Tatsuya Fukuta, Suyog Shaha, Andres da Silva‐Candal, Zongmin Zhao, Samir Mitragotri
Malignant brain tumors, particularly glioblastoma multiforme (GBM), are aggressive and fatal cancers. The clinical efficacy of current standard‐of‐care treatments against brain tumors has been minimal, with no significant improvement over the past 30 years. Driven by the success of chimeric antigen receptor (CAR)‐T cells in the clinic for treating certain types of cancer, adoptive cell therapies have been of interest as a hopeful therapeutic modality for brain tumors. Clinical trials of GBM‐targeting cell therapies, including CAR‐T cells, have been initiated; however, none of them have been approved yet, and new challenges have emerged from the completed clinical trials. These issues are being addressed in ongoing clinical trials and recent preclinical research efforts. Herein, we present an overview of the clinical landscape of cell therapies against brain tumors. We analyze past and active 203 clinical trials focusing on cell therapies for brain tumors, discuss limitations for their clinical translation, and highlight emerging approaches to address these challenges. In addition, we review select preclinical studies that show promise to improve the therapeutic efficacy of therapeutic cells on brain tumors and discuss future prospects.
{"title":"Cell therapies against brain tumors: Clinical development and emerging prospects","authors":"Tatsuya Fukuta, Suyog Shaha, Andres da Silva‐Candal, Zongmin Zhao, Samir Mitragotri","doi":"10.1002/btm2.70018","DOIUrl":"https://doi.org/10.1002/btm2.70018","url":null,"abstract":"Malignant brain tumors, particularly glioblastoma multiforme (GBM), are aggressive and fatal cancers. The clinical efficacy of current standard‐of‐care treatments against brain tumors has been minimal, with no significant improvement over the past 30 years. Driven by the success of chimeric antigen receptor (CAR)‐T cells in the clinic for treating certain types of cancer, adoptive cell therapies have been of interest as a hopeful therapeutic modality for brain tumors. Clinical trials of GBM‐targeting cell therapies, including CAR‐T cells, have been initiated; however, none of them have been approved yet, and new challenges have emerged from the completed clinical trials. These issues are being addressed in ongoing clinical trials and recent preclinical research efforts. Herein, we present an overview of the clinical landscape of cell therapies against brain tumors. We analyze past and active 203 clinical trials focusing on cell therapies for brain tumors, discuss limitations for their clinical translation, and highlight emerging approaches to address these challenges. In addition, we review select preclinical studies that show promise to improve the therapeutic efficacy of therapeutic cells on brain tumors and discuss future prospects.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"3 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841287","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}
Non‐small cell lung cancer (NSCLC) presents significant therapeutic challenges, often characterized by aggressive proliferation and metastasis. This study investigates the role of SLC7A11, a ferroptosis‐related gene, in NSCLC progression and the potential of engineered bacterial extracellular vesicles (BEVs) expressing SLC7A11‐targeting siRNA as a therapeutic strategy. Using TCGA and GEO databases, we identified that SLC7A11 was significantly upregulated in NSCLC tissues. Functional assays demonstrated that SLC7A11 knockdown in NSCLC cell lines (NCI‐H2122 and NCI‐H647) via qPCR, Western blot, and immunofluorescence resulted in impaired proliferation, migration, and invasion abilities. In vivo xenograft models further revealed that SLC7A11 knockdown inhibited tumor growth and metastasis, corroborated by histological analyses. To enhance targeted delivery of SLC7A11 siRNA, we engineered BEVs with a lung cell targeting peptide, verifying their structure and function through transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). In vivo toxicity assessments indicated safety for these bioengineered vesicles. Importantly, treatment with BEVs‐LCTP‐siSLC7A11 not only impaired tumorigenesis but also activated ferroptosis pathways, as evidenced by altered expression levels of SLC7A11 and transferrin in tumor and metastatic tissues. Our findings suggest that targeting SLC7A11 through engineered BEVs presents a promising approach to inhibit NSCLC progression while activating ferroptosis, offering insights into novel therapeutic strategies against lung cancer.
{"title":"Engineered lung cell targeting and SLC7A11 siRNA expressing bacterial extracellular vesicles impair the progression of none‐small cell lung cancer","authors":"Xiao‐dan Wan, Xue‐liang Zhou, Jin‐long Liu, Hua Xu","doi":"10.1002/btm2.70021","DOIUrl":"https://doi.org/10.1002/btm2.70021","url":null,"abstract":"Non‐small cell lung cancer (NSCLC) presents significant therapeutic challenges, often characterized by aggressive proliferation and metastasis. This study investigates the role of SLC7A11, a ferroptosis‐related gene, in NSCLC progression and the potential of engineered bacterial extracellular vesicles (BEVs) expressing SLC7A11‐targeting siRNA as a therapeutic strategy. Using TCGA and GEO databases, we identified that SLC7A11 was significantly upregulated in NSCLC tissues. Functional assays demonstrated that SLC7A11 knockdown in NSCLC cell lines (NCI‐H2122 and NCI‐H647) via qPCR, Western blot, and immunofluorescence resulted in impaired proliferation, migration, and invasion abilities. In vivo xenograft models further revealed that SLC7A11 knockdown inhibited tumor growth and metastasis, corroborated by histological analyses. To enhance targeted delivery of SLC7A11 siRNA, we engineered BEVs with a lung cell targeting peptide, verifying their structure and function through transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). In vivo toxicity assessments indicated safety for these bioengineered vesicles. Importantly, treatment with BEVs‐LCTP‐siSLC7A11 not only impaired tumorigenesis but also activated ferroptosis pathways, as evidenced by altered expression levels of SLC7A11 and transferrin in tumor and metastatic tissues. Our findings suggest that targeting SLC7A11 through engineered BEVs presents a promising approach to inhibit NSCLC progression while activating ferroptosis, offering insights into novel therapeutic strategies against lung cancer.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"14 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841286","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}
Eduardo Barbieri, Gina N. Mollica, Sobhana A. Sripada, Shrirarjun Shastry, Yuxuan Wu, Arianna Minzoni, Will Smith, Elena Wuestenhagen, Annika Aldinger, Heiner Graalfs, Michael S. Crapanzano, Oliver Rammo, Michael M. Schulte, Michael A. Daniele, Stefano Menegatti
Lentiviral vectors (LVVs) are emerging as an enabling tool in gene and cell therapies, yet the toolkit for purifying them at scale is still immature. A pivoting moment in LVV isolation technology was marked by the introduction of affinity ligands for LVVs pseudo‐typed with Vesicular Stomatitis Virus G (VSV‐G) protein. Camelid antibody ligands were initially discovered and utilized to functionalize a resin with a capacity of 1014 LVV particles per liter (vp/L). Shortly thereafter, our team introduced VSV‐G‐targeting peptides and assessed their application as ligands for purifying LVVs from HEK293 cell harvests. In this study, we utilized these peptides to develop novel affinity resins and—first in this field—affinity membranes with optimal binding capacity, productivity, and removal of host cell contaminants. To that end, we evaluated resins of different material, particle and pore size, and functional density, as well as membranes with different fiber morphology, porosity, and ligand distribution. The lead peptide‐functionalized resin and membrane featured high capacity (5 × 109 and 1.2 × 109 transducing LVV units per mL of adsorbent, TU/mL) and productivity (2.9 × 109 and 1.7 × 109 TU/mL min) and afforded a substantial enrichment of cell‐transducing LVVs and reduction of contaminants (110–170‐fold) in the eluates. Finally, we demonstrated an LVV purification process in four steps: clarification and nuclease treatment, affinity capture in bind‐and‐elute mode, polishing in flow‐through mode, and ultra/dia‐filtration and sterile filtration. The processes afforded yields of 33%–46%, a residual HCP level below 5 ng/mL, and productivity of 1.25–1.5 × 1014 active LVV particles per hour and liter of adsorbent.
{"title":"Developing a process of lentivirus purification from recombinant fluids using peptide affinity ligands","authors":"Eduardo Barbieri, Gina N. Mollica, Sobhana A. Sripada, Shrirarjun Shastry, Yuxuan Wu, Arianna Minzoni, Will Smith, Elena Wuestenhagen, Annika Aldinger, Heiner Graalfs, Michael S. Crapanzano, Oliver Rammo, Michael M. Schulte, Michael A. Daniele, Stefano Menegatti","doi":"10.1002/btm2.70017","DOIUrl":"https://doi.org/10.1002/btm2.70017","url":null,"abstract":"Lentiviral vectors (LVVs) are emerging as an enabling tool in gene and cell therapies, yet the toolkit for purifying them at scale is still immature. A pivoting moment in LVV isolation technology was marked by the introduction of affinity ligands for LVVs pseudo‐typed with Vesicular Stomatitis Virus G (VSV‐G) protein. Camelid antibody ligands were initially discovered and utilized to functionalize a resin with a capacity of 10<jats:sup>14</jats:sup> LVV particles per liter (vp/L). Shortly thereafter, our team introduced VSV‐G‐targeting peptides and assessed their application as ligands for purifying LVVs from HEK293 cell harvests. In this study, we utilized these peptides to develop novel affinity resins and—first in this field—affinity membranes with optimal binding capacity, productivity, and removal of host cell contaminants. To that end, we evaluated resins of different material, particle and pore size, and functional density, as well as membranes with different fiber morphology, porosity, and ligand distribution. The lead peptide‐functionalized resin and membrane featured high capacity (5 × 10<jats:sup>9</jats:sup> and 1.2 × 10<jats:sup>9</jats:sup> transducing LVV units per mL of adsorbent, TU/mL) and productivity (2.9 × 10<jats:sup>9</jats:sup> and 1.7 × 10<jats:sup>9</jats:sup> TU/mL min) and afforded a substantial enrichment of cell‐transducing LVVs and reduction of contaminants (110–170‐fold) in the eluates. Finally, we demonstrated an LVV purification process in four steps: clarification and nuclease treatment, affinity capture in bind‐and‐elute mode, polishing in flow‐through mode, and ultra/dia‐filtration and sterile filtration. The processes afforded yields of 33%–46%, a residual HCP level below 5 ng/mL, and productivity of 1.25–1.5 × 10<jats:sup>14</jats:sup> active LVV particles per hour and liter of adsorbent.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"183 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805923","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}
Xue Dong, Sophia Salingaros, Timothy Butler, Skander Limem, Jason A. Spector
Nipple reconstruction in patients who undergo total mastectomy or nipple‐sparing mastectomy is currently limited by a consistent and significant loss of nipple projection over time, which can negatively affect patient satisfaction and quality of life. To address this issue, we have previously shown that 3D‐printed poly‐4‐hydroxybutyrate (P4HB) nipple‐shaped scaffolds promote long‐term maintenance of nipple projection in a rat model. Herein, we further optimize the 3D printing parameters (filament diameter and infill density) of absorbable P4HB latticework scaffolds as well as scaffolds fabricated from rolled P4HB knitted mesh to facilitate tissue formation with similar biomechanical properties of the native nipple, while maintaining long‐term shape and projection. Over 12 months of in vivo implantation in a dorsal, bilateral CV‐flap rat model of nipple reconstruction, 3D‐printed P4HB latticework and knitted mesh scaffolded groups demonstrated significantly greater maintenance in projection (80–100% of initial value) when compared to the Cook Biodesign® Nipple Cylinder (~40% of initial projection), resulting from the infiltration of healthy fibrovascular adipose tissue, which demonstrated biomechanical qualities that approached those of the native human nipple. Overall, our results demonstrate that using a 3D‐printed P4HB latticework and rolled P4HB knitted mesh scaffolds significantly improved long‐term results in our animal model of nipple reconstruction and hold promise for improving nipple reconstruction outcomes in future clinical practice.
{"title":"Optimizing design parameters of 3D‐printed poly‐4‐hydroxybutyrate nipple scaffolds for nipple reconstruction","authors":"Xue Dong, Sophia Salingaros, Timothy Butler, Skander Limem, Jason A. Spector","doi":"10.1002/btm2.70010","DOIUrl":"https://doi.org/10.1002/btm2.70010","url":null,"abstract":"Nipple reconstruction in patients who undergo total mastectomy or nipple‐sparing mastectomy is currently limited by a consistent and significant loss of nipple projection over time, which can negatively affect patient satisfaction and quality of life. To address this issue, we have previously shown that 3D‐printed poly‐4‐hydroxybutyrate (P4HB) nipple‐shaped scaffolds promote long‐term maintenance of nipple projection in a rat model. Herein, we further optimize the 3D printing parameters (filament diameter and infill density) of absorbable P4HB latticework scaffolds as well as scaffolds fabricated from rolled P4HB knitted mesh to facilitate tissue formation with similar biomechanical properties of the native nipple, while maintaining long‐term shape and projection. Over 12 months of in vivo implantation in a dorsal, bilateral CV‐flap rat model of nipple reconstruction, 3D‐printed P4HB latticework and knitted mesh scaffolded groups demonstrated significantly greater maintenance in projection (80–100% of initial value) when compared to the Cook Biodesign® Nipple Cylinder (~40% of initial projection), resulting from the infiltration of healthy fibrovascular adipose tissue, which demonstrated biomechanical qualities that approached those of the native human nipple. Overall, our results demonstrate that using a 3D‐printed P4HB latticework and rolled P4HB knitted mesh scaffolds significantly improved long‐term results in our animal model of nipple reconstruction and hold promise for improving nipple reconstruction outcomes in future clinical practice.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"27 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797859","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}
Adalimumab (Humira) represents a major advance in rheumatoid arthritis (RA) therapy. However, with long‐term administration of Adalimumab, anti‐idiotypic antibody (anti‐Id Ab) accelerates the Adalimumab clearance rate and reduces the therapeutic effect. To avoid the interference of anti‐Id Ab, we used an autologous hinge region as a spatial‐hindrance‐based Ab lock and connected it to the N‐terminal of the light chain and heavy chain via substrate peptides (MMP‐2/9) to cover the CDR binding site of Adalimumab to generate pro‐Adalimumab. The Ab lock masks the complementarity‐determining regions (CDRs) of Adalimumab, thus avoiding interference from anti‐Id Ab. Pro‐Adalimumab demonstrated a 241.6 times weaker binding ability to TNFɑ than Adalimumab. In addition, pro‐Adalimumab showed a 46.6‐fold greater blocking of anti‐Adalimumab Id Ab in comparison to Adalimumab prior to activation. Similar results were observed with other clinical antibodies, such as pro‐Infliximab (anti‐TNFɑ Ab) and pro‐Nivolumab (anti‐PD‐1). Furthermore, pro‐Adalimumab maintained consistent pharmacokinetics regardless of the presence of anti‐Adalimumab Id antibodies, while Adalimumab showed a 49% clearance increase, resulting in a near complete loss of function. Additionally, pro‐Adalimumab was able to avoid neutralization and efficiently reduce RA progression in the presence of anti‐Adalimumab Id Ab in vivo. In summary, we developed a pro‐Adalimumab that avoids interference from anti‐Id Abs, thereby addressing the biggest issue limiting clinical efficacy. The findings enclosed herein may have potentially broad application in antibody therapies.
{"title":"Spatial‐hindrance‐based pro‐Adalimumab prevents anti‐idiotypic antibody interference in pharmacokinetic and therapeutic efficacy","authors":"Bo‐Cheng Huang, Yu‐Tung Chen, Yun‐Chi Lu, Kai‐Wen Ho, Shih‐Ting Hong, Tzu‐Yi Liao, I‐Hsuan Wu, En‐Shuo Liu, Jun‐Min Liao, Fang‐Ming Chen, Chia‐Ching Li, Chih‐Hung Chuang, Chiao‐Yun Chen, Tian‐Lu Cheng","doi":"10.1002/btm2.70015","DOIUrl":"https://doi.org/10.1002/btm2.70015","url":null,"abstract":"Adalimumab (Humira) represents a major advance in rheumatoid arthritis (RA) therapy. However, with long‐term administration of Adalimumab, anti‐idiotypic antibody (anti‐Id Ab) accelerates the Adalimumab clearance rate and reduces the therapeutic effect. To avoid the interference of anti‐Id Ab, we used an autologous hinge region as a spatial‐hindrance‐based Ab lock and connected it to the N‐terminal of the light chain and heavy chain via substrate peptides (MMP‐2/9) to cover the CDR binding site of Adalimumab to generate pro‐Adalimumab. The Ab lock masks the complementarity‐determining regions (CDRs) of Adalimumab, thus avoiding interference from anti‐Id Ab. Pro‐Adalimumab demonstrated a 241.6 times weaker binding ability to TNFɑ than Adalimumab. In addition, pro‐Adalimumab showed a 46.6‐fold greater blocking of anti‐Adalimumab Id Ab in comparison to Adalimumab prior to activation. Similar results were observed with other clinical antibodies, such as pro‐Infliximab (anti‐TNFɑ Ab) and pro‐Nivolumab (anti‐PD‐1). Furthermore, pro‐Adalimumab maintained consistent pharmacokinetics regardless of the presence of anti‐Adalimumab Id antibodies, while Adalimumab showed a 49% clearance increase, resulting in a near complete loss of function. Additionally, pro‐Adalimumab was able to avoid neutralization and efficiently reduce RA progression in the presence of anti‐Adalimumab Id Ab in vivo. In summary, we developed a pro‐Adalimumab that avoids interference from anti‐Id Abs, thereby addressing the biggest issue limiting clinical efficacy. The findings enclosed herein may have potentially broad application in antibody therapies.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"50 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782390","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}
Qunshan Zhu, Gaoyang Chen, Lei Fu, Dawei Cao, Zhenguang Wang, Yan Yang, Wei Wei
Colorectal precancerous lesions (CRP) are early signs of cancer development, and early detection helps prevent progression to colorectal cancer (CRC), reducing incidence and mortality rates. This study developed a serum detection platform integrating surface‐enhanced Raman scattering (SERS) with machine learning (ML) for early detection of CRP. Specifically, a microarray chip with Au/SnO2 nanorope arrays (Au/SnO2 NRAs) substrate was designed for SERS spectral measurement of serum. The Principal Component Analysis (PCA)‐Optimal Class Discrimination and Compactness Optimization (OCDCO) model was proposed to identify CRP spectra. The results demonstrated that the microarray chip exhibited superior portability, SERS activity, stability, and uniformity. Through PCA‐OCDCO, the serum samples from healthy controls, CRP patients, and CRC patients were effectively classified, and several key spectral features for distinguishing different groups were identified. The established PCA‐OCDCO model achieved outstanding performance, with an accuracy of 97%, a sensitivity of 95%, a specificity of 97%, and an AUC of 0.96. This study suggests that the platform, integrating SERS with the PCA‐OCDCO model, holds potential for the early detection of CRP, providing an approach for CRP prevention and clinical diagnostics.
{"title":"Machine learning‐based SERS serum detection platform for high‐sensitive and high‐throughput diagnosis of colorectal precancerous lesions","authors":"Qunshan Zhu, Gaoyang Chen, Lei Fu, Dawei Cao, Zhenguang Wang, Yan Yang, Wei Wei","doi":"10.1002/btm2.70019","DOIUrl":"https://doi.org/10.1002/btm2.70019","url":null,"abstract":"Colorectal precancerous lesions (CRP) are early signs of cancer development, and early detection helps prevent progression to colorectal cancer (CRC), reducing incidence and mortality rates. This study developed a serum detection platform integrating surface‐enhanced Raman scattering (SERS) with machine learning (ML) for early detection of CRP. Specifically, a microarray chip with Au/SnO<jats:sub>2</jats:sub> nanorope arrays (Au/SnO<jats:sub>2</jats:sub> NRAs) substrate was designed for SERS spectral measurement of serum. The Principal Component Analysis (PCA)‐Optimal Class Discrimination and Compactness Optimization (OCDCO) model was proposed to identify CRP spectra. The results demonstrated that the microarray chip exhibited superior portability, SERS activity, stability, and uniformity. Through PCA‐OCDCO, the serum samples from healthy controls, CRP patients, and CRC patients were effectively classified, and several key spectral features for distinguishing different groups were identified. The established PCA‐OCDCO model achieved outstanding performance, with an accuracy of 97%, a sensitivity of 95%, a specificity of 97%, and an AUC of 0.96. This study suggests that the platform, integrating SERS with the PCA‐OCDCO model, holds potential for the early detection of CRP, providing an approach for CRP prevention and clinical diagnostics.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"183 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736612","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}
Current ectopic implantation has shown limited efficacy in promoting reinnervation of the nigrostriatal pathway, which is critically affected in Parkinson's disease (PD). Homotopic transplantation, on the other hand, may facilitate physiological cell rewiring of the basal ganglia, potentially improving PD symptoms. This study aimed to evaluate the efficacy and safety of homotopically engrafting human induced pluripotent stem cells (hiPSCs)‐derived midbrain organoids into the substantia nigra of PD rats. A rat model of PD was induced using 6‐hydroxydopamine (6‐OHDA) and homotopically transplanted into the lesioned SN with hiPSC‐derived hMOs. The engrafted hMOs survived and continually mature in host brains, and were mainly differentiated into dopaminergic lineage neurons, part of which presented TH+ fibers. Behavioral evaluation demonstrated that transplantation of hMOs gradually reverse the motor disorder caused by 6‐OHDA lesioning by 22% at week 5 and 35% by week 10 post‐transplantation, respectively. No tumor formation or migration was detected in either subcutaneous space or vital organs following 10 weeks implantation. These findings support the efficacy and safety of homotopical hMOs transplantation, offering a promising cell‐based strategy for treating Parkinson's disease.
{"title":"Efficacy and safety assessment of homotopical transplantation of iPSCs‐derived midbrain organoids into the substantia nigra of Parkinsonian rats","authors":"Xin Zheng, Jianwei Chen, Zhengzheng Huang, Youcheng Zhang, Liping Zhou","doi":"10.1002/btm2.70014","DOIUrl":"https://doi.org/10.1002/btm2.70014","url":null,"abstract":"Current ectopic implantation has shown limited efficacy in promoting reinnervation of the nigrostriatal pathway, which is critically affected in Parkinson's disease (PD). Homotopic transplantation, on the other hand, may facilitate physiological cell rewiring of the basal ganglia, potentially improving PD symptoms. This study aimed to evaluate the efficacy and safety of homotopically engrafting human induced pluripotent stem cells (hiPSCs)‐derived midbrain organoids into the substantia nigra of PD rats. A rat model of PD was induced using 6‐hydroxydopamine (6‐OHDA) and homotopically transplanted into the lesioned SN with hiPSC‐derived hMOs. The engrafted hMOs survived and continually mature in host brains, and were mainly differentiated into dopaminergic lineage neurons, part of which presented TH<jats:sup>+</jats:sup> fibers. Behavioral evaluation demonstrated that transplantation of hMOs gradually reverse the motor disorder caused by 6‐OHDA lesioning by 22% at week 5 and 35% by week 10 post‐transplantation, respectively. No tumor formation or migration was detected in either subcutaneous space or vital organs following 10 weeks implantation. These findings support the efficacy and safety of homotopical hMOs transplantation, offering a promising cell‐based strategy for treating Parkinson's disease.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"11 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736604","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}
Atherosclerosis is a chronic, systemic, inflammatory disease associated with the build‐up of fatty deposits (“plaques”) in the arteries. A major global health burden, severe atherosclerosis progresses to ischemic heart disease, an underlying condition which can exacerbate the occurrence of fatal events such as heart attack and stroke. Over the past two decades, the use of in vitro models to study atherosclerotic phenomena has increased, with the goal of complementing clinical research for drug and therapy development. In particular, 2D co‐culture models, and in the last decade, 3D spheroid models have been developed to improve our understanding of the atherosclerotic disease mechanism. However, the existing literature lacks information on the relevant parameters which should be considered prior and during the design of these models to promote model robustness and enhance their biomimetic capacities. This review provides an overview of such key parameters, as well as future perspectives on how existing limitations in the field of cell‐based invitro model design can be improved. It is expected that by carefully considering these parameters, researchers will be better equipped with the required knowledge to develop biomedically and clinically relevant in vitro models.
{"title":"Key parameters for designing robust 2D and 3D spheroid models for in vitro atherosclerosis research","authors":"Ibukunoluwa Naiyeju, Stephanie Lehoux, Maryam Tabrizian","doi":"10.1002/btm2.10736","DOIUrl":"https://doi.org/10.1002/btm2.10736","url":null,"abstract":"Atherosclerosis is a chronic, systemic, inflammatory disease associated with the build‐up of fatty deposits (“plaques”) in the arteries. A major global health burden, severe atherosclerosis progresses to ischemic heart disease, an underlying condition which can exacerbate the occurrence of fatal events such as heart attack and stroke. Over the past two decades, the use of <jats:italic>in vitro</jats:italic> models to study atherosclerotic phenomena has increased, with the goal of complementing clinical research for drug and therapy development. In particular, 2D co‐culture models, and in the last decade, 3D spheroid models have been developed to improve our understanding of the atherosclerotic disease mechanism. However, the existing literature lacks information on the relevant parameters which should be considered prior and during the design of these models to promote model robustness and enhance their biomimetic capacities. This review provides an overview of such key parameters, as well as future perspectives on how existing limitations in the field of cell‐based <jats:italic>in</jats:italic> <jats:italic>vitro</jats:italic> model design can be improved. It is expected that by carefully considering these parameters, researchers will be better equipped with the required knowledge to develop biomedically and clinically relevant <jats:italic>in vitro</jats:italic> models.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"20 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677641","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}
{"title":"Correction to “A stretchable, electroconductive tissue adhesive for the treatment of neural injury”","authors":"","doi":"10.1002/btm2.10759","DOIUrl":"https://doi.org/10.1002/btm2.10759","url":null,"abstract":"","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"32 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661299","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}
V. Chandran Suja, A. L. H. S. Detry, N. M. Sims, D. E. Arney, S. Mitragotri, R. A. Peterfreund
Managing delivery of complex multidrug infusions in anesthesia and critical care presents a significant clinical challenge. Current practices relying on manual control of infusion pumps often result in unpredictable drug delivery profiles and dosing errors—key issues highlighted by the United States Food and Drug Administration (FDA). To address these issues, we introduce the SMART (synchronized‐pump management algorithms for reliable therapies) framework, a novel approach that leverages low Reynolds number drug transport physics and machine learning to accurately manage multidrug infusions in real‐time. SMART is activated based on the Shafer number (), a novel non‐dimensional number that quantifies the relative magnitude of a drug's therapeutic action timescale to its transport timescale within infusion manifolds. SMART is useful when , where drug transport becomes the rate limiting step in achieving the desired therapeutic effects. When activated, SMART monitors multidrug concentrations within infusion manifolds and leverages this information to perform end‐to‐end management of drug delivery using an ensemble of deterministic and deep reinforcement learning (RL) decision networks. Notably, SMART RL networks employ differentially sampled split buffer architecture that accelerates learning and improves performance by seamlessly combining deterministic predictions with RL experience during training. SMART deployed in standalone infusion pumps under simulated clinical conditions outperformed state‐of‐the‐art manual control protocols. This framework has the potential to revolutionize critical care by enhancing accuracy of medication delivery and reducing cognitive workloads. Beyond critical care, the ability to accurately manage multi‐liquid delivery via complex manifolds will have important bearings for manufacturing and process control.
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