Seungkuk Ahn, Oliver Siontas, Janis Koester, Jacek Krol, Sascha Fauser, Daniel J. Müller
{"title":"Magnetically Guided Adeno-Associated Virus Delivery for the Spatially Targeted Transduction of Retina in Eyes (Adv. Healthcare Mater. 28/2024)","authors":"Seungkuk Ahn, Oliver Siontas, Janis Koester, Jacek Krol, Sascha Fauser, Daniel J. Müller","doi":"10.1002/adhm.202470176","DOIUrl":"https://doi.org/10.1002/adhm.202470176","url":null,"abstract":"<p><b>Spatially Controlled Viral Transduction of Retina</b></p><p>With more than 140 million nerve cells, the retina is our first stage of the visual system and window to the outside world. The cover of article 2401577 by Sascha Fauser, Daniel J. Müller, and co-workers highlights the neuronal layers of a porcine retina. In their work, the authors have electromagnetically guided viruses to specifically transduce each of the retina layers. Cover design by Martin Oeggerli (Micronaut) 2024, with Seungkuk Ahn and Daniel Müller.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":"13 28","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adhm.202470176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641437","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}
Albertus Ivan Brilian, Sang Ho Lee, Agustina Setiawati, Chang Ho Kim, Soo Ryeon Ryu, Hyo-Jin Chong, Yejin Jo, Hayan Jeong, Bong-Gun Ju, Oh-Sun Kwon, Giyoong Tae, Kwanwoo Shin
{"title":"Topical Nanoliposomal Collagen Delivery for Targeted Fibril Formation by Electrical Stimulation (Adv. Healthcare Mater. 28/2024)","authors":"Albertus Ivan Brilian, Sang Ho Lee, Agustina Setiawati, Chang Ho Kim, Soo Ryeon Ryu, Hyo-Jin Chong, Yejin Jo, Hayan Jeong, Bong-Gun Ju, Oh-Sun Kwon, Giyoong Tae, Kwanwoo Shin","doi":"10.1002/adhm.202470180","DOIUrl":"https://doi.org/10.1002/adhm.202470180","url":null,"abstract":"<p><b>Collagen Delivery</b></p><p>The cover of the article 2400693 by Giyoong Tae, Kwanwoo Shin, and co-workers showcases a novel mechanism: collagen monomers within lipid nanoparticles are applied to the skin and synthesized into collagen fibers within the dermal layer, facilitated by external electrical stimulation. This process is visualized to demonstrate that without electrical stimulation, the liposomes transport the monomers to the skin at a low pH, with synthesis solely occurring in the dermis.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":"13 28","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adhm.202470180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641456","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}
Angel Bu, Ferdows Afghah, Nicolas Castro, Maheera Bawa, Sonika Kohli, Karina Shah, Brandon Rios, Vincent Butty, Ritu Raman
{"title":"Actuating Extracellular Matrices Decouple the Mechanical and Biochemical Effects of Muscle Contraction on Motor Neurons.","authors":"Angel Bu, Ferdows Afghah, Nicolas Castro, Maheera Bawa, Sonika Kohli, Karina Shah, Brandon Rios, Vincent Butty, Ritu Raman","doi":"10.1002/adhm.202403712","DOIUrl":"https://doi.org/10.1002/adhm.202403712","url":null,"abstract":"<p><p>Emerging in vivo evidence suggests that repeated muscle contraction, or exercise, impacts peripheral nerves. However, the difficulty of isolating the muscle-specific impact on motor neurons in vivo, as well as the inability to decouple the biochemical and mechanical impacts of muscle contraction in this setting, motivates investigating this phenomenon in vitro. This study demonstrates that tuning the mechanical properties of fibrin enables longitudinal culture of highly contractile skeletal muscle monolayers, enabling functional characterization of and long-term secretome harvesting from exercised tissues. Motor neurons stimulated with exercised muscle-secreted factors significantly upregulate neurite outgrowth and migration, with an effect size dependent on muscle contraction intensity. Actuating magnetic microparticles embedded within fibrin hydrogels enable dynamically stretching motor neurons and non-invasively mimicking the mechanical effects of muscle contraction. Interestingly, axonogenesis is similarly upregulated in both mechanically and biochemically stimulated motor neurons, but RNA sequencing reveals different transcriptomic signatures between groups, with biochemical stimulation having a greater impact on cell signaling related to axonogenesis and synapse maturation. This study leverages actuating extracellular matrices to robustly validate a previously hypothesized role for muscle contraction in regulating motor neuron growth and maturation from the bottom-up through both mechanical and biochemical signaling.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2403712"},"PeriodicalIF":10.0,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612935","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}
Eszter Mihaly, Neha Chellu, Shama R Iyer, Eileen Y Su, Dallas E Altamirano, Shaquielle T Dias, Warren L Grayson
{"title":"Neuromuscular Regeneration of Volumetric Muscle Loss Injury in Response to Agrin-Functionalized Tissue Engineered Muscle Grafts and Rehabilitative Exercise.","authors":"Eszter Mihaly, Neha Chellu, Shama R Iyer, Eileen Y Su, Dallas E Altamirano, Shaquielle T Dias, Warren L Grayson","doi":"10.1002/adhm.202403028","DOIUrl":"https://doi.org/10.1002/adhm.202403028","url":null,"abstract":"<p><p>Neuromuscular deficits compound the loss of contractile tissue in volumetric muscle loss (VML). Two avenues for promoting recovery are neuromuscular junction (NMJ)-promoting substrates (e.g., agrin) and endurance exercise. Although mechanical stimulation enhances agrin-induced NMJ formation, the two modalities have yet to be evaluated combinatorially. It is hypothesized that the implantation of human myogenic progenitor-seeded tissue-engineered muscle grafts (hTEMGs) in combination with agrin treatment and/or exercise will enhance neuromuscular recovery after VML. The hTEMGs alone transplant into VML defects promote significant regeneration with minimal scarring. A sex-appropriate, low-intensity continuous running exercise paradigm increases acetylcholine receptor (AChR) cluster density in male mice twofold relative to hTEMG alone after 7 weeks of treadmill training (p < 0.05). To further promote neuromuscular recovery, agrin is incorporated into the scaffolds via covalent tethering. In vitro, agrin increases the proliferation of hMPs, and trends toward greater myogenic maturity and AChR clustering. Upon transplantation, both hTEMGs + agrin and hTEMGs + exercise induce near 100% recovery of muscle mass and increase twitch and tetanic force output (p > 0.05). However, agrin treatment in combination with exercise produces no additional benefit. These data highlight the unprecedented regenerative potential of using hTEMGs together with either agrin or exercise supplementation to treat VML injuries.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2403028"},"PeriodicalIF":10.0,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613015","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}
Claudio Luca Alter, Claudia Lotter, Ramya Deepthi Puligilla, Jan Stephan Bolten, Jaroslaw Sedzicki, Jason Marchese, Valentin Schittny, Francesca Rucci, Michael Beverly, Cornelia G Palivan, Pascal Detampel, Tomaž Einfalt, Jörg Huwyler
{"title":"Nano Plasma Membrane Vesicle-Lipid Nanoparticle Hybrids for Enhanced Gene Delivery and Expression.","authors":"Claudio Luca Alter, Claudia Lotter, Ramya Deepthi Puligilla, Jan Stephan Bolten, Jaroslaw Sedzicki, Jason Marchese, Valentin Schittny, Francesca Rucci, Michael Beverly, Cornelia G Palivan, Pascal Detampel, Tomaž Einfalt, Jörg Huwyler","doi":"10.1002/adhm.202401888","DOIUrl":"https://doi.org/10.1002/adhm.202401888","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) have emerged as the leading nonviral nucleic acid (NA) delivery system, gaining widespread attention for their use in COVID-19 vaccines. They are recognized for their efficient NA encapsulation, modifiability, and scalable production. However, LNPs face efficacy and potency limitations due to suboptimal intracellular processing, with endosomal escape efficiencies (ESE) below 2.5%. Additionally, up to 70% of NPs undergo recycling and exocytosis after cellular uptake. In contrast, cell-derived vesicles offer biocompatibility and high-delivery efficacy but are challenging to load with exogenous NAs and to manufacture at large-scale. To leverage the strengths of both systems, a hybrid system is designed by combining cell-derived vesicles, such as nano plasma membrane vesicles (nPMVs), with LNPs through microfluidic mixing and subsequent dialysis. These hybrids demonstrate up to tenfold increase in ESE and an 18-fold rise in reporter gene expression in vitro and in vivo in zebrafish larvae (ZFL) and mice, compared to traditional LNPs. These improvements are linked to their unique physico-chemical properties, composition, and morphology. By incorporating cell-derived vesicles, this strategy streamlines the development process, significantly enhancing the efficacy and potency of gene delivery systems without the need for extensive screening.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2401888"},"PeriodicalIF":10.0,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613014","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}
Donggue Kim, Ji Woo Lee, Yang Tae Kim, Junhyeok Choe, Gaeun Kim, Chang Man Ha, Jae Geun Kim, Kwang Hoon Song, Sunggu Yang
{"title":"Minimally Invasive Syringe-Injectable Hydrogel with Angiogenic Factors for Ischemic Stroke Treatment.","authors":"Donggue Kim, Ji Woo Lee, Yang Tae Kim, Junhyeok Choe, Gaeun Kim, Chang Man Ha, Jae Geun Kim, Kwang Hoon Song, Sunggu Yang","doi":"10.1002/adhm.202403119","DOIUrl":"https://doi.org/10.1002/adhm.202403119","url":null,"abstract":"<p><p>Ischemic stroke (IS) accounts for most stroke incidents and causes intractable damage to brain tissue. This condition manifests as diverse aftereffects, such as motor impairment, emotional disturbances, and dementia. However, a fundamental approach to curing IS remains unclear. This study proposes a novel approach for treating IS by employing minimally invasive and injectable jammed gelatin-norbornene nanofibrous hydrogels (GNF) infused with growth factors (GFs). The developed GNF/GF hydrogels are administered to the motor cortex of a rat IS model to evaluate their therapeutic effects on IS-induced motor dysfunction. GNFs mimic a natural fibrous extracellular matrix architecture and can be precisely injected into a targeted brain area. The syringe-injectable jammed nanofibrous hydrogel system increased angiogenesis, inflammation, and sensorimotor function in the IS-affected brain. For clinical applications, the biocompatible GNF hydrogel has the potential to efficiently load disease-specific drugs, enabling targeted therapy for treating a wide range of neurological diseases.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2403119"},"PeriodicalIF":10.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613012","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":"Chitosan-Modified Hydrogel Microsphere Encapsulating Zinc-Doped Bioactive Glasses for Spinal Cord Injury Repair by Suppressing Inflammation and Promoting Angiogenesis.","authors":"Xinjin Su, Changjiang Gu, Ziheng Wei, Yanqing Sun, Chao Zhu, Xiongsheng Chen","doi":"10.1002/adhm.202402129","DOIUrl":"https://doi.org/10.1002/adhm.202402129","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a common nerve injury caused by external force, resulting in sensory and motor impairments. Previous studies demonstrated that inhibiting the neuroinflammation promoted SCI repair. However, these approaches are low efficient, and lack targeting specificity, and even require repeated and high doses of systemic administration. To address such issues, in the present study, chitosan-modified hydrogel microspheres encapsulating with zinc-doped bioactive glasses (CS-MG@Zn/BGs) is constructed for targeted repair of SCI. In vitro, the CS-MG@Zn/BGs effectively inhibited the acute inflammatory response initiated by microglia and promoted angiogenic activities. In vivo, CS-MG@Zn/BGs targeted the injured site, and attenuated neuroinflammation by inhibiting microglia infiltration and modulating microglia polarization toward M2 type. Furthermore, it facilitated vascular reconstruction, neuronal differentiation, axonal regeneration and remyelination at the injured site, and thereby promoted motor function recovery of SCI mice. The in vitro and in vivo results implied that CS-MG@Zn/BGs may be a promising alternative for the rehabilitation of SCI.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2402129"},"PeriodicalIF":10.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612959","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}
Yue Liu, Shang Chen, Haoyan Huang, Adam C Midgley, Zhibo Han, Zhong-Chao Han, Qiong Li, Zongjin Li
{"title":"Ligand-Tethered Extracellular Vesicles Mediated RNA Therapy for Liver Fibrosis.","authors":"Yue Liu, Shang Chen, Haoyan Huang, Adam C Midgley, Zhibo Han, Zhong-Chao Han, Qiong Li, Zongjin Li","doi":"10.1002/adhm.202403068","DOIUrl":"https://doi.org/10.1002/adhm.202403068","url":null,"abstract":"<p><p>Liver fibrosis poses a significant global health burden, in which hepatic stellate cells (HSCs) play a crucial role. Targeted nanomedicine delivery systems directed at HSCs have shown immense potential in the treatment of liver fibrosis. Herein, a bioinspired material, engineered therapeutic miR-181a-5p (a miRNA known to inhibit fibrotic signaling pathways) and targeted moiety hyaluronic acid (HA) co-functionalized extracellular vesicles (EVs) are developed. HA is incorporated onto the surface of EVs using DSPE-PEG as a linker, allowing preferential binding to CD44 receptors, which are overexpressed on activated HSCs. Our results confirmed enhanced cellular uptake and improved payload delivery, as evidenced by the increased intracellular abundance of miR-181a-5p in activated HSCs and fibrotic livers. HA-equipped EVs loaded with miR-181a-5p (DPH-EVs@miR) significantly reduce HSC activation and extracellular matrix (ECM) deposition by inhibiting the TGF-β/Smad signaling pathway, thus alleviating the progression of liver fibrosis. Additionally, DPH-EVs@miR improves liver function, ameliorates inflammatory infiltration, and mitigates hepatocyte apoptosis, demonstrating superior hepatic protective effects. Collectively, this study reports a prospective nanovesicle therapeutic platform loaded with therapeutic miRNA and targeting motifs for liver fibrosis. The biomarker-guided EV-engineering technology utilized in this study provides a promising tool for nanomedicine and precision medicine.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2403068"},"PeriodicalIF":10.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613003","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":"Bioadhesive First-Aid Patch with Rapid Hemostasis and High Toughness Designed for Sutureless Sealing of Acute Bleeding Wounds.","authors":"Ziyuan Zeng, Jiaming Zhang, Yige Gao, Yuanyuan Song, Luoming Liu, Miaomiao Zhu, Wenjing Ma, Jiajun Fu, Dongyang Miao, Chaobo Huang, Ranhua Xiong","doi":"10.1002/adhm.202403412","DOIUrl":"https://doi.org/10.1002/adhm.202403412","url":null,"abstract":"<p><p>The global military and civilian sectors express widespread concern over the significant hemorrhage associated with various acute wounds. Such bleedings lead to numerous casualties in military confrontations, traffic accidents, and surgical injuries. Consequently, the rapid control of the bleedings, particularly for extensive and pressurized wounds, is crucial in first-aid situations. In this work, a double-layered bioadhesive patch that combines a superabsorbent adhesive hydrogel with a highly tough antibacterial polyurethane film, which is called as Bio-Patch, is proposed. The Bio-Patch demonstrates superior mechanical strength and forms robust bioadhesion to acute bleeding wounds. Furthermore, the Bio-Patch enables protecting against external Gram-negative and Gram-positive bacteria. Thanks to the double-layered structures having synergistic functions of stable barrier and robust adhesion, the Bio-Patch provides optimal wound sealing (burst strength exceeding 310 mmHg) both in vitro and in vivo. It also demonstrates superior hemostatic effects (less than 30 s) in vivo. This offers promising opportunities for rapid control of extensive and pressurized hemorrhage in first-aid clinical scenarios.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2403412"},"PeriodicalIF":10.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612956","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}
Abiramy Jeyagaran, Max Urbanczyk, Daniel Carvajal-Berrio, Teresa Baldissera, Philipp D Kaiser, Laurence Kuhlburger, Stefan Czemmel, Sven Nahnsen, Garry P Duffy, Sara Y Brucker, Shannon L Layland, Katja Schenke-Layland
{"title":"ECM Proteins Nidogen-1 and Decorin Restore Functionality of Human Islets of Langerhans upon Hypoxic Conditions.","authors":"Abiramy Jeyagaran, Max Urbanczyk, Daniel Carvajal-Berrio, Teresa Baldissera, Philipp D Kaiser, Laurence Kuhlburger, Stefan Czemmel, Sven Nahnsen, Garry P Duffy, Sara Y Brucker, Shannon L Layland, Katja Schenke-Layland","doi":"10.1002/adhm.202403017","DOIUrl":"https://doi.org/10.1002/adhm.202403017","url":null,"abstract":"<p><p>Transplantation of donor islets of Langerhans is a potential therapeutic approach for patients with diabetes mellitus; however, its success is limited by islet death and dysfunction during the initial hypoxic conditions at the transplantation site. This highlights the need to support the donor islets in the days post-transplantation until the site is vascularized. It was previously demonstrated that the extracellular matrix (ECM) proteins nidogen-1 (NID1) and decorin (DCN) improve the functionality and survival of the β-cell line, EndoC-βH3, and the viability of human islets post-isolation. To advance the use of these ECM proteins toward a clinical application and elucidate the mechanisms of action in primary islets, the study assesses the effects of ECM proteins NID1 and DCN on isolated human donor islets cultured in normoxic and hypoxic conditions. NID1- and DCN-treatment restore β-cell functionality of human donor islets in a hypoxic environment through upregulation of genes involved in glycolytic pathways and reducing DNA fragmentation in hypoxic conditions comparable to normoxic control islets. The results demonstrate that the utilization of NID1 or DCN with islets of Langerhans may have the potential to overcome the hypoxia-induced cell death observed post-transplantation and improve transplant outcomes.</p>","PeriodicalId":113,"journal":{"name":"Advanced Healthcare Materials","volume":" ","pages":"e2403017"},"PeriodicalIF":10.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602463","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}