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Hilderbrand, Scott A.

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Hilderbrand

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Scott A.

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Hilderbrand, Scott A.
Author's Publications: search.filters.isAuthorOfPublication.3633313a-8342-47a3-90a2-c90d50bf1d3b

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    Blood Accessibility to Fibrin in Venous Thrombosis is Thrombus Age-Dependent and Predicts Fibrinolytic Efficacy: An In Vivo Fibrin Molecular Imaging Study
    (Ivyspring International Publisher, 2015) Stein-Merlob, Ashley F.; Kessinger, Chase; Erdem, S. Sibel; Zelada, Henry; Hilderbrand, Scott A.; Lin, Charles; Tearney, Guillermo; Jaff, Michael; Reed, Guy L.; Henke, Peter K.; McCarthy, Jason; Jaffer, Farouc
    Fibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies.
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    Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry
    (Elsevier BV, 2015) Desai, Rajiv M.; Koshy, Sandeep; Hilderbrand, Scott A.; Mooney, David; Joshi, Neel
    Alginate hydrogels are well-characterized, biologically inert materials that are used in many biomedical applications for the delivery of drugs, proteins, and cells. Unfortunately, canonical covalently crosslinked alginate hydrogels are formed using chemical strategies that can be biologically harmful due to their lack of chemoselectivity. In this work we introduce tetrazine and norbornene groups to alginate polymer chains and subsequently form covalently crosslinked click alginate hydrogels capable of encapsulating cells without damaging them. The rapid, bioorthogonal, and specific click reaction is irreversible and allows for easy incorporation of cells with high post-encapsulation viability. The swelling and mechanical properties of the click alginate hydrogel can be tuned via the total polymer concentration and the stoichiometric ratio of the complementary click functional groups. The click alginate hydrogel can be modified after gelation to display cell adhesion peptides for 2D cell culture using thiol-ene chemistry. Furthermore, click alginate hydrogels are minimally inflammatory, maintain structural integrity over several months, and reject cell infiltration when injected subcutaneously in mice. Click alginate hydrogels combine the numerous benefits of alginate hydrogels with powerful bioorthogonal click chemistry for use in tissue engineering applications involving the stable encapsulation or delivery of cells or bioactive molecules.
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    Upconverting Organic Dye Doped Core-Shell Nano-Composites for Dual-Modality NIR Imaging and Photo-Thermal Therapy
    (Ivyspring International Publisher, 2013) Shan, Guobin; Weissleder, Ralph; Hilderbrand, Scott A.
    Nanotechnology approaches offer the potential for creating new optical imaging agents with unique properties that enable uses such as combined molecular imaging and photo-thermal therapy. Ideal preparations should fluoresce in the near-infrared (NIR) region to ensure maximal tissue penetration depth along with minimal scattering and light absorption. Due to their unique photophysical properties, upconverting ceramics such as NaYF4:Er3+,Yb3+ nanoparticles have become promising optical materials for biological imaging. In this work, the design and synthesis of NaYF4:Er3+,Yb3+@SiO2 core-shell nano-composites, which contain highly absorbing NIR carbocyanine dyes in their outer silica shell, are described. These materials combine optical emission (from the upconverting core nanoparticle) with strong NIR absorption (from the carbocyanine dyes incorporated into the shell) to enable both optical imaging and photo-thermal treatment, respectively. Ultimately, this hybrid composite nanomaterial approach imparts the ability to both visualize, via upconversion imaging, and treat, via photo-thermal heating, using two distinct optical channels. Proof-of-principle in vitro experiments are presented to demonstrate the combined imaging and photo-thermal properties of this new functional nano-composite.