bioRxiv - Bioengineering最新文献_第5页

In Vivo Optical Clearing of Mammalian Brain 哺乳动物大脑的体内光学清除

bioRxiv - Bioengineering Pub Date : 2024-09-11 DOI: 10.1101/2024.09.05.611421

Giovanni Talei Franzesi, Ishan Gupta, Ming Hu, Kiryl Piatkveich, Murat Yildirim, Jian-Ping Zhao, Minho Eom, Seungjae Han, Demian Park, Himashi Andaraarachchi, Zhaohan Li, Jesse Greenhagen, Amirul Muhammad Islam, Parth Vashishtha, Zahid Yaqoob, Nikita Pak, Alexander D. Wissner-Gross, Daniel Martin-Alarcon, Jonathan Veinot, Peter T. So, Uwe Kortshagen, Young-Gyu Yoon, Mriganka Sur, Edward S. Boyden

{"title":"In Vivo Optical Clearing of Mammalian Brain","authors":"Giovanni Talei Franzesi, Ishan Gupta, Ming Hu, Kiryl Piatkveich, Murat Yildirim, Jian-Ping Zhao, Minho Eom, Seungjae Han, Demian Park, Himashi Andaraarachchi, Zhaohan Li, Jesse Greenhagen, Amirul Muhammad Islam, Parth Vashishtha, Zahid Yaqoob, Nikita Pak, Alexander D. Wissner-Gross, Daniel Martin-Alarcon, Jonathan Veinot, Peter T. So, Uwe Kortshagen, Young-Gyu Yoon, Mriganka Sur, Edward S. Boyden","doi":"10.1101/2024.09.05.611421","DOIUrl":"https://doi.org/10.1101/2024.09.05.611421","url":null,"abstract":"Established methods for imaging the living mammalian brain have, to date, taken optical properties of the tissue as fixed; we here demonstrate that it is possible to modify the optical properties of the brain itself to significantly enhance at-depth imaging while preserving native physiology. Using a small amount of any of several biocompatible materials to raise the refractive index of solutions superfusing the brain prior to imaging, we could increase several-fold the signals from the deepest cells normally visible and, under both one-photon and two-photon imaging, visualize cells previously too dim to see. The enhancement was observed for both anatomical and functional fluorescent reporters across a broad range of emission wavelengths. Importantly, visual tuning properties of cortical neurons in awake mice, and electrophysiological properties of neurons assessed ex vivo, were not altered by this procedure.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

De novo design of Ras isoform selective binders 从头设计 Ras 同工酶选择性结合剂

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.08.29.610300

Jason Zhaoxing Zhang, Xinting Li, Caixuan Liu, Hanlun Jiang, Kejia Wu, David Baker

引用次数: 0

Engineered chitosan-derived nanocarrier for efficient siRNA delivery to peripheral and central neurons 将壳聚糖衍生纳米载体用于向外周和中枢神经元高效递送 siRNA

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.611434

Ana P Spencer, Adriana Vilaca, Miguel Xavier, Rafael Santos, Ariel Ionescu, Maria Lazaro, Victoria Leiro, Eran Perlson, Sofia C Guimaraes, Ben M Maoz, Ana P Pego

{"title":"Engineered chitosan-derived nanocarrier for efficient siRNA delivery to peripheral and central neurons","authors":"Ana P Spencer, Adriana Vilaca, Miguel Xavier, Rafael Santos, Ariel Ionescu, Maria Lazaro, Victoria Leiro, Eran Perlson, Sofia C Guimaraes, Ben M Maoz, Ana P Pego","doi":"10.1101/2024.09.05.611434","DOIUrl":"https://doi.org/10.1101/2024.09.05.611434","url":null,"abstract":"Gene therapy using small interfering RNA (siRNA) holds promise for treating neurological disorders by silencing specific genes, such as the phosphatase and tensin homolog (PTEN) gene, which restricts axonal growth. Yet, delivering siRNA to neurons efficiently is challenging due to premature degradation and unspecific delivery. Chitosan-based delivery systems have shown great potential due to their well-established biocompatibility. However, their limited transfection efficiency and lack of neuronal tropism require further modification. Building on our previous successes with neuron-targeted DNA delivery using chitosan, a novel approach for siRNA delivery aimed at PTEN downregulation is proposed. This involves using thiolated trimethyl chitosan (TMCSH)-based siRNA nanoparticles functionalized with the neurotropic C-terminal fragment of the tetanus neurotoxin heavy chain (HC) for efficient delivery to both peripheral and central neurons. These polyplexes demonstrated suitable physicochemical properties, biocompatibility, and no adverse effects on neuronal electrophysiology. Diverse neuronal models, including 3D ex vivo cultures and microfluidics, confirmed polyplexes efficiency and neurospecificity. HC targeting significantly enhanced nanoparticle neuronal binding, and live cell imaging revealed five times faster retrograde transport along axons. Furthermore, siRNA delivery targeting PTEN promoted axonal outgrowth in embryonic cortical neurons. Thus, these polyplexes represent a promising platform for siRNA delivery, offering potential for clinical translation and therapeutic applications.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigation of hemodynamic bulk flow patterns caused by aortic stenosis using a combined 4D Flow MRI-CFD framework 利用 4D Flow MRI-CFD 组合框架研究主动脉瓣狭窄导致的血流动力学大体积流动模式

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.09.611958

Tianai Wang, Christine Quast, Florian Bönner, Malte Kelm, Tobias Zeus, Teresa Lemainque, Ulrich Steinseifer, Michael Neidlin

{"title":"Investigation of hemodynamic bulk flow patterns caused by aortic stenosis using a combined 4D Flow MRI-CFD framework","authors":"Tianai Wang, Christine Quast, Florian Bönner, Malte Kelm, Tobias Zeus, Teresa Lemainque, Ulrich Steinseifer, Michael Neidlin","doi":"10.1101/2024.09.09.611958","DOIUrl":"https://doi.org/10.1101/2024.09.09.611958","url":null,"abstract":"Aortic stenosis (AS) leads to alterations of supra-valvular flow patterns. These patterns might lead to, inter alia, increased damage of red blood cell (RBC) membranes. We investigated these patient specific patterns of a severe AS patient and their reversal in healthy flow through a 4D Flow MRI-based CFD methodology. Computational models of subject-specific aortic geometries were created using in-vivo medical imaging data. Temporally and spatially resolved boundary conditions derived from 4D Flow MRI were implemented for an AS patient and a healthy subject. After validation of the in-silico results with in-vivo data, a healthy inflow profile was set for the AS patient in the CFD model. Pathological versus healthy flow fields were compared regarding their blood flow characteristics, i.e. shear stresses on RBCs and helicity. The accuracy of the 4D Flow MRI-based CFD model was proven with excellent agreement between in-vivo and in-silico velocity fields and R² = 0.9. A pathological high shear stress region in the bulk flow was present during late systole with an increase of 125 % compared to both healthy flow. The physiological bihelical structure with predominantly right-handed helices vanished for the pathological state. Instead, a left-handed helix appeared, accompanied by an overall increase in turbulent kinetic energy in areas of accumulated left-handed helicity. The validated 4D Flow MRI-based CFD model identified marked differences between AS and healthy flow. It suggests that altered turbulent and helical structures in the bulk flow are the cause for increased, potentially damaging forces acting upon RBCs in AS.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Harmonization of Structural Brain Connectivity through Distribution Matching 通过分布匹配协调大脑结构连接性

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.611489

Zhen Zhou, Bruce Fischl, Iman Aganj

{"title":"Harmonization of Structural Brain Connectivity through Distribution Matching","authors":"Zhen Zhou, Bruce Fischl, Iman Aganj","doi":"10.1101/2024.09.05.611489","DOIUrl":"https://doi.org/10.1101/2024.09.05.611489","url":null,"abstract":"The increasing prevalence of multi-site diffusion-weighted magnetic resonance imaging (dMRI) studies potentially offers enhanced statistical power for investigating brain structure. However, these studies face challenges due to variations in scanner hardware and acquisition protocols. While several methods exist for dMRI data harmonization, few specifically address structural brain connectivity. We introduce a new distribution-matching approach to harmonizing structural brain connectivity across different sites and scanners. We evaluate our method using structural brain connectivity data from two distinct datasets of OASIS-3 and ADNI-2, comparing its performance to the widely used ComBat method. Our approach is meant to align the statistical properties of connectivity data from these two datasets. We examine the impact of harmonization on the correlation of brain connectivity with the Mini-Mental State Examination score and age. Our results demonstrate that our distribution-matching technique more effectively harmonizes structural brain connectivity, often producing stronger and more significant correlations compared to ComBat. Qualitative assessments illustrate the desired distributional alignment of ADNI-2 with OASIS-3, while quantitative evaluations confirm robust performance. This work contributes to the growing field of dMRI harmonization, potentially improving the reliability and comparability of structural connectivity studies that combine data from different sources in neuroscientific and clinical research.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"283 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Morphological comparison of astrocytes in the lamina cribrosa and glial lamina 星形胶质层和岩屑层中星形胶质细胞的形态比较

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.07.610493

Susannah Waxman, Hannah Schilpp, Ashley Linton, Tatjana C. Jakobs, Ian A Sigal

{"title":"Morphological comparison of astrocytes in the lamina cribrosa and glial lamina","authors":"Susannah Waxman, Hannah Schilpp, Ashley Linton, Tatjana C. Jakobs, Ian A Sigal","doi":"10.1101/2024.09.07.610493","DOIUrl":"https://doi.org/10.1101/2024.09.07.610493","url":null,"abstract":"Purpose: Although the mechanisms underlying glaucomatous neurodegeneration are not yet well understood, cellular and small animal models suggest that LC astrocytes undergo early morphologic and functional changes, indicating their role as early responders to glaucomatous stress. These models, however, lack the LC found in larger animals and humans, leaving the in situ morphology of LC astrocytes and their role in glaucoma initiation underexplored. In this work, we aimed to characterize the morphology of LC astrocytes in situ and determine differences and similarities with astrocytes in the mouse glial lamina (GL), the analogous structure in a prominent glaucoma model. Methods:\u0000Astrocytes in the LCs of twenty-two eyes from goats, sheep, and pigs were stochastically labeled via Multicolor DiOlistics and imaged in situ using confocal microscopy. 3D models of DiOlistically-labeled LC astrocytes and hGFAPpr-GFP mouse GL astrocytes were constructed to quantify morphological features related to astrocyte functions. LC and GL astrocyte cross-pore contacts, branching complexity, branch tortuosity, and cell and branch span were compared. Results: LC astrocytes displayed distinct spatial relationships with collagen, greater branching complexity, and higher branch tortuosity compared to GL astrocytes. Despite substantial differences in their anatomical environments, LC and GL astrocytes had similar cell and branch spans. Conclusions:\u0000Astrocyte morphology in the LC was characterized through Multicolor DiOlistic labeling. LC and GL astrocytes have both distinct and shared morphological features. Further research is needed to understand the potentially unique roles of LC astrocytes in glaucoma initiation and progression.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"283 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparing continuum and direct fiber models of soft tissues. An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels 比较软组织的连续模型和直接纤维模型。一个眼部生物力学实例表明，连续模型可能会人为地破坏组织和纤维层面的应变

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.610277

Xuehuan He, Mohammad R. Islam, Fengting Ji, Bingrui Wang, Ian A Sigal

{"title":"Comparing continuum and direct fiber models of soft tissues. An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels","authors":"Xuehuan He, Mohammad R. Islam, Fengting Ji, Bingrui Wang, Ian A Sigal","doi":"10.1101/2024.09.05.610277","DOIUrl":"https://doi.org/10.1101/2024.09.05.610277","url":null,"abstract":"Collagen fibers are the main load-bearing component of soft tissues but difficult to incorporate into models. Whilst simplified homogenization models suffice for some applications, a thorough mechanistic understanding requires accurate prediction of fiber behavior, including both detailed fiber-level strains and long-distance transmission. Our goal was to compare the performance of a continuum model of the optic nerve head (ONH) built using conventional techniques with a fiber model we recently introduced which explicitly incorporates the complex 3D organization and interaction of collagen fiber bundles [1]. To ensure a fair comparison, we constructed the continuum model with identical geometrical, structural, and boundary specifications as for the fiber model. We found that: 1) although both models accurately matched the intraocular pressure (IOP)-induced globally averaged displacement responses observed in experiments, they diverged significantly in their ability to replicate specific 3D tissue-level strain patterns. Notably, the fiber model faithfully replicated the experimentally observed depth-dependent variability of radial strain, the ring-like pattern of meridional strain, and the radial pattern of circumferential strain, whereas the continuum model failed to do so; 2) the continuum model disrupted the strain transmission along each fiber, a feature captured well by the fiber model. These results demonstrate limitations of the conventional continuum models that rely on homogenization and affine deformation assumptions, which render them incapable of capturing some complex tissue-level and fiber-level deformations. Our results show that the strengths of explicit fiber modeling help capture intricate ONH biomechanics. They potentially also help modeling other fibrous tissues.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Feasibility of Measuring Magnetic Resonance Elastography-derived Stiffness in Human Thoracic Aorta and Aortic Dissection Phantoms 在人体胸主动脉和主动脉夹层模型中测量磁共振弹性成像衍生刚度的可行性

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.611548

Adnan A Hirad, Faisal S. Fakhouri, Brian Raterman, Ronald Lakony, Maxwell Wang, Dakota Gonring, Baqir Kedwai, Arunark Kolipaka, Doran A Mix

{"title":"Feasibility of Measuring Magnetic Resonance Elastography-derived Stiffness in Human Thoracic Aorta and Aortic Dissection Phantoms","authors":"Adnan A Hirad, Faisal S. Fakhouri, Brian Raterman, Ronald Lakony, Maxwell Wang, Dakota Gonring, Baqir Kedwai, Arunark Kolipaka, Doran A Mix","doi":"10.1101/2024.09.05.611548","DOIUrl":"https://doi.org/10.1101/2024.09.05.611548","url":null,"abstract":"Type-B aortic dissection (TBAD) represents a serious medical emergency with up to a 50% associated 5-year mortality caused by thoracic aorta, dissection-associated aneurysmal (DAA) degeneration, and rupture. Unfortunately, conventional size related diagnostic methods cannot distinguish high-risk DAAs that benefit from surgical intervention from stable DAAs. Our goal is to use DAA stiffness measured with magnetic resonance elastography (MRE) as a biomarker to distinguish high-risk DAAs from stable DAAs. This is a feasibility study using MRE to 1) fabricate human-like geometries TBAD phantoms with different stiffnesses. 2) measure stiffness in TBAD phantoms with rheometry and 3) demonstrate the first successful application of MRE to the thoracic aorta of a human volunteer. Aortic dissection phantoms with heterogenous wall stiffness demonstrated the correlation between MRE-derived stiffness and rheometric measured stiffness. A pilot scan was performed in a healthy volunteer to test the technique's feasibility in the thoracic aorta.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The flexible stalk domain of sTREM2 modulates its interactions with phospholipids in the brain sTREM2 的柔性柄结构域调节其与大脑磷脂的相互作用

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.04.611223

David Saeb, Emma E Lietzke, Daisy I Fuchs, Emma C Aldrich, Kimberley D Bruce, Kayla G Sprenger

{"title":"The flexible stalk domain of sTREM2 modulates its interactions with phospholipids in the brain","authors":"David Saeb, Emma E Lietzke, Daisy I Fuchs, Emma C Aldrich, Kimberley D Bruce, Kayla G Sprenger","doi":"10.1101/2024.09.04.611223","DOIUrl":"https://doi.org/10.1101/2024.09.04.611223","url":null,"abstract":"The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer's disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in stabilizing the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the 'Expanded Surface 2', which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding in the presence of R47H. This suggests that sTREM2's neuroprotective role in AD may, at least in part, arise from the stalk domain's ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in membrane-bound TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted Polymersomes Enable Enhanced Delivery to Peripheral Nerves Post-Injury 靶向聚合体可加强损伤后外周神经的输送

bioRxiv - Bioengineering Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.611478

Kayleigh Trumbull, Sophia Fetten, Dru Montgomery, Vanessa Marahrens, Olivia Myers, Noah Arnold, Jeffery L Twiss, Jessica Larsen

{"title":"Targeted Polymersomes Enable Enhanced Delivery to Peripheral Nerves Post-Injury","authors":"Kayleigh Trumbull, Sophia Fetten, Dru Montgomery, Vanessa Marahrens, Olivia Myers, Noah Arnold, Jeffery L Twiss, Jessica Larsen","doi":"10.1101/2024.09.05.611478","DOIUrl":"https://doi.org/10.1101/2024.09.05.611478","url":null,"abstract":"The gold standard therapy for peripheral nerve injuries involves surgical repair, which is invasive and leads to major variations in therapeutic outcomes. Because of this, smaller injuries often go untreated. However, alternative, non-invasive routes of administration are currently unviable due to the presence of the blood-nerve barrier (BNB), which prevents passage of small molecules from the blood into the endoneurium and the nerve. This paper demonstrates that ligands on the surface of nanoparticles, called polymersomes, can enable delivery to the nerve through non-invasive intramuscular injections. Polymersomes made from polyethylene glycol (PEG)-b-polylactic acid (PLA) were conjugated with either apolipoprotein E (ApoE) or rabies virus glycoprotein-based peptide, RVG29 (RVG) and loaded with near infrared dye, AlexaFluor647. ApoE was used to target receptors upregulated in post-injury inflammation, while RVG targets neural specific receptors. Untagged, ApoE-tagged, and RVG-tagged polymersomes were injected at 100 mM either intranerve (IN) or intramuscular (IM) into Sprague Dawley rats post sciatic nerve injury. The addition of the ApoE and RVG tags enabled increased AlexaFluor647 fluorescence in the injury site at 1 hour post IN injection compared to the untagged polymersome control. However, only the RVG-tagged polymersomes increased AlexaFluor647 fluorescence after intramuscular injection. Ex vivo analysis of sciatic nerves demonstrated that ApoE-tagged polymersomes enabled the greatest retention of AlexaFluor647 regardless of the injection route. This led us to conclude that using ApoE to target inflammation enabled the greatest retention of polymersome-delivered payloads while RVG to target neural cells more specifically enabled the penetration of polymersome-delivered payloads. Observations were confirmed by calculating area under the curve pharmacokinetic parameters and the use of a two-compartment pharmacokinetic model.","PeriodicalId":501308,"journal":{"name":"bioRxiv - Bioengineering","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0