A Pulsing Electric Field (PEF) Increases Human Chondrocyte Proliferation through a Transduction Pathway Involving Nitric Oxide Signaling

Abstract

Apotential treatment modality for joint pain due to cartilage degradation is electromagnetic fields (EMF) that can be delivered, noninvasively, to chondrocytes buried within cartilage. A pulsed EMF in clinical use for recalcitrant bone fracture healing has been modified to be delivered as a pulsed electric field (PEF) through capacitive coupling. It was the objective of this study to determine whether the PEF signal could have a direct effect on chondrocytes in vitro. This study shows that a 30-min PEF treatment can increase DNA content of chondrocyte monolayer by approximately 150% at 72 h poststimulus. Studies intended to explore the biological mechanism showed this PEF signal increased nitric oxide measured in culture medium and cGMP measured in cell extract within the 30-min exposure period. Increasing calcium in the culture media or adding the calcium ionophore A23187, without PEF treatment, also significantly increased short-term nitric oxide production. The inhibitor W7, which blocks calcium/calmodulin, prevented the PEF-stimulated increase in both nitric oxide and cGMP. The inhibitor L-NAME, which blocks nitric oxide synthase, prevented the PEF-stimulated increase in nitric oxide, cGMP, and DNA content. An inhibitor of guanylate cyclase (LY83583) blocked the PEF-stimulated increase in cGMP and DNA content. A nitric oxide donor, when present for only 30 min, increased DNA content 72 h later. Taken together, these results suggest the transduction pathway for PEF stimulated chondrocyte proliferation involves nitric oxide and the production of nitric oxide may be the result of a cascade that involves calcium, calmodulin, and cGMP production.

Effects of pulsed electromagnetic fields on articular hyaline cartilage: review of experimental and clinical studies

Abstract

Osteoarthritis (OA) is the most common disorder of the musculoskeletal system and is a consequence of mechanical and biological events that destabilize tissue homeostasis in articular joints. Controlling chondrocyte death and apoptosis, function, response to anabolic and catabolic stimuli, matrix synthesis or degradation and inflammation is the most important target of potential chondroprotective treatment, aimed to retard or stabilize the progression of OA. Although many drugs or substances have been recently introduced for the treatment of OA, the majority of them relieve pain and increase function, but do not modify the complex pathological processes that occur in these tissues. Pulsed electromagnetic fields (PEMFs) have a number of well-documented physiological effects on cells and tissues including the upregulation of gene expression of members of the transforming growth factor b super family, the increase in glycosaminoglycan levels, and an antiinflammatory action. Therefore, there is a strong rationale supporting the in vivo use of biophysical stimulation with PEMFs for the treatment of OA. In the present paper some recent experimental in vitro and in vivo data on the effect of PEMFs on articular cartilage were reviewed. These data strongly support the clinical use of PEMFs in OA patients.

INVENTORS STIMULATE CARTILAGE WITH ELECTROMAGNETIC STIMULATION

This is the story of an incubator. The company, Minnesota Medical Physics, occupies one of a row of identical office spaces in a business center located in Edina, Minnesota. CEO Ali Jaafar and Principal Scientist Victor Chornenky, Ph.D., started the company in 2001 to develop “Innovative Solutions to Unmet Medical Needs.” Educated as a physicist, Jaafar is no beginner in business. After a career with Westinghouse, Johnson & Johnson and Becton Dickinson, he left his executive position to found his own company. Chornenky is a physicist whose career includes a university professorship in Moscow, physicist at Harvard and the Smithsonian, and visiting scientist at MIT.

Their approach is to look at a disease state and how it is being treated. If they feel that the existing treatment is adequate, they leave it and go on to another. If not, they look to see if a better treatment can be developed. “We make a comprehensive literature search on the nature of the disease, study and evaluate the newest scientific data on it. Then, based on the data, after long brainstorming, begin to develop new approaches to the treatment. We conceive a product, develop it into an initial prototype, test it, build a clinically suitable prototype and license it to other companies.” Their customers include several major medical device manufacturers.

It was perhaps inevitable that, in their search for better medical solutions to improve the quality of life and treatment, they would come upon osteoarthritis and the problem of deteriorating cartilage. Jaafar notes that the standard therapy for osteoarthritis is administration of nonsteroidal antiinflammation drugs (NSAID) and in severe cases, joint replacement surgery. He adds that the NSAID therapy is primarily focused on symptom relief, not on the underlying cause of the disease. The side effects of longterm usage of NSAID, he says, are severe.

In their research the two noted that, over the last decade, investigators have published a number of scientific articles suggesting that pulsed electromagnetic field (PEMF) stimulation, initially developed for treatment of nonunion bone fractures, may be effective in the treatment of osteoarthritis.

Jaafar and Chornenky anticipated the potential of PEMF combined with thermal stimulation and embarked on developing an appropriate delivery system. They envisioned that osteoarthritis, a progressive disorder characterized by cartilage degeneration, could be halted and perhaps even reversed by a combination of appropriately applied thermal stimulation and pulsed electromagnetic stimulation.

After six years of development of the osteoarthritis device, the two have found research papers that appear to support their original thinking. One paper is a Ph.D. dissertation by Italian Frederica Francesca Masieri who studied the therapeutic implications of pulsed magnetic fields in osteoarthritis pathologies. She concluded that PEMF alone can significantly reduce inflammation in osteoarthritic joints and replace NSAID drug therapy.

The second paper, published by the Journal of Orthopaedic Research, reported on multiyear studies carried on by the Department of Orthopedics, Graduate School of Medical Sciences, and Kyoto University. Researchers had found that the effect of mild electrical stimulation (MES) combined with heat stimulation (HS) raised HSP70 protein which plays a crucial role in protecting chondrocytes and stimulating cartilage matrix metabolism. Jaafar and Chornenky present this as the scientific basis for the device they have spent the last six years developing.

They have received a patent on their first product, called the NovoPulse. It is a wearable framework that positions a pad conducting both heat and electromagnetic stimulation to any location on the spine. The NovoPulse contains several microprocessors, controlling application of the PEMF and heat stimulation. Jaafar explains that, “We take an electrical current and run it through a set of treatment coils for a period of 50100 microseconds, which creates the ideal conditions for the electrical field. When the pulse shuts off you have all of this magnetic energy that we capture and convert into heat.”

In 2011 Jaafar and Chornenky licensed the technology to a new company, called BioMagnetic Sciences, LLC (BMS). Initially BMS plans to market the invention as a pain management device, but their true longterm clinical trials to demonstrate that their combination of heat and PEMF stimulation can halt or even reverse the deterioration of cartilage. In the meantime, they have panel tests lined up with physicians overseas in the fall of 2013 and hope to soon have their product on the market.

In a 2012 paper on electromagnetic fields and the human body Chornenky wrote ,”The ability of pulsed electromagnetic fields (PEMF) to regrow cartilage suggests the possibility of positive modification of the underlying condition of osteoarthritis, something that today’s medicine cannot do. PEMF stimulation could be a new effective treatment of the joints that potentially can slow down and even reverse osteoarthritis.”

Modification of osteoarthritis by pulsed electromagnetic field – a morphological study

Abstract

Objective: Hartley guinea pigs spontaneously develop arthritis that bears morphological, biochemical, and immunohistochemical similarities to human osteoarthritis. It is characterized by the appearance of superficial fibrillation by 12 months of age and severe cartilage lesions and eburnation by 18 months of age. This study examines the effect of treatment with a pulsed electromagnetic field (PEMF) upon the morphological progression of osteoarthritis in this animal model.

Design: Hartley guinea pigs were exposed to a specific PEMF for 1 h/day for 6 months, beginning at 12 months of age. Control animals were treated identically, but without PEMF exposure. Tibial articular cartilage was examined with histological/histochemical grading of the severity of arthritis, by immunohistochemistry for cartilage neoepitopes, 3B3(−) and BC-13, reflecting enzymatic cleavage of aggrecan, and by immunoreactivity to collagenase (MMP-13) and stromelysin (MMP-3). Immunoreactivity to TGFβ, interleukin (IL)-1β, and IL receptor antagonist protein (IRAP) antibodies was examined to suggest possible mechanisms of PEMF activity.

Results: PEMF treatment preserves the morphology of articular cartilage and retards the development of osteoarthritic lesions. This observation is supported by a reduction in the cartilage neoepitopes, 3B3(−) and BC-13, and suppression of the matrix-degrading enzymes, collagenase and stromelysin. Cells immunopositive to IL-1 are decreased in number, while IRAP-positive cells are increased in response to treatment. PEMF treatment markedly increases the number of cells immunopositive to TGFβ.

Conclusions: Treatment with PEMF appears to be disease-modifying in this model of osteoarthritis. Since TGFβ is believed to upregulate gene expression for aggrecan, downregulate matrix metalloprotease and IL-1 activity, and upregulate inhibitors of matrix metalloprotease, the stimulation of TGFβ may be a mechanism through which PEMF favorably affects cartilage homeostasis.