Q1 - What is the InStim therapy?

The InStim therapy is designed to get inflammation under control via real time monitoring and real time adjustments to both bioelectric signaling and biologics therapies.  The first line of therapy is 100% bioelectric, preferably non-invasive, and only if this is not successful a second wave of biologics therapy via a re-fillable micro infusion pump is included.  Biologics therapy may include stem cells, exosomes, PRF, PRP, Micro RNAs, nutrient hydrogel, organ specific matrix, oxygenated nanoparticles and selected alkaloids.

Q2 - What inflammatory and anti-inflammatory cytokines does the InStim bioelectric therapy seek to modulate to get inflammation under control?
Anti-inflammatory – Protein tristetraprolin (TTP).  SOCS1 and SOCS3 in T cell mediated inflammatory diseases. The full interleukin family of cytokines including IL6, IL1, IL4, IL6, IL10, IL11, IL13, IL18, IL33, TGF-B and TNF-A with a special focus on IL6.   Anti-inflammatory cytokines and organ regenerative proteins SDF1, SCF, GCSF, IGF1, HGF, EGF, PDGF, VEGF, Follistatin, Tropoelastin, GDF10, GDF11, eNOS, HIF1a, Activin A+B, Neurogenin 3.
Bioelectric signaling sequences that inhibit the production of proinflammatory cytokines such as GM-CSF, IFN- g, and MIP-2.
Q3 - What is the importance of real time monitoring and real time therapy?

The same cytokine delivered at the wrong time at the wrong dose can worsen inflammation but if delivered at the right time in the right dose can reduce inflammation. A certain level of inflammation in a certain sequence is essential to healthy healing but chronic inflammation can be a root cause of many diseases including cancer. The primary purpose of real time treatment is to end chronic inflammation.

Q4 - How does bioelectric signaling work as a therapy?
Precise bioelectric signals can give instructions to the DNA of a cell to build new proteins on demand.  Bioelectric signals can also influence functions of cell membrane including membrane potentials and pore openings and closings on demand.  See slide show here as a Bioelectric Regeneration Basics Educational Primer –
Bioelectric cell properties have been revealed as powerful targets for modulating stem cell function, regenerative response, developmental patterning, and tumor reprograming. Spatio-temporal distributions of endogenous resting potential, ion flows, and electric fields are influenced not only by the genome and external signals but also by their own intrinsic dynamics. Ion channels and electrical synapses (gap junctions) both determine, and are themselves gated by, cellular resting potential. Thus, the origin and progression of bioelectric patterns in multicellular tissues is complex, which hampers the rational control of voltage distributions for biomedical interventions.
Q5 - How does InStim know what bioelectric signals to deliver when?
There are two methods that work together in unison to determine the correct bioelectrical signaling sequences customized real time to reduce inflammation.
A.  Constant real time monitoring of inflammation and constant real time adjustments. Signals chosen to produce anti-inflammatory proteins, such as IL6, IL33, TTP, SOCS1 and SOCS3, based on results and dosing from previous anti-inflammatory cytokine studies dosing stored in our micro-processor.  A variety of means are used for constant real time monitoring including bioelectric, light, blood and cytokine level scans. 
B.  Stored in our microprocessor are the sequences of bioelectric signals and cytokines that were recorded in healthy patients that recover quickly from inflammation causing injuries that do not revert into chronic inflammation.  Our real time monitoring and adjustments check itself against the ideal cytokine expressions found in healthy recovery patients via our microprocessor and the InStim proprietary program. 
Example – Toddlers recover from brain injuries very quickly and do not fall into chronic neuro inflammation as many older adults do.  We have recorded the bioelectric signaling sequences and cytokine expressions that occur in healthy toddler head/brain injury recovery which is stored in our microprocessor database.  Our real time monitoring and real time therapy adjustments are constantly checked against this ideal as well as the results of real time observations if inflammation is subsiding or increasing based on constant adjustments. 

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1. Introduction

1.1. Bioelectricity: Why Model Electrical Activity in Non-Neural Cells?

Explaining and learning to control large-scale pattern is a central unsolved problem, with implications for mitigation of birth defects, and the advancement of regenerative medicine and synthetic bioengineering. The dynamics of signals orchestrating large-scale order in vivo are a key area of research, as understanding these signals is an essential first step in developing interventions that alter anatomical outcomes. The dynamics of chemical signals and their gradients are becoming increasingly well-understood (Reingruber and Holcman, 2014Slack, 2014Werner et al., 2015). However, endogenous bioelectric signals represent a parallel regulatory system that exerts instructive control over large-scale growth and form. Recent work has demonstrated that ionic and bioelectrical signaling of various cell types underpins a powerful system of biological pattern control [reviewed in Nuccitelli (2003a)McCaig et al. (2005)Levin (20122014)Levin and Stephenson (2012), and Tseng and Levin (2013)]. Importantly, endogenous bioelectric gradients across tissues can be a very early pre-pattern for subsequent transcriptional and morphogenetic events. For example, during craniofacial development of frogs, specific transmembrane voltage (Vmem) patterns determine the downstream shape changes and gene expression domains of the developing face (Vandenberg et al., 2011Adams et al., 2016) and brain (Pai et al., 2015). Furthermore, experimental modulation of cell Vmem states can radically alter large-scale anatomy, for example, inducing eye formation in ectopic body areas, such as the gut, where the master eye regulator Pax6 cannot induce eyes (Pai et al., 2012), reprograming the regeneration blastemas of planaria to produce heads instead of tails (Beane et al., 2011), or rescuing normal brain patterning despite the presence of mutated neurogenesis genes, such as Notch (Pai et al., 2015).

1.2. Local and Long-Range Order in Bioelectrical Networks

On the scale of single cells, the Vmem spanning every living cell’s plasma membrane is a demonstrated regulator of key processes, such as cell proliferation (Blackiston et al., 2009), programed cell death (Boutillier et al., 1999Wang et al., 1999), and differentiation (Ng et al., 2010), and is known to be a factor in the activation of immune cells (Bronstein-Sitton, 2004). For example, despite the action of growth factors, stem cells have been inhibited from differentiation by preventing the cells from developing a hyperpolarized Vmem (Sundelacruz et al., 2008). The bioelectric properties of single cells are fairly well-understood (Lodish et al., 2000Wright, 2004). However, bioelectric states often regulate large-scale anatomical properties, such as axial polarity (Marsh and Beams, 1952Beane et al., 2011), organ size (Perathoner et al., 2014) and shape (Beane et al., 2013), and induction of formation of whole appendages (Adams et al., 2007Tseng et al., 2010). Moreover, pattern control involves long-range coordination of bioelectric states. In metastatic conversion (Morokuma et al., 2008Blackiston et al., 2011Lobikin et al., 2012), tumor suppression (Chernet and Levin, 2014Chernet et al., 2015), brain size regulation (Pai et al., 2015), and head–tail polarity in planarian regeneration (Beane et al., 2011), the patterning outcome in one region of the animal is a function of the bioelectric states of both local and remote cells. Thus, it is imperative to understand not only how ion channel and pump activity controls single-cell electrical properties but also how electrical gradients self-organize, propagate, and evolve in multicellular networks. Moreover, understanding the origin of developmental order also requires that we understand how tissue-level gradients of bioelectric properties arise.
In a multicellular collective, endogenous patterns of Vmem and electric fields provide positional information and achieve long-range coordination of cell activity. As in the central nervous system, this occurs because cells in a tissue are not isolated, but are electrochemically connected (and, therefore, communicating) in several ways, including intracellular channels known as gap junctions [GJ (Goodenough and Paul, 2009)], and by ephaptic coupling created by local field potentials, which enable one cell’s Vmem activity to influence that of its neighbor’s (Zhou et al., 2012). These connections between cells create bioelectrical circuits involving long-range signal patterns through whole structures, which have been determined crucial for developing embryos (Jaffe, 1981Hotary and Robinson, 1990Hotary and Robertson, 1994Shi and Borgens, 1995), normal limb development of animals (Altizer et al., 2001), healing of wounds (Nuccitelli, 19922003aMcCaig et al., 2005Zhao, 2009), and even in continuous tumor suppression in adult animals (Chernet and Levin, 20132014). The ability for cells to couple and communicate makes local changes to cell Vmem relevant in terms of long-range signals capable of affecting the whole. Likewise, the inability for cells to form communication networks, for instance, due to improper expression or function of GJ connections, is observed in disease processes, such as cancer (Leithe et al., 2006Trosko, 2007). Even briefly altering the bioelectric connectivity of a cellular network enables rewriting of an organism’s target morphology. For example, genomically normal fragments of planarian flatworms can be induced to regenerate heads with shapes and internal anatomy belonging to other extant species (Emmons-Bell et al., 2015), or changed to a two-headed form that regenerates with two heads in perpetuity, illustrating the ability to stably re-wire bioelectric circuits with permanent changes to the overall anatomy (Oviedo et al., 2010).
Another important bioelectrical signal relevant to multicellular clusters is a voltage gradient known as the trans-epithelial potential (TEP), which forms at the outer boundary of an organ or organism. The TEP is also implicated in normal developmental processes (Shi and Borgens, 1995), wound healing (Zhao, 2009), and disease processes, such as cystic fibrosis (Hay and Geddes, 1985), fungal infection (Gow and Morris, 1995), inflammation, and cancer (Soler et al., 1999). The TEP is created when multicellular structures develop impermeable tight junctions (TJ) between cells at the exterior boundary (Hay and Geddes, 1985); disruptions to this process induce electric fields that serve as guidance cues for many migratory cell types during injury response (McCaig, 1990Zhao, 2009Yamashita, 2013) and limb development (Borgens, 1984Borgens et al., 1987). Understanding plasma membrane voltage gradients and transepithelial potentials, and their spatio-temporal transitions in vivo, is a key enabling step for the field of developmental bioelectricity and its applications.

“Inflammation cannot be managed with a single drug or single bioelectric signal. The body produces inflammation to promote healing and the right cytokines at the right time in the right sequence greatly aide in healing. The very same cytokines at the wrong time in the wrong sequence and at the wrong levels for the wrong duration can cause detrimental damage to health. Our invention is the first to read real-time these inflammatory and anti-inflammatory cytokines and to deliver multiple cytokine up or down regulation real time to best attempt to gain the right inflammatory balance.”

Howard J. Leonhardt

Inventor, Founder and CEO, InStim and Leonhardt’s Launchpads

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