Sandipan Chattaraj, Michele Torre, Constanze Kalcher, Alexander Stukowski, Simone Morganti, A. Reali, F. Pasqualini
{"title":"SEM2: Introducing mechanics in cell and tissue modeling using coarse-grained homogeneous particle dynamics","authors":"Sandipan Chattaraj, Michele Torre, Constanze Kalcher, Alexander Stukowski, Simone Morganti, A. Reali, F. Pasqualini","doi":"10.1063/5.0166829","DOIUrl":"https://doi.org/10.1063/5.0166829","url":null,"abstract":"Modeling multiscale mechanics in shape-shifting engineered tissues, such as organoids and organs-on-chip, is both important and challenging. In fact, it is difficult to model relevant tissue-level large non-linear deformations mediated by discrete cell-level behaviors, such as migration and proliferation. One approach to solve this problem is subcellular element modeling (SEM), where ensembles of coarse-grained particles interacting via empirically defined potentials are used to model individual cells while preserving cell rheology. However, an explicit treatment of multiscale mechanics in SEM was missing. Here, we incorporated analyses and visualizations of particle level stress and strain in the open-source software SEM++ to create a new framework that we call subcellular element modeling and mechanics or SEM2. To demonstrate SEM2, we provide a detailed mechanics treatment of classical SEM simulations including single-cell creep, migration, and proliferation. We also introduce an additional force to control nuclear positioning during migration and proliferation. Finally, we show how SEM2 can be used to model proliferation in engineered cell culture platforms such as organoids and organs-on-chip. For every scenario, we present the analysis of cell emergent behaviors as offered by SEM++ and examples of stress or strain distributions that are possible with SEM2. Throughout the study, we only used first-principles literature values or parametric studies, so we left to the Discussion a qualitative comparison of our insights with recently published results. The code for SEM2 is available on GitHub at https://github.com/Synthetic-Physiology-Lab/sem2.","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":" 3","pages":""},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138613079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-11-22eCollection Date: 2023-12-01DOI: 10.1063/5.0187849
Joe G Troughton, Yaw O Ansong Snr, Nida Duobaite, Christopher M Proctor
{"title":"Erratum: Publisher's Note: \"Finite element analysis of electric field distribution during direct current stimulation of the spinal cord: Implications for device design\" [APL Bioeng. <b>7</b>, 046109 (2023)].","authors":"Joe G Troughton, Yaw O Ansong Snr, Nida Duobaite, Christopher M Proctor","doi":"10.1063/5.0187849","DOIUrl":"https://doi.org/10.1063/5.0187849","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1063/5.0163264.].</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"049902"},"PeriodicalIF":6.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"OCT angiography in the monitoring of vaginal health.","authors":"Saijun Qiu, Afiba Arthur, Yuchen Jiang, Yusi Miao, Yan Li, Jingyi Wang, Yona Tadir, Felicia Lane, Zhongping Chen","doi":"10.1063/5.0153461","DOIUrl":"10.1063/5.0153461","url":null,"abstract":"<p><p>Fractional-pixel CO<sub>2</sub> laser therapy shows promise for treating the genitourinary syndrome of menopause (GSM). Nevertheless, it remains controversial in the field of female pelvic medicine. This is due to the inherent difficulties in obtaining noninvasive biopsies to evaluate the treatment's efficacy and safety objectively. To address this challenge, we developed a noninvasive intravaginal optical coherence tomography (OCT)/OCT angiography (OCTA) endoscopic system, whose probe features a shape identical to the laser treatment probe. This system can provide high-resolution OCT images to identify the microstructure of vaginal tissue and visualize the vasculature network <i>in vivo</i>. We conducted clinical research on 25 post-menopausal patients with GSM. OCT/OCTA scans were acquired at four different locations of the vagina (distal anterior, distal posterior, proximal anterior, and proximal posterior) during the whole laser treatment session. A U-Net deep learning model was applied to segment the vaginal epithelium for assessing vaginal epithelial thickness (VET). Blood vessel density and VET were quantified to monitor the efficacy of fractional-pixel CO<sub>2</sub> laser therapy. Statistical correlation analyses between these metrics and other clinical scores were conducted, validating the utility of our system. This OCT/OCTA endoscopic system has great potential to serve as a noninvasive biopsy tool in gynecological studies to screen, evaluate, and guide laser treatment for GSM.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046112"},"PeriodicalIF":6.6,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72016717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-11-03eCollection Date: 2023-12-01DOI: 10.1063/5.0164951
Sophie C Payne, Peregrine B Osborne, Alex Thompson, Calvin D Eiber, Janet R Keast, James B Fallon
{"title":"Selective recording of physiologically evoked neural activity in a mixed autonomic nerve using a minimally invasive array.","authors":"Sophie C Payne, Peregrine B Osborne, Alex Thompson, Calvin D Eiber, Janet R Keast, James B Fallon","doi":"10.1063/5.0164951","DOIUrl":"10.1063/5.0164951","url":null,"abstract":"<p><p>Real-time closed-loop control of neuromodulation devices requires long-term monitoring of neural activity in the peripheral nervous system. Although many signal extraction methods exist, few are both clinically viable and designed for extracting small signals from fragile peripheral visceral nerves. Here, we report that our minimally invasive recording and analysis technology extracts low to negative signal to noise ratio (SNR) neural activity from a visceral nerve with a high degree of specificity for fiber type and class. Complex activity was recorded from the rat pelvic nerve that was physiologically evoked during controlled bladder filling and voiding, in an extensively characterized <i>in vivo</i> model that provided an excellent test bed to validate our technology. Urethane-anesthetized male rats (n = 12) were implanted with a four-electrode planar array and the bladder instrumented for continuous-flow cystometry, which measures urodynamic function by recording bladder pressure changes during constant infusion of saline. We demonstrated that differential bipolar recordings and cross-correlation analyses extracts afferent and efferent activity, and discriminated between subpopulations of fibers based on conduction velocity. Integrated Aδ afferent fiber activity correlated with bladder pressure during voiding (r<sup>2</sup>: 0.66 ± 0.06) and was not affected by activating nociceptive afferents with intravesical capsaicin (r<sup>2</sup>: 0.59 ± 0.14, <i>P</i> = 0.54, and n = 3). Collectively, these results demonstrate our minimally invasive recording and analysis technology is selective in extracting mixed neural activity with low/negative SNR. Furthermore, integrated afferent activity reliably correlates with bladder pressure and is a promising first step in developing closed-loop technology for bladder control.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046110"},"PeriodicalIF":6.0,"publicationDate":"2023-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-11-02eCollection Date: 2023-12-01DOI: 10.1063/5.0163264
Joe G Troughton, Yaw O Ansong, Nida Duobaite, Christopher M Proctor
{"title":"Finite element analysis of electric field distribution during direct current stimulation of the spinal cord: Implications for device design.","authors":"Joe G Troughton, Yaw O Ansong, Nida Duobaite, Christopher M Proctor","doi":"10.1063/5.0163264","DOIUrl":"10.1063/5.0163264","url":null,"abstract":"<p><p>Spinal cord injury (SCI) arises from damage to the spinal cord, often caused by trauma or disease. The resulting sensorimotor dysfunction is variable and dependent on the extent of the injury. Despite years of research, curative options for SCI remain limited. However, recent advancements in electric field stimulated axonal regrowth have shown promise for neuronal regeneration. One roadblock in the development of therapeutic treatments based on this is a lack of understanding of the exogenous electric field distribution in the injured tissue, and in particular, how this is influenced by electrode geometry and placement. To better understand this electric field, and provide a means by which it can be optimized, we have developed a finite element model of such spinal cord treatment. We investigate the impact of variations in electrode geometry, spinal cord size, and applied current magnitude as well as looking at several injury models in relation to clinically observed outcomes. Through this, we show that electrode shape has little effect on the induced electric field, that the placement of these electrodes has a noticeable influence on the field distribution, and that the magnitude of this field is governed by both the applied current and the spinal cord morphology. We also show that the injury modality influences the induced field distribution and that a stronger understanding of the injury will help decide treatment parameters. This work provides guidance in the design of electrodes for future clinical application in direct current electric field stimulation for axonal regeneration.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046109"},"PeriodicalIF":6.0,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-10-30eCollection Date: 2023-12-01DOI: 10.1063/5.0150532
John C Biber, Andra Sullivan, Joseph A Brazzo, Yuna Heo, Bat-Ider Tumenbayar, Amanda Krajnik, Kerry E Poppenberg, Vincent M Tutino, Su-Jin Heo, John Kolega, Kwonmoo Lee, Yongho Bae
{"title":"Survivin as a mediator of stiffness-induced cell cycle progression and proliferation of vascular smooth muscle cells.","authors":"John C Biber, Andra Sullivan, Joseph A Brazzo, Yuna Heo, Bat-Ider Tumenbayar, Amanda Krajnik, Kerry E Poppenberg, Vincent M Tutino, Su-Jin Heo, John Kolega, Kwonmoo Lee, Yongho Bae","doi":"10.1063/5.0150532","DOIUrl":"10.1063/5.0150532","url":null,"abstract":"<p><p>Stiffened arteries are a pathology of atherosclerosis, hypertension, and coronary artery disease and a key risk factor for cardiovascular disease events. The increased stiffness of arteries triggers a phenotypic switch, hypermigration, and hyperproliferation of vascular smooth muscle cells (VSMCs), leading to neointimal hyperplasia and accelerated neointima formation. However, the mechanism underlying this trigger remains unknown. Our analyses of whole-transcriptome microarray data from mouse VSMCs cultured on stiff hydrogels simulating arterial pathology identified 623 genes that were significantly and differentially expressed (360 upregulated and 263 downregulated) relative to expression in VSMCs cultured on soft hydrogels. Functional enrichment and gene network analyses revealed that these stiffness-sensitive genes are linked to cell cycle progression and proliferation. Importantly, we found that survivin, an inhibitor of apoptosis protein, mediates stiffness-dependent cell cycle progression and proliferation as determined by gene network and pathway analyses, RT-qPCR, immunoblotting, and cell proliferation assays. Furthermore, we found that inhibition of cell cycle progression did not reduce survivin expression, suggesting that survivin functions as an upstream regulator of cell cycle progression and proliferation in response to ECM stiffness. Mechanistically, we found that the stiffness signal is mechanotransduced via the FAK-E2F1 signaling axis to regulate survivin expression, establishing a regulatory pathway for how the stiffness of the cellular microenvironment affects VSMC behaviors. Overall, our findings indicate that survivin is necessary for VSMC cycling and proliferation and plays a role in regulating stiffness-responsive phenotypes.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046108"},"PeriodicalIF":6.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-10-24eCollection Date: 2023-12-01DOI: 10.1063/5.0156463
Abhijith Krishnan, C S Deepak, K S Narayan
{"title":"Investigations on artificially extending the spectral range of natural vision.","authors":"Abhijith Krishnan, C S Deepak, K S Narayan","doi":"10.1063/5.0156463","DOIUrl":"10.1063/5.0156463","url":null,"abstract":"<p><p>Organic semiconductors are being explored as retinal prosthetics with the prime attributes of bio-compatibility and conformability for seamless integration with the retina. These polymer-based artificial photoreceptor films are self-powered with light-induced signal strength sufficient to elicit neuronal firing events. The molecular aspect of these semiconductors provides wide spectral tunability. Here, we present results from a bulk heterostructure semiconductor blend with a wide spectral response range. This combination elicits clear spiking activity from a developing blind-chick embryonic retina in the subretinal configuration in response to white light. The response is largely triggered by the blue-green spectral regime rather than the red-NIR regime for the present polymer semiconductor layer attributes.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046105"},"PeriodicalIF":6.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54231550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-10-20eCollection Date: 2023-12-01DOI: 10.1063/5.0157549
Amanda Krajnik, Erik Nimmer, Joseph A Brazzo, John C Biber, Rhonda Drewes, Bat-Ider Tumenbayar, Andra Sullivan, Khanh Pham, Alanna Krug, Yuna Heo, John Kolega, Su-Jin Heo, Kwonmoo Lee, Brian R Weil, Deok-Ho Kim, Sachin A Gupte, Yongho Bae
{"title":"Survivin regulates intracellular stiffness and extracellular matrix production in vascular smooth muscle cells.","authors":"Amanda Krajnik, Erik Nimmer, Joseph A Brazzo, John C Biber, Rhonda Drewes, Bat-Ider Tumenbayar, Andra Sullivan, Khanh Pham, Alanna Krug, Yuna Heo, John Kolega, Su-Jin Heo, Kwonmoo Lee, Brian R Weil, Deok-Ho Kim, Sachin A Gupte, Yongho Bae","doi":"10.1063/5.0157549","DOIUrl":"10.1063/5.0157549","url":null,"abstract":"<p><p>Vascular dysfunction is a common cause of cardiovascular diseases characterized by the narrowing and stiffening of arteries, such as atherosclerosis, restenosis, and hypertension. Arterial narrowing results from the aberrant proliferation of vascular smooth muscle cells (VSMCs) and their increased synthesis and deposition of extracellular matrix (ECM) proteins. These, in turn, are modulated by arterial stiffness, but the mechanism for this is not fully understood. We found that survivin is an important regulator of stiffness-mediated ECM synthesis and intracellular stiffness in VSMCs. Whole-transcriptome analysis and cell culture experiments showed that survivin expression is upregulated in injured femoral arteries in mice and in human VSMCs cultured on stiff fibronectin-coated hydrogels. Suppressed expression of survivin in human VSMCs significantly decreased the stiffness-mediated expression of ECM components related to arterial stiffening, such as collagen-I, fibronectin, and lysyl oxidase. By contrast, expression of these ECM proteins was rescued by ectopic expression of survivin in human VSMCs cultured on soft hydrogels. Interestingly, atomic force microscopy analysis showed that suppressed or ectopic expression of survivin decreases or increases intracellular stiffness, respectively. Furthermore, we observed that inhibiting Rac and Rho reduces survivin expression, elucidating a mechanical pathway connecting intracellular tension, mediated by Rac and Rho, to survivin induction. Finally, we found that survivin inhibition decreases FAK phosphorylation, indicating that survivin-dependent intracellular tension feeds back to maintain signaling through FAK. These findings suggest a novel mechanism by which survivin potentially modulates arterial stiffness.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046104"},"PeriodicalIF":6.0,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10590228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49692949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-10-16eCollection Date: 2023-12-01DOI: 10.1063/5.0167440
Jounghyun H Lee, Kevin L Shores, Jason J Breithaupt, Caleb S Lee, Daniella M Fodera, Jennifer B Kwon, Adarsh R Ettyreddy, Kristin M Myers, Benny J Evison, Alexandra K Suchowerska, Charles A Gersbach, Kam W Leong, George A Truskey
{"title":"PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system.","authors":"Jounghyun H Lee, Kevin L Shores, Jason J Breithaupt, Caleb S Lee, Daniella M Fodera, Jennifer B Kwon, Adarsh R Ettyreddy, Kristin M Myers, Benny J Evison, Alexandra K Suchowerska, Charles A Gersbach, Kam W Leong, George A Truskey","doi":"10.1063/5.0167440","DOIUrl":"10.1063/5.0167440","url":null,"abstract":"<p><p>Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering lipid metabolism, PCSK9 also influences vascular inflammation, further promoting atherosclerosis. Here, we utilized a vascular microphysiological system to test the effect of PCSK9 activation or repression on the initiation of atherosclerosis and to screen the efficacy of a small molecule PCSK9 inhibitor. We have generated PCSK9 over-expressed (P+) or repressed (P-) human induced pluripotent stem cells (iPSCs) and further differentiated them to smooth muscle cells (viSMCs) or endothelial cells (viECs). Tissue-engineered blood vessels (TEBVs) made from P+ viSMCs and viECs resulted in increased monocyte adhesion compared to the wild type (WT) or P- equivalents when treated with enzyme-modified LDL (eLDL) and TNF-α. We also found significant viEC dysfunction, such as increased secretion of VCAM-1, TNF-α, and IL-6, in P+ viECs treated with eLDL and TNF-α. A small molecule compound, NYX-1492, that was originally designed to block PCSK9 binding with the LDLR was tested in TEBVs to determine its effect on lowering PCSK9-induced inflammation. The compound reduced monocyte adhesion in P+ TEBVs with evidence of lowering secretion of VCAM-1 and TNF-α. These results suggest that PCSK9 inhibition may decrease vascular inflammation in addition to lowering plasma LDL levels, enhancing its anti-atherosclerotic effects, particularly in patients with elevated chronic inflammation.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 4","pages":"046103"},"PeriodicalIF":6.6,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10581720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49683473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APL BioengineeringPub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.1063/5.0168087
Imke Jansen, Hanneke Crielaard, Tamar Wissing, Carlijn Bouten, Frank Gijsen, Ali C Akyildiz, Eric Farrell, Kim van der Heiden
{"title":"A tissue-engineered model of the atherosclerotic plaque cap: Toward understanding the role of microcalcifications in plaque rupture.","authors":"Imke Jansen, Hanneke Crielaard, Tamar Wissing, Carlijn Bouten, Frank Gijsen, Ali C Akyildiz, Eric Farrell, Kim van der Heiden","doi":"10.1063/5.0168087","DOIUrl":"10.1063/5.0168087","url":null,"abstract":"<p><p>Rupture of the cap of an atherosclerotic plaque can lead to thrombotic cardiovascular events. It has been suggested, through computational models, that the presence of microcalcifications in the atherosclerotic cap can increase the risk of cap rupture. However, the experimental confirmation of this hypothesis is still lacking. In this study, we have developed a novel tissue-engineered model to mimic the atherosclerotic fibrous cap with microcalcifications and assess the impact of microcalcifications on cap mechanics. First, human carotid plaque caps were analyzed to determine the distribution, size, and density of microcalcifications in real cap tissue. Hydroxyapatite particles with features similar to real cap microcalcifications were used as microcalcification mimics. Injected clusters of hydroxyapatite particles were embedded in a fibrin gel seeded with human myofibroblasts which deposited a native-like collagenous matrix around the particles, during the 21-day culture period. Second harmonic multiphoton microscopy imaging revealed higher local collagen fiber dispersion in regions of hydroxyapatite clusters. Tissue-engineered caps with hydroxyapatite particles demonstrated lower stiffness and ultimate tensile stress than the control group samples under uniaxial tensile loading, suggesting increased rupture risk in atherosclerotic plaques with microcalcifications. This model supports previous computational findings regarding a detrimental role for microcalcifications in cap rupture risk and can further be deployed to elucidate tissue mechanics in pathologies with calcifying soft tissues.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"7 3","pages":"036120"},"PeriodicalIF":6.6,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41172465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}