Publications by authors named "Ashish Thakur"

34 Publications

Rehabilitation of Auricular Defect with Implant-Retained Auricular Prosthesis - A Case Report.

Ann Maxillofac Surg 2021 Jan-Jun;11(1):164-168. Epub 2021 Jul 24.

Department of Oral Medicine and Radiology, Army Dental Center R&R, Delhi, India.

Rationale: Maxillofacial defect is of great concern physically, emotionally, and psychologically for a patient. However, it is an even bigger challenge for a team attempting rehabilitation, as a crucial decision has to be made between surgical approach and/or prosthetic rehabilitation. However, if both are combined, it will result in best of esthetics and function with ease of maintainance, resulting in a sucessful rehabilitation. This case report represents a case of auricular defect rehabilitated with a combination of implants and bar-retained silicone prosthesis.

Patient Concern: A 38-year-old male patient with right auricular defect reported with the main concern of esthetic rehabilitation of a lost part of the external ear.

Diagnosis: With through evaluation and examination, a diagnosis of acquired partial auricular defect of the right side secondary to trauma was established.

Treatment: An implant-retained auricular prosthesis was planned for this case. Surgically, three intraoral implants were placed in the mastoid bone, and after healing, bar framework was fabricated and attached. Finally, silicone prosthesis was fabricated and delivered to the patient.

Outcome: A successful rehabilitation was carried out in this case using implants and bar attachment for retention of the silicone prosthesis. This prosthesis provided excellent retention and restored the appearance and confidence of the patient.

Take-away Lessons: Rehabilitation of the auricular defect can be carried out with surgical approach, which involves multiple surgeries, and still, the results may not be esthetically favorable. Prosthetic rehabilitation is an option, but retention is generally a hindrance. However, implant-retained prosthesis has really paved a way for rehabilitation of the maxillofacial defect esthetically and more reliably. Cone-beam computerized tomography (CT) can be used for planning and evaluation instead of CT, which will save the patient from a lot of radiation exposure. Hence, in the maxillofacial defect, attempts should be made to explore the option of implant-retained prosthesis.
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http://dx.doi.org/10.4103/ams.ams_343_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407634PMC
July 2021

Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Nat Commun 2020 Nov 19;11(1):5988. Epub 2020 Nov 19.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19869-5.
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http://dx.doi.org/10.1038/s41467-020-19869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678822PMC
November 2020

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Nat Commun 2020 10 7;11(1):5038. Epub 2020 Oct 7.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.
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http://dx.doi.org/10.1038/s41467-020-18752-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541486PMC
October 2020

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

EMBO J 2020 09 3;39(18):e105759. Epub 2020 Aug 3.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Parvalbumin-positive (PV ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2 PV interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.
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http://dx.doi.org/10.15252/embj.2020105759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507454PMC
September 2020

Prosthetic Management of Microstomia with Customized Dynamic Splint.

Int J Prosthodont 2020 May/Jun;33(3):347-353

Microstomia is a clinical condition of reduced mouth opening that can be acquired or congenital in origin. Problems associated with microstomia can be related to function, esthetics, or both. Management of microstomia due to facial burns is complex due to the presence of hypertrophic and contracture scars. Available treatment options can be broadly classified as surgical, nonsurgical, or both. Splints can be used to prevent the contraction of perioral musculature or to recuperate lost mouth opening. Various intraoral or extraoral, tooth-borne or tissue-borne, and static or dynamic appliances are in clinical use, but their designs are case specific. This case report explains the management of microstomia secondary to facial burns by using a dynamic splint in combination with intralesional injections of triamcinolone acetonide and hyaluronidase.
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http://dx.doi.org/10.11607/ijp.6325DOI Listing
April 2020

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

J Med Chem 2020 04 8;63(8):4256-4292. Epub 2020 Apr 8.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound , induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238858PMC
April 2020

Total Synthesis of Indolizidine Alkaloids via Nickel-Catalyzed (4 + 2) Cyclization.

Org Lett 2020 02 13;22(3):924-928. Epub 2020 Jan 13.

Department of Chemistry , University of Utah , 315 South 1400 East , Salt Lake City , Utah 84112-8450 , United States.

A Ni-catalyzed (4 + 2) cycloaddition of alkynes and azetidinones toward piperidinones was used as key reaction in the enantioselective synthesis of naturally occurring indolizidine alkaloids. The reaction benefits from the use of an easily accessible azetidinone as an advanced and divergent intermediate to build the indolizidine core. This methodology has been applied in the total syntheses of (+)-septicine, (+)-ipalbidine, and (+)--antofine to illustrate the applicability of the general approach.
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http://dx.doi.org/10.1021/acs.orglett.9b04479DOI Listing
February 2020

Viral hepatitis among acute hepatitis patients attending tertiary care hospital in central India.

Virusdisease 2019 Sep 26;30(3):367-372. Epub 2019 Jul 26.

Division of Virology and Zoonoses, ICMR-National Institute of Research in Tribal Health (NIRTH), ICMR, Nagpur Road, Garha, Jabalpur, Madhya Pradesh India.

Viral hepatitis is a considerable public health burden affecting millions of people throughout the world. The incidence of viral hepatitis varies greatly depending upon geographic locations, age and gender. Exploring the etiological spectrum and clinic-epidemiological profile of acute viral hepatitis (AVH) becomes essential for strategizing the preventive measures to control the diseases. An epidemiological data depicting AVH situation and its etiologies is missing from central India. With the aim of fulfilling this lacuna, the present analysis was done on samples tested over a period of 2 years from July 2015 to June 2017. Of the 1901 hepatitis cases, 597 individuals (31.4%) were positive for AVH infection and HEV was the predominant cause followed by HBV, HAV and HCV. Co-infections of hepatitis viruses were detected in 42 cases. Co-infection of HEV with HBV was the commonest pattern. Male preponderance was observed among AVH positive cases and the age group of 26-45 years was the most susceptible to the viral hepatitis infections, except hepatitis A, which was the most frequent among children. Two hundred patients (33.45%) required hospitalization and 51 deaths were attributed to AVH infections. The analysis for the first time reports intricacies and viral etiologies of AVH in central India. Regular diagnosis of AVH etiology and monitoring of cases will help in patient management and assist disease control programs to take policy decisions.
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http://dx.doi.org/10.1007/s13337-019-00541-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863987PMC
September 2019

The NCATS Pharmaceutical Collection: a 10-year update.

Drug Discov Today 2019 12 1;24(12):2341-2349. Epub 2019 Oct 1.

Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD 20850, USA.

The National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (NPC), a comprehensive collection of clinically approved drugs, was made a public resource in 2011. Over the past decade, the NPC has been systematically profiled for activity across an array of pathways and disease models, generating an unparalleled amount of data. These data have not only enabled the identification of new repurposing candidates with several in clinical trials, but also uncovered new biological insights into drug targets and disease mechanisms. This retrospective provides an update on the NPC in terms of both successes and lessons learned. We also report our efforts in bringing the NPC up-to-date with drugs approved in recent years.
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http://dx.doi.org/10.1016/j.drudis.2019.09.019DOI Listing
December 2019

Fabrication of ocular prosthesis with a digital customization technique - A case report.

J Family Med Prim Care 2019 Mar;8(3):1239-1242

Department of Prosthodontics and Crown and Bridge, Army Dental Centre, Research and Referral, Delhi Cantt, India.

Loss of an eye can be caused by cancer, trauma, or congenital defects. A loss of eye creates functional, esthetic, and psychological lacunae in individual's personal and professional life. Rehabilitation of ocular defect can be done by a custom ocular prosthesis fabricated with heat cure polymethylmethacrylate. The custom-made prosthesis provides a better fit, is more comfortable to use and gives better cosmetic results than a stock prosthesis. The main objective of this article is to describe a new technique of customization using digital photograph of the patient's iris made using a digital camera to give excellent cosmetic results to the patient.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_133_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482809PMC
March 2019

Rapid prototyping technology for cranioplasty: A case series.

J Indian Prosthodont Soc 2019 Apr-Jun;19(2):184-189

Department of Prosthodontics and Crown and Bridge, Army Dental Centre R and R, New Delhi, India.

Cranial vault defects may be acquired or congenital in origin. Rehabilitation of these patients often poses challenge to the operating team and prosthodontist. Polymethylmethacrylate is a commonly used alloplastic graft material which is used for the fabrication of cranial prosthesis. Nowadays, with the advancement in the bioengineering, custom-made template and cranial prosthesis can be made by rapid prototyping technology (RPT) by patient three-dimensional (3D) computed tomography (CT) scan images. This series of two cases explained two different techniques for the rehabilitation of the patient with frontotemporoparietal cranial defect. Case 1 had a history of cerebrovascular accident, followed by decompression craniotomy which led to frontotemporoparietal defect of the left side. This defect area was associated with the cerebrospinal fluid accumulation which made delineation of underlying bony margins difficult and interfered with conventional impression procedures. Case 2 had a road traffic accident which led to intracerebral hemorrhage followed by decompression craniotomy which resulted in frontotemporoparietal defect of the right side. The patient had a poor neuromuscular control which impedes with the upright posture of the head during impression making of the defect area. Therefore, these cases were planned to rehabilitate by RPT. In these techniques, the prosthesis was made using custom-made skull template produced by RPT, using the data of 3D-CT scan images. This technique resulted in the prosthesis with good esthetics and better fit of the prosthesis. The contours of the prosthesis were replicated in the same manner as compared to the contralateral side. RPT is an additive manufacturing technology which is now used in the field of dentistry too. This technique is easy to use; fabricate prosthesis with high precision is less time-consuming and has fewer chances of error.
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http://dx.doi.org/10.4103/jips.jips_295_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482620PMC
September 2018

Pectin Methacrylate (PEMA) and Gelatin-Based Hydrogels for Cell Delivery: Converting Waste Materials into Biomaterials.

ACS Appl Mater Interfaces 2019 Apr 22;11(13):12283-12297. Epub 2019 Mar 22.

Department of Health Technology, Center for Intestinal Absorption and Transport of Biopharmaceuticals , Technical University of Denmark , 2800 Kgs. Lyngby , Denmark.

The emergence of nontoxic, eco-friendly, and biocompatible polymers derived from natural sources has added a new and exciting dimension to the development of low-cost and scalable biomaterials for tissue engineering applications. Here, we have developed a mechanically strong and durable hydrogel composed of an eco-friendly biopolymer that exists within the cell walls of fruits and plants. Its trade name is pectin, and it bears many similarities with natural polysaccharides in the native extracellular matrix. Specifically, we have employed a new pathway to transform pectin into a ultraviolet (UV)-cross-linkable pectin methacrylate (PEMA) polymer. To endow this hydrogel matrix with cell differentiation and cell spreading properties, we have also incorporated thiolated gelatin into the system. Notably, we were able to fine-tune the compressive modulus of this hydrogel in the range ∼0.5 to ∼24 kPa: advantageously, our results demonstrated that the hydrogels can support growth and viability for a wide range of three-dimensionally (3D) encapsulated cells that include muscle progenitor (C2C12), neural progenitor (PC12), and human mesenchymal stem cells (hMSCs). Our results also indicate that PEMA-gelatin-encapsulated hMSCs can facilitate the formation of bonelike apatite after 5 weeks in culture. Finally, we have demonstrated that PEMA-gelatin can yield micropatterned cell-laden 3D constructs through UV light-assisted lithography. The simplicity, scalability, processability, tunability, bioactivity, and low-cost features of this new hydrogel system highlight its potential as a stem cell carrier that is capable of bridging the gap between clinic and laboratory.
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http://dx.doi.org/10.1021/acsami.9b00154DOI Listing
April 2019

Blending Electronics with the Human Body: A Pathway toward a Cybernetic Future.

Adv Sci (Weinh) 2018 Oct 1;5(10):1700931. Epub 2018 Aug 1.

Technical University of Denmark DTU Nanotech Center for Nanomedicine and Theranostics 2800 Kgs Denmark.

At the crossroads of chemistry, electronics, mechanical engineering, polymer science, biology, tissue engineering, computer science, and materials science, electrical devices are currently being engineered that blend directly within organs and tissues. These sophisticated devices are mediators, recorders, and stimulators of electricity with the capacity to monitor important electrophysiological events, replace disabled body parts, or even stimulate tissues to overcome their current limitations. They are therefore capable of leading humanity forward into the age of cyborgs, a time in which human biology can be hacked at will to yield beings with abilities beyond their natural capabilities. The resulting advances have been made possible by the emergence of conformal and soft electronic materials that can readily integrate with the curvilinear, dynamic, delicate, and flexible human body. This article discusses the recent rapid pace of development in the field of cybernetics with special emphasis on the important role that flexible and electrically active materials have played therein.
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http://dx.doi.org/10.1002/advs.201700931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193179PMC
October 2018

Combinatorial Screening of Nanoclay-Reinforced Hydrogels: A Glimpse of the "Holy Grail" in Orthopedic Stem Cell Therapy?

ACS Appl Mater Interfaces 2018 Oct 5;10(41):34924-34941. Epub 2018 Oct 5.

DTU Nanotech, Center for Intestinal Absorption and Transport of Biopharmaceutical , Technical University of Denmark , 2800 Kgs, Lyngby , Denmark.

Despite the promise of hydrogel-based stem cell therapies in orthopedics, a significant need still exists for the development of injectable microenvironments capable of utilizing the  regenerative potential of donor cells. Indeed, the quest for biomaterials that can direct stem cells into bone without the need of external factors has been the "Holy Grail" in orthopedic stem cell therapy for decades. To address this challenge, we have utilized a combinatorial approach to screen over 63 nanoengineered hydrogels made from alginate, hyaluronic acid, and two-dimensional nanoclays. Out of these combinations, we have identified a biomaterial that can promote osteogenesis in the absence of well-established differentiation factors such as bone morphogenetic protein 2 (BMP2) or dexamethasone. Notably, in our "hit" formulations we observed a 36-fold increase in alkaline phosphate (ALP) activity and a 11-fold increase in the formation of mineralized matrix, compared to the control hydrogel. This induced osteogenesis was further supported by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy. Additionally, the Montmorillonite-reinforced hydrogels exhibited high osteointegration as evident from the relatively stronger adhesion to the bone explants as compared to the control. Overall, our results demonstrate the capability of combinatorial and nanoengineered biomaterials to induce bone regeneration through osteoinduction of stem cells in a natural and differentiation-factor-free environment.
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http://dx.doi.org/10.1021/acsami.8b11436DOI Listing
October 2018

Emerging Biofabrication Strategies for Engineering Complex Tissue Constructs.

Adv Mater 2017 May 3;29(19). Epub 2017 Apr 3.

Laboratory for Innovations in Microengineering (LiME), Department of Mechanical Engineering, University of Victoria, Victoria, BC, V8P 5C2, Canada.

The demand for organ transplantation and repair, coupled with a shortage of available donors, poses an urgent clinical need for the development of innovative treatment strategies for long-term repair and regeneration of injured or diseased tissues and organs. Bioengineering organs, by growing patient-derived cells in biomaterial scaffolds in the presence of pertinent physicochemical signals, provides a promising solution to meet this demand. However, recapitulating the structural and cytoarchitectural complexities of native tissues in vitro remains a significant challenge to be addressed. Through tremendous efforts over the past decade, several innovative biofabrication strategies have been developed to overcome these challenges. This review highlights recent work on emerging three-dimensional bioprinting and textile techniques, compares the advantages and shortcomings of these approaches, outlines the use of common biomaterials and advanced hybrid scaffolds, and describes several design considerations including the structural, physical, biological, and economical parameters that are crucial for the fabrication of functional, complex, engineered tissues. Finally, the applications of these biofabrication strategies in neural, skin, connective, and muscle tissue engineering are explored.
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http://dx.doi.org/10.1002/adma.201606061DOI Listing
May 2017

Nanoreinforced Hydrogels for Tissue Engineering: Biomaterials that are Compatible with Load-Bearing and Electroactive Tissues.

Adv Mater 2017 Feb 14;29(8). Epub 2016 Dec 14.

Technical University of Denmark, DTU Nanotech, Center for Nanomedicine and Theranostics, 2800 Kgs, Ørsteds Plads, Kongens Lyngby, Denmark.

Given their highly porous nature and excellent water retention, hydrogel-based biomaterials can mimic critical properties of the native cellular environment. However, their potential to emulate the electromechanical milieu of native tissues or conform well with the curved topology of human organs needs to be further explored to address a broad range of physiological demands of the body. In this regard, the incorporation of nanomaterials within hydrogels has shown great promise, as a simple one-step approach, to generate multifunctional scaffolds with previously unattainable biological, mechanical, and electrical properties. Here, recent advances in the fabrication and application of nanocomposite hydrogels in tissue engineering applications are described, with specific attention toward skeletal and electroactive tissues, such as cardiac, nerve, bone, cartilage, and skeletal muscle. Additionally, some potential uses of nanoreinforced hydrogels within the emerging disciplines of cyborganics, bionics, and soft biorobotics are highlighted.
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http://dx.doi.org/10.1002/adma.201603612DOI Listing
February 2017

Nanoengineered biomaterials for repair and regeneration of orthopedic tissue interfaces.

Acta Biomater 2016 09 17;42:2-17. Epub 2016 Jun 17.

Department of Biomedical Engineering, Texas A&M University, College Station, TX 77841, USA; Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77841, USA; Center for Remote Health Technologies and Systems, Texas A&M University, College Station, TX 77843, USA. Electronic address:

Unlabelled: Orthopedic interface tissue engineering aims to mimic the structure and function of soft-to-hard tissue junctions, particularly bone-ligament, bone-tendon, and bone-cartilage interfaces. A range of engineering approaches has been proposed to mimic the gradient architecture, physical properties and chemical characteristics of interface tissues using conventional polymeric biomaterials. Recent developments in nanomaterials and nanofabrication technologies introduce a range of synthesis and fabrication tools to effectively engineer the structure and function of native tissue interfaces. In this review, we will focus on nanoengineered strategies used to replicate the structural and functional aspects of native biological tissues for engineering bone-cartilage, bone-ligament, and bone-tendon interfaces. This review will also highlight some of the emerging applications and future potential of nanomaterials and fabrication technologies in engineering tissue interfaces.

Statement Of Significance: A major challenge in engineering interfaces is to control the physical and structural characteristics of an artificial environment. The use of nanomaterials and nanoengineered strategies allow for greater control over the changes in structure and function at molecular and nanometer length scale. This review focuses on advanced nanomaterials and nanofabrication approaches developed to emulate bone-cartilage, bone-ligament, and bone-tendon interface regions. Some of the emerging nanoengineered biomaterials proposed to mimic tissue interfaces are also highlighted.
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http://dx.doi.org/10.1016/j.actbio.2016.06.023DOI Listing
September 2016

Injectable shear-thinning nanoengineered hydrogels for stem cell delivery.

Nanoscale 2016 Jun;8(24):12362-72

Department of Biomedical Engineering, Texas A&M University, College Station, TX-77843, USA. and Department of Materials Sciences, Texas A&M University, College Station, TX-77843, USA and Center for Remote Health Technologies and Systems, Texas A&M University, College Station, TX 77843, USA.

Injectable hydrogels are investigated for cell encapsulation and delivery as they can shield cells from high shear forces. One of the approaches to obtain injectable hydrogels is to reinforce polymeric networks with high aspect ratio nanoparticles such as two-dimensional (2D) nanomaterials. 2D nanomaterials are an emerging class of ultrathin materials with a high degree of anisotropy and they strongly interact with polymers resulting in the formation of shear-thinning hydrogels. Here, we present 2D nanosilicate reinforced kappa-carrageenan (κCA) hydrogels for cellular delivery. κCA is a natural polysaccharide that resembles native glycosaminoglycans and can form brittle hydrogels via ionic crosslinking. The chemical modification of κCA with photocrosslinkable methacrylate groups renders the formation of a covalently crosslinked network (MκCA). Reinforcing the MκCA with 2D nanosilicates results in shear-thinning characteristics, and enhanced mechanical stiffness, elastomeric properties, and physiological stability. The shear-thinning characteristics of nanocomposite hydrogels are investigated for human mesenchymal stem cell (hMSC) delivery. The hMSCs showed high cell viability after injection and encapsulated cells showed a circular morphology. The proposed shear-thinning nanoengineered hydrogels can be used for cell delivery for cartilage tissue regeneration and 3D bioprinting.
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http://dx.doi.org/10.1039/c6nr02299eDOI Listing
June 2016

An in Situ Approach to Nickel-Catalyzed Cycloaddition of Alkynes and 3-Azetidinones.

J Org Chem 2015 Oct 6;80(20):9951-8. Epub 2015 Oct 6.

Department of Chemistry, University of Utah , 315 South, 1400 East, Salt Lake City, Utah 84112-0850, United States.

An efficient and convenient procedure that generates the active Ni(0) catalyst in situ from cheap, air stable Ni(II) precursors is developed for the [4 + 2]-cycloaddition of alkynes and 3-azetidinones. The reaction affords useful 3-dehydropiperidinones in comparable yields to the reported Ni(0) procedure. Additionally, the cycloaddition with 3-oxetanone afforded the 3-dehydropyranone product. Chiral 2-substituted azetidinones were also tolerated to form substituted dehydropiperidinones in high yield and enantiomeric excess.
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http://dx.doi.org/10.1021/acs.joc.5b01458DOI Listing
October 2015

Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles.

Acc Chem Res 2015 Aug 22;48(8):2354-65. Epub 2015 Jul 22.

Department of Chemistry, University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112-0850, United States.

Transition-metal catalysis has revolutionized the field of organic synthesis by facilitating the construction of complex organic molecules in a highly efficient manner. Although these catalysts are typically based on precious metals, researchers have made great strides in discovering new base metal catalysts over the past decade. This Account describes our efforts in this area and details the development of versatile Ni complexes that catalyze a variety of cycloaddition reactions to afford interesting carbocycles and heterocycles. First, we describe our early work in investigating the efficacy of N-heterocyclic carbene (NHC) ligands in Ni-catalyzed cycloaddition reactions with carbon dioxide and isocyanate. The use of sterically hindered, electron donating NHC ligands in these reactions significantly improved the substrate scope as well as reaction conditions in the syntheses of a variety of pyrones and pyridones. The high reactivity and versatility of these unique Ni(NHC) catalytic systems allowed us to develop unprecedented Ni-catalyzed cycloadditions that were unexplored due to the inefficacy of early Ni catalysts to promote hetero-oxidative coupling steps. We describe the development and mechanistic analysis of Ni/NHC catalysts that couple diynes and nitriles to form pyridines. Kinetic studies and stoichiometric reactions confirmed a hetero-oxidative coupling pathway associated with this Ni-catalyzed cycloaddition. We then describe a series of new substrates for Ni-catalyzed cycloaddition reactions such as vinylcyclopropanes, aldehydes, ketones, tropones, 3-azetidinones, and 3-oxetanones. In reactions with vinycyclopropanes and tropones, DFT calculations reveal noteworthy mechanistic steps such as a C-C σ-bond activation and an 8π-insertion of vinylcyclopropane and tropone, respectively. Similarly, the cycloaddition of 3-azetidinones and 3-oxetanones also requires Ni-catalyzed C-C σ-bond activation to form N- and O-containing heterocycles.
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http://dx.doi.org/10.1021/acs.accounts.5b00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681814PMC
August 2015

Ni(NHC)]-catalyzed cycloaddition of diynes and tropone: apparent enone cycloaddition involving an 8π insertion.

J Am Chem Soc 2014 Dec 5;136(51):17844-51. Epub 2014 Dec 5.

Department of Chemistry, University of Utah , 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.

A Ni/N-heterocyclic carbene catalyst couples diynes to the C(α)-C(β) double bond of tropone, a type of reaction that is unprecedented for metal-catalyzed cycloadditions with aromatic tropone. Many different diynes were efficiently coupled to afford [5-6-7] fused tricyclic products, while [5-7-6] fused tricyclic compounds were obtained as minor byproducts in a few cases. The reaction has broad substrate scope and tolerates a wide range of functional groups, and excellent regioselectivity is found with unsymmetrical diynes. Theoretical calculations show that the apparent enone cycloaddition occurs through a distinctive 8π insertion of tropone. The initial intramolecular oxidative cyclization of diyne produces the nickelacyclopentadiene intermediate. This intermediate undergoes an 8π insertion of tropone, and subsequent reductive elimination generates the [5-6-7] fused tricyclic product. This initial product undergoes two competing isomerizations, leading to the observed [5-6-7] and [5-7-6] fused tricyclic products.
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http://dx.doi.org/10.1021/ja5105206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291811PMC
December 2014

Nickel-catalyzed cycloaddition of 1,3-dienes with 3-azetidinones and 3-oxetanones.

Angew Chem Int Ed Engl 2013 Nov 23;52(46):12161-5. Epub 2013 Sep 23.

Department of Chemistry, University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112-0850 (USA) http://www.chem.utah.edu/directory/faculty/louie.html.

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http://dx.doi.org/10.1002/anie.201306869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113093PMC
November 2013

Application of real-time RT-PCR in vector surveillance and assessment of replication kinetics of an emerging novel ECSA genotype of Chikungunya virus in Aedes aegypti.

J Virol Methods 2013 Nov 11;193(2):419-25. Epub 2013 Jul 11.

Division of Virology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, M.P., India.

Chikungunya has emerged as one of the most important arboviral infection of global significance. Expansion of Chikungunya virus endemic areas can be ascribed to naive population, increasing vector population and adaptability of virus to new vector. In this study, a SYBR Green I based quantitative RT-PCR assay was developed. The assay was found to be 10-fold more sensitive than conventional RT-PCR and no cross reactivity was observed with related alphaviruses and flaviviruses. The detection efficiency of the assay was impervious to mosquitoes of different pool sizes. Vector surveillance has resulted in detection of CHIKV RNA in Aedes aegypti, confirming its vectorial potential for CHIKV in northern India. The assessment of the assay was further carried out by studying the competence of Indian Ae. aegypti for CHIKV, which revealed 100% infection rate and dissemination rate with 60% transmission rate. The replication kinetics of CHIKV in different anatomical sites of Ae. aegypti revealed highest titre at day 6 post infection in midgut and at day 10 post infection in saliva, legs and wings. The implementation of the assay in detecting lower viral load makes it a remarkable tool for surveillance of virus activity in mosquitoes.
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http://dx.doi.org/10.1016/j.jviromet.2013.07.004DOI Listing
November 2013

Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice.

Nanotechnology 2012 Dec 27;23(50):505101. Epub 2012 Nov 27.

Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation.Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well.NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone.In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy.
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http://dx.doi.org/10.1088/0957-4484/23/50/505101DOI Listing
December 2012

Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chlorides.

Chem Commun (Camb) 2012 Jan 14;48(2):203-5. Epub 2011 Nov 14.

Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA.

A protocol for the Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chlorides that minimizes protodeboronation is described. A combination of catalytic amounts of Pd(OAc)(2) and SPhos in conjunction with CsF in isopropanol effectively affords a variety of coupled products. Surprisingly, a dramatic temperature dependence in product selectivity was observed.
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http://dx.doi.org/10.1039/c1cc15990aDOI Listing
January 2012

Pazopanib, a multitargeted tyrosine kinase inhibitor, reduces diabetic retinal vascular leukostasis and leakage.

Microvasc Res 2011 Nov 16;82(3):346-50. Epub 2011 Sep 16.

Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, Aurora, CO 80045, USA.

Objective: To determine the efficacy of pazopanib eye drops in the streptozotocin induced diabetic retinopathy rat model.

Methods: A 0.5% w/v pazopanib suspension was prepared in phosphate buffered saline (PBS, pH 7.4) in the presence of 0.5% w/v sodium carboxymethyl cellulose. Brown Norway rats were divided into three groups (n=4) - (1) healthy, (2) diabetic, and (3) diabetic with treatment. The drug suspension was administered twice daily as eye drops to group 3 for 30 days. Efficacy parameters including the number of adherent leukocytes in the retinal vasculature (leukostasis), blood-retinal FITC-dextran leakage, and vitreous-to-plasma protein ratio were measured.

Results: Pazopanib suspension in the form of eye drops significantly reduced leukostasis (32%), FITC-dextran leakage (39%), and the vitreous-to-plasma protein ratio (64%) in diabetic animals compared to untreated diabetic group.

Conclusion: Pazopanib eye drops can alleviate retinal complications of diabetic retinopathy.
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http://dx.doi.org/10.1016/j.mvr.2011.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233473PMC
November 2011

Polyamidoamine dendrimer hydrogel for enhanced delivery of antiglaucoma drugs.

Nanomedicine 2012 Jul 17;8(5):776-83. Epub 2011 Sep 17.

Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia 23284, USA.

Unlabelled: Dendrimer hydrogel (DH), made from ultraviolet-cured polyamidoamine dendrimer G3.0 tethered with three polyethylene glycol (PEG, 12,000 Da)-acrylate chains (8.1% w/v) in pH 7.4 phosphate buffered saline (PBS), was studied for the delivery of brimonidine (0.1% w/v) and timolol maleate (0.5% w/v), two antiglaucoma drugs. DH was found to be mucoadhesive to mucin particles and nontoxic to human corneal epithelial cells. DH increased the PBS solubility of brimonidine by 77.6% and sustained the in vitro release of both drugs over 56-72 hours. As compared to eye drop formulations (PBS-drug solutions), DH brought about substantially higher human corneal epithelial cells uptake and significantly increased bovine corneal transport for both drugs. DH increased timolol maleate uptake in bovine corneal epithelium, stroma, and endothelium by 0.4- to 4.6-fold. This work demonstrated that DH can enhance the delivery of antiglaucoma drugs in multiple aspects and represents a novel platform for ocular drug delivery.

From The Clinical Editor: Dendrimer hydrogel was studied as agent for simultaneous delivery of two anti-glaucoma drugs, one hydrophobic and one hydrophilic. Superiority over standard PBS-based formulation was clearly demonstrated for both drugs. The work may be a novel platform for ocular drug delivery.
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http://dx.doi.org/10.1016/j.nano.2011.08.018DOI Listing
July 2012

Trabecular meshwork and lens partitioning of corticosteroids: implications for elevated intraocular pressure and cataracts.

Arch Ophthalmol 2011 07 14;129(7):914-20. Epub 2011 Mar 14.

Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.

Objective: To determine whether adverse effects such as elevated intraocular pressure and cataracts, which are lower with dexamethasone when compared with fluocinolone acetonide or triamcinolone acetonide, may be explained in part by the differences in drug lipophilicity and partitioning of these drugs into the trabecular meshwork and lens.

Methods: The n-octanol/phosphate-buffered saline (pH 7.4) partition coefficient (log distribution coefficient [D]) and bovine/human ocular tissue partition coefficients were determined for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide at 37°C.

Results: The log D of the corticosteroids ranged from 0.712 to 2.970. The ranges of tissue:PBS partition coefficients following drug incubation at 0.4, 2.0, and 10.0 μg/mL were 0.35 to 1.56, 0.30 to 2.12, and 0.30 to 1.95, respectively, for the bovine lens, 0.87 to 4.18, 0.71 to 4.40, and 0.69 to 5.86, respectively, for the human lens, and 2.98 to 9.48, 2.41 to 9.16, and 1.71 to 9.96, respectively, for the bovine trabecular meshwork. In general, tissue partitioning showed a positive correlation with log D. Dexamethasone, with lipophilicity less than triamcinolone acetonide and fluocinolone acetonide, exhibited the least amount of partitioning in the trabecular meshwork and lens among these 3 corticosteroids commonly used for treating diseases at the back of the eye.

Conclusion: Binding of corticosteroids to the trabecular meshwork and lens increases as drug lipophilicity increases.

Clinical Relevance: Less lipophilic corticosteroids with limited partitioning to the trabecular meshwork and lens may result in reduced incidence of elevated intraocular pressure and cataracts.
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http://dx.doi.org/10.1001/archophthalmol.2011.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407594PMC
July 2011

Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids.

Drug Metab Dispos 2011 May 23;39(5):771-81. Epub 2011 Feb 23.

Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ∼ 17 to 300 μg/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues. Transport across sclera and SCRPE was in the range of 3.9 to 10.7% and 0.3 to 1.8%, respectively, with the transport declining with an increase in lipophilicity. Ex vivo and in vivo transscleral delivery indicated tissue distribution in the order CRPE ≥ sclera > retina > vitreous. Tissue partitioning showed a positive correlation with drug lipophilicity (R(2) = 0.66-0.96). Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with drug solubility (R(2) = 0.91-1.0) but not lipophilicity (R(2) = 0.24-0.41) or tissue partitioning (R(2) = 0.24-0.46) when delivered as suspensions. In vivo delivery was lower in all eye tissues assessed than ex vivo delivery, with the in vivo/ex vivo ratios being the lowest in the vitreous (0.085-0.212). Upon exposure to corticosteroid suspensions ex vivo or in vivo, transscleral intraocular tissue distribution was primarily driven by the drug solubility.
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http://dx.doi.org/10.1124/dmd.110.037408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082374PMC
May 2011

An unusual presentation of atrial myxoma in an elderly patient: a case report.

Cases J 2008 Dec 10;1(1):384. Epub 2008 Dec 10.

Consultant Cardiologist, Dewsbury Hospital, Halifax Road, Dewsbury, WF13 4HS, UK.

Left atrial myxoma is the most common intracardiac tumour. It could be seen in patients between 3-83 years of age, with the majority presenting in fifth decade of life as sporadic cases (90%) and second decade as familial cases (10%) 1. It is an important source of central nervous system embolism 2. Elderly patients often present with non specific symptoms that are often overlooked in the absence of a supporting cardiac history which makes an early diagnosis challenging. This case report discusses an unusual presentation of left atrial myxoma in an elderly patient.
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http://dx.doi.org/10.1186/1757-1626-1-384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614940PMC
December 2008
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