Posts Tagged ‘Battistini’

3D printing: Improvising the Next-generation Batteries

Reporter: Vaishnavee Joshi BSc and MSc.

Batteries are the building blocks of 21st-century technology; it has been with us for a long time. The true significance of the batteries can be traced down to the 1800s when the first true battery was invented by the Italian physicist Alessandro Volta. With the pace of time and invention, many great contributions were made in the production and advancement of batteries. The two great leaps that are a first great leap forward:

  • Lithium-ion batteries and second leap forward:
  • Nanotechnology, completely transformed the production.

What began as an experiment, developed as an indispensable item in our world.

Dawn of 3-D printing technology

Astonishingly, the rapid growth in high throughput computer-aided technology and the earliest 3D printing manufacturing equipment which was developed by Hideo Kodama increased the development of three broad types of 3D manufacturing technologies that is :

  • Sintering,
  • Melting
  • Stereolithography.

3-D printing, also known as additive manufacturing is a method of creating a 3D object layer by layer using a computer created design since the last decade 3D printed batteries have been an area of interest for both consumer electronics and electric vehicles. The benefit of 3D printing of batteries are that the production of batteries is flexible, customizable for one particular application and printing can save weight or reduce mass, and even higher energy densities can be achieved by transforming the internal topologies. Production and research in 3D printing technologies are at their highest peaks in Asia and America many American firms considers battery 3D printing to be a publicly traded U.S branch.

Blackstone Resources AG(Swx: BLS) is a Swiss holding company focused on battery technology and metals they are creating processes tagged as Blackstone thick layer technology for 3D printing lithium-ion batteries. The patented process can fabricate both electrolyte and solid-state batteries and also cutting the expenditure by 70  percent the other demonstrated organizations that are located at Canada, Peru, Mongolia. It also claims to have begun exploring several minerals


Sakuu Corporation

A bay area start up that developed a unique Blackstone thick layer technology that process and combines materials such as ceramics and metals for a variety of applications. It also claims that the production of lithium SSBs can be manufactured at scale using its multi-material multi-method (4M) technology. it uses standard cathode materials but in the future, it will also feature higher voltage cathodes with the potential of 25 % more energy the firms also states that “They are focused on finishing the platform that can do it.

We are working in parallel with all of the battery chemistry and everything else

Blackstone and Sakuu are some of many firms that are competing in re-creating and patenting the 3D printing methods. Nevertheless, the 4M technology of Sakuu holds a promising future in the world of lithium batteries with this elixir the applications are immense and beyond the scope.   


First Lithium Solid State Battery Produced by 3D Printing Startup Sakuu

2. Battery 3D printing firm considers publicly traded U.S. branch. June 22,20121, Michael Molitch-Hou, 3D printing. LIVE

3. 3D printed batteries: here comes the future. August 10, 2020, Jeff Butler.

4. The history and development of batteries. April 30, 2015, Jose Alarco and Peter Talbot


5. Sakuu to Release Multi-Material, Multi-Process Battery 3D Printer


Other related articles published in this Open Access Online Scientific Journal include the following:

Series E, Volume Four: Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices

Editors: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Available on Kindle Store @ Amazon.com since 12/30/2017

  • Volume 4: Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices. On Amazon.com since 12/30/2017

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Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Curator: Aviva Lev-Ari, PhD, RN


UPDATED on 8/17/2018

Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension.

The peptide endothelin constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA).[1] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).[2]

Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency, and designated an orphan drug, for the treatment of pulmonary hypertension.[3][4][5][6][7]

Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.

Ambrisentan was first approved by the U.S. Food and Drug Administration (FDA) on Jun 15, 2007, then approved by the European Medicines Agency (EMA) on Apr 21, 2008 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 23, 2010. In 2000, Abbott, originator of ambrisentan, granted Myogen (acquired by Gilead in 2006) a license to the compound for the treatment of PAH. In 2006, GlaxoSmithKline obtained worldwide rights to market the compound for PAH worldwide, with the exception of the U.S. It is marketed as Letairis® by Gilead in US.

Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Letairis® is available as film-coated tablet for oral use, containing 5 or 10 mg of free Ambrisentan. The recommended starting dose is 5 mg once daily with or without food, and increase the dose to 10 mg once daily if 5 mg is tolerated.


Introduction to Endothelin

Endothelin (ET) derived from vascular endothelial cells (ECs), which consists of a 21 amino acid peptide, has a strong and persistent vasoconstrictive action (1). ET has three family peptides (ET-1, ET-2, and ET-3). As the distribution and properties of these peptides are different, each peptide is believed to play specific physiological roles. ET has two types of receptor: the ETA receptor with a high affinity for ET-1 and ET-2 is mainly located on muscle cells, whereas the ETB receptor with an affinity for all three peptides lies on endothelial, epithelial, endocrine, and nerve cells. Of the three ET isoforms,

ET-1 plays a much more important role in the regulation of vascular tone than the others and has a powerful effect on the cardiovascular system. Thus, the role of ET-1 and its receptors as the etiology or precipitating factors in various cardiovascular diseases (CVD) has been investigated (2, 3). In addition, numerous studies have reported effective treatment targeted at ET-1 in pulmonary hypertension, salt-sensitive hypertension, diabetes, and acute and chronic kidney diseases using ETconverting enzyme (ECE) inhibitors and ET-receptor antagonists (2, 4). Several animal models genetically lacking ET-1 and ET receptors have also been used as a tool for determining the physiological and pathophysiological roles of ET-1 and ET receptors in CVD (5 – 10).

Fig. 1.

Schematic illustration of ET-1 production and ET receptor–mediated actions on vascular endothelial cells and smooth muscle cells. G: G protein, ROS: reactive oxygen species, CaM: calmodulin, AA: arachidonic acid, PGI2: prostaglandin I2, AC: adenylate cyclase, sGC: soluble guanylate cyclase.

Figure Source: Journal of Pharmacological Sciences, 119, 302 – 313 (2012)

Introduction to the ET system

Endothelial Cells (ECs) are known as the main physiological source of vascular ET-1. Vascular smooth muscle cells (VSMCs), macrophages, leukocytes, cardiomyocytes, and fibroblasts are also capable of ET-1 production (11 – 13).

Several studies have indicated that various physical and chemical factors such as thrombin, angiotensin II, cytokines, hypoxia, and shear stress stimulate ET-1 gene expression in ECs by DNA binding of transcription factors including activator protein-1, GATA-2, Smad, nuclear factor-kappa B (NF-κB), and hypoxia inducible factor-1 (14 – 18). On the other hand, ET-1 is synthesized as an inactive 203-amino-acid precursor, preproET-1, which is proteolytically cleaved to yield a second inactive 39 (or 38)-amino-acid segment called ‘big’ ET-1.

The last part of the proteolytic process is mainly carried out by ECE (ECE-1 and ECE-2) and leads to the production of the bioactive form of 21-amino-acid peptide ET-1. As ET-1 release from ECs is constitutive, ET-1 biosynthesis and release appear to be mainly controlled via regulation of gene transcription and/or ECE activity.

On the other hand, although another ETB-receptor subtype (ETB2) located on VSMCs exerts vasoconstriction, it has become clear that ETB2 receptor–induced vasoconstriction is negligible under normal conditions but becomes more important in some kinds of diseases such as atherosclerosis and essential hypertension (24 – 26).

Has the considerable promise of ET-1 manipulation as a therapeutic option been realized? Its release, perhaps from a dysfunctional endothelium, could have a major role in the pathogenesis of a variety of cardiovascular diseases (reviewed by Haynes and Webb, 1992 andRubanyi and Polokoff, 1994). The discovery of endothelin-1 (ET-1) almost 20 years ago (Yanagisawa et al., 1988) was rapidly followed by prospects that pharmacological manipulation of the ET-1 system might provide powerful new treatments for many clinically significant cardiovascular conditions.
Fig. 2.
Proposed explanation for the interaction between the ET-1 system and norepinephrine (NE) release from cardiac sympathetic nerve endings in protracted myocardial ischemia. ATP is depleted and axoplasmic pH is reduced under ischemic conditions.This diminishes vesicular storage of NE, leading to a large increase in free axoplasmic NE. Compensatory activation of the neuronal Na+/H+ exchanger (NHE) by axoplasmic acidification causes influx of Na+ in exchange for H+. The resulting Na+ accumulation triggers a massive release of free axoplasmic NE via a reversal of the NE transporter (NET). Released NE acts on postsynaptic adrenoceptors on myocytes. Stimulation of the ETA receptor existing in sympathetic nerve endings by endogenously generated or exogenously applied ET-1 enhances neuronal NHE activity and results in increases in NE release. In contrast, exogenously applied big ET-1 is converted to ET-1 by ECE-1 expressed on the cell surface, and this ET-1 preferentially binds to the ETB receptor located on NOS-containing cells. As a result, increments in NO production cause inhibition of NE release. NCX: Na+/Ca2+ exchanger, VMAT: vesicular monoamine transporter.
Over 200 references in this paper trace the trail of experiments and clinical trials conducted by induction of therapeutic potential compounds that target the ET system. The role of ET-1 in cardiovascular disease and development of pharmacological tools that manipulate its activity, include agents that
The rapid identification of such compounds led remarkably quickly to the development of orally active antagonists (Clozel et al., 1994) and their administration to patients (Kiowski et al., 1995). Additional insight into ET physiology has been gained from studies with
most dramatically revealing the crucial role of ET-1 in development (Kurihara et al., 1994) and regulation of salt excretion (Ahn et al., 2004Bagnall et al., 2006Ge et al., 2006).

The recent licensing of

  • bosentan
  • sitaxsentan and
  • ambrisentan

for treatment of PAH is the most obvious demonstration of the clinical benefit derived from therapeutic manipulation of the ET-1 system in cardiovascular disease. This development of one of the first effective treatments for a condition with poor prognosis has obvious clinical significance and is likely to be extended to include PAH associated with connective tissue disorders.

Thus, ET antagonists are already realizing their potential in treatment of cardiovascular diseases, while early clinical data suggest these compounds may prove beneficial in other conditions, such as resistant hypertension, chronic kidney disease and SAH. In contrast, a potential role in conditions associated with vascular remodelling (restenosis, chronic obstructive pulmonary disease and transplant graft rejection) remains speculative and requires further investigation. It should also be noted that the clinical experience with ET antagonists in patients with cardiovascular disease remains relatively limited and the design of new trials could be improved using knowledge gained from previous studies, particularly with regard to drug dose and selectivity. These successes must obviously be balanced against the failure of ET antagonists to realize their potential in the treatment of heart failure, and the fact that teratogenic effects have restricted their possible use to treatment of conditions where childbearing potential is unlikely to be an issue.

Several reasons have been proposed to account for the disappointing outcomes in clinical trials as compared to investigations using animal models of disease, including

  • inadequate models or a bias in publication towards positive outcomes;
  • incorrect dose/timing of administration;
  • the need to show additional benefit over existing treatments; and
  • ET activation being a consequence rather than a cause of the condition.

Whatever the reason, this experience urges caution in extrapolating data obtained in vitro and in animals to humans. It is hoped that additional information will emerge from unpublished clinical trials that will shed light on previous failures (Kelland and Webb, 2006), and that the combination of powerful pharmacological and molecular approaches will help us to better understand the role of ETA and ETB receptors in health and disease so as to fully realize the clinical potential created by the identification of the powerful vasoconstrictor peptide, ET-1.

Further studies have addressed the role of ET receptor antagonism in erectile dysfunction and aneurysmal SAH, with mixed results. A double-blind pilot study of 53 patients with mild-to-moderate erectile dysfunction demonstrated no benefit of the ETA-selective antagonist BMS-193884 (100mg by mouth) over placebo (Kim et al., 2002).

The ETA-selective antagonist clazosentan was specifically designed for intravenous use in conditions characterized by cerebral vasoconstriction. Its potential in treating severe aneurysmal SAH has recently been addressed in a phase IIa pilot study for the Clazosentan to Overcome Neurological iSChaemia and Infarction OccUrring after Sub-arachnoid haemorrhage (CONSCIOUS-1) trial (Vajkoczy et al., 2005). This ‘pre-CONSCIOUS-1′ study documented a reduction in the frequency and severity of cerebral vasospasm following SAH.

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ETA receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH).
In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including
  • resistant hypertension,
  • chronic kidney disease,
  • connective tissue disease and
  • sub-arachnoid haemorrhage
are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies.

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