Nayiri M. Kaissarian, Stephanie L. Sandefur, Arnab Ghosh, Upendra K. Katneni, Wendy Walton, Christopher C. Frye, Anton A. Komar, Chava Kimchi‐Sarfaty
Monoclonal antibodies (mAbs) are commonly used biologic therapeutics with a wide variety of clinical applications. During the development process, manufacturers consider different production parameters to improve protein yield and achieve appropriate quality of the product. Synonymous gene recoding is one of such attributes that is often considered and implemented to enhance protein expression. However, it has to be used with caution, as it may lead to protein misfolding and ER stress, which complicates efforts to manufacture the desired mAb. To investigate how changing mRNA sequence composition under different protein production parameters might affect the quality of recombinantly produced mAbs, we performed a comprehensive and systematic study assessing impact of synonymous gene recoding (commonly referred to as codon optimization) strategies in the context of varied cell culture parameters on product quality, biochemical and functional characteristics. We report the impact of these parameters on mAb glycosylation profiles, charge variant profile, aggregation, fragmentation, and mAb functional response from combinations of different production parameters. These results uncovered a complex interplay of sequence composition and manufacturing parameters and emphasize the importance of assessing changes to key quality attributes when optimizing mAb manufacturing, including the use of synonymous gene recoding.
{"title":"Investigating the impact of synonymous gene recoding on a recombinantly expressed monoclonal antibody under different process parameters","authors":"Nayiri M. Kaissarian, Stephanie L. Sandefur, Arnab Ghosh, Upendra K. Katneni, Wendy Walton, Christopher C. Frye, Anton A. Komar, Chava Kimchi‐Sarfaty","doi":"10.1002/btm2.10750","DOIUrl":"https://doi.org/10.1002/btm2.10750","url":null,"abstract":"Monoclonal antibodies (mAbs) are commonly used biologic therapeutics with a wide variety of clinical applications. During the development process, manufacturers consider different production parameters to improve protein yield and achieve appropriate quality of the product. Synonymous gene recoding is one of such attributes that is often considered and implemented to enhance protein expression. However, it has to be used with caution, as it may lead to protein misfolding and ER stress, which complicates efforts to manufacture the desired mAb. To investigate how changing mRNA sequence composition under different protein production parameters might affect the quality of recombinantly produced mAbs, we performed a comprehensive and systematic study assessing impact of synonymous gene recoding (commonly referred to as codon optimization) strategies in the context of varied cell culture parameters on product quality, biochemical and functional characteristics. We report the impact of these parameters on mAb glycosylation profiles, charge variant profile, aggregation, fragmentation, and mAb functional response from combinations of different production parameters. These results uncovered a complex interplay of sequence composition and manufacturing parameters and emphasize the importance of assessing changes to key quality attributes when optimizing mAb manufacturing, including the use of synonymous gene recoding.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"206 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054910","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}
Amir Hejri, Micah A. Chrenek, Nolan T. Goehring, Isabella I. Bowland, Richard Noel, Jiong Yan, John M. Nickerson, Mark R. Prausnitz
Novel therapeutics have emerged for treating neurodegenerative eye diseases but are limited by non‐optimal methods of ocular administration. Subretinal injection is the preferred method of delivery for retinal gene and stem‐cell therapies, but its invasive and complex surgical procedure is a major limiting factor in clinical investigations and practice. Here, we engineered a novel trans‐scleral injection technique to safely administer to the subretinal space in a simple, non‐surgical, and minimally invasive procedure. Subretinal injection using this technique in rodents and rabbits took <1 min per injection and did not require a surgical microscope. Extensive safety examinations in rats showed that the injection technique reliably administered into the subretinal space with no incidence of retinal perforation, little or no choroidal bleeding, and no evidence of retinal toxicity. We further found that repeated subretinal injection in the same eye, in rats, was well tolerated. The developed technique may enable non‐surgical subretinal injection without vitrectomy, potentially increasing safety, efficacy, and access to ocular therapies.
{"title":"A non‐surgical method for subretinal delivery by trans‐scleral microneedle injection","authors":"Amir Hejri, Micah A. Chrenek, Nolan T. Goehring, Isabella I. Bowland, Richard Noel, Jiong Yan, John M. Nickerson, Mark R. Prausnitz","doi":"10.1002/btm2.10755","DOIUrl":"https://doi.org/10.1002/btm2.10755","url":null,"abstract":"Novel therapeutics have emerged for treating neurodegenerative eye diseases but are limited by non‐optimal methods of ocular administration. Subretinal injection is the preferred method of delivery for retinal gene and stem‐cell therapies, but its invasive and complex surgical procedure is a major limiting factor in clinical investigations and practice. Here, we engineered a novel trans‐scleral injection technique to safely administer to the subretinal space in a simple, non‐surgical, and minimally invasive procedure. Subretinal injection using this technique in rodents and rabbits took <1 min per injection and did not require a surgical microscope. Extensive safety examinations in rats showed that the injection technique reliably administered into the subretinal space with no incidence of retinal perforation, little or no choroidal bleeding, and no evidence of retinal toxicity. We further found that repeated subretinal injection in the same eye, in rats, was well tolerated. The developed technique may enable non‐surgical subretinal injection without vitrectomy, potentially increasing safety, efficacy, and access to ocular therapies.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"59 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054907","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}
Autism spectrum disorder (ASD) is a group of developmental diseases, which still lacks effective treatments. Pregnant exposure of Valproic acid (VPA) is an important environmental risk factor for ASD, but it's long‐term effects on the development of human neural cells, particularly in vivo, and the corresponding treatment have yet been fully investigated. In the present study, we first made a humanized ASD mouse model by transplanting VPA‐pretreated human neural progenitor cells (hNPCs) into the cortex of immune‐deficient mice. In comparison with wild type and control chimeric mice, ASD chimeric mice (VPAhNPC mice) exhibit core syndromes of ASD, namely dramatic reduction of sociability, social interaction and social communication, and remarkable increase of stereotype repetitive behaviors and anxiety‐like behaviors. At cellular level, VPA‐pretreatment biased the differentiation of human excitatory neurons and their axonal projections in host brain. Chemogenetic suppression of human neuronal activity restored most behavior abnormalities of VPAhNPC mice. Further, specific modulation of human neurons by a newly developed transcranial magnetic stimulation (TMS) device which could precisely target hPNCs effectively recued the core syndromes of ASD‐like behaviors, restored the excitatory‐inhibitory neuronal differentiation and axonal projection, and reversed the expression of over half of the VPA‐affected genes. These data demonstrated that VPAhNPC mice could be used as a humanized model of ASD and that precisely targeted TMS could ameliorate the VPA‐biased human neuronal differentiation in vivo.
{"title":"Amelioration of biased neuronal differentiation in humanized mouse model of valproic acid‐induced autism by precisely targeted transcranial magnetic stimulation","authors":"Yilin Hou, Youyi Zhao, Dingding Yang, Tingwei Feng, Yuqian Li, Xiang Li, Zhou'an Liu, Xiao Yan, Hui Zhang, Shengxi Wu, Xufeng Liu, Yazhou Wang","doi":"10.1002/btm2.10748","DOIUrl":"https://doi.org/10.1002/btm2.10748","url":null,"abstract":"Autism spectrum disorder (ASD) is a group of developmental diseases, which still lacks effective treatments. Pregnant exposure of Valproic acid (VPA) is an important environmental risk factor for ASD, but it's long‐term effects on the development of human neural cells, particularly in vivo, and the corresponding treatment have yet been fully investigated. In the present study, we first made a humanized ASD mouse model by transplanting VPA‐pretreated human neural progenitor cells (hNPCs) into the cortex of immune‐deficient mice. In comparison with wild type and control chimeric mice, ASD chimeric mice (<jats:sup>VPA</jats:sup>hNPC mice) exhibit core syndromes of ASD, namely dramatic reduction of sociability, social interaction and social communication, and remarkable increase of stereotype repetitive behaviors and anxiety‐like behaviors. At cellular level, VPA‐pretreatment biased the differentiation of human excitatory neurons and their axonal projections in host brain. Chemogenetic suppression of human neuronal activity restored most behavior abnormalities of <jats:sup>VPA</jats:sup>hNPC mice. Further, specific modulation of human neurons by a newly developed transcranial magnetic stimulation (TMS) device which could precisely target hPNCs effectively recued the core syndromes of ASD‐like behaviors, restored the excitatory‐inhibitory neuronal differentiation and axonal projection, and reversed the expression of over half of the VPA‐affected genes. These data demonstrated that <jats:sup>VPA</jats:sup>hNPC mice could be used as a humanized model of ASD and that precisely targeted TMS could ameliorate the VPA‐biased human neuronal differentiation in vivo.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"38 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030923","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}
Spencer R. Marsh, Claire E. Beard, Robert G. Gourdie
Mammalian milk, a multifaceted developmental biofluid, has attracted new attention due to its diverse constituents and their implications for health and disease. Among these constituents, extracellular vesicles (EVs) have emerged as focal points of investigation. EVs, including exosomes and small EVs, have demonstrated biological activity in preclinical studies—including reports of enhancement of cognition and neural complexity, promotion of gastrointestinal development, barrier function and microbiome richness, the bolstering of immune response, and facilitation of musculoskeletal maturation in neonates. The richness of milk as a source of EVs is noteworthy, with hundreds of milliliters (at >1012 EVs/mL) of nanovesicles extractable from a single liter of milk (>1014 EVs/starting liter of milk). Techniques such as tangential flow filtration hold promise for scalable production, potentially extending to thousands of liters. Together with the scale and increasing sophistication of the dairy industry, the abundance of EVs in milk underscores their commercial potential in various nutraceutical applications. Beyond natural bioactivity, milk EVs (mEVs) present intriguing possibilities as orally deliverable, non‐immunogenic pharmaceutical carriers, with burgeoning interest in their utilization for heart disease and cancer chemotherapy and as vectors for gene‐editing modules such as CrispR. This review synthesizes current knowledge on mEV biogenesis, characterization, isolation methodologies, and cargo contents. Moreover, it delves into the therapeutic potential of mEVs, both as inherently bioactive nanovesicles and as versatile platforms for drug delivery. As efforts progress toward large‐scale implementation, rigorous attention to safe, industrial‐scale production and robust assay development will be pivotal in harnessing the translational promise of small EVs from milk.
{"title":"Milk extracellular vesicles: A burgeoning new presence in nutraceuticals and drug delivery","authors":"Spencer R. Marsh, Claire E. Beard, Robert G. Gourdie","doi":"10.1002/btm2.10756","DOIUrl":"https://doi.org/10.1002/btm2.10756","url":null,"abstract":"Mammalian milk, a multifaceted developmental biofluid, has attracted new attention due to its diverse constituents and their implications for health and disease. Among these constituents, extracellular vesicles (EVs) have emerged as focal points of investigation. EVs, including exosomes and small EVs, have demonstrated biological activity in preclinical studies—including reports of enhancement of cognition and neural complexity, promotion of gastrointestinal development, barrier function and microbiome richness, the bolstering of immune response, and facilitation of musculoskeletal maturation in neonates. The richness of milk as a source of EVs is noteworthy, with hundreds of milliliters (at >10<jats:sup>12</jats:sup> EVs/mL) of nanovesicles extractable from a single liter of milk (>10<jats:sup>14</jats:sup> EVs/starting liter of milk). Techniques such as tangential flow filtration hold promise for scalable production, potentially extending to thousands of liters. Together with the scale and increasing sophistication of the dairy industry, the abundance of EVs in milk underscores their commercial potential in various nutraceutical applications. Beyond natural bioactivity, milk EVs (mEVs) present intriguing possibilities as orally deliverable, non‐immunogenic pharmaceutical carriers, with burgeoning interest in their utilization for heart disease and cancer chemotherapy and as vectors for gene‐editing modules such as CrispR. This review synthesizes current knowledge on mEV biogenesis, characterization, isolation methodologies, and cargo contents. Moreover, it delves into the therapeutic potential of mEVs, both as inherently bioactive nanovesicles and as versatile platforms for drug delivery. As efforts progress toward large‐scale implementation, rigorous attention to safe, industrial‐scale production and robust assay development will be pivotal in harnessing the translational promise of small EVs from milk.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"25 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027199","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}
Christian R. Moya‐Garcia, Meghana Munipalle, Alain Pacis, Nader Sadeghi, Maryam Tabrizian, Nicole Y. K. Li‐Jessen
Tumor resistance to chemotherapy is a common cause of cancer recurrence in patients with head and neck squamous cell carcinoma. The goal of this study is to establish and characterize a chemoresistant laryngeal cancer cell model and test its potential utility for chemosensitizing therapy. At the genotypic level, RNA sequencing confirmed that the cells acquired putative resistance with upregulated docetaxel‐resistant (DR) genes (e.g., TUBB3, CYP24A1) and signaling pathways (e.g., PI3K/mTOR, autophagy). For phenotypic analysis, DR cells were co‐cultured with laryngeal fibroblasts in a 2‐channel microfluidic chip that mimics a hypoxic tumor core in vivo. A drug sensitivity test with a chemosensitizer, metformin (MTF), was performed on the laryngeal tumor‐on‐a‐chip. Compared to non‐treated controls, MTF‐primed cancer cells exhibit higher sensitivity to docetaxel (DTX), that is, cell death. Collectively, this resistance‐acquired cell model displayed presumed genotypic and phenotypic profiles of chemoresistance providing a viable option for testing new therapeutic strategies for restoring tumor sensitivity to DTX.
{"title":"Establishment of a chemoresistant laryngeal cancer cell model to study chemoresistance and chemosensitization responses via transcriptomic analysis and a tumor‐on‐a‐chip platform","authors":"Christian R. Moya‐Garcia, Meghana Munipalle, Alain Pacis, Nader Sadeghi, Maryam Tabrizian, Nicole Y. K. Li‐Jessen","doi":"10.1002/btm2.10741","DOIUrl":"https://doi.org/10.1002/btm2.10741","url":null,"abstract":"Tumor resistance to chemotherapy is a common cause of cancer recurrence in patients with head and neck squamous cell carcinoma. The goal of this study is to establish and characterize a chemoresistant laryngeal cancer cell model and test its potential utility for chemosensitizing therapy. At the genotypic level, RNA sequencing confirmed that the cells acquired putative resistance with upregulated docetaxel‐resistant (DR) genes (e.g., TUBB3, CYP24A1) and signaling pathways (e.g., PI3K/mTOR, autophagy). For phenotypic analysis, DR cells were co‐cultured with laryngeal fibroblasts in a 2‐channel microfluidic chip that mimics a hypoxic tumor core in vivo. A drug sensitivity test with a chemosensitizer, metformin (MTF), was performed on the laryngeal tumor‐on‐a‐chip. Compared to non‐treated controls, MTF‐primed cancer cells exhibit higher sensitivity to docetaxel (DTX), that is, cell death. Collectively, this resistance‐acquired cell model displayed presumed genotypic and phenotypic profiles of chemoresistance providing a viable option for testing new therapeutic strategies for restoring tumor sensitivity to DTX.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020087","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}
Pearlson Prashanth Austin Suthanthiraraj, Sydney Bone, Kyung‐Ho Roh
As the prospect of engineering primary B‐cells for cellular therapies in cancer, autoimmune diseases, and infectious diseases grows, there is an increasing demand for robust in vitro culture systems that effectively activate human B‐cells isolated from peripheral blood for consistent and efficient expansion and differentiation into various effector phenotypes. Feeder cell‐based systems have shown promise in providing long‐term signaling for expanding B‐cells in vitro. However, these co‐culture systems necessitate more rigorous downstream processing to prevent various feeder cell‐related contaminations in the final product, which limits their clinical potential. In this study, we introduce a microbead‐based CD40L‐presentation platform for stable and consistent activation of human naïve B‐cells. By employing a completely synthetic in vitro culture approach integrating B‐cell receptor, CD21 co‐receptor, toll‐like receptor (TLR‐9), and cytokine signals, we demonstrate that naïve B‐cells can differentiate into memory B‐cells (IgD‐CD38‐/lo + CD27+) and antibody‐secreting cells (IgD‐CD38++CD27+). During this process, B‐cells underwent up to a 50‐fold expansion, accompanied by isotype class switching and low levels of somatic hypermutation, mimicking physiological events within the germinal center. The reproducible generation of highly expanded and differentiated effector B‐cells from naïve B‐cells of multiple donors positions this feeder‐free in vitro synthetic niche as a promising platform for large‐scale production of effector B‐cell therapeutics.
{"title":"Microbead‐based synthetic niches for in vitro expansion and differentiation of human naïve B‐cells","authors":"Pearlson Prashanth Austin Suthanthiraraj, Sydney Bone, Kyung‐Ho Roh","doi":"10.1002/btm2.10751","DOIUrl":"https://doi.org/10.1002/btm2.10751","url":null,"abstract":"As the prospect of engineering primary B‐cells for cellular therapies in cancer, autoimmune diseases, and infectious diseases grows, there is an increasing demand for robust in vitro culture systems that effectively activate human B‐cells isolated from peripheral blood for consistent and efficient expansion and differentiation into various effector phenotypes. Feeder cell‐based systems have shown promise in providing long‐term signaling for expanding B‐cells in vitro. However, these co‐culture systems necessitate more rigorous downstream processing to prevent various feeder cell‐related contaminations in the final product, which limits their clinical potential. In this study, we introduce a microbead‐based CD40L‐presentation platform for stable and consistent activation of human naïve B‐cells. By employing a completely synthetic in vitro culture approach integrating B‐cell receptor, CD21 co‐receptor, toll‐like receptor (TLR‐9), and cytokine signals, we demonstrate that naïve B‐cells can differentiate into memory B‐cells (IgD‐CD38‐/lo + CD27+) and antibody‐secreting cells (IgD‐CD38++CD27+). During this process, B‐cells underwent up to a 50‐fold expansion, accompanied by isotype class switching and low levels of somatic hypermutation, mimicking physiological events within the germinal center. The reproducible generation of highly expanded and differentiated effector B‐cells from naïve B‐cells of multiple donors positions this feeder‐free in vitro synthetic niche as a promising platform for large‐scale production of effector B‐cell therapeutics.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"7 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988889","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}
Ziyan An, Pengchao Wang, Zhengyun Ling, Kaipeng Bi, Zheng Wang, Jinpeng Shao, Jian Zhao, Zhouyang Fu, Meng Huang, Wenjie Wei, Shuwei Xiao, Jin Zhou, Weijun Fu
Previous studies of bladder tissue engineering simply seeded cells onto the surface of the material, which makes the cells lack protection and makes it difficult to face the complex in vivo environment. The gelatin methacryloyl (GelMA) hydrogel possesses outstanding biocompatibility and distinctive photo‐crosslinking characteristics and is capable of offering a suitable three‐dimensional growth environment for cells. This study explored the optimal concentration of GelMA for encapsulating adipose‐derived stem cells (ADSCs) and combined it with bladder acellular matrix (BAM) to create a tissue‐engineered bladder patch. Results indicated that 10% GelMA more effectively promoted ADSCs proliferation and spreading compared to 7.5% and 12.5% concentrations, which can offer a better extracellular matrix environment for cells. BAM performed as an excellent substrate with mechanical properties and stitchability similar to natural tissues. Animal experiments demonstrated that the encapsulated ADSCs in GelMA enhanced patch vascularization in vivo and BAM‐GelMA‐ADSCs tissue‐engineered bladder patch can repair large‐scale bladder defects in beagles and promote bladder tissue regeneration and functional recovery. This photocrosslinking hydrogel‐acellular matrix patch provides a protective semi‐controlled environment for ADSCs, supporting the growth and viability of encapsulated cells in vivo, while being easy to suture and preventing leakage, and has significant clinical potential.
{"title":"The BAM‐GelMA‐ADSCs bilayer patch promotes tissue regeneration and functional recovery after large‐area bladder defects in beagles","authors":"Ziyan An, Pengchao Wang, Zhengyun Ling, Kaipeng Bi, Zheng Wang, Jinpeng Shao, Jian Zhao, Zhouyang Fu, Meng Huang, Wenjie Wei, Shuwei Xiao, Jin Zhou, Weijun Fu","doi":"10.1002/btm2.10745","DOIUrl":"https://doi.org/10.1002/btm2.10745","url":null,"abstract":"Previous studies of bladder tissue engineering simply seeded cells onto the surface of the material, which makes the cells lack protection and makes it difficult to face the complex in vivo environment. The gelatin methacryloyl (GelMA) hydrogel possesses outstanding biocompatibility and distinctive photo‐crosslinking characteristics and is capable of offering a suitable three‐dimensional growth environment for cells. This study explored the optimal concentration of GelMA for encapsulating adipose‐derived stem cells (ADSCs) and combined it with bladder acellular matrix (BAM) to create a tissue‐engineered bladder patch. Results indicated that 10% GelMA more effectively promoted ADSCs proliferation and spreading compared to 7.5% and 12.5% concentrations, which can offer a better extracellular matrix environment for cells. BAM performed as an excellent substrate with mechanical properties and stitchability similar to natural tissues. Animal experiments demonstrated that the encapsulated ADSCs in GelMA enhanced patch vascularization in vivo and BAM‐GelMA‐ADSCs tissue‐engineered bladder patch can repair large‐scale bladder defects in beagles and promote bladder tissue regeneration and functional recovery. This photocrosslinking hydrogel‐acellular matrix patch provides a protective semi‐controlled environment for ADSCs, supporting the growth and viability of encapsulated cells in vivo, while being easy to suture and preventing leakage, and has significant clinical potential.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"23 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986004","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}
Hoi Y. Kwon, Christopher Streilein, R. Chase Cornelison
Spinal cord injury (SCI) initiates a complex cascade of chemical and biophysical phenomena that result in tissue swelling, progressive neural degeneration, and formation of a fluid-filled cavity. Previous studies show fluid pressure above the spinal cord (supraspinal) is elevated for at least 3 days after injury and contributes to a phase of damage called secondary injury. Currently, it is unknown how fluid forces within the spinal cord itself (interstitial) are affected by SCI and if they contribute to secondary injury. We find spinal interstitial pressure increases from −3 mmHg in the naive cord to a peak of 13 mmHg at 3 days post-injury (DPI) but relatively normalizes to 2 mmHg by 7 DPI. A computational fluid dynamics model predicts interstitial flow velocities up to 0.9 μm/s at 3 DPI, returning to near baseline by 7 DPI. By quantifying vascular leakage of Evans Blue dye after a cervical hemi-contusion in rats, we confirm an increase in dye infiltration at 3 DPI compared to 7 DPI, suggestive of higher fluid velocities at the time of peak fluid pressure. In vivo expression of the apoptosis marker caspase-3 is strongly correlated with regions of interstitial flow at 3 DPI, and exogenously enhancing interstitial flow exacerbates tissue damage. In vitro, we show overnight exposure of neuronal cells to low pathological shear stress (0.1 dynes/cm2) significantly reduces cell count and neurite length. Collectively, these results indicate that interstitial fluid flow and shear stress may play a detrimental role in post-traumatic neural degeneration.
{"title":"Convective forces contribute to post-traumatic degeneration after spinal cord injury","authors":"Hoi Y. Kwon, Christopher Streilein, R. Chase Cornelison","doi":"10.1002/btm2.10739","DOIUrl":"10.1002/btm2.10739","url":null,"abstract":"<p>Spinal cord injury (SCI) initiates a complex cascade of chemical and biophysical phenomena that result in tissue swelling, progressive neural degeneration, and formation of a fluid-filled cavity. Previous studies show fluid pressure above the spinal cord (supraspinal) is elevated for at least 3 days after injury and contributes to a phase of damage called secondary injury. Currently, it is unknown how fluid forces within the spinal cord itself (interstitial) are affected by SCI and if they contribute to secondary injury. We find spinal interstitial pressure increases from −3 mmHg in the naive cord to a peak of 13 mmHg at 3 days post-injury (DPI) but relatively normalizes to 2 mmHg by 7 DPI. A computational fluid dynamics model predicts interstitial flow velocities up to 0.9 μm/s at 3 DPI, returning to near baseline by 7 DPI. By quantifying vascular leakage of Evans Blue dye after a cervical hemi-contusion in rats, we confirm an increase in dye infiltration at 3 DPI compared to 7 DPI, suggestive of higher fluid velocities at the time of peak fluid pressure. In vivo expression of the apoptosis marker caspase-3 is strongly correlated with regions of interstitial flow at 3 DPI, and exogenously enhancing interstitial flow exacerbates tissue damage. In vitro, we show overnight exposure of neuronal cells to low pathological shear stress (0.1 dynes/cm<sup>2</sup>) significantly reduces cell count and neurite length. Collectively, these results indicate that interstitial fluid flow and shear stress may play a detrimental role in post-traumatic neural degeneration.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"10 2","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10739","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981182","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}
This comprehensive review explores the implications of artificial intelligence (AI) in addressing cochlear implant (CI) issues and revolutionizing the landscape of auditory prosthetics. It begins with an overview of ear anatomy and hearing loss, then explores a review of CI technology and its current challenges. The review emphasizes how advanced AI algorithms and data‐driven approaches enhance CI adaptability and functionality, enabling personalized rehabilitation strategies and improving speech enhancement. It highlights diverse AI applications in auditory rehabilitation, including real‐time adaptive control mechanisms and cognitive hearing assistants that help users manage their auditory health. By outlining innovative pathways and future directions for AI‐enhanced CIs, the paper sets the stage for a transformative shift in auditory prosthetics, aiming to improve the quality of life for individuals with hearing loss.
{"title":"Artificial intelligence‐enabled innovations in cochlear implant technology: Advancing auditory prosthetics for hearing restoration","authors":"Guodao Zhang, Rui Chen, Hamzeh Ghorbani, Wanqing Li, Arsen Minasyan, Yideng Huang, Sen Lin, Minmin Shao","doi":"10.1002/btm2.10752","DOIUrl":"https://doi.org/10.1002/btm2.10752","url":null,"abstract":"This comprehensive review explores the implications of artificial intelligence (AI) in addressing cochlear implant (CI) issues and revolutionizing the landscape of auditory prosthetics. It begins with an overview of ear anatomy and hearing loss, then explores a review of CI technology and its current challenges. The review emphasizes how advanced AI algorithms and data‐driven approaches enhance CI adaptability and functionality, enabling personalized rehabilitation strategies and improving speech enhancement. It highlights diverse AI applications in auditory rehabilitation, including real‐time adaptive control mechanisms and cognitive hearing assistants that help users manage their auditory health. By outlining innovative pathways and future directions for AI‐enhanced CIs, the paper sets the stage for a transformative shift in auditory prosthetics, aiming to improve the quality of life for individuals with hearing loss.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"129 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961440","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}
Emily H. Powsner, Stephanie M. Kronstadt, Kristin Nikolov, Amaya Aranda, Steven M. Jay
Mesenchymal stem cell‐derived extracellular vesicles (MSC EVs) are an attractive therapeutic option for regenerative medicine applications due to their inherently pro‐angiogenic and anti‐inflammatory properties. However, reproducible and cost‐effective production of highly potent therapeutic MSC EVs is challenging, limiting their translational potential. Here, we investigated whether the well‐characterized responsiveness of MSCs to their mechanical environment—specifically, substrate stiffness—could be exploited to generate EVs with increased therapeutic bioactivity without the need for biochemical priming or genetic manipulation. Using polydimethylsiloxane and bone marrow‐derived MSCs (BM‐MSCs), we show that decreasing the stiffness of MSC substrates to as low as 3 kPa significantly improves the pro‐angiogenic bioactivity of EVs as measured by tube formation and gap closure assays. We also demonstrate that lower substrate stiffness improves EV production and overall yield, important for clinical translation. Furthermore, we establish the mechanoresponsiveness of induced pluripotent stem cell‐derived MSC (iMSC) EVs and their comparability to BM‐MSC EVs, again using tube formation and gap closure assays. With this data, we confirm iMSCs' feasibility as an alternative, renewable cell source for EV production with reduced donor variability. Overall, these results suggest that utilizing substrate stiffness is a promising, simple, and a potentially scalable approach that does not require exogenous cargo or extraneous reagents to generate highly potent pro‐angiogenic MSC EVs.
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