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1.
Nanoscale Horiz ; 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39018043

RESUMO

Many pathological conditions are predominantly associated with oxidative stress, arising from reactive oxygen species (ROS); therefore, the modulation of redox activities has been a key strategy to restore normal tissue functions. Current approaches involve establishing a favorable cellular redox environment through the administration of therapeutic drugs and redox-active nanomaterials (RANs). In particular, RANs not only provide a stable and reliable means of therapeutic delivery but also possess the capacity to finely tune various interconnected components, including radicals, enzymes, proteins, transcription factors, and metabolites. Here, we discuss the roles that engineered RANs play in a spectrum of pathological conditions, such as cancer, neurodegenerative diseases, infections, and inflammation. We visualize the dual functions of RANs as both generator and scavenger of ROS, emphasizing their profound impact on diverse cellular functions. The focus of this review is solely on inorganic redox-active nanomaterials (inorganic RANs). Additionally, we deliberate on the challenges associated with current RANs-based approaches and propose potential research directions for their future clinical translation.

2.
Small ; : e2401982, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992997

RESUMO

Most organophosphates (OPs) are hydrophobic, and after exposure, can sequester into lipophilic regions within the body, such as adipose tissue, resulting in long term chronic effects. Consequently, there is an urgent need for therapeutic agents that can decontaminate OPs in these hydrophobic regions. Accordingly, an enzyme-polymer surfactant nanocomplex is designed and tested comprising chemically supercharged phosphotriesterase (Agrobacterium radiobacter; arPTE) electrostatically conjugated to amphiphilic polymer surfactant chains ([cat.arPTE][S-]). Experimentally-derived structural data are combined with molecular dynamics (MD) simulations to provide atomic level detail on conformational ensembles of the nanocomplex using dielectric constants relevant to aqueous and lipidic microenvironments. These show the formation of a compact admicelle pseudophase surfactant corona under aqueous conditions, which reconfigures to yield an extended conformation at a low dielectric constant, providing insight into the mechanism underpinning cell membrane binding. Significantly, it demonstrated that [cat.arPTE][S-] spontaneously binds to human mesenchymal stem cell membranes (hMSCs), resulting in on-cell OP hydrolysis. Moreover, the nanoconstruct can endocytose and partition into the intracellular fatty vacuoles of adipocytes and hydrolyze sequestered OP.

3.
Soft Matter ; 20(24): 4828, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38841883

RESUMO

Correction for 'Flax fibre reinforced alginate poloxamer hydrogel: assessment of mechanical and 4D printing potential' by Charles de Kergariou et al., Soft Matter, 2024, 20, 4021-4034, https://doi.org/10.1039/D4SM00135D.

4.
Soft Matter ; 20(19): 4021-4034, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38695256

RESUMO

The mechanical and printing performance of a new biomaterial, flax fibre-reinforced alginate-poloxamer based hydrogel, for load-bearing and 4D printing biomedical applications is described in this study. The-self suspendable ability of the material was evaluated by optimising the printing parameters and conducting a collapse test. 1% of the flax fibre weight fraction was sufficient to obtain an optimum hydrogel composite from a mechanical perspective. The collapse test showed that the addition of flax fibres allowed a consistent print without support over longer distances (8 and 10 mm) than the unreinforced hydrogel. The addition of 1% of flax fibres increased the viscosity by 39% and 129% at strain rates of 1 rad s-1 and 5 rad s-1, respectively, compared to the unreinforced hydrogel. The distributions of fibre size and orientation inside the material were also evaluated to identify the internal morphology of the material. The difference of coefficients of moisture expansion between the printing direction (1.29 × 10-1) and the transverse direction (6.03 × 10-1) showed potential for hygromorphic actuation in 4D printing. The actuation authority was demonstrated by printing a [0°; 90°] stacking sequence and rosette-like structures, which were then actuated using humidity gradients. Adding fibres to the hydrogel improved the repeatability of the actuation, while lowering the actuation authority from 0.11 mm-1 to 0.08 mm-1. Overall, this study highlighted the structural and actuation-related benefits of adding flax fibres to hydrogels.

5.
STAR Protoc ; 5(1): 102899, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38367231

RESUMO

Surgical treatment of pediatric congenital heart disease with tissue grafts is a lifesaving intervention. Decellularization to reduce immunogenicity of tissue grafts is an increasingly popular alternative to glutaraldehyde fixation. Here, we present a protocol to decellularize porcine right ventricular outflow tracts using a 3D printed flow chamber. We describe steps for 3D printing the flow rig, preparing porcine tissue, and using the flow rig to utilize shear forces for decellularization. We then detail procedures for characterizing the acellular scaffold. For complete details on the use and execution of this protocol, please refer to Vafaee et al.1.


Assuntos
Ventrículos do Coração , Impressão Tridimensional , Suínos , Humanos , Criança , Animais , Ventrículos do Coração/diagnóstico por imagem
6.
J Am Chem Soc ; 145(41): 22659-22670, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37812759

RESUMO

Lipid nanoparticles (LNPs) are becoming widely adopted as vectors for the delivery of therapeutic payloads but generally lack intrinsic tissue-homing properties. These extracellular vesicle (EV) mimetics can be targeted toward the liver, lung, or spleen via charge modification of their lipid headgroups. Homing to other tissues has only been achieved via covalent surface modification strategies using small-molecule ligands, peptides, or monoclonal antibodies─methods that are challenging to couple with large-scale manufacturing. Herein, we design a novel modular artificial membrane-binding protein (AMBP) platform for the modification of LNPs postformation. The system is composed of two protein modules that can be readily coupled using bioorthogonal chemistry to yield the AMBP. The first is a membrane anchor module comprising a supercharged green fluorescent protein (scGFP) electrostatically conjugated to a dynamic polymer surfactant corona. The second is a functional module containing a cardiac tissue fibronectin homing sequence from the bacterial adhesin CshA. We demonstrate that LNPs modified using the AMBP exhibit a 20-fold increase in uptake by fibronectin-rich C2C12 cells under static conditions and a 10-fold increase under physiologically relevant shear stresses, with no loss of cell viability. Moreover, we show targeted localization of the AMBP-modified LNPs in zebrafish hearts, highlighting their therapeutic potential as a vector for the treatment of cardiac disease and, more generally, as a smart vector.


Assuntos
Fibronectinas , Nanopartículas , Animais , Peixe-Zebra , Lipossomos , Nanopartículas/química , RNA Interferente Pequeno/química
7.
Drug Deliv Transl Res ; 13(11): 2719-2738, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37301780

RESUMO

The burden of cancer is increasing globally. Several challenges facing its mainstream treatment approaches have formed the basis for the development of targeted delivery systems to carry and distribute anti-cancer payloads to their defined targets. This site-specific delivery of drug molecules and gene payloads to selectively target druggable biomarkers aimed at inducing cell death while sparing normal cells is the principal goal for cancer therapy. An important advantage of a delivery vector either viral or non-viral is the cumulative ability to penetrate the haphazardly arranged and immunosuppressive tumour microenvironment of solid tumours and or withstand antibody-mediated immune response. Biotechnological approaches incorporating rational protein engineering for the development of targeted delivery systems which may serve as vehicles for packaging and distribution of anti-cancer agents to selectively target and kill cancer cells are highly desired. Over the years, these chemically and genetically modified delivery systems have aimed at distribution and selective accumulation of drug molecules at receptor sites resulting in constant maintenance of high drug bioavailability for effective anti-tumour activity. In this review, we highlighted the state-of-the art viral and non-viral drug and gene delivery systems and those under developments focusing on cancer therapy.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Vetores Genéticos , Terapia Genética/métodos , Técnicas de Transferência de Genes , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapêutico , Microambiente Tumoral
8.
Biofabrication ; 15(1)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36321254

RESUMO

We describe the development of a high-throughput bioprinted colorectal cancer (CRC) spheroid platform with high levels of automation, information content, and low cell number requirement. This is achieved via the formulation of a hydrogel bioink with a compressive Young's modulus that is commensurate with that of colonic tissue (1-3 kPa), which supports exponential growth of spheroids from a wide range of CRC cell lines. The resulting spheroids display tight cell-cell junctions, bioink matrix-cell interactions and necrotic hypoxic cores. By combining high content light microscopy imaging and processing with rapid multiwell plate bioprinting, dose-response profiles are generated from CRC spheroids challenged with oxaliplatin (OX) and fluorouracil (5FU), as well as radiotherapy. Bioprinted CRC spheroids are shown to exhibit high levels of chemoresistance relative to cell monolayers, and OX was found to be significantly less effective against tumour spheroids than in monolayer culture, when compared to 5FU.


Assuntos
Bioimpressão , Neoplasias Colorretais , Humanos , Esferoides Celulares , Bioimpressão/métodos , Fluoruracila , Linhagem Celular , Oxaliplatina
9.
ACS Appl Mater Interfaces ; 13(50): 60433-60445, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34894651

RESUMO

Catalytically active materials for the enhancement of personalized protective equipment (PPE) could be advantageous to help alleviate threats posed by neurotoxic organophosphorus compounds (OPs). Accordingly, a chimeric protein comprised of a supercharged green fluorescent protein (scGFP) and phosphotriesterase from Agrobacterium radiobacter (arPTE) was designed to drive the polymer surfactant (S-)-mediated self-assembly of microclusters to produce robust, enzymatically active materials. The chimera scGFP-arPTE was structurally characterized via circular dichroism spectroscopy and synchrotron radiation small-angle X-ray scattering, and its biophysical properties were determined. Significantly, the chimera exhibited greater thermal stability than the native constituent proteins, as well as a higher catalytic turnover number (kcat). Furthermore, scGFP-arPTE was electrostatically complexed with monomeric S-, driving self-assembly into [scGFP-arPTE][S-] nanoclusters, which could be dehydrated and cross-linked to yield enzymatically active [scGFP-arPTE][S-] porous films with a high-order structure. Moreover, these clusters could self-assemble within cotton fibers to generate active composite textiles without the need for the pretreatment of the fabrics. Significantly, the resulting materials maintained the biophysical activities of both constituent proteins and displayed recyclable and persistent activity against the nerve agent simulant paraoxon.


Assuntos
Materiais Biocompatíveis/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Hidrolases de Triester Fosfórico/metabolismo , Polímeros/metabolismo , Tensoativos/metabolismo , Têxteis , Agrobacterium tumefaciens/enzimologia , Materiais Biocompatíveis/química , Proteínas de Fluorescência Verde/química , Teste de Materiais , Modelos Moleculares , Tamanho da Partícula , Hidrolases de Triester Fosfórico/química , Polímeros/química , Tensoativos/química
10.
Biomaterials ; 276: 120996, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34280823

RESUMO

One of the major challenges within the emerging field of injectable stem cell therapies for articular cartilage (AC) repair is the retention of sufficient viable cell numbers at the site of injury. Even when delivered via intra-articular injection, the number of stem cells retained at the target is often low and declines rapidly over time. To address this challenge, an artificial plasma membrane binding nanocomplex was rationally designed to provide human mesenchymal stem cells (hMSCs) with increased adhesion to articular cartilage tissue. The nanocomplex comprises the extracellular matrix (ECM) binding peptide of a placenta growth factor-2 (PlGF-2) fused to a supercharged green fluorescent protein (scGFP), which was electrostatically conjugated to anionic polymer surfactant chains to yield [S-]scGFP_PlGF2. The [S-]scGFP_PlGF2 nanocomplex spontaneously inserts into the plasma membrane of hMSCs, is not cytotoxic, and does not inhibit differentiation. The nanocomplex-modified hMSCs showed a significant increase in affinity for immobilised collagen II, a key ECM protein of cartilage, in both static and dynamic cell adhesion assays. Moreover, the cells adhered strongly to bovine ex vivo articular cartilage explants resulting in high cell numbers. These findings suggest that the re-engineering of hMSC membranes with [S-]scGFP_PlGF2 could improve the efficacy of injectable stem cell-based therapies for the treatment of damaged articular cartilage.


Assuntos
Cartilagem Articular , Células-Tronco Mesenquimais , Animais , Proteínas de Transporte , Bovinos , Adesão Celular , Diferenciação Celular , Condrogênese , Matriz Extracelular , Humanos , Membranas Artificiais , Polímeros , Células-Tronco , Tensoativos
11.
Int J Nanomedicine ; 16: 2585-2595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833513

RESUMO

BACKGROUND: In cancer nanomedicine, drugs are transported by nanocarriers through a biological system to produce a therapeutic effect. The efficacy of the treatment is affected by the ability of the nanocarriers to overcome biological transport barriers to reach their target. In this work, we focus on the process of nanocarrier penetration through tumour tissue after extravasation. Visualising the dynamics of nanocarriers in tissue is difficult in vivo, and in vitro assays often do not capture the spatial and physical constraints relevant to model tissue penetration. METHODS: We propose a new simple, low-cost method to observe the transport dynamics of nanoparticles through a tissue-mimetic microfluidic chip. After loading a chip with triplicate conditions of gel type and loading with microparticles, microscopic analysis allows for tracking of fluorescent nanoparticles as they move through hydrogels (Matrigel and Collagen I) with and without cell-sized microparticles. A bespoke image-processing codebase written in MATLAB allows for statistical analysis of this tracking, and time-dependent dynamics can be determined. RESULTS: To demonstrate the method, we show size-dependence of transport mechanics can be observed, with diffusion of fluorescein dye throughout the channel in 8 h, while 20 nm carboxylate FluoSphere diffusion was hindered through both Collagen I and Matrigel™. Statistical measurements of the results are generated through the software package and show the significance of both size and presence of microparticles on penetration depth. CONCLUSION: This provides an easy-to-understand output for the end user to measure nanoparticle tissue penetration, enabling the first steps towards future automated experimentation of transport dynamics for rational nanocarrier design.


Assuntos
Géis/química , Microfluídica/métodos , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Alicerces Teciduais/química , Colágeno/química , Colágeno/metabolismo , Difusão , Humanos , Nanomedicina/métodos , Nanopartículas/química
12.
ACS Appl Polym Mater ; 3(12): 6070-6077, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-35983011

RESUMO

Here, we describe a facile route to the synthesis of enzymatically active highly fabricable plastics, where the enzyme is an intrinsic component of the material. This is facilitated by the formation of an electrostatically stabilized enzyme-polymer surfactant nanoconstruct, which, after lyophilization and melting, affords stable macromolecular dispersions in a wide range of organic solvents. A selection of plastics can then be co-dissolved in the dispersions, which provides a route to bespoke 3D enzyme plastic nanocomposite structures using a wide range of fabrication techniques, including melt electrowriting, casting, and piston-driven 3D printing. The resulting constructs comprising active phosphotriesterase (arPTE) readily detoxify organophosphates with persistent activity over repeated cycles and for long time periods. Moreover, we show that the protein guest molecules, such as arPTE or sfGFP, increase the compressive Young's modulus of the plastics and that the identity of the biomolecule influences the nanomorphology and mechanical properties of the resulting materials. Overall, we demonstrate that these biologically active nanocomposite plastics are compatible with state-of-the-art 3D fabrication techniques and that the methodology could be readily applied to produce robust and on-demand smart nanomaterial structures.

13.
Front Cardiovasc Med ; 7: 598890, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33330660

RESUMO

Cell therapies are emerging as a new therapeutic frontier for the treatment of ischemic disease. However, femoral occlusions can be challenging environments for effective therapeutic cell delivery. In this study, cell-engineered hybrid scaffolds are implanted around the occluded femoral artery and the therapeutic benefit through the formation of new collateral arteries is investigated. First, it is reported the fabrication of different hybrid "hard-soft" 3D channel-shaped scaffolds comprising either poly(ε-caprolactone) (PCL) or polylactic-co-glycolic acid (PLGA) and electro-spun of gelatin (GL) nanofibers. Both PCL-GL and PLGA-GL scaffolds show anisotropic characteristics in mechanical tests and PLGA displays a greater rigidity and faster degradability in wet conditions. The resulting constructs are engineered using human adventitial pericytes (APCs) and both exhibit excellent biocompatibility. The 3D environment also induces expressional changes in APCs, conferring a more pronounced proangiogenic secretory profile. Bioprinting of alginate-pluronic gel (AG/PL), containing APCs and endothelial cells, completes the hybrid scaffold providing accurate spatial organization of the delivered cells. The scaffolds implantation around the mice occluded femoral artery shows that bioengineered PLGA hybrid scaffold outperforms the PCL counterpart accelerating limb blood flow recovery through the formation arterioles with diameters >50 µm, demonstrating the therapeutic potential in stimulating reparative angiogenesis.

14.
Adv Biosyst ; 4(11): e2000101, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33166084

RESUMO

The extent to which biologic payloads can be effectively delivered to cells is a limiting factor in the development of new therapies. Limitations arise from the lack of pharmacokinetic stability of biologics in vivo. Encapsulating biologics in a protective delivery vector has the potential to improve delivery profile and enhance performance. Coacervate microdroplets are developed as cell-mimetic materials with established potential for the stabilization of biological molecules, such as proteins and nucleic acids. Here, the development of biodegradable coacervate microvectors (comprising synthetically modified amylose polymers) is presented, for the delivery of biologic payloads to cells. Amylose-based coacervate microdroplets are stable under physiological conditions (e.g., temperature and ionic strength), are noncytotoxic owing to their biopolymeric structure, spontaneously interacted with the cell membrane, and are able to deliver and release proteinaceous payloads beyond the plasma membrane. In particular, myoglobin, an oxygen storage and antioxidant protein, is successfully delivered into human mesenchymal stem cells (hMSCs) within 24 h. Furthermore, coacervate microvectors are implemented for the delivery of human bone morphogenetic protein 2 growth factor, inducing differentiation of hMSCs into osteoprogenitor cells. This study demonstrates the potential of coacervate microdroplets as delivery microvectors for biomedical research and the development of new therapies.


Assuntos
Proteína Morfogenética Óssea 2 , Diferenciação Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Células-Tronco Mesenquimais/metabolismo , Amilose/química , Biopolímeros/química , Proteína Morfogenética Óssea 2/química , Proteína Morfogenética Óssea 2/farmacocinética , Proteína Morfogenética Óssea 2/farmacologia , Células Cultivadas , Humanos
15.
J Am Chem Soc ; 142(49): 20640-20650, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33252237

RESUMO

Controlling the assembly and disassembly of nanoscale protein cages for the capture and internalization of protein or non-proteinaceous components is fundamentally important to a diverse range of bionanotechnological applications. Here, we study the reversible, pressure-induced dissociation of a natural protein nanocage, E. coli bacterioferritin (Bfr), using synchrotron radiation small-angle X-ray scattering (SAXS) and circular dichroism (CD). We demonstrate that hydrostatic pressures of 450 MPa are sufficient to completely dissociate the Bfr 24-mer into protein dimers, and the reversibility and kinetics of the reassembly process can be controlled by selecting appropriate buffer conditions. We also demonstrate that the heme B prosthetic group present at the subunit dimer interface influences the stability and pressure lability of the cage, despite its location being discrete from the interdimer interface that is key to cage assembly. This indicates a major cage-stabilizing role for heme within this family of ferritins.


Assuntos
Proteínas de Bactérias/metabolismo , Grupo dos Citocromos b/metabolismo , Escherichia coli/metabolismo , Ferritinas/metabolismo , Proteínas de Bactérias/química , Dicroísmo Circular , Grupo dos Citocromos b/química , Dimerização , Ferritinas/química , Pressão Hidrostática , Cinética , Espalhamento a Baixo Ângulo , Termodinâmica , Difração de Raios X
16.
Artigo em Inglês | MEDLINE | ID: mdl-32266231

RESUMO

Smart biomaterials with an inherent capacity to elicit specific behaviors in lieu of biological prompts would be advantageous for regenerative medicine applications. In this work, we employ an electrospinning technique to model the in vivo nanofibrous extracellular matrix (ECM) of cartilage using a chondroinductive cellulose and silk polymer blend (75:25 ratio). This natural polymer composite is directly electrospun for the first time, into nanofibers without post-spun treatment, using a trifluoroacetic acid and acetic acid cosolvent system. Biocompatibility of the composite nanofibres with human mesenchymal stem cells (hMSCs) is demonstrated and its inherent capacity to direct chondrogenic stem cell differentiation, in the absence of stimulating growth factors, is confirmed. This chondrogenic stimulation could be countered biochemically using fibroblast growth factor-2, a growth factor used to enhance the proliferation of hMSCs. Furthermore, the potential mechanisms driving this chondroinduction at the cell-biomaterial interface is investigated. Composite substrates are fabricated as two-dimensional film surfaces and cultured with hMSCs in the presence of chemicals that interfere with their biochemical and mechanical signaling pathways. Preventing substrate surface elasticity transmission resulted in a significant downregulation of chondrogenic gene expression. Interference with the classical chondrogenic Smad2/3 phosphorylation pathway did not impact chondrogenesis. The results highlight the importance of substrate mechanical elasticity on hMSCs chondroinduction and its independence to known chondrogenic biochemical pathways. The newly fabricated scaffolds provide the foundation for designing a robust, self-inductive, and cost-effective biomimetic biomaterial for cartilage tissue engineering.

17.
Adv Healthc Mater ; 9(15): e1900554, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31407502

RESUMO

Until recently, bioprinting was largely limited to highly interdisciplinary research teams, as the process requires significant input from specialists in the fields of materials science, engineering, and cell biology. With the advent of commercially available high-performance bioprinters, the field has become accessible to a wider range of research groups, who can now buy the hardware off the shelf instead of having to build it from scratch. As a result, bioprinting has rapidly expanded to address a wide array of research foci, which include organotypic in vitro models, complex engineered tissues, and even bioprinted microbial systems. Moreover, in the early days, the range of suitable bioinks was limited. Now, there is a plethora of viable options to suit many cell phenotypes. This rapidly evolving dynamic environment creates endless opportunities for scientists to design and construct highly complex biological systems. However, this scientific diversity presents its own set of challenges, such as defining standardized protocols for characterizing bioprinted structures, which is essential for eventual organ replacement. In this progress report, the current state-of-the-art in the field of bioprinting is discussed, with a special emphasis on recent hardware developments, bioprinting for regenerative medicine, and late-breaking nontraditional topics.


Assuntos
Bioimpressão , Impressão Tridimensional , Medicina Regenerativa , Engenharia Tecidual
18.
Bioconjug Chem ; 30(11): 2771-2776, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31603664

RESUMO

We present a new methodology for the generation of discrete molecularly dispersed enzyme-polymer-surfactant bioconjugates. Significantly, we demonstrate that >3-fold increase in the catalytic efficiency of the diffusion-limited phosphotriesterase arPTE can be achieved through sequential electrostatic addition of cationic and anionic polymer surfactants, respectively. Here, the polymer surfactants assemble on the surface of the enzyme via ion exchange to yield a compact corona. The observed rate enhancement is consistent with a mechanism whereby the polymer-surfactant corona gives rise to a decrease in the dielectric constant in the vicinity of the active site of the enzyme, accelerating the rate-determining product diffusion step. The facile methodology has significant potential for increasing the efficiency of enzymes and could therefore have a substantially positive impact for industrial enzymology.


Assuntos
Agrobacterium tumefaciens/enzimologia , Hidrolases de Triester Fosfórico/metabolismo , Polímeros/química , Tensoativos/química , Cátions , Hidrolases de Triester Fosfórico/química , Conformação Proteica , Eletricidade Estática
19.
Chem Sci ; 10(32): 7610-7618, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31588312

RESUMO

We present a new cell membrane modification methodology where the inherent heart tissue homing properties of the infectious bacteria Streptococcus gordonii are transferred to human stem cells. This is achieved via the rational design of a chimeric protein-polymer surfactant cell membrane binding construct, comprising the cardiac fibronectin (Fn) binding domain of the bacterial adhesin protein CshA fused to a supercharged protein. Significantly, the protein-polymer surfactant hybrid spontaneously inserts into the plasma membrane of stem cells without cytotoxicity, instilling the cells with a high affinity for immobilized fibronectin. Moreover, we show that this cell membrane reengineering approach significantly improves retention and homing of stem cells delivered either intracardially or intravenously to the myocardium in a mouse model.

20.
Nat Commun ; 10(1): 1887, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015421

RESUMO

Cell membrane re-engineering is emerging as a powerful tool for the development of next generation cell therapies, as it allows the user to augment therapeutic cells to provide additional functionalities, such as homing, adhesion or hypoxia resistance. To date, however, there are few examples where the plasma membrane is re-engineered to display active enzymes that promote extracellular matrix protein assembly. Here, we report on a self-contained matrix-forming system where the membrane of human mesenchymal stem cells is modified to display a novel thrombin construct, giving rise to spontaneous fibrin hydrogel nucleation and growth at near human plasma concentrations of fibrinogen. The cell membrane modification process is realised through the synthesis of a membrane-binding supercationic thrombin-polymer surfactant complex. Significantly, the resulting robust cellular fibrin hydrogel constructs can be differentiated down osteogenic and adipogenic lineages, giving rise to self-supporting monoliths that exhibit Young's moduli that reflect their respective extracellular matrix compositions.


Assuntos
Engenharia Celular/métodos , Membrana Celular/química , Fibrina/metabolismo , Trombina/química , Cicatrização , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Membrana Celular/metabolismo , Modelos Animais de Doenças , Módulo de Elasticidade , Matriz Extracelular/metabolismo , Fibroblastos , Humanos , Hidrogéis/química , Hidrogéis/metabolismo , Células-Tronco Mesenquimais , Polímeros/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tensoativos/química , Trombina/genética , Trombina/metabolismo , Peixe-Zebra
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