Browsing by Author "Mammadov, Rashad"

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Open Access
Cooperative effect of heparan sulfate and laminin mimetic peptide nanofibers on the promotion of neurite outgrowth
(Elsevier, 2012) Mammadov, Busra; Mammadov, Rashad; Güler, Mustafa O.; Tekinay, Ayse B.
Extracellular matrix contains an abundant variety of signals that are received by cell surface receptors contributing to cell fate, via regulation of cellular activities such as proliferation, migration and differentiation. Cues from extracellular matrix can be used for the development of materials to direct cells into their desired fate. Neural extracellular matrix (ECM) is rich in axonal growth inducer proteins, and by mimicking these permissive elements in the cellular environment, neural differentiation as well as neurite outgrowth can be induced. In this paper, we used a synthetic peptide nanofiber system that can mimic not only the activity of laminin, an axonal growth-promoting constituent of the neural ECM, but also the activity of heparan sulfate proteoglycans in order to induce neuritogenesis. Heparan sulfate mimetic groups that were utilized in our system have an affinity to growth factors and induce the neuroregenerative effect of laminin mimetic peptide nanofibers. The self-assembled peptide nanofibers with heparan sulfate mimetic and laminin-derived epitopes significantly promoted neurite outgrowth by PC-12 cells. In addition, these scaffolds were even effective in the presence of chondroitin sulfate proteoglycans (CSPGs), which are the major inhibitory components of the central nervous system. In the presence of these nanofibers, cells could overcome CSPG inhibitory effect and extend neurites on peptide nanofiber scaffolds. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Open Access
Generation of chimeric "aBS nanohemostat" complex and comparing its histomorphological in vivo effects to the traditional ankaferd hemostat in controlled experimental partial nephrectomy model
(Hindawi, 2013) Huri, Emre; Beyazit, Y.; Mammadov, Rashad; Toksoz, Sıla; Tekinay, Ayşe B.; Güler, Mustafa O.; Ustun H.; Kekilli, M.; Dadali, Mumtaz; Celik, T.; Astarci, M.; Haznedaroglu I.C.
Purpose. Using the classical Ankaferd Blood Stopper (ABS) solution to create active hemostasis during partial nephrectomy (PN) may not be so effective due to insufficient contact surface between the ABS hemostatic liquid agent and the bleeding area. In order to broaden the contact surface, we generated a chimeric hemostatic agent, ABS nanohemostat, via combining a self-assembling peptide amphiphile molecule with the traditional Ankaferd hemostat. Materials and Methods. In order to generate ABS nanohemostat, a positively charged Peptide Amphiphile (PA) molecule was synthesized by using solid phase peptide synthesis. For animal experiments, 24 Wistar rats were divided into the following 4 groups: Group 1: control; Group 2: conventional PN with only 0.5 ml Ankaferd hemostat; Group 3: conventional PN with ABS + peptide gel; Group 4: conventional PN with only 0.5 ml peptide solution. Results. Mean warm ischemia times (WITs) were 232.8 ± 56.3, 65.6 ± 11.4, 75.5 ± 17.2, and 58.1 ± 17.6 seconds in Group 1 to Group 4, respectively. Fibrosis was not different among the groups, while inflammation was detected to be significantly different in G3 and G4. Conclusions. ABS nanohemostat has comparable hemostatic efficacy to the traditional Ankaferd hemostat in the partial nephrectomy experimental model. Elucidation of the cellular and tissue effects of this chimeric compound may establish a catalytic spark and open new avenues for novel experimental and clinical studies in the battlefield of hemostasis. © 2013 Emre Huri et al.
Open Access
Growth factor binding on heparin mimetic peptide nanofibers
(American Chemical Society, 2012) Mammadov, Rashad; Mammadov, Busra; Güler, Mustafa O.; Tekinay, Ayşe B.
Immobilization of growth factors in scaffolds is important for controlling their dose and bioactivity for regenerative medicine applications. Although numerous covalent and noncovalent immobilization strategies have been proposed, better growth factor loading and dose control inside the scaffold is necessary. Nature of the binding site on the growth factor interacting with scaffold is critical for preserving and achieving maximal growth factor functionality, which has been a relatively less emphasized issue in previous studies. We recently reported heparin mimetic peptide nanofibers, which mimic chemistry of heparan sulfates. Heparin mimetic nanofibers were shown to bind to vascular endothelial growth factor (VEGF) and direct endothelial cells to angiogenesis. Here, we further investigated interactions between heparin mimetic peptide nanofibers and growth factors. We tested bioactivity of the nanofiber bound growth factors in order to understand the potential use of these peptide nanofiber scaffolds as analogues of heparan sulfates. We observed that heparin mimetic peptide nanofibers demonstrate better binding profiles to VEGF, hepatocyte growth factor (HGF), and fibroblast growth factor-2 (FGF-2) than control peptide nanofibers. We also identified that the heparin-binding domain of VEGF is critical for its interaction with these nanofibers. However, the heparin-binding site is not indispensable for binding of all growth factors to nanofibers. We also showed that binding of growth factors to nanofibers does not cause any loss in bioactivity through in vitro cell culture assays with PC-12 cells. These results reveal that heparin mimetic peptide nanofibers can effectively mimic heparan sulfates in extracellular matrix and provide an optimal milieu for spatial presentation of important growth factors. These properties make peptide nanofiber scaffolds promising materials for regenerative medicine applications through efficient and precisely controlled growth factor delivery. © 2012 American Chemical Society.
Open Access
Heparin mimetic peptide nanofibers promote angiogenesis
(Biomacromolecules, 2011) Mammadov, Rashad; Mammadov, Busra; Toksoz, Sıla; Aydin, B.; Yagci, R.; Tekinay, Ayse B.; Güler, Mustafa O.
New blood vessel formation (angiogenesis) is one of the most important processes required for functional tissue formation. Induction of angiogenesis is usually triggered by growth factors released by cells. Glycosaminoglycans (e.g., heparan sulphates) in the extracellular matrix aid in proper functioning of these growth factors. Therefore, exogeneous heparin or growth factors were required for promoting angiogenesis in previous regenerative medicine studies. Here we report for the first time induction of angiogenesis by a synthetic nanofibrous peptide scaffold without the addition of any exogenous growth factors or heparin. We designed and synthesized a self-assembling peptide amphiphile molecule that is functionalized with biologically active groups to mimic heparin. Like heparin, this molecule has the ability to interact with growth factors and effectively enhance their bioactivity. The nanofibers formed by these molecules were shown to form a 3D network mimicking the structural proteins in the extracellular matrix. Because of heparin mimicking capabilities of the peptide nanofibers, angiogenesis was induced without the addition of exogenous growth factors in vitro. Bioactive interactions between the nanofibers and the growth factors enabled robust vascularization in vivo as well. Heparin mimetic peptide nanofibers presented here provide new opportunities for angiogenesis and tissue regeneration by avoiding the use of heparin and exogenous growth factors. The synthetic peptide nanofiber scaffolds enriched with proper chemical functional groups shown in this study can be used to induce various desired physiological responses for tissue regeneration. © 2011 American Chemical Society.
Open Access
Microscopic characterization of peptide nanostructures
(Elsevier, 2012) Mammadov, Rashad; Tekinay, Ayse B.; Dana, Aykutlu; Güler, Mustafa O.
Peptide-based nanomaterials have been utilized for various applications from regenerative medicine to electronics since they provide several advantages including easy synthesis methods, numerous routes for functionalization and biomimicry of secondary structures of proteins which leads to design of self-assembling peptide molecules to form nanostructures. Microscopic characterization at nanoscale is critical to understand processes directing peptide molecules to self-assemble and identify structure-function relationship of the nanostructures. Here, fundamental studies in microscopic characterization of peptide nanostructures are discussed to provide insights in widely used microscopy tools. In this review, we will encompass characterization studies of peptide nanostructures with modern microscopes, such as TEM, SEM, AFM, and advanced optical microscopy techniques. We will also mention specimen preparation methods and describe interpretation of the images. © 2011 Elsevier Ltd.
Open Access
Peptide nanofibers for engineering tissues and immune system
(2014) Mammadov, Rashad
Interdisciplinary work at the interface of biology and materials science is important for finding cures to complex diseases. Achievements in materials science allow us to control materials at nanoscale and design them according to specific therapeutic purposes. This includes incorporating biophysical and biochemical signals into materials to make them biologically functional. These signals are sensed by cells in normal or pathological cases and influence their decision-making process, which eventually alters cellular behavior. However, cellular environment is so complex in terms of these signals that recapitulating it with synthetic materials is unattainable considering our limited resources. Therefore, we need to distinguish those signals that are structurally simple, but at the same time biologically critical, that would drive cellular behavior to desired outcome. In this thesis, I will describe peptide nanofiber systems for tissue engineering and vaccinology applications. First system is inspired from heparan sulfate (HS) – a natural polymer in extracellular matrix – that bind to growth factors and regulate their functioning, therefore central for induction of various physiological processes. Peptide nanofibers with right composition of bioactive chemical functional groups from HS showed specific interaction with growth factors and induced endothelial cells to form blood vessels similar to natural matrices carrying HS. Considering mentioned features, these peptide nanofibers could be useful for effective regeneration of tissues. Secondly, the peptide nanofiber system carrying pathogenic DNA motives, which is an infection signal, was developed. While non-immunogenic by itself, these nanofibers shifted immune response against pathogenic DNA towards a context that is useful for fighting intracellular pathogens and cancer. Overall, this thesis demonstrates that structurally simple but appropriate biophysical and biochemical signals could be synergistic for inducing desired biological processes at the nanoscale.
Open Access
Self-nanoparticle forming immunostimulatory DNA : structure-function relationship studies
(2009) Mammadov, Rashad
Toll-like receptors (TLRs) are one the most critical and widely studied members of the family of pattern recognition receptors expressed on innate immune cells. They recognize microbial signatures, such as bacterial/viral DNA, LPS, from gram negative bacteria, peptidoglycan from gram positive bacteria, zymosan from yeast, lipopeptides or profilin protein from parasites, and even single or double stranded RNA of viruses. Among several members of TLR family, TLR9, that recognizes microbial unmethylated dinucleotide motifs on DNA initiate a robust Th1- biased inflammatory response. Synthetic oligodeoxynucleotides expressing unmethylated CpG motifs, mimic bacterial DNA effect and can be harnessed for the treatment of health problems ranging from infectious diseases to cancer, or to allergy/asthma as well as stand alone immunoprotective agents and also as a vaccine adjuvants that improve protection against pathogens. To date, various classes of CpG ODNs have been identified and were shown to induce differential immune activation in mice and man. Distinct structure-function relationship analyses revealed that these single-stranded linear ODNs alter the immune milieu as they are formulated to form complex multimeric DNA aggregates. Recently, Guanosine-rich D type CpG ODNs has been reported to form complex aggregates, that are differentially regulating immune cells to mount an anti-viral immunity. However, the clinical trials of this type are hampered mainly due to batch to batch variation during large-scale synthesis. To the best of our knowledge, there is no report on self-nanoparticle forming DNA except G-rich sequences. This thesis project was designed to generate stable, selfnanoparticle forming, G-run free, CpG expressing ODNs. In this thesis, we designed a new generation CpG ODN, then characterized their structural and immunological properties. Our results suggest that dendrimeric structure confers higher immunostimulatory potential unparallel to conventional ODNs. Following four hours of in vivo ODN administration into mice indicated that nanoparticle-forming CpG ODNs initiated substantially high spleen and peritoneal exudate cell activation as evidenced by IFNγ and IL-12 production from culture medium. In order to shed light on the uptake and binding mechanisms, blocking experiments revealed that at least one type of scavenger receptor is critical for nanoparticle ODN internalization. Collectively, these data suggested that the improved stability to nucleases along with significantly higher binding to immune cells (no additional ODN formulation is required) seem to be the critical factors contributing to the nanoparticle CpG ODN mediated immune activation. The in vitro and in vivo performances implicated that these next generation immune stimulatory DNA molecules are promising candidates for various clinical applications.
Open Access
Wound healing applications of nanomaterials
(John Wiley & Sons, 2016-03-11) Şentürk, Berna; Uzunalli, Gözde; Mammadov, Rashad; Güler, Mustafa O.; Tekinay, Ayşe B.; Güler, Mustafa O.; Tekinay, Ayşe B.
This chapter first provides an overview of skin structure and its biological response to the tissue loss in wound healing process and reviews the classical and next‐generation scaffolds and materials that are used to minimize scar formation while accelerating the healing process. The chapter also provides a snapshot of the natural and synthetic biomaterials currently in clinical use in this field. Wound healing occurs in nearly all tissue types, and the order of events during the healing process is similar across different tissues. Natural materials are required to exhibit certain characteristics to be considered suitable for use as wound dressings. A large number of natural materials, such as collagen, gelatin, laminin, and chitin/chitosan, have been used as electrospun scaffolds for tissue engineering. Salient features of these materials are designed in an attempt to provide a desired niche for robust wound healing process.