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Brubaker C.E.,Northwestern University | Brubaker C.E.,Institute for BioNanotechnology in Medicine | Messersmith P.B.,Northwestern University | Messersmith P.B.,Institute for BioNanotechnology in Medicine
Biomacromolecules | Year: 2011

Mussel-inspired adhesive hydrogels represent innovative candidate medical sealants or glues. In the present work, we describe an enzyme-degradable mussel-inspired adhesive hydrogel formulation, achieved by incorporating minimal elastase substrate peptide Ala-Ala into the branched poly(ethylene glycol) (PEG) macromonomer structure. The system takes advantage of neutrophil elastase expression upregulation and secretion from neutrophils upon recruitment to wounded or inflamed tissue. By integrating adhesive degradation behaviors that respond to cellular cues, we expand the functional range of our mussel-inspired adhesive hydrogel platforms. Rapid (>1 min) and simultaneous gelation and adhesion of the proteolytically active, catechol-terminated precursor macromonomer was achieved by addition of sodium periodate oxidant. Rheological analysis and equilibrium swelling studies demonstrated that the hydrogel is appropriate for soft tissuecontacting applications. Notably, hydrogel storage modulus (G') achieved values on the order of 10 kPa, and strain at failure exceeded 200% strain. Lap shear testing confirmed the material's adhesive behavior (shear strength: 30.4 ± 3.39 kPa). Although adhesive hydrogel degradation was not observed during short-term (27 h) in vitro treatment with neutrophil elastase, in vivo degradation proceeded over several months following dorsal subcutaneous implantation in mice. This work represents the first example of an enzymatically degradable mussel-inspired adhesive and expands the potential biomedical applications of this family of materials. © 2011 American Chemical Society.


Hogg M.E.,Institute for BioNanotechnology in Medicine | Varu V.N.,Institute for BioNanotechnology in Medicine | Varu V.N.,University of Illinois at Chicago | Vavra A.K.,Institute for BioNanotechnology in Medicine | And 8 more authors.
Free Radical Biology and Medicine | Year: 2011

Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G0/G1 cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.


Angeloni N.L.,Northwestern University | Bond C.W.,Northwestern University | Tang Y.,Chongqing Medical and Pharmaceutical College | Harrington D.A.,Rice University | And 5 more authors.
Biomaterials | Year: 2011

SHH plays a significant role in peripheral nerve regeneration and has clinical potential to be used as a regenerative therapy for the CN in prostatectomy patients and in other patients with neuropathy of peripheral nerves. Efforts to regenerate the cavernous nerve (CN), which provides innervation to the penis, have been minimally successful, with little translation into improved clinical outcomes. We propose that, Sonic hedgehog (SHH), is critical to maintain CN integrity, and that SHH delivered to the CN by novel peptide amphiphile (PA) nanofibers, will promote CN regeneration, restore physiological function, and prevent penile morphology changes that result in erectile dysfunction (ED). We performed localization studies, inhibition of SHH signaling in the CN, and treatment of crushed CNs with SHH protein via linear PA gels, which are an innovative extended release method of delivery. Morphological, functional and molecular analysis revealed that SHH protein is essential to maintain CN architecture, and that SHH treatment promoted CN regeneration, suppressed penile apoptosis and caused a 58% improvement in erectile function in less than half the time reported in the literature. These studies show that SHH has substantial clinical application to regenerate the CN in prostatectomy and diabetic patients, that this methodology has broad application to regenerate any peripheral nerve that SHH is necessary for maintenance of its structure, and that this nanotechnology method of protein delivery may have wide spread application as an in vivo delivery tool in many organs. © 2010 Elsevier Ltd.


Webber M.J.,Northwestern University | Matson J.B.,Northwestern University | Tamboli V.K.,Northwestern University | Stupp S.I.,Northwestern University | Stupp S.I.,Institute for BioNanotechnology in Medicine
Biomaterials | Year: 2012

New biomaterials that have the ability to locally suppress an immune response could have broad therapeutic use in the treatment of diseases characterized by acute or chronic inflammation or as a strategy to facilitate improved efficacy in cell or tissue transplantation. We report here on the preparation of a modular peptide amphiphile (PA) capable of releasing an anti-inflammatory drug, dexamethasone (Dex), by conjugation via a labile hydrazone linkage. This molecule self-assembled in water into long supramolecular nanofibers when mixed with a similar PA lacking the drug conjugate, and the addition of calcium salt to screen electrostatic repulsion between nanofibers promoted gel formation. These nanofiber gels demonstrated sustained release of soluble Dex for over one month in physiologic media. The Dex released from these gels maintained its anti-inflammatory activity when evaluated in vitro using a human inflammatory reporter cell line and furthermore preserved cardiomyocyte viability upon induced oxidative stress. The ability of this gel to mitigate the inflammatory response in cell transplantation strategies was evaluated using cell-surrogate polystyrene microparticles suspended in the nanofiber gel that were then subcutaneously injected into mice. Live animal luminescence imaging using the chemiluminescent reporter molecule luminol showed a significant reduction in inflammation at the site where particles were injected with Dex-PA compared to the site of injection for particles within a control PA in the same animal. Histological evidence suggested a marked reduction in the number of infiltrating inflammatory cells when particles were delivered within Dex-PA nanofiber gels, and very little inflammation was observed at either 3 days or 21 days post-implantation. The use of Dex-PA could facilitate localized anti-inflammatory activity as a component of biomaterials designed for various applications in regenerative medicine and could specifically be a useful module for PA-based therapies. More broadly, these studies define a versatile strategy for facile synthesis of self-assembling peptide-based materials with the ability to control drug release. © 2012 Elsevier Ltd.


Tsai W.-W.,Northwestern University | Tevis I.D.,Northwestern University | Tayi A.S.,220 Campus Drive | Cui H.,220 Campus Drive | And 2 more authors.
Journal of Physical Chemistry B | Year: 2010

Conjugated organic molecules can be designed to self-assemble from solution into nanostructures for functions such as charge transport, light emission, or light harvesting. We report here the design and synthesis of a novel hairpin-shaped self-assembling molecule containing electronically active sexithiophene moieties. In several nonpolar organic solvents, such as toluene or chlorocyclohexane, this compound was found to form organogels composed of nanofibers with uniform diameters of 3.0 (±0.3) nm. NMR analysis and spectroscopic measurements revealed that the self-assembly is driven by π-π interactions of the sexithiophene moieties and hydrogen bonding among the amide groups at the head of the hairpin. Field effect transistors built with this molecule revealed p-type semiconducting behavior and higher hole mobilities when films were cast from solvents that promote self-assembly. We propose that hydrogen bonding and π-π stacking act synergistically to create ordered stacking of sexithiophene moieties, thus providing an efficient pathway for charge carriers within the nanowires. The nanostructures formed exhibit unusually broad absorbance in their UV-vis spectrum, which we attribute to the coexistence of both H and J aggregates from face-to-face π-π stacking of sexithiophene moieties and hierarchical bundling of the nanowires. The large absorption range associated with self-assembly of the hairpin molecules makes them potentially useful in light harvesting for energy applications. © 2010 American Chemical Society.


Webber M.J.,Northwestern University | Webber M.J.,Institute for Bionanotechnology in Medicine | Tongers J.,Northwestern University | Renault M.-A.,Northwestern University | And 3 more authors.
Acta Biomaterialia | Year: 2010

There is great clinical interest in cell-based therapies for ischemic tissue repair in cardiovascular disease. However, the regenerative potential of these therapies is limited due to poor cell viability and minimal retention following application. We report here the development of bioactive peptide amphiphile nanofibers displaying the fibronectin-derived RGDS cell adhesion epitope as a scaffold for therapeutic delivery of bone marrow derived stem and progenitor cells. When grown on flat substrates, a binary peptide amphiphile system consisting of 10 wt.% RGDS-containing molecules and 90 wt.% negatively charged diluent molecules was found to promote optimal cell adhesion. This binary system enhanced adhesion 1.4-fold relative to substrates composed of only the non-bioactive diluent. Additionally, no enhancement was found upon scrambling the epitope and adhesion was no longer enhanced upon adding soluble RGDS to the cell media, indicating RGDS-specific adhesion. When encapsulated within self-assembled scaffolds of the binary RGDS nanofibers in vitro, cells were found to be viable and proliferative, increasing in number by 5.5 times after only 5 days, an effect again lost upon adding soluble RGDS. Cells encapsulated within a non-bioactive scaffold and those within a binary scaffold with scrambled epitope showed minimal viability and no proliferation. Cells encapsulated within this RGDS nanofiber gel also increase in endothelial character, evident by a decrease in the expression of CD34 paired with an increase in the expression of endothelial-specific markers VE-Cadherin, VEGFR2 and eNOS after 5 days. In an in vivo study, nanofibers and luciferase-expressing cells were co-injected subcutaneously in a mouse model. The binary RGDS material supported these cells in vivo, evident by a 3.2-fold increase in bioluminescent signal attributable to viable cells; this suggests the material has an anti-apoptotic and/or proliferative effect on the transplanted bone marrow cells. We conclude that the binary RGDS-presenting nanofibers developed here demonstrate enhanced viability, proliferation and adhesion of associated bone marrow derived stem and progenitor cells. This study suggests potential for this material as a scaffold to overcome current limitations of stem cell therapies for ischemic diseases. © 2009 Acta Materialia Inc.


Woodruff T.K.,Northwestern University | Shea L.D.,Northwestern University | Shea L.D.,Institute for Bionanotechnology in Medicine
Journal of Assisted Reproduction and Genetics | Year: 2011

The mammalian ovary consists of a large number of dormant immature follicles, each containing a single oocyte and located on the periphery of the ovary. With each reproductive cycle, a group of immature follicles is sequentially activated to resume growth, and pituitary gonadotropins and ovarian steroid and peptide hormones cooperate to ensure further growth and development. A single dominant follicle eventually emerges, ovulates, and then involutes to allow the selection of the next group of follicles. While hormones are known to control the later stages of folliculogenesis, little is known about the pathways that activate individual immature primordial follicles in the dormant follicle pool. We advance a new hypothesis: that follicle activation is dependent on the physical environment of the ovary in addition to well-established hormonal cues. This novel perspective on ovarian function may provide new avenues to study follicle dynamics and identify therapeutic targets for ovarian dysfunction. © 2010 Springer Science+Business Media, LLC.


Webber M.J.,Northwestern University | Webber M.J.,Institute for Bionanotechnology in Medicine | Tongers J.,Northwestern University | Renault M.-A.,Northwestern University | And 3 more authors.
Acta Biomaterialia | Year: 2015

There is great clinical interest in cell-based therapies for ischemic tissue repair in cardiovascular disease. However, the regenerative potential of these therapies is limited due to poor cell viability and minimal retention following application. We report here the development of bioactive peptide amphiphile nanofibers displaying the fibronectin-derived RGDS cell adhesion epitope as a scaffold for therapeutic delivery of bone marrow derived stem and progenitor cells. When grown on flat substrates, a binary peptide amphiphile system consisting of 10 wt.% RGDS-containing molecules and 90 wt.% negatively charged diluent molecules was found to promote optimal cell adhesion. This binary system enhanced adhesion 1.4-fold relative to substrates composed of only the non-bioactive diluent. Additionally, no enhancement was found upon scrambling the epitope and adhesion was no longer enhanced upon adding soluble RGDS to the cell media, indicating RGDS-specific adhesion. When encapsulated within self-assembled scaffolds of the binary RGDS nanofibers in vitro, cells were found to be viable and proliferative, increasing in number by 5.5 times after only 5 days, an effect again lost upon adding soluble RGDS. Cells encapsulated within a non-bioactive scaffold and those within a binary scaffold with scrambled epitope showed minimal viability and no proliferation. Cells encapsulated within this RGDS nanofiber gel also increase in endothelial character, evident by a decrease in the expression of CD34 paired with an increase in the expression of endothelial-specific markers VE-Cadherin, VEGFR2 and eNOS after 5 days. In an in vivo study, nanofibers and luciferase-expressing cells were co-injected subcutaneously in a mouse model. The binary RGDS material supported these cells in vivo, evident by a 3.2-fold increase in bioluminescent signal attributable to viable cells; this suggests the material has an anti-apoptotic and/or proliferative effect on the transplanted bone marrow cells. We conclude that the binary RGDS-presenting nanofibers developed here demonstrate enhanced viability, proliferation and adhesion of associated bone marrow derived stem and progenitor cells. This study suggests potential for this material as a scaffold to overcome current limitations of stem cell therapies for ischemic diseases. © 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Webber M.J.,Northwestern University | Newcomb C.J.,Northwestern University | Bitton R.,Institute for Bionanotechnology in Medicine | Stupp S.I.,Northwestern University | Stupp S.I.,Institute for Bionanotechnology in Medicine
Soft Matter | Year: 2011

Peptide self-assembly has been shown to be a useful tool for the preparation of bioactive nanostructures, and recent work has demonstrated their potential as therapies for regenerative medicine. In principle, one route to make these nanostructures more biomimetic would be to incorporate in their molecular design the capacity for biological sensing. We report here on the use of a reversible enzymatic trigger to control the assembly and disassembly of peptide amphiphile (PA) nanostructures. The PA used in these studies contained a consensus substrate sequence specific to protein kinase A (PKA), a biological enzyme important for intracellular signaling that has also been shown to be an extracellular cancer biomarker. Upon treatment with PKA, this PA molecule becomes phosphorylated causing the high aspect-ratio filamentous PA nanostructures to disassemble. Treatment with an enzyme to cleave the phosphate group results in reformation of the filamentous nanostructures. We also show that disassembly in the presence of PKA allows the enzyme-triggered release of an encapsulated cancer drug. In addition, these drug-loaded nanostructures were found to induce preferential cytotoxicity in a cancer cell line that is known to secrete high levels of PKA. This ability to control nanostructure through an enzymatic switch could allow for the preparation of highly sophisticated and biomimetic materials that incorporate a biological sensing capability to enable therapeutic specificity. © 2011 The Royal Society of Chemistry.


PubMed | Northwestern University and Institute for Bionanotechnology in Medicine
Type: | Journal: Acta biomaterialia | Year: 2015

There is great clinical interest in cell-based therapies for ischemic tissue repair in cardiovascular disease. However, the regenerative potential of these therapies is limited due to poor cell viability and minimal retention following application. We report here the development of bioactive peptide amphiphile nanofibers displaying the fibronectin-derived RGDS cell adhesion epitope as a scaffold for therapeutic delivery of bone marrow derived stem and progenitor cells. When grown on flat substrates, a binary peptide amphiphile system consisting of 10 wt.% RGDS-containing molecules and 90 wt.% negatively charged diluent molecules was found to promote optimal cell adhesion. This binary system enhanced adhesion 1.4-fold relative to substrates composed of only the non-bioactive diluent. Additionally, no enhancement was found upon scrambling the epitope and adhesion was no longer enhanced upon adding soluble RGDS to the cell media, indicating RGDS-specific adhesion. When encapsulated within self-assembled scaffolds of the binary RGDS nanofibers in vitro, cells were found to be viable and proliferative, increasing in number by 5.5 times after only 5 days, an effect again lost upon adding soluble RGDS. Cells encapsulated within a non-bioactive scaffold and those within a binary scaffold with scrambled epitope showed minimal viability and no proliferation. Cells encapsulated within this RGDS nanofiber gel also increase in endothelial character, evident by a decrease in the expression of CD34 paired with an increase in the expression of endothelial-specific markers VE-Cadherin, VEGFR2 and eNOS after 5days. In an in vivo study, nanofibers and luciferase-expressing cells were co-injected subcutaneously in a mouse model. The binary RGDS material supported these cells in vivo, evident by a 3.2-fold increase in bioluminescent signal attributable to viable cells; this suggests the material has an anti-apoptotic and/or proliferative effect on the transplanted bone marrow cells. We conclude that the binary RGDS-presenting nanofibers developed here demonstrate enhanced viability, proliferation and adhesion of associated bone marrow derived stem and progenitor cells. This study suggests potential for this material as a scaffold to overcome current limitations of stem cell therapies for ischemic diseases.

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