ABSTRACT
CONTENTS 11.1 Introduction ..................................................................................................................... 352 11.2 Tissue Repair ................................................................................................................... 353
11.2.1 Orthopedic Applications................................................................................ 353 11.2.1.1 Cellular Studies .............................................................................. 354 11.2.1.2 Animal Studies ............................................................................... 355 11.2.1.3 Clinical Studies............................................................................... 355
11.2.2 Soft Tissue Applications ................................................................................ 356 11.2.2.1 Cellular and Animal Studies........................................................ 357 11.2.2.2 Clinical Studies............................................................................... 358
11.3 Biophysical Considerations of EMF Therapeutics .................................................... 359 11.3.1 Introduction ..................................................................................................... 359 11.3.2 Inductively Coupled Clinical EMF Waveforms ........................................ 360 11.3.3 Electrochemistry at Cell Surfaces................................................................. 364 11.3.4 Electrochemical Information Transfer Model ............................................ 365 11.3.5 Magnetic Field Effects .................................................................................... 368 11.3.6 Larmor Precession Model.............................................................................. 370 11.3.7 Resonance in Larmor Precession Model..................................................... 373 11.3.8 Dynamical Systems Model............................................................................ 374
11.3.8.1 Calcium-Calmodulin-Dependent Myosin Phosphorylation as a Dynamical System ................................................................. 376
11.3.9 Dosimetry for Induced Electric Fields ........................................................ 377 11.3.10 Cell Array Model ............................................................................................ 378 11.3.11 Resonance with Electric Field Signals ......................................................... 382 11.3.12 Signal to Thermal Noise ................................................................................ 384
11.4 Ultrasound for Tissue Repair ....................................................................................... 387 11.5 Effect of Initial Cell or Tissue State on EMF Sensitivity .......................................... 389 11.6 The Future........................................................................................................................ 392 Acknowledgments ..................................................................................................................... 393 References ................................................................................................................................... 394
It is now commonplace to learn the successful use of weak, nonthermal electromagnetic fields (EMF) in the quest to heal, or relieve the symptoms of a variety of debilitating ailments. This chapter attempts to give the reader an introduction and assessment of EMF modalities that have demonstrated therapeutic benefit for bone and wound repair and chronic and acute pain relief. This chapter will concentrate on the use of exogenous timevarying and static magnetic fields. There is, however, a large body of research, including many clinical studies, describing the successful application of electrical signals via electrodes in electrochemical contact with the skin for pain relief and to enhancewound repair. Consideration of thesemodalities is beyond the scope of this chapter. The reader is referred to several excellent reviews of such electrical stimulation modalities [1-5]. Electroporation (see Ch apte r 9 in this volume ) [6-8,3 72], wh ich appli es high-amplit ude ( > 100 V/cm ), shortduration (1ms) voltage pulseswith electrodes in contactwith the target, allows controlled transient opening of the cell and other membranes, and has shown promise for gene transvection [9] and treatment of certain cancers [10], and is also beyond the scope of this chapter. Finally radio frequency (RF) (>100 MHz) and microwave signals are also beyond the scope of this chapter because these modalities are rarely utilized to enhance bone or wound repair, but rather for tissue heating, thermal ablation, or as surgical tools. Nonthermal bioeffects at these frequencies have been reported, but there are many controversial findings. Excellent reviews are available for the reader interested in detail [11,373]. As of this writing, there are a considerable number of peer-reviewed publications, which
show EMF can result in physiologically beneficial in vivo and in vitro bioeffects. The number of people who have received substantial clinical benefit from exogenous EMF is certainly in the millions worldwide and is increasing rapidly as new clinical indications emerge. The EMF therapies also present as alternatives to many pharmacologic treatments with virtually no toxicity or side effects. The time-varying EMFs consisting of rectangular or arbitrary waveforms, referred to as pulsing electromagnetic fields (PEMFs), the pulse modulated radio frequency waveforms, particularly in the 15-40 MHz range, referred to as pulsed radio frequency fields (PRFs), and the low-frequency sinusoidal waveforms (<100 Hz) have been shown to enhance healing when used as adjunctive therapies for a variety of musculoskeletal injuries. Indeed, peer-reviewedmeta-analyses clearly show that both PEMF and PRF modalities, now approved by regulatory bodies worldwide and widely used on patients to enhance bone and wound repair, are clinically effective [12,13]. Although still not completely elucidated, the mechanism of action of EMF signals at the molecular and cellular level is now much better understood and strongly suggests ion or ligand binding in a regulatory cascade could be the signal transduction pathway [14-28]. Furthermore, a priori configuration of physiologically effective waveforms via tuning the electrical properties of the exogenous EMF signal to the endogenous electrical properties of ion binding has recently been reported [29,30]. This chapter will provide a brief overview of the basic and clinical evidence that time-
varying magnetic fields (EMF) can modulate molecular, cellular, and tissue function in a physiologically significant manner. The fundamental questions relating to the biophysical conditions under which EMF signals could modulate cell and tissue function will be discussed in detail. Particular attention will be paid to the manner by which signal parameters are related to dosimetry. In other words, the properties that render an EMF signal bioeffective. An attempt is made to correlate dosimetry for weak magnetic field with that for electric field effects. The ratio of signal to (endogenous) thermal noise (SNR) in the target is used in an SNR and Dynamical Systems model which has been successful for the a priori configuration of physiologically significant waveforms and which the
reader may find useful to decipher the myriad of waveforms that have been utilized. The model may also allow the reader to perform an a posteriori analysis of waveforms for doserelated explanations for the presence or absence of a biological effect. Examples of in vivo and in vitro studies are given, illustrating specific EMF waveforms, including several examples of the use of the model.
