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1.
Front Physiol ; 12: 720190, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675815

RESUMO

Optogenetic technology provides researchers with spatiotemporally precise tools for stimulation, sensing, and analysis of function in cells, tissues, and organs. These tools can offer low-energy and localized approaches due to the use of the transgenically expressed light gated cation channel Channelrhodopsin-2 (ChR2). While the field began with many neurobiological accomplishments it has also evolved exceptionally well in animal cardiac research, both in vitro and in vivo. Implantable optical devices are being extensively developed to study particular electrophysiological phenomena with the precise control that optogenetics provides. In this review, we highlight recent advances in novel implantable optogenetic devices and their feasibility in cardiac research. Furthermore, we also emphasize the difficulties in translating this technology toward clinical applications and discuss potential solutions for successful clinical translation.

2.
Nat Mater ; 20(11): 1559-1570, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34326506

RESUMO

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

3.
Nat Biotechnol ; 39(10): 1228-1238, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34183859

RESUMO

Temporary cardiac pacemakers used in periods of need during surgical recovery involve percutaneous leads and externalized hardware that carry risks of infection, constrain patient mobility and may damage the heart during lead removal. Here we report a leadless, battery-free, fully implantable cardiac pacemaker for postoperative control of cardiac rate and rhythm that undergoes complete dissolution and clearance by natural biological processes after a defined operating timeframe. We show that these devices provide effective pacing of hearts of various sizes in mouse, rat, rabbit, canine and human cardiac models, with tailored geometries and operation timescales, powered by wireless energy transfer. This approach overcomes key disadvantages of traditional temporary pacing devices and may serve as the basis for the next generation of postoperative temporary pacing technology.


Assuntos
Implantes Absorvíveis , Marca-Passo Artificial , Animais , Bloqueio Atrioventricular/terapia , Modelos Animais de Doenças , Cães , Desenho de Equipamento , Humanos , Camundongos , Coelhos , Ratos , Tecnologia sem Fio
4.
Nat Commun ; 10(1): 5742, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848334

RESUMO

Small animals support a wide range of pathological phenotypes and genotypes as versatile, affordable models for pathogenesis of cardiovascular diseases and for exploration of strategies in electrotherapy, gene therapy, and optogenetics. Pacing tools in such contexts are currently limited to tethered embodiments that constrain animal behaviors and experimental designs. Here, we introduce a highly miniaturized wireless energy-harvesting and digital communication electronics for thin, miniaturized pacing platforms weighing 110 mg with capabilities for subdermal implantation and tolerance to over 200,000 multiaxial cycles of strain without degradation in electrical or optical performance. Multimodal and multisite pacing in ex vivo and in vivo studies over many days demonstrate chronic stability and excellent biocompatibility. Optogenetic stimulation of cardiac cycles with in-animal control and induction of heart failure through chronic pacing serve as examples of modes of operation relevant to fundamental and applied cardiovascular research and biomedical technology.


Assuntos
Engenharia Biomédica/métodos , Dispositivos de Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/etiologia , Miniaturização , Optogenética/métodos , Animais , Modelos Animais de Doenças , Fontes de Energia Elétrica , Feminino , Humanos , Preparação de Coração Isolado , Masculino , Camundongos , Camundongos Transgênicos , Tecnologia sem Fio
5.
Prog Biophys Mol Biol ; 144: 139-150, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29960680

RESUMO

Human cardiac slices have emerged as a promising model of the human heart for scientific research and drug testing. Retaining the normal tissue architecture, a multi-cell type environment, and the native extracellular matrix, human cardiac slices faithfully replicate organ-level adult cardiac physiology. Previously, we demonstrated that human cardiac tissue slices cultured for 24 h maintained normal electrophysiology. In this project, we further optimized the organotypic culture condition to maintain normal electrophysiology of the human cardiac slices for 4 days. The prolonged culture of human cardiac tissue slices demonstrated here enables the study of chronic drug effects, gene therapies, and gene editing. To achieve greater control of the culture environment, we have also developed an automated, self-contained heart-on-a-chip system. The culture system supports media circulation, oxygenation, temperature control, electrical stimulation, and static mechanical loading. The culture parameters can be individually adjusted to establish the optimal culture condition to achieve long-term culture and to minimize tissue dedifferentiation. The development of the heart-on-a-chip technology presented here further encourages the use of organotypic human cardiac slices as a platform for pre-clinical drug testing and research in human cardiac physiology.


Assuntos
Coração/fisiologia , Técnicas de Cultura de Órgãos/métodos , Animais , Fenômenos Eletrofisiológicos , Humanos , Camundongos , Procedimentos Analíticos em Microchip , Técnicas de Cultura de Órgãos/instrumentação , Temperatura , Fatores de Tempo , Sobrevivência de Tecidos
6.
Toxicol Lett ; 285: 74-80, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29305325

RESUMO

Trastuzumab (Herceptin®), a monoclonal antibody against the ErbB2 (HER2) receptor, has significantly improved clinical outcomes for HER2+ breast cancer patients. However, the drug also has known cardiotoxic side effects through mechanisms that are not fully understood. Here we utilized human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the cardioprotective effects of ErbB2/4 signaling is observed. We observed no cardioprotective effects of ErbB2/4 signaling without cellular stress (doxorubicin exposure in this study). In addition to neuregulin-1 (NRG-1), we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF) also provides cardioprotective effects for iPS-CMs. Finally, we demonstrate a simple, high-throughput co-culture platform utilizing iPS-CMs and endothelial cells that is capable of detecting trastuzumab-related cardiotoxicity. We conclude that iPS-CMs can recapitulate trastuzumab-related cardiotoxicity, and may be used to elucidate additional modes of toxicity of trastuzumab and related compounds.


Assuntos
Antineoplásicos Imunológicos/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/toxicidade , Cardiotoxicidade , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Ensaios de Triagem em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/enzimologia , L-Lactato Desidrogenase/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/enzimologia
7.
Tissue Eng Part C Methods ; 23(8): 474-484, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28622076

RESUMO

Microphysiological systems (MPS), or "organ-on-a-chip" platforms, aim to recapitulate in vivo physiology using small-scale in vitro tissue models of human physiology. While significant efforts have been made to create vascularized tissues, most reports utilize primary endothelial cells that hinder reproducibility. In this study, we report the use of human induced pluripotent stem cell-derived endothelial cells (iPS-ECs) in developing three-dimensional (3D) microvascular networks. We established a CDH5-mCherry reporter iPS cell line, which expresses the vascular endothelial (VE)-cadherin fused to mCherry. The iPS-ECs demonstrate physiological functions characteristic of primary endothelial cells in a series of in vitro assays, including permeability, response to shear stress, and the expression of endothelial markers (CD31, von Willibrand factor, and endothelial nitric oxide synthase). The iPS-ECs form stable, perfusable microvessels over the course of 14 days when cultured within 3D microfluidic devices. We also demonstrate that inhibition of TGF-ß signaling improves vascular network formation by the iPS-ECs. We conclude that iPS-ECs can be a source of endothelial cells in MPS providing opportunities for human disease modeling and improving the reproducibility of 3D vascular networks.


Assuntos
Técnicas de Cultura de Células/métodos , Células Endoteliais/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Neovascularização Fisiológica , Inibidores da Angiogênese/farmacologia , Antígenos CD/metabolismo , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Separação Celular , Células Endoteliais/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Microfluídica , Neovascularização Fisiológica/efeitos dos fármacos , Fenótipo , Resistência ao Cisalhamento , Bibliotecas de Moléculas Pequenas/farmacologia , Fator de Crescimento Transformador beta/farmacologia
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