Endonovo to Fund All Currently Planned and Future Clinical Trials for Traumatic Brain Injury, Post-Concussion Syndrome, Stroke and Other Central Nervous System Disorders
Under the terms of the settlement agreement, RGN paid $150,000 to Endonovo Therapeutics and granted an exclusive option to Endonovo to acquire the PEMF assets of RGN for $4.5 million, which the Company exercised per the settlement agreement. The settlement has resulted in the dismissal of the case in the Superior Court of California, County of Los Angeles.
Endonovo believes settling the case at this time is in the best interest of all parties, and its acquisition of RGN's PEMF assets could result in substantial benefit to its shareholders.
The PEMF assets includes a portfolio of intellectual property, including 27 issued patents with foreign patent protection covering the therapeutic use of PEMF for the treatment of various central nervous system disorders. Endonovo Therapeutics will initiate and fund both currently planned and all future clinical trials to evaluate the use of PEMF in the treatment of central nervous system disorders, including traumatic brain injury, post-concussion syndrome, stroke and multiple sclerosis.
The PEMF assets additionally include a portable, disposable PEMF device with a CE Mark and an FDA 510(k) clearance for the treatment of soft tissue injuries and post-surgical pain and edema in addition to medical reimbursement for the treatment of chronic wounds. Endonovo Therapeutics will begin the commercialization of the PEMF assets through licensing and joint venture agreements and the creation of various sales channels and distribution agreements.
Traumatic Brain Injury (TBI), also called craniocerebral trauma is a brain dysfunction caused by an outside force, usually a violent blow to the head. In 2010, approximately 2.5 million people sustained a traumatic brain injury. More than half of all brain injuries are bad enough to require people to go to the hospital. A severe TBI not only affects the quality of life of an individual and their family, but also imposes a large economic toll on society. The economic cost of TBI in 2010 was estimated to be approximately $76.5 billion. Severe brain injuries can lead to permanent brain damage or death. Half of all TBIs are from motor vehicle accidents, with military personnel in combat zones and athletes also being at risk.
A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do. Wounds that do not heal within three months are often considered chronic. Some of the most common types of chronic wounds include, ischemic wounds, radiation poisoning wounds, surgical wounds and ulcers, such as arterial ulcers, venous ulcers, diabetic ulcers and pressure ulcers. The increasing prevalence of diabetes mellitus is a driving factor in the occurrence of chronic wounds, such as diabetic ulcers. A recent study published in Value in Health, found that approximately 15% of Medicare beneficiaries in 2014 (8.2 million) had at least one type of wound or infection at an estimated cost of nearly $32 billion to CMS. As the US Centers for Medicare and Medicaid Services (CMS) moves toward an outcome-based model, CMS needs to take a careful look at wound care, according to the authors of the study. New, more effective and equally important, more cost effective therapies are needed as the cost associated with treating these chronic wounds continues to rise.
“We are very excited about this acquisition and the value it will provide our shareholders,” said Endonovo CEO, Alan Collier. “We are adding clinical stage programs and expanding our pipeline of non-invasive electroceuticals into central nervous system disorders, strengthening our intellectual property, and adding market-ready products for the treatment of various soft tissue injuries, post-surgical pain and swelling, as well as chronic wounds,” stated Mr. Collier.
“This acquisition represents a significant milestone for Endonovo and positions the company as the leader in bioelectronic medicine allowing for more favorable financing, uplisting the company’s common stock onto a national stock exchange and providing the company a valuation comparable to other companies in the electrical stimulation/electroceuticals sector,” concluded Mr. Collier.
Non-Invasive Electroceutical Significantly Increased Cardiac Function and Reduced Ventricular Remodeling in Infarcted Animals
Physiological and Molecular Genetic Effects of Time-Varying Electromagnetic Fields on Human Neuronal Cells
Thomas J. Goodwin, PH.D., Lyndon B. Johnson Space Center
National Aeronautics and Space Administration (NASA), Johnson Space Center, Houston, Texas
The present investigation details the development of model systems for growing two- and three dimensional human neural progenitor (NHNP) stem cells within a culture medium facilitated by a time-varying electromagnetic field (TVEMF), i.e. PEMF.
The cells and culture medium are contained within a two- or three-dimensional culture vessel, and the electromagnetic field is emitted from an electrode or coil. These studies further provide methods to promote neural tissue regeneration by means of culturing the neural cells in either configuration. Grown in two dimensions, neuronal cells extended longitudinally, forming tissue strands extending axially along and within electrodes comprising electrically conductive channels or guides through which a time-varying electrical current was conducted.
In the three-dimensional aspect, exposure to TVEMF resulted in the development of three-dimensional aggregates, which emulated organized neural tissues.
In both experimental configurations, the proliferation rate of the TVEMF cells was 2.5 to 4.0 times the rate of the non-waveform cells. Each of the experimental setups resulted in similar molecular genetic changes regarding the growth potential of the tissues as measured by gene chip analyses, which measured more than 10,000 human genes simultaneously.
This study clearly shows the ability to use TVEMF to control the proliferative rate, directional attitude, and molecular genetic expression of normal human neural progenitor cells. The procedure is applicable to, but not limited to, the control of NHNP cells in both two-dimensional and three-dimensional culture.
The genetic responses both up-regulated and down-regulated genes which were maturation- and growth-regulatory in nature. These genes are also primarily involved in the embryogenic process.
Therefore it is reasonable to conclude that control over the embryogenic development process may be achieved via the presently demonstrated methodology. Specific genes such as human germline oligomeric matrix protein, prostaglandin endoperoxide synthase 2, early growth response protein 1, and insulin-like growth factor binding protein 3 precursor are highly up-regulated. Keratin Type II cytoskelatal 7, mytotic kinesin like protein 1, transcription factor 6 like 1, mytotic feedback 27 control protein, and cellular retinoic acid binding protein are down-regulated. Each of these two sets is only an example from the approximately 320 genes changes expressed as a consequence of exposure to TVEMF.
There is significant precedent in the literature for the results reported above. Kepler et al. (1990) reported the effects of the neurons with oscillatory properties on the composite of neural networks. This work illustrates the likelihood that a pulse width modulated system might bring on specific responses in neural tissues. As previously discussed, Valentini et al. (1993) demonstrated the ability to enhance the outgrowth of neural fibers on materials that possess a weak electric charge. This would indicate that intense electric fields are not necessarily an essential component of this process, and that a weak and persistent stimulus might yield a measurable effect.
Additional evidence of the effects of magnetic fields exists in the work of Sandyk et al. (1992a). This communication details dramatic improvement of a patient with progressive degenerative multiple sclerosis. Briefly, the patient showed considerable improvement when subjected to treatment at a frequency of 2-7 Hz and an intensity of the magnetic field of 7.5 pico Tesla. These parameters marginally parallel those of this report. In a similar fashion, Sandyk et al. (1992b) reported significant improvement in patients treated with the same field strength and intensity. The ability to suppress or stimulate the growth of non-excitable cells has been reported in mouse lymphoma cells by Lyte et al. (1991). A narrow range of electric field was found to be effective at one end to stimulate and at the other to inhibit the growth of these cells. These data might suggest cellular receptors in all cells. To sustain this notion, Brüstle et al. (1996) reported the potential to use neural progenitors for recapitulation of neural tissues. As would be expected, this would require genetic control at the embryonic level. We believe this study indicates our ability to trigger these parametric events.
As is clearly demonstrated in the human body, the bioelectric, biochemical process of electrical nerve stimulation is a documented reality. The present investigation demonstrates that a similar phenomenon can be potentiated in a synthetic atmosphere, i.e., two-dimensionally or in rotating wall cell culture vessels.
One may use this electrical potentiation for a number of purposes, including developing tissues for transplantation, repairing traumatized tissues, and moderating some neurodegenerative diseases and perhaps controlling the degeneration of tissue as might be effected in a bioelectric stasis field.
The basis for Endonovo’s Time-Varying Electromagnetic Field (TVEMF) technology was created at NASA in conjunction with the development of cell therapies to treat injuries and diseases that astronauts might encounter during long term manned missions in outer space.
The original concept of TVEMF was developed when NASA realized that cellular growth increased as the space shuttle crossed the earth’s magnetic poles. It took over eight years to define and develop a device that produced the same effect. This magnetic field device (TVEMF) was originally designed to enhance cellular expansion (growth) in NASA’s rotating wall bioreactor. After numerous experimental studies, the results were so significant with the bioreactor that a prototype was designed for use directly on the human body.
Moving Beyond the Petri Dish
Cells grown in Petri dishes cannot form complex 3D tissues because they tend to sink within their growth mediums. This posed a limitation on researchers studying how tissues form inside the body.
In the 1970’s, a small group at NASA’s Johnson Space Center (JSC) began to think about outer space as a possible answer. Researchers at JSC theorized that if cells could be grown without the influence of the earth’s gravity, they would not sink to the bottom of the culture container; rather, they would stay suspended in the medium and therefore might assemble and form tissue that more closely resembles tissue in the body.
NASA Bioreactor Simulates Microgravity on Earth
NASA researchers developed a soup can-sized bioreactor that spun on its side, preventing cells from sinking to the bottom by maintaining a continuously free-falling state through the culture media. The bioreactor was able to simulate microgravity on earth, providing researchers with the ability to study how tissues form in the body three-dimensionally. The original goal was to attempt tissue growth on Space Shuttle missions. However, the Challenger disaster in 1986 resulted in the grounding of NASA’s space fleet. Subsequently, NASA researchers switched their efforts to creating a culturing device that simulated some aspects of microgravity on earth.
Experiments in Outer Space
NASA researchers conducted multiple experiments using the bioreactor aboard STS-70, STS-85 and STS-90.
During STS-70 in 1995, researchers tested the performance of the bioreactor in microgravity using colon cancer cells. The cells were able to aggregate and form masses 10 mm in diameter. These masses were 30 times the volume of those grown in the control experiment on the ground.
During STS-85 in 1997, researchers repeated the experiment using colon cancer cells and again, mature, differentiated tissue samples were grown. This confirmed previous results – microgravity is an environment beneficial to cell culture and tissue growth.
During STS-90 in 1998, human renal tubular cells were cultured in the bioreactor for 6 days. Researchers compared the activity of 10,000 genes in the flight and ground cultures and identified several of the control genes for differentiation and three-dimensional tissue formation.
Early on, as NASA researchers analyzed data from their experiments aboard the Space Shuttle, they discovered that cells were growing at an increased rate when passing over the earth’s magnetic poles; suggesting that the earth’s magnetic field was influencing cell growth.
Earth’s Magnetic Field Influences Cell Growth
Additionally, several growth factors and cytokines were upregulated in the bioreactor during cellular expansions.
NASA Researchers Add Pulsed Electromagnetic Fields to Bioreactor
Initially, NASA researchers could not replicate the cell growth achieved aboard the Space Shuttle. NASA was using basic sine waves, which could not produce the same effect.
Over the subsequent eight years, researchers experimented with multiple waveforms, frequencies, and slew rates and found the square waveform was able to help deliver the required results and allowed NASA to identify the exact magnetic field format that increased cell growth 400% and upregulated over 200 growth factors and cytokines (G-CSF, GM-CSF, IL-2) in the rotating wall bioreactor.
It was determined that a square waveform with a low frequency (5-10 Hz) and a very rapid slew rate provided optimized results for cellular expansion.
Shifting Away from Stem Cell Transplants
After achieving astounding results with the TVEMF-bioreactor, NASA researchers began to explore whether the effects of TVEMF on cell growth and growth factor production could be done inside the body.
The basic idea was to create a device that could stimulate the body to mobilize and expand stem cells and then promote their homing to the sites of injury without having to extract stem cells from patients, expand the stem cells in vitro and then re-inject the expanded stem cells into the patient for the treatment.
The goal of the TVEMF device is to mitigate many of the problems that current stem cell treatments face, such as the use of drugs to mobilize stem cells and the use of external growth factors and genetic manipulation for stem cell expansion.
Rabbit Osteotomy Study
This is work conducted at Texas A&M University College of Veterinary Medicine on New Zealand White Rabbits using TVEMF.
An osteotomy was performed on the ulna (forearm) leaving a significant gap that would not heal under normal conditions.
The control group used “sham” TVEMF over the area of the osteotomy and the treatment group used TVEMF stimulation.
The study was not conducted until full healing had occurred, but there were obvious differences between the control group and the treatment group.
The study was actually discontinued because researchers could easily distinguish the difference between the control group and treatment group animals. The treatment group animals were mobile, while the control group animals were immobile.
Photo of the incision: Notice the significant gap in the bone
After 14 days with sham TVEMF stimulation:
No bone growth – notice the gap
After 14 days with TVEMF stimulation:
Already some bone growth
After 28 days with sham TVEMF stimulation:
Still no bone growth – notice the gap
After 28 days with TVEMF stimulation:
Dramatic increase in bone growth
Nude Mouse Study
The “nude mouse” study was performed by the independent firm, Charles Rivers Laboratories Inc. using athymic mice. The lack of a thymus leaves the mice without the ability to mount most types of immune responses.
The purpose of the study was to determine whether a cell line was tumorigenic when injected by the subcutaneous route into athymic nude mice.
TVEMF-expanded stem cells were injected into athymic nude mice. It was determined that the TVEMF-expanded stem cells caused no tumors in the mice within 85 days of the injection of the TVEMF-expanded stem cells.
The study validated that expanded stem cells could be transplanted without harmful effects that have been demonstrated with genetic modification.
The multicolor fluorescence in situ hybridization “mFISH” study was conducted at NASA’s Johnson Space Center to determine whether TVEMF technology caused chromosomal damage to stem cells expanded using the NASA technology.
The mFISH study found that there was no chromosomal damage or change in the expanded adult stem cells 90 days after their expansion.
The presence of chromosomal damage or change could cause a wide array of problems such as tumor formation.
The study verified that stem cells grown in the NASA bioreactor are safer for potential therapies than current methods that use genetic manipulation.
Electromagnetic pulses are responsible for many of the activities in our bodies. They are an integral part of what keeps our hearts beating and brains functioning.
The bioelectronics device is a portable Time-Varying Electromagnetic Field (TVEMF) system. The unit uses a sophisticated miniaturized circuit board that delivers the specifically designed and patented electromagnetic field to a designated area of the body through the use of antennas (coils).
TVEMF vs PEMF
Time-Varying Electromagnetic Field (TVEMF) technology is fundamentally different from other magnetic pulse devices. TVEMF is based on the physics of electricity and magnetism as well as the physiology of cells and tissues.
- PEMF devices do not produce square waves, the optimal waveform for a tissue response.
PEMF devices do not produce enough intensity to stimulate a response; most do not even produce 1 Gauss of intensity.
PEMF devices do not produce a rate of induction (slew rate) that is quick enough to penetrate deep within tissues. TVEMF produces pulses that are only 0.0001 seconds wide.
Furthermore, TVEMF features repeating patterns of pulses that are selected based on known motor-neuron stimulation patterns of musculoskeletal tissues.
Sine waves take too long to reach their peak intensity. The lower slew rate means that they are not effective in producing a cellular/tissue response.
Triangle and sawtooth waves also suffer from a lower slew rate, meaning that they are not effective in producing a cellular/tissue response.
Endonovo’s TVEMF device produces a patented square waveform, which was proven the most effective waveform to increase cell growth and the production of over 200 growth factors and cytokines.
Our Cytotronics™ platform uses Time-Varying Electromagnetic Field (TVEMF) technology to expand and enhance the therapeutic properties of stem cells, immune cells and for use in tissue engineering. The goal of our Cytotronics™ platform is to create optimized cell-based therapies with greater therapeutic potential than the un-modulated cells currently being used in regenerative medicine.
The origins of our Cytotronics™ platform dates back to experiments conducted at NASA to expand stem cells ex vivo and to create therapies that could be used to treat astronauts during long term space exploration. The results of those experiments revealed that Time-Varying Electromagnetic Fields (TVEMF) could be used to expand stem cells in the lab and resulted in the increased expression of dozens of genes related to cell growth, tumor suppression, cell adhesion and extracellular matrix production.
A Physics Approach to Biology – Ex Vivo Modulation
We have built upon over 15 years of research and development to create a novel therapeutic paradigm – the systematic enhancement of the biological and therapeutic properties of cells ex vivo. This allows for the creation of a precise, scalable and cost effective approach to maximize the safety and effectiveness of cell-based therapies.
While our competitors are using genetic modification and pharmacological modulation to alter and enhance the biological properties of cells, we are taking A Physics Approach to Biology™ in the use of bioelectronics to create ex vivo modulated cells with enhanced biological and therapeutic properties. Using our Cytotronics™ platform, we are able to create cells that express higher levels of key genes related to stem cell maintenance, cell growth, cell homing and engraftment. Cytotronic™ expansion of peripheral blood stem cells resulted in an over 80-fold expansion of CD34+ cells in as few as 6 days.
Our Cytotronic™ platform was shown to be able to maintain normal human neural progenitor (NHNP) cells in long term culture (180 days), undifferentiated with the ability to be cryogenically preserved then subsequently reintroduced into culture with stem and progenitor markers still intact. NHNP cells that were expanded using our technology were then shown to not be tumorigenic when introduced into nude (athymic) mice for 85 days. Multi-color Fluorescence In Situ Hybridization (mFISH) showed that there was no chromosomal damage to cells subjected to Time-Varying Electromagnetic Fields (TVEMF).
Perivascular Cell Therapy Created Using Cytotronics™
Each year, an estimated 60,000 patients with leukemia and lymphoma need bone marrow transplantation. However, only 25,000 of those patients actually receive a transplant, primarily because the other 35,000 patients are unable to find a fully matched bone marrow donor.
Umbilical cord blood from newborn children is an excellent source of hematopoietic stem cells for stem cell transplants because their immune system is still immature and the stem cells have a lower probability of inducing an adverse immune response in patients. Furthermore, a perfect immunological match between donor and recipient is not necessary, unlike in bone marrow transplants.
However, in most cases a unit of umbilical cord blood contains too few stem cells to treat an adult patient and its use is confined above all to the treatment of children. Numerous patients have better matched cord blood products available (5/6 or 6/6 HLA match), however those products have low cell doses and are not suitable for use in adult patients. This is one of the reasons why less than 3 percent of cord blood collected in the United States is ever used. Low volume cord blood units present the opportunity to expand and/or enhance these unused cord blood units for the widespread use of hematopoietic stem cells in regenerative medicine.
Our Perivascular Cell Therapy is created using immunologically privileged and immune-modulating stem cells from a portion of the human umbilical cord and co-cultured with adipose-derived stem cells along with cord blood cells to create a perivascular cell mixture that can be used to treat malignant and non-malignant hematological disorders.
Endonovo’s cell therapy is an off-the-shelf therapeutic that can be stored indefinitely in a low temperature freeze without requiring cryopreservation. Our technologies are particularly suited to expand the use and effectiveness of low-volume cord blood units.
More In Vivo-Like Stem Cells
Our off-the-shelf therapeutic is created in a three-dimensional bioreactor using our proprietary Cytotronics™ platform to further expand and enhance the biological properties of the stem cells within the perivascular cell mixture. Our use of a perivascular co-culture in a three-dimensional bioreactor is meant to mimic the way that blood-forming stem cells renew and reside in the body. This simulated stem cell niche allows for the expansion of long-term self-renewing stem cells. Researchers had previously identified endothelial and perivascular cells as the cells that were functionally responsible for the maintenance of blood-forming stem cells (HSCs) in the body. Our technologies provide a method for the expansion of HSCs in an environment that resembles their native stem cell niche.
Endonovo is using a three-dimensional bioreactor that allows for the large-scale expansion of blood-forming stem cells that enhances cell-to-cell contact between perivascular cells and HSCs, providing a culture method that more closely resembles the stem cell niche. As seen below, (A) cells grown in three-dimensions become more spherical that those grown in (B) static two-dimensional cultures. Cells grown two dimensionally in Petri dishes or t-flasks sink within their growth medium. These cells do not look or function like real human cells, which grow three-dimensionally in the body.
Alan Collier – Chairman & Chief Executive Officer
Mr. Collier has more than twenty years of experience in corporate finance, IP development, telecommunications and technology with a concentration in healthcare and technology over the last five years. Prior to his appointment as Endonovo’s CEO and chairman, Mr. Collier served as CEO and director of IP Resources International, Inc. where he was instrumental in developing a platform for for the licensing and acquisition of life science and technology companies.
Previously, Mr. Collier served as a Senior Managing Director at Mid-Market Securities, a FINRA-registered Broker-Dealer. Prior to joining Mid-Market Securities, Mr. Collier was a Managing Director at Mosaic capital and co-managed its Capital Markets Group. He was previously a Vice President at Corporate Capital Group and Managing Director and CEO of Greenbridge Capital Group.
Over the progression of his career, he has specialized in the development and financing of early stage, high growth, and acquisitive companies (public and private). He has structured, participated in, and completed numerous transactions including mergers and acquisitions, equity and debt placements, capital restructuring, joint venture development, and channel partner procurement. He has held numerous board and executive positions throughout his career in the telecommunications, technology, specialty finance, corporate finance and healthcare industries. Mr. Collier holds FINRA Series 7, 79, 63, and 24 Licenses.
Michael Scott Mann – President
Mr. Mann has over 30 years experience in merger and acquisitions and operational management. In 2008 Mr. Mann acquired the assets of Hanover Asset Management, now Endonovo Therapeutics, Inc,. and led the company to become listed on the OTCBB in 2012.
From January 2003 to April, 2011, Mr. Mann was the Founder, President and Chief Executive Officer of U.S. Debt Settlement, Inc. (USDS), a Frankfurt listed company, where he implemented a growth by acquisition strategy successfully acquiring numerous companies.
From January 2002 to July 2003, Mr. Mann was the Chief Executive Officer of Shared Vision Capital, a boutique investment banking firm that assisted emerging companies with early seed capital and bridge loans. Earlier still, from October 1998 to December 2001, Mr. Mann was the Vice President of Investor Relations for JuriSearch.com, an online legal research platform. During his tenure with JuriSearch.com, Mr. Mann was directly responsible for funding the company’s growth and development. In addition, Mr. Mann founded Universal Pacific Communications, a privately owned telecommunications company. Under his leadership as President, Universal Pacific developed a fiber optic disaster recovery telecommunications network, designed for and successfully marketed to Fortune 1000 companies.