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1.
Chem Sci ; 12(38): 12719-12725, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34703558

RESUMO

Anticoagulant therapeutics are a mainstay of modern surgery and of clotting disorder management such as venous thrombosis, yet performance and supply limitations exist for the most widely used agent - heparin. Herein we report the first synthesis, characterization, and performance of sulfated poly-amido-saccharides (sulPASs) as heparin mimetics. sulPASs inhibit the intrinsic pathway of coagulation, specifically FXa and FXIa, as revealed by ex vivo human plasma clotting assays and serine protease inhibition assays. sulPASs activity positively correlates with molecular weight and degree of sulfation. Importantly, sulPASs are not degraded by heparanases and are non-hemolytic. In addition, their activity is reversed by protamine sulfate, unlike small molecule anticoagulants. In an in vivo murine model, sulPASs extend clotting time in a dose dependent manner with bleeding risk comparable to heparin. These findings support continued development of synthetic anticoagulants to address the clinical risks and shortages associated with heparin.

3.
Biomaterials ; 276: 121011, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34303154

RESUMO

Despite the potential of anti-thrombogenic coatings, including heparinized surfaces, to improve the performance of blood-contacting devices, the inevitable deterioration of bioactivity remains an important factor in device failure and related thrombotic complications. As a consequence, the ability to restore the bioactivity of a surface coating after implantation of a blood-contacting device provides a potentially important strategy to enhance its clinical performance. Here, we report the regeneration of a multicomponent anti-thrombogenic coating through use of an evolved sortase A to mediate reversible transpeptidation. Both recombinant thrombomodulin and a chemoenzymatically synthesized ultra-low molecular weight heparin were repeatedly and selectively immobilized or removed in a sequential, alternating, or simultaneous manner. The generation of activated protein C (aPC) and inhibition of activated factor X (FXa) was consistent with the molecular composition of the surface. The fabrication of a rechargeable anti-thrombogenic surface was demonstrated on an expanded polytetrafluoroethylene (ePTFE) vascular graft with reconstitution of the surface bound coating 4 weeks after in vivo implantation in a rat model.


Assuntos
Heparina , Trombose , Animais , Prótese Vascular , Materiais Revestidos Biocompatíveis , Politetrafluoretileno , Ratos , Trombose/prevenção & controle
7.
J Vasc Surg ; 74(5): 1527-1536.e1, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33957227

RESUMO

OBJECTIVE: Endovascular aneurysm repair (EVAR) is a widely used option for patients with suitable vascular anatomy who have a large infrarenal abdominal aortic aneurysm (AAA). Patients with small AAAs are managed with careful surveillance and it is a common concern that their anatomy may change with AAA growth, and their option for EVAR may become limited. Device innovation has resulted in expanded ranges of anatomy that may be eligible for EVAR. This study sought to identify changes in anatomic eligibility for repair with contemporary endovascular devices in AAA patients, monitored by computed tomography scan over the course of 2 years. METHODS: Patients from the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT, NCT01756833) were included in this analysis. Females had baseline AAA maximum transverse diameter between 3.5 and 4.5 cm, and males had baseline maximum transverse diameter between 3.5 and 5.0 cm. Patients were included in this analysis if they completed pre-enrollment and 2-year follow-up computed tomography imaging. Pertinent anatomic measurements were performed on a postprocessing workstation in a centralized imaging core laboratory. EVAR candidacy was determined by measuring proximal aortic neck diameter, AAA length, and infrarenal neck angulation. Patients were considered to be eligible for EVAR if they qualified for at least one of the seven studied devices' instructions for use at baseline and at 2 years. A paired t test analysis was used to detect differences in aortic measurements over 2 years, and the McNemar test was used to compare eligibility over 2 years. RESULTS: We included 192 patients in this analysis-168 male and 24 female. Of these patients, 85% were eligible for EVAR at baseline and 85% after 2 years of follow-up (P = 1.00; 95% confidence interval -0.034 to 0.034). Of the 164 EVAR candidates at baseline, 160 (98%) remained eligible over 2 years of surveillance. Insufficient neck length was the most common reason for both ineligibility at baseline (18 of 28 patients) as well as loss of candidacy over 2 years (3 of 4 patients). CONCLUSIONS: The majority of patients eligible for EVAR when entering a surveillance program for small AAA remain eligible after 2 years. Substantial changes in AAA neck anatomy resulting in loss of EVAR treatment options are infrequent. Patients with anatomic AAA progression beyond EVAR eligibility remain candidates for complex EVAR and open repair.

8.
Blood ; 138(13): 1182-1193, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33945603

RESUMO

Events mediated by the P-selectin/PSGL-1 pathway play a critical role in the initiation and propagation of venous thrombosis by facilitating the accumulation of leukocytes and platelets within the growing thrombus. Activated platelets and endothelium express P-selectin, which binds P-selectin glycoprotein ligand-1 (PSGL-1) that is expressed on the surface of all leukocytes. We developed a pegylated glycomimetic of the N terminus of PSGL-1, PEG40-GSnP-6 (P-G6), which proved to be a highly potent P-selectin inhibitor with a favorable pharmacokinetic profile for clinical translation. P-G6 inhibits human and mouse platelet-monocyte and platelet-neutrophil aggregation in vitro and blocks microcirculatory platelet-leukocyte interactions in vivo. Administration of P-G6 reduces thrombus formation in a nonocclusive model of deep vein thrombosis with a commensurate reduction in leukocyte accumulation, but without disruption of hemostasis. P-G6 potently inhibits the P-selectin/PSGL-1 pathway and represents a promising drug candidate for the prevention of venous thrombosis without increased bleeding risk.

9.
Nature ; 592(7853): 195-204, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33828315

RESUMO

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.


Assuntos
Células/metabolismo , Edição de Genes/métodos , Genoma Humano/genética , National Institutes of Health (U.S.)/organização & administração , Animais , Terapia Genética , Objetivos , Humanos , Estados Unidos
11.
Microsc Microanal ; : 1-6, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33785078

RESUMO

The ability to accurately and precisely measure the thickness of biomaterial constructs is critical for characterizing both specific dimensional features and related mechanical properties. However, in the absence of a standardized approach for thickness measurements, a variety of imaging modalities have been employed, which have been associated with varying limits of accuracy, particularly for ultrathin hydrated structures. Electron microscopy (EM), a commonly used modality, yields thickness values for extensively processed and nonhydrated constructs, potentially resulting in overestimated mechanical properties, including elastic modulus and ultimate tensile strength. Confocal laser scanning microscopy (CLSM) has often been used as a nondestructive imaging alternative. However, published CLSM-derived image analysis protocols use arbitrary signal intensity cutoffs and provide minimal information regarding thickness variability across imaged surfaces. To address the aforementioned limitations, we present a standardized, user-independent CLSM image acquisition and analysis approach developed as a custom ImageJ macro and validated with collagen-based scaffolds. In the process, we also quantify thickness discrepancies in collagen-based scaffolds between CLSM and EM techniques, further illustrating the need for improved strategies. Employing the same image acquisition protocol, we also demonstrate that this approach can be used to estimate the surface roughness of the same scaffolds without the use of specialized instrumentation.

12.
Acad Med ; 96(9): 1306-1310, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33538475

RESUMO

PROBLEM: Health professions education does not routinely incorporate training in innovation or creative problem solving. Although some models of innovation education within graduate medical education exist, they often require participants' full-time commitment and removal from clinical training or rely upon participants' existing expertise. There is a need for curricula that teach innovation skills that will enable trainees to identify and solve unmet clinical challenges in everyday practice. To address this gap in surgical graduate education, the authors developed the Surgical Program in Innovation (SPIN). APPROACH: SPIN, a 6-month workshop-based curriculum, was established in 2016 in the Beth Israel Deaconess Medical Center Department of Surgery to teach surgical trainees the basics of the innovation process, focusing on surgeon-driven problem identification, product design, prototype fabrication, and initial steps in the commercialization process. Participating surgical residents and graduate students attend monthly workshops taught by medical, engineering, and medical technology (MedTech) industry faculty. Participants collaborate in teams to develop a novel device, fabricate a protype, and pitch their product to a panel of judges. OUTCOMES: From academic years 2015-2016 to 2017-2018, 49 trainees, including 41 surgical residents, participated in SPIN. Across this period, 13 teams identified an unmet need, ideated a solution, and designed and pitched a novel device. Ten teams fabricated prototypes. The 22 SPIN participants who responded to both pre- and postcourse surveys reported significant increases in confidence in generating problem statements, computer-aided design, fabrication of a prototype, and initial commercialization steps (product pitching and business planning). NEXT STEPS: Incorporating innovation education and design thinking into clinical training will prove essential in preparing future physicians to be lifelong problem finders and solvers. The authors plan to expand SPIN to additional clinical specialties, as well as to assess its impact in fostering future innovation and collaboration among program participants.


Assuntos
Currículo , Educação de Pós-Graduação em Medicina/métodos , Invenções , Aprendizagem Baseada em Problemas/métodos , Cirurgiões/educação , Difusão de Inovações , Humanos , Internato e Residência/métodos , Determinação de Necessidades de Cuidados de Saúde
15.
Cell Chem Biol ; 28(4): 567-582.e4, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33378651

RESUMO

The pleiotropic functions of macrophages in immune defense, tissue repair, and maintenance of tissue homeostasis are supported by the heterogeneity in macrophage sub-populations that differ both in ontogeny and polarization. Although glycans and glycan-binding proteins (GBPs) are integral to macrophage function and may contribute to macrophage diversity, little is known about the factors governing their expression. Here, we provide a resource for characterizing the N-/O-glycomes of various murine peritoneal macrophage sub-populations, demonstrating that glycosylation primarily reflects developmental origin and, to a lesser degree, cellular polarization. Furthermore, comparative analysis of GBP-coding genes in resident and elicited macrophages indicated that GBP expression is consistent with specialized macrophage functions and correlates with specific types of displayed glycans. An integrated, semi-quantitative approach was used to confirm distinct expression patterns of glycans and their binding proteins across different macrophages. The data suggest that regulation of glycan-protein complexes may be central to macrophage residence and recruitment.


Assuntos
Proteínas de Transporte/genética , Glicômica , Macrófagos/metabolismo , Polissacarídeos/genética , Animais , Proteínas de Transporte/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/metabolismo
17.
ACS Biomater Sci Eng ; 6(7): 4236-4246, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32685675

RESUMO

The multiscale organization of protein-based fibrillar materials is a hallmark of many organs, but the recapitulation of hierarchal structures down to fibrillar scales, which is a requirement for withstanding physiological loading forces, has been challenging. We present a microfluidic strategy for the continuous, large-scale formation of strong, handleable, free-standing, multicentimeter-wide collagen sheets of unprecedented thinness through the application of hydrodynamic focusing with the simultaneous imposition of strain. Sheets as thin as 1.9 µm displayed tensile strengths of 0.5-2.7 MPa, Young's moduli of 3-36 MPa, and modulated the diffusion of molecules as a function of collagen nanoscale structure. Smooth muscle cells cultured on engineered sheets oriented in the direction of aligned collagen fibrils and generated coordinated vasomotor responses. The described biofabrication approach enables rapid formation of ultrathin collagen sheets that withstand physiologically relevant loads for applications in tissue engineering and regenerative medicine, as well as in organ-on-chip and biohybrid devices.


Assuntos
Colágeno , Matriz Extracelular , Anisotropia , Resistência à Tração , Engenharia Tecidual
18.
J Vasc Surg ; 72(2): 387-388, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32711903
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