Publications by authors named "Shahriar Sharifi"

28 Publications

  • Page 1 of 1

The Possible Role of Sex As an Important Factor in Development and Administration of Lipid Nanomedicine-Based COVID-19 Vaccine.

Mol Pharm 2021 06 13;18(6):2448-2453. Epub 2021 May 13.

Department of Radiology and Precision Health Program, Michigan State University, East Lansing, Michigan 48824, United States.

Nanomedicine has demonstrated a substantial role in vaccine development against severe acute respiratory syndrome coronavirus (SARS-CoV-2 and COVID-19). Although nanomedicine-based vaccines have now been validated in millions of individuals worldwide in phase 4 and tracking of sex-disaggregated data on COVID-19 is ongoing, immune responses that underlie COVID-19 disease outcomes have not been clarified yet. A full understanding of sex-role effects on the response to nanomedicine products is essential to building an effective and unbiased response to the pandemic. Here, we exposed model lipid nanoparticles (LNPs) to whole blood of 18 healthy donors (10 females and 8 males) and used flow cytometry to measure cellular uptake by circulating leukocytes. Our results demonstrated significant differences in the uptake of LNP between male and female natural killer (NK) cells. The results of this proof-of-concept study show the importance of recipient sex as a critical factor which enables researchers to better consider sex in the development and administration of vaccines for safer and more-efficient sex-specific outcomes.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130523PMC
June 2021

The role of sex as a biological variable in the efficacy and toxicity of therapeutic nanomedicine.

Adv Drug Deliv Rev 2021 Jul 4;174:337-347. Epub 2021 May 4.

Department of Radiology and Precision Health Program, Michigan State University, MI, USA; Mary Horrigan Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Harvard Medical School, MA, USA. Electronic address:

Males and females have physiological, hormonal, and genetic differences that can cause different responses to medicinal treatments. The role of sex in the pharmacokinetics and pharmacodynamics of drugs is well established in the literature. However, researchers have yet to robustly and consistently consider the impact of sex differences on the pharmacokinetics and pharmacodynamics of nanomedicine formulations when designing nanomedicine therapeutics and/or constructing clinical trials. In this review, we highlight the physiological and anatomical differences between sexes and discuss how these differences can influence the therapeutic efficacy, side effects, and drug delivery safety of nanomedicine products. A deep understanding of the effects of sex on nano-based drug delivery agents will robustly improve the risk assessment process, resulting in safer formulations, successful clinical translation, and improved therapeutic efficacies for both sexes.
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http://dx.doi.org/10.1016/j.addr.2021.04.028DOI Listing
July 2021

Interdependency of influential parameters in therapeutic nanomedicine.

Expert Opin Drug Deliv 2021 May 12:1-15. Epub 2021 May 12.

Department of Radiology and Precision Health Program, College of Human Medicine, Michigan State University, East Lansing, MI, USA.

Current challenges to successful clinical translation of therapeutic nanomedicine have discouraged many stakeholders, including patients. Significant effort has been devoted to uncovering the reasons behind the less-than-expected success, beyond failures or ineffectiveness, of therapeutic nanomedicine products (e.g. cancer nanomedicine). Until we understand and address the factors that limit the safety and efficacy of NPs, both individually and in combination, successful clinical development will lag.This review highlights the critical roles of interdependent factors affecting the safety and therapeutic efficacy of therapeutic NPs for drug delivery applications.Deep analysis of the current nanomedical literature reveals ahistory of unanticipated complexity by awide range of stakeholders including researchers. In the manufacture of nanomedicines themselves, there have been persistent difficulties with reproducibility and batch-to-batch variation. The unanticipated complexity and interdependency of nano-bio parameters has delayed our recognition of important factors affecting the safety and therapeutic efficacy of nanomedicine products. These missteps have had many factors including our lack of understanding of the interdependency of various factors affecting the biological identity and fate of NPs and biased interpretation of data. All these issues could raise significant concern regarding the reproducibility- or even the validity- of past publications that in turn formed the basis of many clinical trials of therapeutic nanomedicines. Therefore, the individual and combined effects of previously overlooked factors on the safety and therapeutic efficacy of NPs need to be fully considered in nanomedicine reports and product development.
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http://dx.doi.org/10.1080/17425247.2021.1921732DOI Listing
May 2021

COVID-19: Nanomedicine Uncovers Blood-Clot Mystery.

J Proteome Res 2020 11 31;19(11):4364-4373. Epub 2020 Aug 31.

Precision Health Program and Department of Radiology, Michigan State University, East Lansing, Michigan 48824, United States.

Further complications associated with infection by severe acute respiratory syndrome coronavirus 2 (a.k.a. SARS-CoV-2) continue to be reported. Very recent findings reveal that 20-30% of patients at high risk of mortality from COVID-19 infection experience blood clotting that leads to stroke and sudden death. Timely assessment of the severity of blood clotting will be of enormous help to clinicians in determining the right blood-thinning medications to prevent stroke or other life-threatening consequences. Therefore, rapid identification of blood-clotting-related proteins in the plasma of COVID-19 patients would save many lives. Several nanotechnology-based approaches are being developed to diagnose patients at high risk of death due to complications from COVID-19 infections, including blood clots. This Perspective outlines (i) the significant potential of nanomedicine in assessing the risk of blood clotting and its severity in SARS-CoV-2 infected patients and (ii) its synergistic roles with advanced mass-spectrometry-based proteomics approaches in identifying the important protein patterns that are involved in the occurrence and progression of this disease. The combination of such powerful tools might help us understand the clotting phenomenon and pave the way for development of new diagnostics and therapeutics in the fight against COVID-19.
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http://dx.doi.org/10.1021/acs.jproteome.0c00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640964PMC
November 2020

Biomolecular Corona Affects Controlled Release of Drug Payloads from Nanocarriers.

Trends Pharmacol Sci 2020 09 23;41(9):641-652. Epub 2020 Jul 23.

Department of Radiology and Precision Health Program, Michigan State University, East Lansing, MI, USA. Electronic address:

Nanomedicine has been widely used for a wide range of biomedical applications including drug delivery. Although many factors including the physicochemical properties of nanoparticles (NPs) and the payload efficacy of nanocarriers have been thoroughly investigated, the crucial role of the biomolecular corona in drug delivery and the release efficacy of nanocarriers demands further attention. This review highlights not only the crucial importance of the biomolecular corona to the drug release capacity of various types of nanocarriers, but also its interference with drug release measurements. A full consideration of the effects of the biomolecular corona on the controlled release and drug delivery of nanocarriers will help researchers design safer and more efficient nanobased drug delivery systems.
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http://dx.doi.org/10.1016/j.tips.2020.06.011DOI Listing
September 2020

Effect of cell imprinting on viability and drug susceptibility of breast cancer cells to doxorubicin.

Acta Biomater 2020 09 7;113:119-129. Epub 2020 Jun 7.

Departments of Bioengineering, Chemical and Biomolecular Engineering and Radiological Sciences, Center for Minimally Invasive Therapeutics, California NanoSystems Institute, University of California - Los Angeles, Los Angeles, CA, USA; Terasaki Institute for Biomedical Innovation, Los Angeles, CA, USA. Electronic address:

This study demonstrates the effect of substrate's geometrical cues on viability and the efficacy of an anti-cancer drug, doxorubicin (DOX), on breast cancer cells. It is hypothesized that the surface topographical properties can mediate the cellular drug intake. Pseudo-three dimensional (3D) platforms were fabricated using imprinting technique from polydimethylsiloxane (PDMS) and gelatin methacryloyl (GelMA) hydrogel to recapitulate topography of cells' membranes. The cells exhibited higher viability on the cell-imprinted platforms for both PDMS and GelMA materials compared to the plain/flat counterparts. For instance, MCF7 cells showed a higher metabolic activity (11.9%) on MCF7-imprinted PDMS substrate than plain PDMS. The increased metabolic activity for the imprinted GelMA was about 44.2% compared to plain hydrogel. The DOX response of cells was monitored for 24 h. Although imprinted substrates demonstrated enhanced biocompatibility, the cultured cells were more susceptible to the drug compared to the plain substrates. In particular, MCF7 cells on imprinted PDMS and GelMA substrates showed 37% and 50% higher in cell death compared to the corresponding plain PDMS and GelMA, respectively. Interestingly, the drug susceptibility of the cells on the imprinted hydrogel was about 70% higher than the cells cultured on imprinted PDMS substrates. Having MCF7 cell-imprinted substrates, DOX responses of two other breast cancer cell lines, SKBR3 and ZR-75-1, were also evaluated. The results support that cell membrane curvature developed by multiscale topography is able to mediate intracellular signaling and drug intake. STATEMENT OF SIGNIFICANCE: Research in biological sciences and drug discovery mostly rely on two dimensional (2D) cell culture techniques which cannot provide a reliable physiologically relevant environment. Lack of extracellular matrix and a large shift in physicochemical properties of conventional 2D substrates can induce aberrant cellular behaviors. While chemical composition, topographical, and mechanical properties of substrates have remarkable impacts on drug susceptibility, gene expression, and protein synthesis, the most cell culture plates are from rigid and plain substrates. A number of (bio)polymeric 3D-platforms have been introduced to resemble innate cell microenvironment. However, their intricate culture protocols restrain their applications in demanding high-throughput drug screening. To address the above concerns, in the present study, a hydrogel-based pseudo-3D substrate with imprinted cell features has been introduced.
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http://dx.doi.org/10.1016/j.actbio.2020.06.007DOI Listing
September 2020

Nanomedicine in Healing Chronic Wounds: Opportunities and Challenges.

Mol Pharm 2021 02 10;18(2):550-575. Epub 2020 Jun 10.

Department of Radiology and Precision Health Program, Michigan State University, East Lansing, Michigan 48824, United States.

The poor healing associated with chronic wounds affects millions of people worldwide through high mortality rates and associated costs. Chronic wounds present three main problems: First, the absence of a suitable environment to facilitate cell migration, proliferation, and angiogenesis; second, bacterial infection; and third, unbalanced and prolonged inflammation. Unfortunately, current therapeutic approaches have not been able to overcome these main issues and, therefore, have limited clinical success. Over the past decade, incorporating the unique advantages of nanomedicine into wound healing approaches has yielded promising outcomes. Nanomedicine is capable of stimulating various cellular and molecular mechanisms involved in the wound microenvironment via antibacterial, anti-inflammatory, and angiogenetic effects, potentially reversing the wound microenvironment from nonhealing to healing. This review briefly discusses wound healing mechanisms and pathophysiology and then highlights recent findings regarding the opportunities and challenges of using nanomedicine in chronic wound management.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00346DOI Listing
February 2021

Fabrication and characterization of polycaprolactone fumarate/gelatin-based nanocomposite incorporated with silicon and magnesium co-doped fluorapatite nanoparticles using electrospinning method.

Mater Sci Eng C Mater Biol Appl 2020 Jan 6;106:110172. Epub 2019 Sep 6.

Department of Materials Engineering, Isfahan University of Technology, Isfahan 8415683111, Iran.

The aim of this study was to fabricate and characterize biodegradable polycaprolactone fumarate(PCLF)/gelatin-based nanocomposite incorporated with the 0, 5 and 10 wt% silicon and magnesium co-doped fluorapatite nanoparticles (Si-Mg-FA) membranes using electrospinning process for guided bone regeneration (GBR) and guided tissue regeneration (GTR) applications. Results demonstrated the formation of randomly-oriented and defect-free fibers with various fiber sizes depending on the Si-Mg-FA content. Moreover, incorporation of 5 wt% Si-Mg-FA significantly improved the mechanical strength (1.5times) compared to the mechanical strength of PCLF/gelatin membrane and nanocomposite with 10 wt% nanoparticles. There was no clear difference between degradation rate of PCLF/gelatin and PCLF/gelatin with 5 wt% nanoparticles at 7, 14 and 28 days of immersion in phosphate buffer saline while 10 wt% nanoparticles significantly increased biodegradation of PCLF/gelatin, and no cytotoxic effect of membranes was seen. Finally, scanning electron microscopy (SEM) micrographs of fibroblast cells cultured on the samples demonstrated that the cells were completely attached and spread on the surface of nanocomposites. In summary, PCLF/gelatin membranes consisting of 5 wt% Si-Mg-FA nanoparticles could provide appropriate mechanical and biological properties and fairly good degradation rate, making it appropriate for GTR/GBR applications.
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http://dx.doi.org/10.1016/j.msec.2019.110172DOI Listing
January 2020

Surface curvature in triply-periodic minimal surface architectures as a distinct design parameter in preparing advanced tissue engineering scaffolds.

Biofabrication 2017 04 12;9(2):025001. Epub 2017 Apr 12.

MIRA Institute for Biomedical Technology and Technical Medicine, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, 7500 AE Enschede, The Netherlands. Institut Charles Gerhardt de Montpellier UMR5253 CNRS-UM-ENSCM-Equipe Ingénierie et Architectures Macromoléculaires, Université de Montpellier, F-34095 Montpellier, France.

Reproduction of the anatomical structures and functions of tissues using cells and designed 3D scaffolds is an ongoing challenge. For this, scaffolds with appropriate biomorphic surfaces promoting cell attachment, proliferation and differentiation are needed. In this study, eight triply-periodic minimal surface (TPMS)-based scaffolds were designed using specific trigonometric equations, providing the same porosity and the same number of unit cells, while presenting different surface curvatures. The scaffolds were fabricated by stereolithography using a photocurable resin based on the biocompatible, biodegradable and rubber-like material, poly(trimethylene carbonate) (PTMC). A numerical approach was developed to calculate the surface curvature distributions of the TPMS architectures. Moreover, the scaffolds were characterized by scanning electron microscopy, micro-computed tomography and water permeability measurements. These original scaffold architectures will be helpful to decipher the biofunctional role of the surface curvature of scaffolds intended for tissue engineering applications.
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http://dx.doi.org/10.1088/1758-5090/aa6553DOI Listing
April 2017

Cell-Imprinted Substrates Modulate Differentiation, Redifferentiation, and Transdifferentiation.

ACS Appl Mater Interfaces 2016 Jun 27;8(22):13777-84. Epub 2016 May 27.

Laboratory of Microsystems (LMIS4), École Polytechnique Fédérale de Lausanne , Station 17, CH-1015 Lausanne, Switzerland.

Differentiation of stem cells into mature cells through the use of physical approaches is of great interest. Here, we prepared smart nanoenvironments by cell-imprinted substrates based on chondrocytes, tenocytes, and semifibroblasts as templates and demonstrated their potential for differentiation, redifferentiation, and transdifferentiation. Analysis of shape and upregulation/downregulation of specific genes of stem cells, which were seeded on these cell-imprinted substrates, confirmed that imprinted substrates have the capability to induce specific shapes and molecular characteristics of the cell types that were used as templates for cell-imprinting. Interestingly, immunofluorescent staining of a specific protein in chondrocytes (i.e., collagen type II) confirmed that adipose-derived stem cells, semifibroblasts, and tenocytes can acquire the chondrocyte phenotype after a 14 day culture on chondrocyte-imprinted substrates. In summary, we propose that common polystyrene tissue culture plates can be replaced by this imprinting technique as an effective and promising way to regulate any cell phenotype in vitro with significant potential applications in regenerative medicine and cell-based therapies.
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http://dx.doi.org/10.1021/acsami.6b03302DOI Listing
June 2016

Nanotoxicology: advances and pitfalls in research methodology.

Nanomedicine (Lond) 2015 15;10(18):2931-52. Epub 2015 Sep 15.

Nanotechnology Research Center & Department of Pharmacology & Toxicology Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

As research progresses, nanoparticles (NPs) are becoming increasingly promising tools for medical diagnostics and therapeutics. Despite this rise, their potential risks to human health, together with environmental issues, has led to increasing concerns regarding their use. As such, a comprehensive understanding of the interactions that occur at the nano-bio interface is required in order to design safe, reliable and efficient NPs for biomedical applications. To this end, extensive studies have been dedicated to probing the factors that define various properties of the nano-bio interface. However, the literature remains unclear and contains conflicting reports on cytotoxicity and biological fates, even for seemingly identical NPs. This uncertainty reveals that we frequently fail to identify and control relevant parameters that unambiguously and reproducibly determine the toxicity of nanoparticles, both in vitro and in vivo. An effective understanding of the toxicological impact of NPs requires the consideration of relevant factors, including the temperature of the target tissue, plasma gradient, cell shape, interfacial effects and personalized protein corona. In this review, we discuss the factors that play a critical role in nano-bio interface processes and nanotoxicity. A proper combinatorial assessment of these factors substantially changes our insight into the cytotoxicity, distribution and biological fate of NPs.
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http://dx.doi.org/10.2217/nnm.15.130DOI Listing
June 2016

Superparamagnetic iron oxide nanoparticles for in vivo molecular and cellular imaging.

Contrast Media Mol Imaging 2015 Sep-Oct;10(5):329-55. Epub 2015 Apr 16.

Nanotechnology Research Center and Department of Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

In the last decade, the biomedical applications of nanoparticles (NPs) (e.g. cell tracking, biosensing, magnetic resonance imaging (MRI), targeted drug delivery, and tissue engineering) have been increasingly developed. Among the various NP types, superparamagnetic iron oxide NPs (SPIONs) have attracted considerable attention for early detection of diseases due to their specific physicochemical properties and their molecular imaging capabilities. A comprehensive review is presented on the recent advances in the development of in vitro and in vivo SPION applications for molecular imaging, along with opportunities and challenges.
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http://dx.doi.org/10.1002/cmmi.1638DOI Listing
July 2016

A review of key challenges of electrospun scaffolds for tissue-engineering applications.

J Tissue Eng Regen Med 2016 09 26;10(9):715-38. Epub 2015 Jan 26.

Nanoscience and Nanotechnology Initiative, National University of Singapore, Singapore.

Tissue engineering holds great promise to develop functional constructs resembling the structural organization of native tissues to improve or replace biological functions, with the ultimate goal of avoiding organ transplantation. In tissue engineering, cells are often seeded into artificial structures capable of supporting three-dimensional (3D) tissue formation. An optimal scaffold for tissue-engineering applications should mimic the mechanical and functional properties of the extracellular matrix (ECM) of those tissues to be regenerated. Amongst the various scaffolding techniques, electrospinning is an outstanding one which is capable of producing non-woven fibrous structures with dimensional constituents similar to those of ECM fibres. In recent years, electrospinning has gained widespread interest as a potential tissue-engineering scaffolding technique and has been discussed in detail in many studies. So why this review? Apart from their clear advantages and extensive use, electrospun scaffolds encounter some practical limitations, such as scarce cell infiltration and inadequate mechanical strength for load-bearing applications. A number of solutions have been offered by different research groups to overcome the above-mentioned limitations. In this review, we provide an overview of the limitations of electrospinning as a tissue-engineered scaffolding technique, with emphasis on possible resolutions of those issues. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.1978DOI Listing
September 2016

A biodegradable glue for annulus closure: evaluation of strength and endurance.

Spine (Phila Pa 1976) 2015 May;40(9):622-8

*Department of Orthopedic Surgery, VU University Medical Center, Amsterdam, the Netherlands †MOVE Research Institute Amsterdam, Amsterdam, the Netherlands ‡Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands §Department of Orthopedics, Orthopedic Research Laboratory, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands ¶Department of Biomedical Engineering, University of Groningen, University Medical Centre Groningen, W.J. Kolff Institute, Groningen, the Netherlands; and ‖Department of Human Movement Sciences, VU University, Amsterdam, the Netherlands.

Study Design: A biodegradable glue was biomechanically tested for annulus closure using nondegenerated goat intervertebral discs. Ultimate strength and endurance tests were performed using native and punctured discs as positive and negative controls, respectively.

Objective: The aim of this study was to investigate the feasibility and biomechanical properties of a biodegradable glue for annulus closure.

Summary Of Background Data: There is an unmet clinical need for annulus closure techniques. Isocyanate-terminated tissue glues show potential because they adhere to annulus tissue, have an elastic modulus similar to the annulus, and show limited cytotoxicity to human annulus fibrosus cells.

Methods: Three biomechanical tests were performed divided in 2 parts: part 1: ultimate strength tests comparing native, punctured (2.4-mm needle), and glued caprine intervertebral discs (n = 11 per group); part 2: 10 discs per group were subjected to a 10-day ex vivo endurance test of 864,000 load cycles, followed by ultimate strength tests. Outcome parameters include the restoration of strength after puncture, reduction of herniation in the endurance test, and conservation of glue strength after endurance testing.

Results: Part 1: The glue partially restored subsidence to failure and yield strength/ultimate strength ratio of intervertebral discs. Part 2: During endurance testing, 40% of punctured discs failed compared with none of the glued discs. Endurance testing did not affect glue strength, and pooling of ultimate strength tests showed that the glue restored ultimate strength, work to failure, and yield strength/ultimate strength to 79%, 75%, and 119% of native values, respectively.

Conclusion: A biodegradable isocyanate-terminated glue increases the force at which nucleus protrusion occurs, and it limits herniations during endurance or ultimate strength tests. Biomechanical tests in a bioreactor provide a low-cost assessment for annulus repair strategies; however, the clinical efficacy needs to be further addressed using long-term in vivo studies.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000000792DOI Listing
May 2015

Cell-imprinted substrates act as an artificial niche for skin regeneration.

ACS Appl Mater Interfaces 2014 Aug 10;6(15):13280-92. Epub 2014 Jul 10.

Department of Medical Nanotechnology, School of Advanced Technologies in Medicine (SATiM), Tehran University of Medical Sciences , P.O. Box 14177-55469, Tehran, Iran.

Bioinspired materials can mimic the stem cell environment and modulate stem cell differentiation and proliferation. In this study, biomimetic micro/nanoenvironments were fabricated by cell-imprinted substrates based on mature human keratinocyte morphological templates. The data obtained from atomic force microscopy and field emission scanning electron microscopy revealed that the keratinocyte-cell-imprinted poly(dimethylsiloxane) casting procedure could imitate the surface morphology of the plasma membrane, ranging from the nanoscale to the macroscale, which may provide the required topographical cell fingerprints to induce differentiation. Gene expression levels of the genes analyzed (involucrin, collagen type I, and keratin 10) together with protein expression data showed that human adipose-derived stem cells (ADSCs) seeded on these cell-imprinted substrates were driven to adopt the specific shape and characteristics of keratinocytes. The observed morphology of the ADSCs grown on the keratinocyte casts was noticeably different from that of stem cells cultivated on the stem-cell-imprinted substrates. Since the shape and geometry of the nucleus could potentially alter the gene expression, we used molecular dynamics to probe the effect of the confining geometry on the chain arrangement of simulated chromatin fibers in the nuclei. The results obtained suggested that induction of mature cell shapes onto stem cells can influence nucleus deformation of the stem cells followed by regulation of target genes. This might pave the way for a reliable, efficient, and cheap approach of controlling stem cell differentiation toward skin cells for wound healing applications.
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http://dx.doi.org/10.1021/am503045bDOI Listing
August 2014

Treatment of the degenerated intervertebral disc; closure, repair and regeneration of the annulus fibrosus.

J Tissue Eng Regen Med 2015 Oct 25;9(10):1120-32. Epub 2014 Feb 25.

University of Groningen, University Medical Center Groningen, W. J. Kolff Institute, Department of Biomedical Engineering, Groningen, The Netherlands.

Degeneration of the intervertebral disc (IVD) and disc herniation are two causes of low back pain. The aetiology of these disorders is unknown, but tissue weakening, which primarily occurs due to inherited genetic factors, ageing, nutritional compromise and loading history, is the basic factor causing disc degeneration. Symptomatic disc herniation mainly causes radicular pain. Current treatments of intervertebral disc degeneration and low back pain are based on alleviating the symptoms and comprise administration of painkillers or surgical methods such as spinal fusion. None of these methods is completely successful. Current research focuses on regeneration of the IVD and particularly on regeneration of the nucleus pulposus. Less attention has been directed to the repair or regeneration of the annulus fibrosus, although this is the key to successful nucleus pulposus, and therewith IVD, repair. This review focuses on the importance of restoring the function of the annulus fibrosus, as well as on the repair, replacement or regeneration of the annulus fibrosus in combination with restoration of the function of the nucleus pulposus, to treat low back pain.
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http://dx.doi.org/10.1002/term.1866DOI Listing
October 2015

Novel antifouling self-healing poly(carboxybetaine methacrylamide-co-HEMA) nanocomposite hydrogels with superior mechanical properties.

J Mater Chem B 2013 Nov 17;1(41):5644-5650. Epub 2013 Sep 17.

Institute of Macromolecular Chemistry, Academy of Science of the Czech Republic, v.v.i., Heyrovsky Sq. 2, Prague, 162 06, Czech Republic.

Novel antifouling highly wettable hydrogels with superior mechanical and self-healing properties are presented. Hydrogels were prepared by UV-initiated copolymerisation of non-fouling zwitterionic carboxybetaine methacrylamide (CBMAA-3) and 2-hydroxyethyl methacrylate (HEMA) in the presence of uniformly dispersed clay nanoparticles (Laponite XLG) in water. The nanoparticles acted as physical cross-linkers resulting in excellent mechanical resistance. The effects of composition such as the amount of nanoclay and the HEMA/CBMAA-3 molar ratio on the physical properties of the nanocomposite hydrogels were investigated. These gels showed outstanding composition-dependent mechanical properties, exhibiting remarkably large elongations at break (≥1800%) and high strengths and moduli even at higher molar contents of CBMAA-3 and higher degrees of swelling (DS). Furthermore, these hydrogels were able to repair mechanical damage without the use of any healing agent by spontaneous reconstruction of cross-links across a damaged interface.
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http://dx.doi.org/10.1039/c3tb20704hDOI Listing
November 2013

An annulus fibrosus closure device based on a biodegradable shape-memory polymer network.

Biomaterials 2013 Nov 6;34(33):8105-13. Epub 2013 Aug 6.

University of Groningen, University Medical Center Groningen, Department of Biomedical Engineering, W.J. Kolff Institute, PO Box 196, 9700 AD Groningen, The Netherlands.

Injuries to the intervertebral disc caused by degeneration or trauma often lead to tearing of the annulus fibrosus (AF) and extrusion of the nucleus pulposus (NP). This can compress nerves and cause lower back pain. In this study, the characteristics of poly(D,L-lactide-co-trimethylene carbonate) networks with shape-memory properties have been evaluated in order to prepare biodegradable AF closure devices that can be implanted minimally invasively. Four different macromers with (D,L-lactide) to trimethylene carbonate (DLLA:TMC) molar ratios of 80:20, 70:30, 60:40 and 40:60 with terminal methacrylate groups and molecular weights of approximately 30 kg mol(-1) were used to prepare the networks by photo-crosslinking. The mechanical properties of the samples and their shape-memory properties were determined at temperatures of 0 °C and 40 °C by tensile tests- and cyclic, thermo-mechanical measurements. At 40 °C all networks showed rubber-like behavior and were flexible with elastic modulus values of 1.7-2.5 MPa, which is in the range of the modulus values of human annulus fibrosus tissue. The shape-memory characteristics of the networks were excellent with values of the shape-fixity and the shape-recovery ratio higher than 98 and 95%, respectively. The switching temperatures were between 10 and 39 °C. In vitro culture and qualitative immunocytochemistry of human annulus fibrosus cells on shape-memory films with DLLA:TMC molar ratios of 60:40 showed very good ability of the networks to support the adhesion and growth of human AF cells. When the polymer network films were coated by adsorption of fibronectin, cell attachment, cell spreading, and extracellular matrix production was further improved. Annulus fibrosus closure devices were prepared from these AF cell-compatible materials by photo-polymerizing the reactive precursors in a mold. Insertion of the multifunctional implant in the disc of a cadaveric canine spine showed that these shape-memory devices could be implanted through a small slit and to some extent deploy self-sufficiently within the disc cavity.
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http://dx.doi.org/10.1016/j.biomaterials.2013.07.061DOI Listing
November 2013

Polymeric microstructures with shape-memory properties for biomedical use built by stereolithography.

J Appl Biomater Funct Mater 2012 ;10(3):280-6

Department of Biomedical Engineering, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.

Purpose: The aim of this study was to design and build porous microstructures with shape memory behaviour using biodegradable poly(D,L-lactide-co-trimethylene carbonate) dimethacrylate macromers. These microstructures could be advantageous for tissue engineering and other advanced biomedical applications.

Methods: Porous structures with a gyroid pore network architecture showing average pore sizes of 930 µm and complete pore interconnectivity were prepared by stereolithography. Built structures were characterized by Micro-computed tomography (µ-CT). Shape recovery and shape fixity of microstructures after 40% and 70% compression were evaluated.

Results: At 37 °C the flexible structures showed compression modulus values of 60 KPa and could be fully compressed. Thermal analysis showed that the built networks were amorphous with Tg values of 23 °C. After compression to 40 and 70%, shape fixity and shape recovery of the structures at respectively 0 °C and 37 °C was almost quantitative.

Conclusions: The well-defined pore network characteristics and the shape-memory properties of these structures allow their use as deployable tissue engineering scaffolds.
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http://dx.doi.org/10.5301/JABFM.2012.10367DOI Listing
September 2013

Development of poly(trimethylene carbonate) network implants for annulus fibrosus tissue engineering.

J Appl Biomater Funct Mater 2012 ;10(3):177-84

Department of Biomaterials Science and Technology, University of Twente, Enschede, The Netherlands.

Purpose: Intervertebral disk degeneration is the main cause of chronic back pain. Disk degeneration often leads to tearing of the annulus fibrosus (AF) and extrusion of the nucleus pulposus (NP), which compresses the nerves. Current treatment involves removing the herniated NP and suturing the damaged AF tissue. This surgical approach has several drawbacks. In this study, we designed a biodegradable AF closure system comprising a tissue engineering scaffold, a supporting membrane and an adhesive material, to not only restore the function of the herniated disc but also to promote tissue regeneration.

Materials And Methods: Porous scaffolds with precisely defined architectures were built by stereolithography using resins based on poly(trimethylene carbonate) (PTMC) macromers functionalized with methacrylate endgroups. In addition, a porous photo-cross-linked PTMC membrane was developed that can be used to keep the scaffold in place in the AF tissue.

Results: After synthesis and characterization, the components of the implant are glued together and to the AF tissue using a diisocyanate glue based on polyethylene glycol-PTMC triblock copolymers. The adhesion strengths of the materials to each other and to AF tissue were determined in lap-shear tests.

Conclusions: This study showed that a device for AF tissue engineering can be prepared from PTMC-based scaffolds, membranes and glues.
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http://dx.doi.org/10.5301/JABFM.2012.10354DOI Listing
September 2013

Biodegradable nanocomposite hydrogel structures with enhanced mechanical properties prepared by photo-crosslinking solutions of poly(trimethylene carbonate)-poly(ethylene glycol)-poly(trimethylene carbonate) macromonomers and nanoclay particles.

Acta Biomater 2012 Dec 17;8(12):4233-43. Epub 2012 Sep 17.

W.J. Kolff Institute, Department of Biomedical Engineering, University Medical Centre Groningen, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands.

Soft hydrogels with elasticity modulus values lower than 100kPa that are tough and biodegradable are of great interest in medicine and in tissue engineering applications. We have developed a series of soft hydrogel structures from different methacrylate-functionalized triblock copolymers of poly(ethylene glycol) (PEG) with poly(trimethylene carbonate) (PTMC) by photo-crosslinking aqueous solutions of the macromonomers in 2.5 and 5wt.% colloidal dispersions of clay nanoparticles (Laponite XLG). The length of the PTMC blocks of the macromonomers and the clay content determined the physicomechanical properties of the obtained hydrogels. While an increase in the PTMC block length in the macromonomers from 0.2 to 5kg/mol resulted in a decrease in the gel content, the addition of 5wt.% Laponite nanoclay to the crosslinking solution lead to very high gel contents of the hydrogels of more than 95%. The effect of PTMC block length on the mechanical properties of the hydrogels was not as pronounced, and soft gels with a compressive modulus of less than 15kPa and toughness values of 25kJm(-3) were obtained. However, the addition of 5wt.% Laponite nanoclay to the formulations considerably increased the compressive modulus and resilience of the hydrogels; swollen nanocomposite networks with compressive modulus and toughness values of up to 67kPa and 200kJm(-3), respectively, could then be obtained. The prepared hydrogels were shown to be enzymatically degradable by cholesterol esterase and by the action of macrophages. With an increase in PTMC block length in the hydrogels, the rates of mass loss increased, while the incorporated Laponite nanoclay suppressed degradation. Nanocomposite hydrogel structures with a designed gyroid pore network architecture were prepared by stereolithography. Furthermore, in the swollen state the porous gyroid structures were mechanically stable and the pore network remained fully open and interconnected.
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http://dx.doi.org/10.1016/j.actbio.2012.09.014DOI Listing
December 2012

Resilient amorphous networks prepared by photo-crosslinking high-molecular-weight D,L-lactide and trimethylene carbonate macromers: mechanical properties and shape-memory behavior.

Macromol Biosci 2012 Oct 10;12(10):1423-35. Epub 2012 Sep 10.

Department of Biomedical Engineering, University Medical Centre Groningen, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands.

Tough networks are prepared by photo-crosslinking high-molecular-weight DLLA and TMC macromers. These amorphous networks exhibit tunable thermal and mechanical properties and have excellent shape-memory features. Variation of the monomer ratio allows adjustment of T(g) between approximately -13 and +51 °C. The elastic moduli at room temperature can be varied between 4.5 and 2730 MPa. The crosslinks allow the networks to return to their original shape after deformation. 60:40 DLLA:TMC networks have T(g) values between room temperature and body temperature, with mechanical properties at body temperature close to soft tissues. Several medical devices are prepared from these networks.
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http://dx.doi.org/10.1002/mabi.201200155DOI Listing
October 2012

Magnetic targeting of surface-modified superparamagnetic iron oxide nanoparticles yields antibacterial efficacy against biofilms of gentamicin-resistant staphylococci.

Acta Biomater 2012 Jul 8;8(6):2047-55. Epub 2012 Mar 8.

Department of Biomedical Engineering, WJ Kolff Institute, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

Biofilms on biomaterial implants are hard to eradicate with antibiotics due to the protection offered by the biofilm mode of growth, especially when caused by antibiotic-resistant strains. Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used in various biomedical applications, such as targeted drug delivery and magnetic resonance imaging. Here, we evaluate the hypothesis that SPIONs can be effective in the treatment of biomaterial-associated infection. SPIONs can be targeted to the infection site using an external magnetic field, causing deep penetration in a biofilm and possibly effectiveness against antibiotic-resistant strains. We report that carboxyl-grafted SPIONs, magnetically concentrated in a biofilm, cause an approximately 8-fold higher percentage of dead staphylococci than does gentamicin for a gentamicin-resistant strain in a developing biofilm. Moreover, magnetically concentrated carboxyl-grafted SPIONs cause bacterial killing in an established biofilm. Thus magnetic targeting of SPIONs constitutes a promising alternative for the treatment of costly and recalcitrant biomaterial-associated infections by antibiotic-resistant strains.
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http://dx.doi.org/10.1016/j.actbio.2012.03.002DOI Listing
July 2012

Toxicity of nanomaterials.

Chem Soc Rev 2012 Mar 14;41(6):2323-43. Epub 2011 Dec 14.

Department of Biomedical Engineering, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technology. Presently, nanomaterials are used in a wide variety of commercial products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufacturing processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atmosphere during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This critical review discusses the biophysicochemical properties of various nanomaterials with emphasis on currently available toxicology data and methodologies for evaluating nanoparticle toxicity (286 references).
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http://dx.doi.org/10.1039/c1cs15188fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703119PMC
March 2012

Hydroxyapatite scaffolds infiltrated with thermally crosslinked polycaprolactone fumarate and polycaprolactone itaconate.

J Biomed Mater Res A 2011 Aug 27;98(2):257-67. Epub 2011 May 27.

Department of Novel Drug Delivery Systems, Iran Polymer and Petrochemical Institute, PO Box 14965/115, Tehran, Iran.

In this work, two unsaturated derivatives of polycaprolactone (PCL), polycaprolactone fumarate (PCLF), and polycaprolactone itaconate (PCLI), have been synthesized and used as an infiltrating polymer to improve the mechanical properties of brittle hydroxyapatite (HA) scaffolds. PCLF and PCLI were first synthesized through polyesterification of the low molecular weight PCL diols with fumaryl chloride and itaconyl chloride respectively, and then characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, gel permeation chromatography, and differential scanning calorimetry analysis. HA scaffolds were sintered using a foam replication technique, with porosity of about 60%. Polymer-HA composites were obtained by infiltrating the HA scaffolds with PCLF and PCLI solution (12.5 and 30 w/v in dichloromethane) followed by thermal crosslinking. The polymer infiltrated HA scaffolds were characterized by scanning electron microscopy, porosimetry, and gravimetrical analysis. The polyesterification reaction of PCL diols with fumarate chloride was more efficient than itaconyl chloride and dependent upon the molecular weight of the initial PCL precursor; the resultant PCLF demonstrated a degree of substitution of 1.2, 4.2, and 2.7 times higher than PCLIs. Polymer infiltration improved the compressive strength of the HA scaffolds, and based upon the type of macromer (PCLF or PCLI) and also their concentration in infiltrating solution (12.5 or 30 w/v %) compressive strength increased about 14-328%. In all studied samples, the reinforcement effect of PCLF infiltration was higher than PCLI. The macromers and their corresponding infiltrated HA scaffolds did not show any significant cytotoxicity toward human primary osteogenic sarcoma cell (G92 cell lines), in vitro.
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http://dx.doi.org/10.1002/jbm.a.33108DOI Listing
August 2011

Injectable in situ forming drug delivery system based on poly(epsilon-caprolactone fumarate) for tamoxifen citrate delivery: Gelation characteristics, in vitro drug release and anti-cancer evaluation.

Acta Biomater 2009 Jul 12;5(6):1966-78. Epub 2009 Feb 12.

Biomedical Engineering Department, Amirkabir University of Technology, Tehran, Iran.

The present study deals with the preparation and characterization of an injectable and in situ forming drug delivery system based on photocrosslinked poly(epsilon-caprolactone fumarate) (PCLF) networks loaded with tamoxifen citrate (TC). Networks were made of PCLF macromers, a photoinitiation system (comprising initiator and accelerator) and the active ingredient N-vinyl-2-pyrrolidone (NVP) as a crosslinker and reactive diluent. Shrinkage behavior, equilibrium swelling and sol fraction ratios of photocrosslinked PCLF gels were determined as functions of NVP content. It was shown that the crosslinking is facilitated up to a certain concentration of NVP and most of NVP remained unreacted above this value. In vitro drug release, biocompatibility evaluation and activity against MCF-7 breast cancer cell line were also investigated. Accurate but simple bipartite expressions were also derived that enable rapid determination of effective diffusion coefficients of TC in photocrosslinked PCLF/NVP disks. Cytotoxicity assay showed that while the photocrosslinked PCLF network with optimum NVP content exhibits no significant cytotoxicity against MCF-7 and L929 cell lines, 40-60% of the MCF-7 cells were killed after incubation with TC-loaded devices.
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http://dx.doi.org/10.1016/j.actbio.2009.02.004DOI Listing
July 2009

Synthesis, characterization, and biocompatibility of novel injectable, biodegradable, and in situ crosslinkable polycarbonate-based macromers.

J Biomed Mater Res A 2009 Sep;90(3):830-43

Novel Drug Delivery Systems Department, Iran Polymer and Petrochemical Institute, P.O. Box 14965/115, Tehran, Iran.

A series of novel self-crosslinkable and biodegradable polymers, poly(hexamethylene carbonate-fumarate) and poly(hexamethylene carbonate) diacrylate, and their amphiphilic copolymers with polyethylene glycol, poly(ethylene glycol fumarate-co-hexamethylene carbonate-fumarate) (PEGF-co-PHMCF), were developed for tissue engineering using propylene oxide as an acid scavenger. The synthesized polymers are white, which makes them more suitable for self-crosslinking via photopolymerization. These novel polymers were fully characterized using nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, gel permeation chromatography, differential scanning calorimetry, and rheometry. The cytocompatibility of the photocrosslinked networks were evaluated by [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. These polymers can be used as precursors to prepare polymer networks and scaffolds with controlled hydrophilicity, biodegradability, and mechanical characteristics. Results obtained suggest that these polymers are potentially useful as injectable and photocrosslinkable materials for cell delivery, tissue engineering, and drug delivery applications.
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http://dx.doi.org/10.1002/jbm.a.32138DOI Listing
September 2009

Photopolymerization and shrinkage kinetics of in situ crosslinkable N-vinyl-pyrrolidone/poly(epsilon-caprolactone fumarate) networks.

J Biomed Mater Res A 2008 Feb;84(2):545-56

Biomedical Engineering Department, Amirkabir University of Technology, PO Box 15875/4413, Tehran, Iran.

Biodegradable, injectable and in situ photocrosslinkable macromers based on fumaric acid and polycaprolactone (PCLF) were prepared and characterized by FTIR, 1HNMR, and 13CNMR spectroscopy. The multifunctional macromers dissolved in N-vinyl pyrollidone (NVP) were photopolymerized by visible light irradiation in the presence of camphorquinone as photoinitiator. The photocrosslinking reaction was monitored by measuring shrinkage strain and shrinkage strain rate. The degree of photopolymerization reaction i.e. degree of conversion (DC%) was traced using FTIR spectroscopy. A three level factorial design was developed to study the effects of initiator concentration, NVP concentration, and molecular weight of PCLF upon photocrosslinking characteristics including degree of conversion and shrinkage strain. Results revealed that although neat PCLF was photopolymerized, but it was putty like after 220 seconds of irradiation and showed a very low degree of conversion (29%). Adding about 20% NVP caused a dramatic increase in its degree of conversion (63.33%). Increasing NVP up to 50% resulted in a decrease in DC% because of lower reactivity of NVP and leaving more unreacted NVP monomers. Sol fraction studies supported these results indicating that at higher NVP concentration, most of NVP and PCLF have not undergone the crosslinking reaction, leading to 55% decrease in DC%. Shrinkage strain measurement also confirmed the FTIR results.
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http://dx.doi.org/10.1002/jbm.a.31384DOI Listing
February 2008