus on three major classes of nucleic acid delivery systems including adeno‐associated viruses, lipid nanoparticles, and polymeric nanoparticles (PNPs) which are all being explored for tissue‐specific gene delivery. We will go on to describe how new, highly efficient adeno‐associated virus variants as well as engineered lipid and PNPs can be discovered or rationally designed. We also discuss high throughput approaches for screening of these systems to establish important structure‐to‐function relationships that determine the fate of these gene delivery systems once administered.
{"title":"Tissue‐specific gene delivery approaches","authors":"Sarah S. Nasr, Yahya Cheema, Alexa Stern, Owen Tabah, Stephanie Poore, Gregg A. Duncan","doi":"10.1002/btm2.70125","DOIUrl":"https://doi.org/10.1002/btm2.70125","url":null,"abstract":"For genetic therapies to have their intended benefit, delivery systems must be designed which reach disease‐affected organs with high efficiency. To accomplish this, gene delivery systems must overcome multiple intra‐ and extracellular barriers to avoid rapid clearance from the body and/or significant accumulation in off‐target sites which can lead to undesired side effects (e.g., genotoxicity, immunogenicity). This requires an in‐depth knowledge of biomolecular and biophysical interactions at the nano–bio interface to engineer gene vectors which preferentially access specific organs such as the liver, spleen, and brain after systemic administration. In this review, we will discuss the strategies employed to engineer genetic therapies which selectively target organs of interest after systemic administration. We focus on three major classes of nucleic acid delivery systems including adeno‐associated viruses, lipid nanoparticles, and polymeric nanoparticles (PNPs) which are all being explored for tissue‐specific gene delivery. We will go on to describe how new, highly efficient adeno‐associated virus variants as well as engineered lipid and PNPs can be discovered or rationally designed. We also discuss high throughput approaches for screening of these systems to establish important structure‐to‐function relationships that determine the fate of these gene delivery systems once administered.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tingyu Zhang, Jie Lan, Wangrui Peng, Huai Yang, Yiyang Huang, Linyuan Jin, Meng Du, Zhiyi Chen
Tumor‐associated macrophages (TAMs) shape the tumor microenvironment through plastic transitions between pro‐inflammatory M1‐like and immunosuppressive M2‐like states, yet clinical drug therapies are limited by toxicity, resistance, and delivery barriers. This review explains how non‐invasive physical stimulation (NIPS) reprograms TAMs via defined couplings between physical inputs and signaling pathways. Hypoxia‐tolerant photodynamic strategies and mild photothermal heating reset hypoxia‐ and lactate‐driven programs; cavitation‐dominant ultrasound and sonodynamic therapy trigger danger signaling and reactive oxygen species; ultrasound microbubble destruction provides endothelial repair cues; nanosecond pulsed electric fields activate cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS–STING) pathway; piezoelectric materials convert mechanical input into calcium‐dependent transcription; and appropriately dosed radiotherapy elicits immune‐active responses while avoiding hypoxia‐driven M2 recruitment. Across models, these regimens promote pro‐inflammatory reprogramming, normalize aberrant vasculature, and strengthen antitumor immunity while restraining immunosuppression. We synthesize parameter windows, delivery options, and combination strategies with checkpoint blockade and macrophage‐directed agents to guide the translation of NIPS into precise, low‐toxicity TAM‐targeted immunotherapy.
{"title":"Engineering the tumor immune landscape: Translating non‐invasive physical stimulation into tumor‐associated macrophage‐targeted cancer immunotherapy","authors":"Tingyu Zhang, Jie Lan, Wangrui Peng, Huai Yang, Yiyang Huang, Linyuan Jin, Meng Du, Zhiyi Chen","doi":"10.1002/btm2.70126","DOIUrl":"https://doi.org/10.1002/btm2.70126","url":null,"abstract":"Tumor‐associated macrophages (TAMs) shape the tumor microenvironment through plastic transitions between pro‐inflammatory M1‐like and immunosuppressive M2‐like states, yet clinical drug therapies are limited by toxicity, resistance, and delivery barriers. This review explains how non‐invasive physical stimulation (NIPS) reprograms TAMs via defined couplings between physical inputs and signaling pathways. Hypoxia‐tolerant photodynamic strategies and mild photothermal heating reset hypoxia‐ and lactate‐driven programs; cavitation‐dominant ultrasound and sonodynamic therapy trigger danger signaling and reactive oxygen species; ultrasound microbubble destruction provides endothelial repair cues; nanosecond pulsed electric fields activate cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS–STING) pathway; piezoelectric materials convert mechanical input into calcium‐dependent transcription; and appropriately dosed radiotherapy elicits immune‐active responses while avoiding hypoxia‐driven M2 recruitment. Across models, these regimens promote pro‐inflammatory reprogramming, normalize aberrant vasculature, and strengthen antitumor immunity while restraining immunosuppression. We synthesize parameter windows, delivery options, and combination strategies with checkpoint blockade and macrophage‐directed agents to guide the translation of NIPS into precise, low‐toxicity TAM‐targeted immunotherapy.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tiantian Su, Yanling Wan, Fang Fang, Ziyu Li, Cheng Cheng, Jiajia Ai, Nannan Huang, Rong Liang, Jingrong Song, Xiaowei Li, Jiangen Xu, Jianliu Wang, Li Tian
Ovarian aging, a major contributor to declining fertility in women of advanced reproductive age (ARA), is strongly associated with impaired mitochondrial function within oocytes. Although current mitochondrial‐targeted strategies can improve ovarian function, their clinical application remains limited by cost and side effects. In this study, 630 nm light‐emitting diode (LED) phototherapy is shown to ameliorate ovarian aging phenotypes in ARA mice by enhancing mitochondrial complex II activity via upregulation of succinate dehydrogenase subunit B (SDHB). This intervention restores oocyte adenosine triphosphate (ATP) production, improves meiotic progression, and significantly increases blastocyst formation. To assess translational feasibility, a wearable 630 nm LED phototherapy device is developed and evaluated in a pilot clinical study in women with diminished ovarian reserve (DOR). After treatment, the antral follicle count (AFC) significantly increases from a median of 2 (IQR 1–5) to 6 (IQR 2–7; p = 0.011), and the number of oocytes retrieved showed a non‐significant tendency to increase from 2 (IQR 1–5) to 5 (IQR 2–7; p = 0.083), indicating a potential improvement in ovarian reserve. These findings demonstrate that 630 nm LED phototherapy enhances mitochondrial function and oocyte competence, providing a promising non‐invasive strategy to improve fertility in women affected by ovarian aging.
{"title":"630 nm LED phototherapy enhances ovarian function and fertility potential in advanced reproductive age females","authors":"Tiantian Su, Yanling Wan, Fang Fang, Ziyu Li, Cheng Cheng, Jiajia Ai, Nannan Huang, Rong Liang, Jingrong Song, Xiaowei Li, Jiangen Xu, Jianliu Wang, Li Tian","doi":"10.1002/btm2.70117","DOIUrl":"https://doi.org/10.1002/btm2.70117","url":null,"abstract":"Ovarian aging, a major contributor to declining fertility in women of advanced reproductive age (ARA), is strongly associated with impaired mitochondrial function within oocytes. Although current mitochondrial‐targeted strategies can improve ovarian function, their clinical application remains limited by cost and side effects. In this study, 630 nm light‐emitting diode (LED) phototherapy is shown to ameliorate ovarian aging phenotypes in ARA mice by enhancing mitochondrial complex II activity via upregulation of succinate dehydrogenase subunit B (SDHB). This intervention restores oocyte adenosine triphosphate (ATP) production, improves meiotic progression, and significantly increases blastocyst formation. To assess translational feasibility, a wearable 630 nm LED phototherapy device is developed and evaluated in a pilot clinical study in women with diminished ovarian reserve (DOR). After treatment, the antral follicle count (AFC) significantly increases from a median of 2 (IQR 1–5) to 6 (IQR 2–7; <jats:italic>p</jats:italic> = 0.011), and the number of oocytes retrieved showed a non‐significant tendency to increase from 2 (IQR 1–5) to 5 (IQR 2–7; <jats:italic>p</jats:italic> = 0.083), indicating a potential improvement in ovarian reserve. These findings demonstrate that 630 nm LED phototherapy enhances mitochondrial function and oocyte competence, providing a promising non‐invasive strategy to improve fertility in women affected by ovarian aging.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"11 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mugdha Pol, Apoorva S. Metkari, Stephen M. Frazier, Joshua B. Macugay, Hanyuan Gao, Robert L. Witt, David M. Cognetti, Charles‐Antoine Assenmacher, Xinqiao Jia
Salivary gland development requires vascular input signals. However, whether endothelial cell‐secreted angiocrine factors have any inductive effects on adult human salivary gland stem/progenitor cells (hS/PCs) is unknown. To advance the engineering of functional salivary glands, we probed the effects of epithelial and endothelial crosstalk on the growth and differentiation of hS/PCs. Culture of hS/PCs in agarose microwells led to the formation of multicellular spheroids with close cell–cell contacts. Compared with the day 3 culture maintained in the hepatocyte media (HEP) typically used for hS/PCs, 7‐day culture in the endothelial cell growth media (EMG2), significantly increased the expression of genes encoding the E‐cadherin ( CDH1 ), stem/progenitor markers ( KRT5 , KRT14 , MYC ), acinar markers ( AQP5 , AMY, SLC12A1 ), and extracellular matrix proteins ( LAMA1 , FN1 ). Subsequent cultivation of hS/PC spheroids in a hyaluronic acid (HA)‐derived, cell‐adhesive, and proteolytically degradable hydrogel yielded hydrogel‐encapsulated microtissues with complex, multilobulated structures, consisting of fibronectin‐encased lobules connected by F‐actin structures. Addition of a CD31+/vWF+ endothelial cell monolayer on top of the hS/PC‐laden gel construct led to the development of salivary gland microtissues containing differentiated cells expressing key acinar and ductal cell markers. In vivo work showed that the cell‐free HA gels implanted in the partially resected rat parotid gland were degraded in 21 days and did not adversely affect the native tissue structure. Collectively, fostering epithelial cell–cell interaction and integrating endothelial cell‐secreted angiocrine signals led to the development of pro‐acinar salivary gland mimetics from adult salivary gland stem/progenitor cells.
{"title":"Fostering cell–cell interactions and integrating angiocrine factors to promote the development of salivary microtissues in 3D","authors":"Mugdha Pol, Apoorva S. Metkari, Stephen M. Frazier, Joshua B. Macugay, Hanyuan Gao, Robert L. Witt, David M. Cognetti, Charles‐Antoine Assenmacher, Xinqiao Jia","doi":"10.1002/btm2.70118","DOIUrl":"https://doi.org/10.1002/btm2.70118","url":null,"abstract":"Salivary gland development requires vascular input signals. However, whether endothelial cell‐secreted angiocrine factors have any inductive effects on adult human salivary gland stem/progenitor cells (hS/PCs) is unknown. To advance the engineering of functional salivary glands, we probed the effects of epithelial and endothelial crosstalk on the growth and differentiation of hS/PCs. Culture of hS/PCs in agarose microwells led to the formation of multicellular spheroids with close cell–cell contacts. Compared with the day 3 culture maintained in the hepatocyte media (HEP) typically used for hS/PCs, 7‐day culture in the endothelial cell growth media (EMG2), significantly increased the expression of genes encoding the E‐cadherin ( <jats:italic>CDH1</jats:italic> ), stem/progenitor markers ( <jats:italic>KRT5</jats:italic> , <jats:italic>KRT14</jats:italic> , <jats:italic>MYC</jats:italic> ), acinar markers ( <jats:italic>AQP5</jats:italic> , <jats:italic>AMY, SLC12A1</jats:italic> ), and extracellular matrix proteins ( <jats:italic>LAMA1</jats:italic> , <jats:italic>FN1</jats:italic> ). Subsequent cultivation of hS/PC spheroids in a hyaluronic acid (HA)‐derived, cell‐adhesive, and proteolytically degradable hydrogel yielded hydrogel‐encapsulated microtissues with complex, multilobulated structures, consisting of fibronectin‐encased lobules connected by F‐actin structures. Addition of a CD31+/vWF+ endothelial cell monolayer on top of the hS/PC‐laden gel construct led to the development of salivary gland microtissues containing differentiated cells expressing key acinar and ductal cell markers. <jats:italic>In vivo</jats:italic> work showed that the cell‐free HA gels implanted in the partially resected rat parotid gland were degraded in 21 days and did not adversely affect the native tissue structure. Collectively, fostering epithelial cell–cell interaction and integrating endothelial cell‐secreted angiocrine signals led to the development of pro‐acinar salivary gland mimetics from adult salivary gland stem/progenitor cells.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"35 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rohan Basu, Mackenzie K. Madison, Ali Sualeh, Theresa S. Clark, Jennifer Stashevsky, Hanaa Dakour Aridi, Nancy Zhang, Sunjay Anekal, Michael P. Murphy, Steven J. Miller, Chang‐Hyun Gil
Chronic limb threatening ischemia (CLTI), the most severe stage of peripheral arterial disease, affects over 500,000 patients in the United States and is associated with a 25% annual risk of amputation. Diabetic CLTI patients experience exceedingly high rates of lower extremity amputation. Many of these patients fail or are not suitable for revascularization, yet no effective non‐surgical therapies exist for this population. This study examined how human induced pluripotent stem cell (hiPSC)‐derived mesenchymal stromal cells (MSC) interrupt ischemic limb changes and stimulate muscle regeneration in a diabetic murine CLTI model. Mice treated with hiPSC‐MSC demonstrated muscle regeneration, angiogenesis, and decreased inflammation. RT‐qPCR expression of embryonic myosin heavy chain 3 ( p < 0.01) and myoblast determination protein 1 ( p = 0.03) mRNA was increased in ischemic muscle, at 30‐ and 7‐days post‐hiPSC‐MSC injection, respectively, indicating muscle regeneration. Vascular endothelial growth factor‐A mRNA expression was also increased at 7 days ( p = 0.04), signifying increased angiogenic signaling. Treatment with hiPSC‐MSC decreased expression of the nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox at 30 days ( p = 0.02), suggesting decreased oxidative stress. Finally, hiPSC‐MSC‐treated mice had increased mRNA expression for the anti‐inflammatory markers, including regulatory T cell (Treg) marker Foxp3 ( p = 0.01) at 7 days and M2‐biased macrophage marker CD206 at 7 and 30 days ( p = 0.04 and p = 0.02, respectively). Our hiPSC‐MSC preparation promoted muscle regeneration, partially through Treg‐mediated M1 to M2 macrophage polarization. The use of hiPSC‐MSC to improve CLTI outcomes in diabetic patients appears promising and warrants further study.
{"title":"Human induced pluripotent stem cell‐derived mesenchymal stromal cells regenerate diabetic ischemic muscle","authors":"Rohan Basu, Mackenzie K. Madison, Ali Sualeh, Theresa S. Clark, Jennifer Stashevsky, Hanaa Dakour Aridi, Nancy Zhang, Sunjay Anekal, Michael P. Murphy, Steven J. Miller, Chang‐Hyun Gil","doi":"10.1002/btm2.70119","DOIUrl":"https://doi.org/10.1002/btm2.70119","url":null,"abstract":"Chronic limb threatening ischemia (CLTI), the most severe stage of peripheral arterial disease, affects over 500,000 patients in the United States and is associated with a 25% annual risk of amputation. Diabetic CLTI patients experience exceedingly high rates of lower extremity amputation. Many of these patients fail or are not suitable for revascularization, yet no effective non‐surgical therapies exist for this population. This study examined how human induced pluripotent stem cell (hiPSC)‐derived mesenchymal stromal cells (MSC) interrupt ischemic limb changes and stimulate muscle regeneration in a diabetic murine CLTI model. Mice treated with hiPSC‐MSC demonstrated muscle regeneration, angiogenesis, and decreased inflammation. RT‐qPCR expression of embryonic myosin heavy chain 3 ( <jats:italic>p</jats:italic> < 0.01) and myoblast determination protein 1 ( <jats:italic>p</jats:italic> = 0.03) mRNA was increased in ischemic muscle, at 30‐ and 7‐days post‐hiPSC‐MSC injection, respectively, indicating muscle regeneration. Vascular endothelial growth factor‐A mRNA expression was also increased at 7 days ( <jats:italic>p</jats:italic> = 0.04), signifying increased angiogenic signaling. Treatment with hiPSC‐MSC decreased expression of the nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox at 30 days ( <jats:italic>p</jats:italic> = 0.02), suggesting decreased oxidative stress. Finally, hiPSC‐MSC‐treated mice had increased mRNA expression for the anti‐inflammatory markers, including regulatory T cell (Treg) marker Foxp3 ( <jats:italic>p</jats:italic> = 0.01) at 7 days and M2‐biased macrophage marker CD206 at 7 and 30 days ( <jats:italic>p</jats:italic> = 0.04 and <jats:italic>p</jats:italic> = 0.02, respectively). Our hiPSC‐MSC preparation promoted muscle regeneration, partially through Treg‐mediated M1 to M2 macrophage polarization. The use of hiPSC‐MSC to improve CLTI outcomes in diabetic patients appears promising and warrants further study.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"42 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tays Troncoso‐Bravo, Valentina Pavez, Pedro Letelier, Javier Del Río, Cristian Anabalón, Hernán F. Peñaloza, Pablo A. González, Susan M. Bueno, Alexis M. Kalergis
Monoclonal antibodies have revolutionized modern medicine due to their target‐specific properties and effectiveness in treating a wide range of diseases, including cancer, autoimmune disorders, infectious diseases, and neurological conditions. Importantly, their large‐scale production for human use requires strict adherence to good manufacturing practice (GMP) standards to ensure quality, safety, and efficacy. This article reviews key aspects of monoclonal antibody production under GMP standards, from cell‐line selection to culture strategies, antibody purification, formulation, and quality control processes. Additionally, we discuss the significance of validation and traceability in production, as well as the implementation of emerging technologies to enhance manufacturing efficiency and safety. Despite progress in bioprocesses and regulatory frameworks, several challenges, such as batch‐to‐batch variability, high production costs, and the need to continuously adapt processes to new regulations, remain to be solved. The integration of innovative approaches with evolving regulations will enable the optimization of monoclonal antibody production and ensure their global accessibility.
{"title":"Current GMP standards for the large‐scale production of monoclonal antibodies","authors":"Tays Troncoso‐Bravo, Valentina Pavez, Pedro Letelier, Javier Del Río, Cristian Anabalón, Hernán F. Peñaloza, Pablo A. González, Susan M. Bueno, Alexis M. Kalergis","doi":"10.1002/btm2.70121","DOIUrl":"https://doi.org/10.1002/btm2.70121","url":null,"abstract":"Monoclonal antibodies have revolutionized modern medicine due to their target‐specific properties and effectiveness in treating a wide range of diseases, including cancer, autoimmune disorders, infectious diseases, and neurological conditions. Importantly, their large‐scale production for human use requires strict adherence to good manufacturing practice (GMP) standards to ensure quality, safety, and efficacy. This article reviews key aspects of monoclonal antibody production under GMP standards, from cell‐line selection to culture strategies, antibody purification, formulation, and quality control processes. Additionally, we discuss the significance of validation and traceability in production, as well as the implementation of emerging technologies to enhance manufacturing efficiency and safety. Despite progress in bioprocesses and regulatory frameworks, several challenges, such as batch‐to‐batch variability, high production costs, and the need to continuously adapt processes to new regulations, remain to be solved. The integration of innovative approaches with evolving regulations will enable the optimization of monoclonal antibody production and ensure their global accessibility.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"387 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146145936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kun Yu, Liang Ma, Pengkun Han, Yinshen Liu, Longfei Zou, Sen Wang, Jiesi Hu, Kai Zhong, Jiaqiang Liu, Bo Guo, Jie Zou, Houyin Shi, Xing Guo, Meiyun Tan
Osteoarthritis (OA) is a widespread degenerative condition marked by inflammation‐induced damage to chondrocytes and gradual breakdown of the cartilage extracellular matrix. Adipose‐derived mesenchymal stem cells (ADSCs) hold potential for treating OA due to their capacity to differentiate into various cell types and their paracrine signaling functions. However, the inflammatory environment in OA reduces ADSC viability post‐injection, while the absence of a supportive carrier causes significant cell loss, impairing their capacity for cartilage repair. To address these challenges, we improved the stemness and paracrine activity of ADSCs through hypoxia preconditioning and integrated them into an injectable small intestinal submucosa (SIS) tissue repair scaffold. This resulted in an SIS + ADSC composite material, designed for intra‐articular injection to enhance cartilage repair in arthritis. Our findings revealed that exposing ADSCs to 2% oxygen during hypoxia preconditioning and incorporating them into injectable SIS significantly increased the secretion of growth factors (VEGF, bFGF, EGF) and upregulated key hypoxia and stem cell markers (HIF‐1α, NANOG, SOX‐2, Oct‐4). In a rat OA model, hypoxia‐preconditioned SIS + ADSC composites markedly enhanced cartilage repair by stimulating anabolic activity, suppressing catabolic pathways, and reducing inflammation, thereby exhibiting strong protective and reparative effects. In summary, combining hypoxia preconditioning with injectable SIS offers an innovative and effective approach to optimize OA treatment by enhancing paracrine signaling, paving the way for new insights and technologies in cartilage repair within regenerative medicine.
{"title":"Hypoxia‐preconditioned adipose‐derived stem cells with injectable small intestinal submucosa for enhanced cartilage repair in osteoarthritis","authors":"Kun Yu, Liang Ma, Pengkun Han, Yinshen Liu, Longfei Zou, Sen Wang, Jiesi Hu, Kai Zhong, Jiaqiang Liu, Bo Guo, Jie Zou, Houyin Shi, Xing Guo, Meiyun Tan","doi":"10.1002/btm2.70116","DOIUrl":"https://doi.org/10.1002/btm2.70116","url":null,"abstract":"Osteoarthritis (OA) is a widespread degenerative condition marked by inflammation‐induced damage to chondrocytes and gradual breakdown of the cartilage extracellular matrix. Adipose‐derived mesenchymal stem cells (ADSCs) hold potential for treating OA due to their capacity to differentiate into various cell types and their paracrine signaling functions. However, the inflammatory environment in OA reduces ADSC viability post‐injection, while the absence of a supportive carrier causes significant cell loss, impairing their capacity for cartilage repair. To address these challenges, we improved the stemness and paracrine activity of ADSCs through hypoxia preconditioning and integrated them into an injectable small intestinal submucosa (SIS) tissue repair scaffold. This resulted in an SIS + ADSC composite material, designed for intra‐articular injection to enhance cartilage repair in arthritis. Our findings revealed that exposing ADSCs to 2% oxygen during hypoxia preconditioning and incorporating them into injectable SIS significantly increased the secretion of growth factors (VEGF, bFGF, EGF) and upregulated key hypoxia and stem cell markers (HIF‐1α, NANOG, SOX‐2, Oct‐4). In a rat OA model, hypoxia‐preconditioned SIS + ADSC composites markedly enhanced cartilage repair by stimulating anabolic activity, suppressing catabolic pathways, and reducing inflammation, thereby exhibiting strong protective and reparative effects. In summary, combining hypoxia preconditioning with injectable SIS offers an innovative and effective approach to optimize OA treatment by enhancing paracrine signaling, paving the way for new insights and technologies in cartilage repair within regenerative medicine.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"42 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hakan Ceylan, Edoardo Sinibaldi, Sanjay Misra, Pankaj J. Pasricha, Dietmar W. Hutmacher
Untethered mobile milli/microrobots hold transformative potential for interventional medicine by enabling more precise and entirely non‐invasive diagnosis and therapy. Realizing this promise requires bridging the gap between groundbreaking laboratory demonstrations and successful clinical integration. Despite remarkable technical progress over the past two decades, most millirobots and microrobots remain confined to laboratory proof‐of‐concept demonstrations, with limited real‐world feasibility. Here, we identify key factors that slow translation from bench to bedside, focusing on the disconnect between technical innovation and meaningful patient outcomes. We argue that the long‐term impact and sustainability of the field depend on aligning development with unmet clinical needs, demonstrating feasibility, value and integration potential into existing clinical workflows. To foster translational research of milli/microrobots, we introduce a strategic milli/microrobot Technology Readiness Level framework (mTRL), which maps system development from initial conceptualization to clinical adoption through clearly defined milestones and their associated stepwise activities. The mTRL model provides a structured gauge of technological maturity, a common language for multi‐disciplinary collaboration and actionable guidance to accelerate translational development toward new, safer and more efficient interventions.
{"title":"How microrobots should be translated: A clinical and value‐centered readiness framework","authors":"Hakan Ceylan, Edoardo Sinibaldi, Sanjay Misra, Pankaj J. Pasricha, Dietmar W. Hutmacher","doi":"10.1002/btm2.70112","DOIUrl":"https://doi.org/10.1002/btm2.70112","url":null,"abstract":"Untethered mobile milli/microrobots hold transformative potential for interventional medicine by enabling more precise and entirely non‐invasive diagnosis and therapy. Realizing this promise requires bridging the gap between groundbreaking laboratory demonstrations and successful clinical integration. Despite remarkable technical progress over the past two decades, most millirobots and microrobots remain confined to laboratory proof‐of‐concept demonstrations, with limited real‐world feasibility. Here, we identify key factors that slow translation from bench to bedside, focusing on the disconnect between technical innovation and meaningful patient outcomes. We argue that the long‐term impact and sustainability of the field depend on aligning development with unmet clinical needs, demonstrating feasibility, value and integration potential into existing clinical workflows. To foster translational research of milli/microrobots, we introduce a strategic milli/microrobot Technology Readiness Level framework (mTRL), which maps system development from initial conceptualization to clinical adoption through clearly defined milestones and their associated stepwise activities. The mTRL model provides a structured gauge of technological maturity, a common language for multi‐disciplinary collaboration and actionable guidance to accelerate translational development toward new, safer and more efficient interventions.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"91 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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