ACS Biomaterials Science & Engineering最新文献

{"title":"Engineered PLGA Nanoparticles for Brain-Targeted Codelivery of Cannabidiol and pApoE2 through the Intranasal Route for the Treatment of Alzheimer's Disease.","authors":"Arun Kumar Mahanta, Bivek Chaulagain, Avinash Gothwal, Jagdish Singh","doi":"10.1021/acsbiomaterials.5c00465","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00465","url":null,"abstract":"<p><p>Neuroinflammation induced by the accumulation of amyloid beta plaques expedites the progression of Alzheimer's disease (AD). Reducing Aβ plaques and associated neuroinflammation could potentially help to delay the progression of AD. Cannabidiol (CBD) is well-known for its antioxidant, anti-inflammatory, and neuroprotective nature, and the ApoE2 is effective in binding and clearing Aβ plaques in the brain. Therefore, codelivery of CBD and pApoE2 to the brain would be a promising therapeutic approach in developing effective therapeutics against AD. This research aims to design a nonviral delivery agent that delivers both drugs and genes to the brain through a noninvasive intranasal route. We have developed mPEG-PLGA nanoparticles coated with mannose, a brain-targeting ligand, to deliver CBD and pApoE2. The designed CBD-loaded coated nanoparticles showed an average diameter of 179.3 ± 4.57 nm and a zeta potential of 30.3 ± 6.45 mV. The coated nanoparticles prolonged the CBD release and showed a 93% release of its payload in 30 days. CBD-loaded nanoparticles, as compared to the free CBD, significantly reduced lipopolysaccharide and amyloid beta-induced inflammation in immortalized microglia cells. Cytotoxicity of the designed nanoparticles was assessed against brain endothelial cells (bEND.3) and found to be nontoxic in nature. The mannose-conjugated chitosan-coated nanoparticles were cationic and able to bind with the pApoE2, protecting the encapsulated pApoE2 from enzymatic degradation. Quantitative in vitro transfection efficiency study in primary astrocytes and primary neurons revealed that the ApoE2 expression level is significantly (<i>P</i> < 0.0001) higher for mPLGA-CBD-MC/pApoE2 than the control. The ApoE2 expression level in the brain of C57BL6/J mice was significantly (<i>P</i> < 0.0001) increased after intranasal administration of mPLGA-CBD-MC/pApoE2. Henceforth, the mannose-conjugated chitosan-coated mPLGA nanoparticles could serve as a nonviral delivery system to deliver both drugs and genes to the brain through the intranasal route for the management of AD.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085540","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":"Rheological Characterization and 3D Fabrication of Artificial Bacterial Biofilms.","authors":"Annie Scutte, Kiram Harrison, Tyler Gregory, David Quashie, Subramanian Ramakrishnan, Jamel Ali","doi":"10.1021/acsbiomaterials.5c00223","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00223","url":null,"abstract":"<p><p>Biofilms are significantly involved in the progression of many diseases, such as cancer and upper respiratory infections, due to their ability to adhere to soft tissues. Factors influencing biofilm development have been extensively studied on planar substrates; however, there is limited understanding regarding biofilm growth and interactions within 3D matrices. Developing biofilm models that closely mimic natural bacterial communities' chemical and mechanical properties in soft tissues is essential for developing next-generation antibacterial compounds and therapeutics, as 3D biofilms are more complex and less susceptible to treatment than their 2D counterparts. Here, to understand environmental viscoelastic effects on biofilms within 3D matrix environments, two types of alginate-based hydrogels are formulated and used to encapsulatevarying concentrations of <i>Salmonella</i> Typhimurium. We explore the effects of increasing <i>S</i>. Typhimurium concentrations on hydrogel rheological properties and assess the impact of printing parameters on bacterial viability. Results show that hydrogels exhibit shear thinning behavior and that increasing the bacterial concentration up to 1 × 10⁷ CFU mL^-1 has no significant effect on the hydrogel precursor moduli and low shear viscosity. However, increasing the bacterial concentration to 1 × 10¹⁰ CFU mL^-1 significantly decreases the hydrogel shear viscosity and modulus. Utilizing extrusion-based bioprinting, the optimal printing parameters (Pr > 0.8) have minimal effects on bacterial viability (>80%) over a 4 day incubation period. Additionally, we find that lower concentrations of bacteria form larger aggregates over time than hydrogels with higher cell concentrations. We show that biofilm growth in 3D depends on both initial bacterial density and matrix rigidity. Further development of physicochemically tuned bioprinted bacterial communities will aid our understanding of bacterial interactions within their 3D environments and enable the use of <i>in vitro</i> tissue models that incorporate biofilms for high-throughput therapeutic screening.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074877","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":"Structural and Mechanical Characterization of Collagen-Hyaluronan Hydrogels Used to Study Cancer Cell Invasion through the Bladder Wall.","authors":"Sara Metwally, Justyna Śmiałek-Bartyzel, Joanna Pabijan, Małgorzata Lekka","doi":"10.1021/acsbiomaterials.5c00136","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00136","url":null,"abstract":"<p><p>Collagen-hyaluronic acid (Col-HA) hydrogels are widely studied as biomimetic materials that recapitulate the environmental physical and mechanical properties crucial for understanding the cell behavior during cancer invasion and progression. Our research focused on Col-HA hydrogels as an environment to study the invasion of bladder cancer cells through the bladder wall. The bladder is a heterogeneous structure composed of three main layers: urothelium (the softest), lamina propria (the stiffest), and the muscle outer layer, with elastic properties lying between the two. Thus, the bladder cancer cells migrate through the mechanically distinct environments. We investigated the impact of Col-HA hydrogel microstructure and rheology on migrating bladder cancer T24 cells from the cancer spheroid surface to the surrounding environment formed from various collagen I and HA concentrations and chemical structures. The designed hydrogels showed variability in network density and rheological properties. The migration of bladder cancer cells was inhibited inside hydrogels of ∼1 kPa storage modulus. The correlation analysis showed that collagen concentration primarily defined the rheological properties of Col-HA hydrogels, but hydrogels can soften or stiffen depending on the type of HA used. Within soft Col-HA hydrogels, cells freely invade the surrounding environment, while its stiffening impedes cell movement and almost inhibits cell migration. Only individual, probably leading, cells are observed at the spheroid edges initiating the invasion. Our findings showed that the rheological properties of the hydrogels dominate in regulating cancer cell migration, providing a platform to study how bladder cancer cells migrate through the heterogeneous structure of the bladder wall.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074878","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":"Addition of Microscale Topographies to Silk Fibroin Film Modulates Corneal Endothelial Cell Behavior.","authors":"Swatilekha Hazra, Souradeep Dey, Biman B Mandal, Charanya Ramachandran","doi":"10.1021/acsbiomaterials.5c00200","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00200","url":null,"abstract":"<p><p>Biomimicry in tissue engineering has been used to improve the function of a structure by closely replicating the native architecture. One such method is the introduction of micro- and nanotopographical patterns on biomaterials that mimic the native extracellular environment to enhance cell behavior and function before and after clinical transplantation. Earlier studies from our laboratory had shown that silk fibroin films offer promising potential for corneal endothelial regeneration because of their optimum optical, mechanical, and functional properties. In this study, we hoped to improve upon the design by incorporating micropatterns that are present in the native tissue on the surface of silk films. Fibroin protein from <i>Antheraea assamensis</i> worms was used to prepare films with and without patterns (hexagons and microgrooves) on their surface. The mechanical and optical properties of these films were analyzed by measuring the Young's modulus and light transmittance in the visible spectrum. Cell adhesion and proliferation were determined using the MTT assay and Ki67 staining, respectively. Morphometric analysis of cell shape and size was performed using the ImageJ software, and the expression of markers was visualized and quantified using immunostaining and Western blot. Patterned films demonstrated enhanced elasticity, roughness, and hydrophilicity compared to flat films. No significant difference was observed in cell adhesion between the flat and patterned films. The percentage of proliferating cells was significantly reduced on the patterned films, especially on hexagons. The cell area and circularity on flat films were comparable to microgrooves, whereas cells on hexagons displayed larger and more variable sizes. Notably, the expression of Na-K ATPase (a critical pump protein) was significantly higher in cells grown on microgrooves than on other substrates. These findings suggest that incorporating simple micropatterns on the surface of silk fibroin films can improve the morphology and functional quality of corneal endothelial cells, providing insights into the development of biomaterial-based strategies for endothelial transplantation.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950931","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":"Adaptations of Gram-Negative and Gram-Positive Probiotic Bacteria in Engineered Living Materials.","authors":"Varun Sai Tadimarri, Tanya Amit Tyagi, Cao Nguyen Duong, Sari Rasheed, Rolf Müller, Shrikrishnan Sankaran","doi":"10.1021/acsbiomaterials.5c00325","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00325","url":null,"abstract":"<p><p>Encapsulation of microbes in natural or synthetic matrices is a key aspect of engineered living materials, although the influence of such confinement on microbial behavior is poorly understood. A few recent studies have shown that the spatial confinement and mechanical properties of the encapsulating material significantly influence microbial behavior, including growth, metabolism, and gene expression. However, comparative studies within different bacterial species under identical confinement conditions are limited. In this study, Gram-negative <i>Escherichia coli</i> Nissle 1917 and Gram-positive <i>Lactiplantibacillus plantarum</i> WCFS1 were encapsulated in hydrogel matrices, and their growth, metabolic activity, and recombinant gene expression were examined under varying degrees of hydrogel stiffness, achieved by adjusting the polymer concentration and chemical cross-linking. Both bacteria grow from single cells into confined colonies, but more interestingly, in <i>E. coli</i> gels, mechanical properties influenced colony growth, size, and morphology, whereas this did not occur in <i>L. plantarum</i> gels. However, with both bacteria, increased matrix stiffness led to higher levels of recombinant protein production within the colonies. By measuring metabolic heat from the bacterial gels using the isothermal microcalorimetry technique, it was inferred that <i>E. coli</i> adapts to the mechanical restrictions through multiple metabolic transitions and is significantly affected by the different hydrogel properties. Contrastingly, both of these aspects were not observed with <i>L. plantarum</i>. These results revealed that despite both bacteria being gut-adapted probiotics with similar geometries, mechanical confinement affects them considerably differently. The weaker influence of matrix stiffness on <i>L. plantarum</i> is attributed to its slower growth and thicker cell wall, possibly enabling the generation of higher turgor pressures to overcome restrictive forces under confinement. By providing fundamental insights into the interplay between mechanical forces and bacterial physiology, this work advances our understanding of how matrix properties shape bacterial behavior. The implications of these findings will aid the design of engineered living materials for therapeutic applications.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950842","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":"SiRNA-Targeting TGF-β1 Based on Nanoparticle-Coated Ureteral Stents to Inhibit Ureteral Stricture.","authors":"Wei Meng, Ningning Li, Feng Lv, Bo Chen, Shuaijiang Lu, Jiayi Zhang, Tong Zhang, Qianyu Tao, Youlang Zhou, Limin Ma, Yangbo Guan","doi":"10.1021/acsbiomaterials.4c01925","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.4c01925","url":null,"abstract":"<p><p>Ureteral stricture is a difficult urological problem with no optimal solution and is the result of scar hyperplasia and fibrosis caused by ureteral injury. Preventing the formation of ureteral strictures around drug-loaded ureteral stents is at the heart of the current research. TGF-β1 is a key factor affecting collagen deposition and fiber formation. Therefore, in this study, we established a rabbit ureteral stricture model, implanted a ureteral stent loaded with TGF-β1-siRNA for treatment, and compared the histopathology of ureteral stricture and the protein expression of genes related to the formation of stricture between different groups to test their therapeutic effects. We used sustained- and slow-release properties of the nanoparticles that were confirmed through in vitro experiments. The results of the fluorescence immunoassay showed that siRNA loaded by ureteral stents had high transfection efficiency on human ureter epithelial cells in vivo. In addition, the rabbit ureteral stricture model experiment verified that TGF-β1-siRNA could effectively transfect into ureteral tissues and inhibit the expression of TGF-β1, thereby inhibiting ureteral stricture. At the same time, the images of rabbit gross anatomy specimens showed that the hydronephrosis could also be effectively relieved. In summary, all the results mentioned above suggest that ureteral stents combined with RNA interference technology and a nanoparticle delivery system have broad prospects for clinical application in the suppression of ureteral stricture.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951072","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":"Novel Mitochondria-Targeted NIR Cyanine Cy750M-C1 Nanoparticles for Chemotherapy against Triple-Negative Breast Cancer.","authors":"Zhilin Shen, Fenglin Zhang, Jiawang Yang, Kaihang Zhang, Feng Liang, Han Mu, Li Shi, Jijun Jiang, Yuanzhi Yang, Zhixuan Lin, Jie Gao, Ning Gao","doi":"10.1021/acsbiomaterials.5c00343","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00343","url":null,"abstract":"<p><p>Mitochondrial metabolism plays an important role in promoting cancer development, making mitochondria a novel promising target for cancer therapy. Current mitochondria-targeted fluorescent agents can specifically accumulate in the mitochondria of cancer cells and can be applied for cancer imaging and therapy. However, their clinical application is still limited due to the poor solubility and lower tumor-specific distribution. In the present study, we synthesized a novel NIR small-molecule dye, Cy750M-C1, and evaluated its optical properties, mitochondrial distribution, and anticancer activity. We also synthesized nanoparticles loading Cy750M-C1 (Cy750M-C1-FA-NPs) and demonstrated that Cy750M-C1-FA-NPs are specifically targeted to the tumor and dramatically inhibited tumor growth <i>in vivo</i>. The mechanistic study revealed that Cy750M-C1 specifically targeted mitochondria of TNBC cells, subsequently promoting ROS production through inhibition of mitochondrial complexes (complexes I, III, and IV) and OXPHOS and depletion of ATP, leading, in turn, to AMPK activation and Drp1 dephosphorylation mediating the mitochondrial translocation of Drp1 and BAX and ultimately inducing mitochondrial fission, caspase activation, as well as apoptosis. Overall, our data implicate that Cy750M-C1 could be developed as a novel anticancer agent with mitochondria-targeting ability and NIR fluorescence imaging and that Cy750M-C1-FA-NPs could also be considered as promising drug delivery carriers for antitumor agents.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950877","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":"Developing a Bone-Mimicking Microenvironment: Surface Coating Method for Investigating Bone Remodeling <i>in Vitro</i>.","authors":"A Sieberath, D Eglin, C M Sprecher, A M Ferreira, P Gentile, K Dalgarno, E Della Bella","doi":"10.1021/acsbiomaterials.4c02330","DOIUrl":"10.1021/acsbiomaterials.4c02330","url":null,"abstract":"<p><p>To investigate bone formation and resorption <i>in vitro</i>, it is essential to create bone-like microenvironments on cell culture substrates. Here, we present a coating technique to create such a microenvironment on cell culture plastic (CCP) multiwell plates for studying bone remodeling <i>in vitro</i>. Utilizing this coating, we have developed an assay to simultaneously measure cellular mineral formation and resorption in osteoblast and osteoclast coculture models. A composite matrix of collagen type I and carbonated apatitic calcium phosphate was deposited onto CCP in a reproducible manner using a 10× simulated body fluid solution (SBF) supplemented with type I collagen. qPCR analysis and cellular imaging using fluorescence microscopy demonstrated the promotion of osteogenic differentiation, cell attachment, and proliferation of human bone-marrow-derived mesenchymal stem cells on coated substrates. Moreover, human bone-marrow-derived mononuclear cells successfully differentiated into osteoclasts and resorbed the coated substrate. Using the developed coating, an osteoblast and osteoclast coculture system was established, enabling real-time monitoring of mineral formation and resorption. By providing a controlled and physiologically relevant <i>in vitro</i> model, this assay facilitates the screening of therapeutic compounds, the study of bone cell interactions, and the identification of factors influencing bone remodeling, thereby enhancing translational research in bone health.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"11 5","pages":"2690-2704"},"PeriodicalIF":5.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952493","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}

{"title":"Screening <i>Isodon rubescens</i>-Derived Vesicles Harvested at Different Periods as Carriers for the Treatment of Colitis-Associated Cancer.","authors":"Junli Zhang, Yaqi Zhang, Xiaoji Ma, Haibo Wang, Chaofeng Zhang, Chengxue Pan","doi":"10.1021/acsbiomaterials.5c00160","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00160","url":null,"abstract":"<p><p>Plant-derived extracellular vesicles are of great significance in practical applications due to their availability, low immunogenicity, and effective carrier performance. <i>Isodon rubescens</i>-derived vesicles (IRDVs) not only have the capability for drug-carrying targeted therapy but also exhibit certain anti-inflammatory and antitumor effects as part of traditional Chinese medicine. The harvest time is closely related to the quality of its medicinal ingredients; however, whether there are differences in the IRDVs harvested at different times has yet to be explored. Herein, we analyzed the morphology and chemical composition of IRDVs collected at different time points and identified six-month-harvested IRDVs as the most suitable delivery vector. To further enhance their therapeutic potential, we modified the IRDVs with deoxycholic acid to facilitate the oral delivery of the chemotherapy drug doxorubicin (DOX). This novel nanotherapy, termed DOX-IRDVs@DA, was developed as an oral targeted treatment for colitis-associated cancer (CAC). The results demonstrated that DOX-IRDVs@DA effectively delivered DOX to colon tumor 26 (CT26) cells, induced cancer cell apoptosis by modulating apoptosis-related proteins, and inhibited the proliferation of CT26 cells. In vivo studies in a mouse model of CAC revealed that DOX-IRDVs@DA achieved superior targeted therapeutic effects, reducing the number of colonic nodules, restoring the structural integrity of the colon, and causing minimal systemic toxicity.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"11 5","pages":"2653-2663"},"PeriodicalIF":5.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951412","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":"Female Fibroblast Activation Is Estrogen-Mediated in Sex-Specific 3D-Bioprinted Pulmonary Artery Adventitia Models.","authors":"Mikala C Mueller, Rachel Blomberg, Alicia E Tanneberger, Duncan Davis-Hall, Keith B Neeves, Chelsea M Magin","doi":"10.1021/acsbiomaterials.5c00123","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.5c00123","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a form of pulmonary vascular disease characterized by scarring of the small blood vessels that results in reduced blood flow and increased blood pressure in the lungs. Over time, this increase in blood pressure causes damage to the heart. Idiopathic (IPAH) impacts male and female patients differently, with female patients showing a higher disease susceptibility (4:1 female-to-male ratio) but experiencing longer survival rates postdiagnosis compared to male patients. This complex sex dimorphism is known as the estrogen paradox. Prior studies suggest that estrogen signaling may be pathologic in the pulmonary vasculature and protective in the heart, yet the mechanisms underlying these sex differences in IPAH remain unclear. Many previous studies of PAH relied on male cells or cells of undisclosed origin for <i>in vitro</i> modeling. Here, we present a dynamic, three-dimensional (3D)-bioprinted model incorporating cells and circulating sex hormones from female patients to specifically study how female patients respond to changes in microenvironmental stiffness and sex hormone signaling on the cellular level. Poly(ethylene glycol)-α methacrylate (PEGαMA)-based hydrogels containing female human pulmonary artery adventitia fibroblasts (hPAAFs) from IPAH or control donors were 3D bioprinted to mimic pulmonary artery adventitia. These biomaterials were initially soft, like healthy blood vessels, and then stiffened using light to mimic vessel scarring in PAH. These 3D-bioprinted models showed that stiffening the microenvironment around female IPAH hPAAFs led to hPAAF activation. On both the protein and gene-expression levels, cellular activation markers significantly increased in stiffened samples and were highest in IPAH patient-derived cells. Treatment with a selective estrogen receptor modulator, which is currently in clinical trials for IPAH treatment, reduced the expression of hPAAF activation markers, demonstrating that hPAAF activation is one pathologic response mediated by estrogen signaling in the vasculature. These results showed the utility of sex-specific, 3D-bioprinted pulmonary artery adventitia models for preclinical drug discovery and validation.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"11 5","pages":"2935-2945"},"PeriodicalIF":5.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950844","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}