Muscle, ligament, bone, cartilage, blood, and adult stem-cell production all respond to electric and electromagnetic fields, and these biophysical field agents can be applied in therapeutic contexts. Postulated mechanisms at the cellular, subcellular, and molecular level are discussed. Electric and electromagnetic field stimulation enhance the repair of bone through the mediation of three areas at the cellular level: (1) the complex interplay of the physical environment; (2) growth factors; and (3) the signal transduction cascade. Studies of electric and electromagnetic fields suggest that an intermediary mechanism of action may be an increase in morphogenetic bone proteins, transforming growth factor-beta, and the insulin-like growth factor II, which results in an increase of the extracellular matrix of cartilage and bone. Investigations have begun to clarify how cells respond to biophysical stimuli by means of transmembrane signaling and gene expression for structural and signaling proteins.
The use of electric and magnetic forces to treat disease has fascinated the general public and scientists alike since antiquity. Interest in these treatment modalities, both scientific and public, persists today; and, in an era of expanding research in bioelectromagnetics, perhaps it is time the paradigm was reexamined. It has been known for many years that endogenous electrical potentials and currents are generated in wounded tissues and terminate when healing is complete 1-4).
Despite a growing understanding of the intricate bio-electrical properties of many tissues, few have researched whether these properties can be manipulated to enhance the healing process. Widespread acceptance and use of this treatment has not followed, probably because of the dearth of objective data. In an exhaustive meta-analysis of the impact of electrical field stimulation on health, Akai and Hayashi (5) concluded that, although definitive judgment was difficult, it was still more difficult to ignore the statistically significant supportive data from the few investigators who have published in this field-mainly scientists who have not been restricted by considerations that weigh against publication before commercialization.
Many hypotheses and postulates have been developed in an attempt to explain the therapeutic or biological effects of electric and magnetic fields on musculoskeletal tissues, particularly those of cartilage and bone. In 1982, Fukada hypothesized that the growth of bone is regulated to best resist external force, and the controlling signal seems to be the electric potential generated by shear piezoelectricity in collagen fibers and/or steaming potential in canaliculae (13). He also demonstrated that application of a small direct current or of piezoelectric polymer film stimulates bone formation and that PEMF energy enhances the proliferation of cell culture. More recently, it has been demonstrated that polarized hydroxyapetite ceramics increase bone formation in vivo in the early phase of healing and regeneration relative to controls. In 1950, Yasuda (14) conducted experiments to explain the piezoelectric effect in bone. He reported that when bone was under compression, an electronegative potential was induced. Conversely, an electropositive potential was produced by bone under tension.
There exist various techniques through which electrical current may be administered to assist bone healing. The two most popular techniques employed in the orthopedic community have been (1) direct current contact and (2) capacitive coupling. In the first case, current is delivered to the bone through insulated electrodes, which are placed on the skin so current may be induced in bone tissue with pulsed electric fields. Direct current electrodes can be either implanted or applied percutaneously (15). Implantable devices have the advantages of providing constant stimulation of bone directly at the desired body site, with increased patient compliance, so that optimization of the position of the electrodes is possible over time. Disadvantages include the risk of an infection, the potential for a painful implant, which might necessitate early removal, and in the case of a high-risk patient, the usual stress of any operative procedure.
Electrical field stimulation has been applied with dramatic beneficial effect in the treatment of nonunions in bone. Numerous authors have reported remarkable success in treating these chronic conditions, stress fractures, osteotomies, spinal fusions, and acquired and congenital pseudoarthroses with various forms of electrical stimulation. Unfortunately, the heterogeneity of trial design, dosage, and method of delivery throughout this group has failed to lead to the establishment of electrical field stimulation as an everyday treatment modality. Notwithstanding these shortcomings, a consistent finding among the studies is the osteogenic impact of electrical stimulation on the early phase of bone healing. Schubert et al. postulated that this early effect is caused by the restitution of normal, or near normal, piezoelectric properties by the exogenous electric field, which otherwise is lost after fracture and interruption of the Haversian canalicular network (27). The normal 2-week lag seen in unstimulated bone healing is obviated and healing begins at an accelerated rate. This theory of enhanced reorganization is borne out by observations of improved callus realignment in bone and collagen orientation in skin (28).
Electrical field stimulation is also beneficial in tendon and ligament repair. It has been demonstrated to reduce adhesion formation, increase hydroxyprolene content, and beneficially affect breaking strength by altering collagen types (29). It is likely that these effects are the result of the pronounced modulation of fibroblast function induced by electrical fields.
Several thoughts emerge with regard to chondrocytes in articular cartilage and growth plate stimulation by electromagnetic fields. First, one would assume that the longer the period of electromagnetic stimulation, the more accelerated chondrocyte proliferation and extracellular production. However, a question that will have an important biologic implication is: Will the closure of a bone growth plate be delayed more by electric or magnetic stimulation? That is, will specific electronic energy stimuli allow the growth plate to remain open longer than it should so that more longitu-dinal growth will occur?
Lippiello et al (50) examined the exposure of a pulsing direct current on osteochondral defects in the distal femoral condyles of rabbits. This is one of the very few studies in which an attempt has been made to correlate the biologic response of tissue exposed to external DC stimulation by in situ measurement of the electrical parameters. The stimulation apparatus involved an undefined signal period with a peak value of 2 A, imposing an electric field in the tissue of 20-60 mV/cm2, recurring at 100 Hz. It is noteworthy that a shorter exposure period (40 hours versus 160 hours) proved more efficacious. Could DC polarization damage be time dependent? These authors also reported the appearance of unorganized hyaline cartilage on the surface of the repaired tissue of these rabbits. In an attempt to explain a possible mechanism for this action, they postulate similarly with Guerkov et al (51) that such treatment stimulates differentiation of mesenchymal cells derived from marrow elements into chondrocytes and induces the proliferation of existing chondrocytes at the wound margins. There have been several studies testing the incorporation of calcium and its relation to various electric and or magnetic field stimulation (13,52). For example, Norton and Rovetti (53)hypothesized that the incorporation of Ca in the extracellular matrix of cartilage is influenced by electromagnetic field stimulation. They proved that the largest biologic response in chondrocytes occurred after 24 hours of this stimulation, as defined by autoradiography data. The effect of low-energy, combined AC and DC (unipolar) magnetic fields on the metabolism of articular cartilage was studied by Grande D et al (13).
After 30 minutes of such unipolar magnetic field exposure, there was a significant increase in radioactive calcium uptake. This uptake was insignificant with exposures of only 1 and 2 minutes and also after 24 hours. The authors concluded that the metabolism of articular cartilage can be stimulated by low-energy pulsating-unipolar, effective DC, magnetic fields, and this unipolar effect is associated with an increase in calcium ion uptake by the cells.
How, and at what level, do various electric, magnetic, electromagnetic, and pulsed EM field devices initiate changes in cell behavior? For the time being, answers to these questions remain to be accurately determined. Notwithstanding the limitations of currently accepted insights into the exact mechanism by which electrical field stimulation works, it is clear that it has a potentially beneficial role to play in clinical practice. The problems in accurately delineating the electromagnetic mechanisms are not only complicated by cellular complexities, but also by the complexities inherent in properly defining the electric, magnetic, and pulsed combinations of these energy fields.
Further research should be directed at establishing the parameters of high-frequency electromagnetic, PEMF, PG, PC, and both static Gauss and static Coulomb field transduction. All related phenomena need to be considered in order to provide a viable foundation for interpreting biologic interactions of the different energy fields with living systems. The literature dealing with electric and magnetic energy stimuli is full of a bewildering array of model systems, clinical situations, signal configurations, and stimulation devices. From these data, one can tentatively propose concepts of energy and tissue specificity. Electronic signal specificity involves a very wide range of pulse repetition rates, electric and magnetic waveforms, frequencies energy amplitudes, dose regimens, and other parameters of a particular electromedicine application that result in a favorable biologic response. The concept of tissue specificity refers to the nature of the biological response to the applied energy.
The complexity of tissue and energy specificity should not be unexpected; rather, it should help illuminate the wide variety of synthetic and clinical responses presently reported. As the energy responses become better understood, one can anticipate increasingly efficacious techniques for electronic energy stimulation of tissue repair.
REFERENCES
1. Burr HS, Taffel M, Harvey SC. An electrometric study of the healing wound in man. Yale J Bio Med 12, 483-485, 1940.
2. Fukada E, Yasuda I. On the piezoelectric effect of bone. J Physiol Soc Jpn 12, 1957;1158-1162.
3. Becker RO. The biolelectric factors in amphibian limb regeneration. J Bone Joint Surg Am 1961;43:643-656.
4. Barker AT, Jaffee LF, Vanable JW, Jr. The glabrous epidermis of cavies contains a powerful battery. Am J Physiol 1982;242:R358-R366.
5. Akai M, Hayashi K. Effect of electrical stimulation on musculoskeletal systems; a meta-analysis of controlled clinical trials. Bioelectromagnetics 2002;23:132-143.
6. Luden RA, Cain CD, Chen MC-Y, et al. Effects of electromagnetic stimuli on bone and bone cells in vivo: Inhibition of responses to parathyroid hormone by low- energy, low-frequency fields. Proc Natl Acad Sci USA 1982;79:4180-4184.
7. Cain CD, Adey WR, Luben RA. Evidence that pulsed electromagnetic fields inhibit coupling of adenylate cyclase by parathyroid hormone in bone cells. J Bone Miner Res 1987; 2:437-441.
8. Brighton CT, McCluskey W. Response of cultured bone cells to a capacitively coupled electric field: Inhibition of cAMP response to parathyroid hormone. J Orthop Res 1988;6:567-571.
9. Cho MR, Thatte HS, Lee RC, et al. Induced redistribution of cell surface receptors by alternating current electric fields. FASEB J 1994;8:771-776.
10. Varani K, Gessi S, Merighi S, et al. Effect of low frequency electromagnetic fields on A2A adenosine receptors in human neutrophils. Br J Pharmacol 2002;136:57-66.
11. Brighton CT. Treatment of nonunion of the tibia with constant direct current. J Trauma 1981;21:3-11.
12. Goodman R, Shirley-Henderson A. A transcription and translation in cells exposed to extremely low frequency electromagnetic fields. Bioelectrochem Bioenerget 1991;25:335-355.
13. Grande D, Magee F, Weinstein A. The effect of low energy combined AC and DC magnetic fields on articular cartilage metabolism. Ann NY Acad Sci 1983;31:18-22.
14. Fukuda E, Yasuda I. On the piezoelectric affect of bone. J Physiol Soc Jpn 1957;12:1158-1164.
15. Anglen J. The clinical use of bone stimulators. J South Orthop Assoc 2003;12:46-54.
16. Abeed RI, Naseer M, Abel EW. Capacitively coupled electrical stimulation treatment: Results from patients with failed long bone fracture unions. J Orthop Trauma 1998;12:510-513.
17. Zamora-Navas P, Borras VA, Antelo LR, et al. Electrical stimulation of bone nonunion with the presence of a gap. Acta Orthop Belg 1995;61:169-176.
18. Kleczynski S. Electrical stimulation to promote the union of fractures. Int Orthop 1988;12:83-87.
19. Ahl T, Anderson G, Herberts P, Kalen R. Electrical treatment of nonunited fractures. Acta Orthop Scand 1984;55:585-588.
20. Rettig AC, Shelbourne KD, McCarroll JR. The natural history and treatment of delayed union stress fractures of the anterior cortex of the tibia. Am J Sports Med 1988;16:250-255.
21. Breighton CT. Fracture healing in the rabbit fibula when subjected to various capacitively coupled electrical fields. J Orthop Res 1985;3:331-340.
22. Masureik C, Ericksson C. Preliminary clinical evaluation of the effect of small electrical currents on the healing of jaw fractures. Clin Orthop 1977;84-91.
23. Dejardin LM, Kahanovitz N, Arnocyzky SP, Simon BJ. The effect of varied electrical current densities on lumbar spinal fusions in dogs. Spine J 2001;1:341-347.
24. Akai M, Kawashima N, Kimura T, Hayashi K. Electrical stimulation as an adjunct to spinal fusion: A meta-analysis of controlled clinical trials. Bioelectromagnetics 2002;23:496-504.
25. Toth JM, Seim HB 3rd, Schwardt JD, et al. Direct current electrical stimulation increases the fusion rate of spinal fusion cages. Spine 2000;25:2580-2587.
26. Haupt HA. Electrical stimulation of osteogenesis. South Med 1984;77:56-64.
27. Schubert T, Kleditzsch J, Wolf E. Results of fluorescense microscopy studies of bone healing by direct stimulation with bipolar impulse currents and with the interference current procedure in the animal experiment. Z Orthop Ihre Grenzgeb 1986;124:6-12. 28. Reger SI, Hyodo A, Negami S, Kambic HE, Sahgal V. Experimental wound healing with electrical stimulation. Artif Organs 1999;23:460-462. 29. Naegele RJ, Lipari J, Chakkalakal D, et al. Electric field stimulation of human osteosarcoma-derived cells: A dose-response study. Cancer Biochem Biophys 1991;12:95-101.
30. Goodman R, Shirley-Henderson A. A transcription and translation in cells exposed to extremely low frequency electromagnetic fields. Bioelectrochem Bioenerget 1991;25:335-355.
31. Zhuang H, Wang W, Seldes R, et al. Electrical stimulation induces the level of TGF-beta1 mRNA in osteoblastic cells by a mechanism involving calcium/camodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
32. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Relat Res 2001;384:265-279. 33. Aaron RK, Ciombor DM, Keeping HS. Power frequency fields promote cell differentiation coincident with an increase in transforming TGF-1 expression. Biolelectromagnetics 1999; 10:453-458.
34. Aoran RK, Wang S, Ciombor DM. Upregulation of basal TGF1 levels by EMF coincident with chondrogenesis: Implications for skeletal repair and tissue engineering. J Orthop Res 2002;20:233-240.
35. Bodamyali T, Bhatt B, Highes FJ, et al. Pulsed electromagnetic fields simultaneously induce osteogenesis and upregulate transcription of bone morphogenetic proteins 2 ad 4 in rat osteoblasts in vitro. Biophys Biochem Res Commun 1998;250:458-461.
36. Aaron RK, Boyan BD, Ciombor DM, et al. Stimulation of growth factor synthesis by electric and electromagnetic fields. Clin Orthop 2004;419:30-37.
37. Aaron RK, Ciombor D, Jones AR. Bone induction by decalcified bone matrix and mRNA of TGFB and IGF-1 are increased by ELF field stimulation. Trans Orthop Res Soc 1997;22:548-564.
38. Zhuang H, Wang W, Seldes R, et al. Electrical stimulation induces the level of TGF-beta1 mRNA in osteoblastic cells by a mechanism involving calcium/camodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
39. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Relat Res 2001;384:265-279.
40. Fitzsimmons R, Farley J, Adey W, Baylink D. Embryonic bone matrix formation is increased after exposure to a low amplitude capacitively coupled electric field in vitro. Biochem Biophys Acta 1986;882:51-56.
41. Aaron RK, Ciombor D. Stimulation of chondrogenesis in experimental endochondral ossification by pulsing electromagnetic fields. Trans Bioelectric Repair Growth Soc 1987;737A.
42. Zhuang H, Wang W, Seldes RM, et al. Electrical stimulation induces the level of TGF-1 MRNA in osteoblastic cells by a mechanism involving calcium calmodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
43. lohmann CH, Schwartz Z, Hummert TW, et al. Pulsed electromagnetic field stimulation of MG36 osteoblast-like cells affects differentiation and local factor production. J Orthop Res 2000.
44. Falanga V, Bourguignon GJ, Bourguignon LWY. Electrical stimulation increases the expression of fibroblasts receptors for transforming growth factor-beta. J Invest Dermatol 1987;88:488-491.
45. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Rel Res 2001;84:265-279.
46. Hang H, Wang W, Selves RM, et al. Electrical stimulation induces the level of TGF-1 MRNA in osteoblastic cells by a mechanism involving calcium calmodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
47. Lohmann CH, Schwartz Z, Hummert TW, et al. Pulsed electromagnetic field stimulation of MG36 osteoblast-like cells affects differentiation and local factor production. J Orthop Res 2000;56A:237-243.
48. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Rel Res 2001;384:265-279.
49. Bourguignon GJ, Bourguignon LYW. Electric stimulation of human fibroblasts causes an increase in Ca influx and the exposure of additional insulin receptors. J Cell Physiol 1989;140: 379-385.
50. Lippiello L, Chakkalakal D, Connolly J. Pulsing direct current-induced repair of articular cartilage in rabbit osteochondral defects. J Orthop Res 1990;8:266-275.
51. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Rel Res 2001;384:265-279.
52. Norton LA, Rovetti LA. Calcium incorporation culltured chondroblasts perturbed by an electromagnetic field. J Orthop Res 1988;6:559-566.
53. Trock DH, Bollet AJ, Markoll R. The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. J Rheumatol 1994;21:1903-1911.
54. Perrot S, Marty M, Kahan A, et al. Efficacy of pulsed electromagnetic therapy in painful knee osteoarthritis [abstract]. In: Proceedings of the 62nd Annual Meeting of the American College of Rheumatology, San Diego, 1998:5357.
The use of electric and magnetic forces to treat disease has fascinated the general public and scientists alike since antiquity. Interest in these treatment modalities, both scientific and public, persists today; and, in an era of expanding research in bioelectromagnetics, perhaps it is time the paradigm was reexamined. It has been known for many years that endogenous electrical potentials and currents are generated in wounded tissues and terminate when healing is complete 1-4).
Despite a growing understanding of the intricate bio-electrical properties of many tissues, few have researched whether these properties can be manipulated to enhance the healing process. Widespread acceptance and use of this treatment has not followed, probably because of the dearth of objective data. In an exhaustive meta-analysis of the impact of electrical field stimulation on health, Akai and Hayashi (5) concluded that, although definitive judgment was difficult, it was still more difficult to ignore the statistically significant supportive data from the few investigators who have published in this field-mainly scientists who have not been restricted by considerations that weigh against publication before commercialization.
Many hypotheses and postulates have been developed in an attempt to explain the therapeutic or biological effects of electric and magnetic fields on musculoskeletal tissues, particularly those of cartilage and bone. In 1982, Fukada hypothesized that the growth of bone is regulated to best resist external force, and the controlling signal seems to be the electric potential generated by shear piezoelectricity in collagen fibers and/or steaming potential in canaliculae (13). He also demonstrated that application of a small direct current or of piezoelectric polymer film stimulates bone formation and that PEMF energy enhances the proliferation of cell culture. More recently, it has been demonstrated that polarized hydroxyapetite ceramics increase bone formation in vivo in the early phase of healing and regeneration relative to controls. In 1950, Yasuda (14) conducted experiments to explain the piezoelectric effect in bone. He reported that when bone was under compression, an electronegative potential was induced. Conversely, an electropositive potential was produced by bone under tension.
There exist various techniques through which electrical current may be administered to assist bone healing. The two most popular techniques employed in the orthopedic community have been (1) direct current contact and (2) capacitive coupling. In the first case, current is delivered to the bone through insulated electrodes, which are placed on the skin so current may be induced in bone tissue with pulsed electric fields. Direct current electrodes can be either implanted or applied percutaneously (15). Implantable devices have the advantages of providing constant stimulation of bone directly at the desired body site, with increased patient compliance, so that optimization of the position of the electrodes is possible over time. Disadvantages include the risk of an infection, the potential for a painful implant, which might necessitate early removal, and in the case of a high-risk patient, the usual stress of any operative procedure.
Electrical field stimulation has been applied with dramatic beneficial effect in the treatment of nonunions in bone. Numerous authors have reported remarkable success in treating these chronic conditions, stress fractures, osteotomies, spinal fusions, and acquired and congenital pseudoarthroses with various forms of electrical stimulation. Unfortunately, the heterogeneity of trial design, dosage, and method of delivery throughout this group has failed to lead to the establishment of electrical field stimulation as an everyday treatment modality. Notwithstanding these shortcomings, a consistent finding among the studies is the osteogenic impact of electrical stimulation on the early phase of bone healing. Schubert et al. postulated that this early effect is caused by the restitution of normal, or near normal, piezoelectric properties by the exogenous electric field, which otherwise is lost after fracture and interruption of the Haversian canalicular network (27). The normal 2-week lag seen in unstimulated bone healing is obviated and healing begins at an accelerated rate. This theory of enhanced reorganization is borne out by observations of improved callus realignment in bone and collagen orientation in skin (28).
Electrical field stimulation is also beneficial in tendon and ligament repair. It has been demonstrated to reduce adhesion formation, increase hydroxyprolene content, and beneficially affect breaking strength by altering collagen types (29). It is likely that these effects are the result of the pronounced modulation of fibroblast function induced by electrical fields.
Several thoughts emerge with regard to chondrocytes in articular cartilage and growth plate stimulation by electromagnetic fields. First, one would assume that the longer the period of electromagnetic stimulation, the more accelerated chondrocyte proliferation and extracellular production. However, a question that will have an important biologic implication is: Will the closure of a bone growth plate be delayed more by electric or magnetic stimulation? That is, will specific electronic energy stimuli allow the growth plate to remain open longer than it should so that more longitu-dinal growth will occur?
Lippiello et al (50) examined the exposure of a pulsing direct current on osteochondral defects in the distal femoral condyles of rabbits. This is one of the very few studies in which an attempt has been made to correlate the biologic response of tissue exposed to external DC stimulation by in situ measurement of the electrical parameters. The stimulation apparatus involved an undefined signal period with a peak value of 2 A, imposing an electric field in the tissue of 20-60 mV/cm2, recurring at 100 Hz. It is noteworthy that a shorter exposure period (40 hours versus 160 hours) proved more efficacious. Could DC polarization damage be time dependent? These authors also reported the appearance of unorganized hyaline cartilage on the surface of the repaired tissue of these rabbits. In an attempt to explain a possible mechanism for this action, they postulate similarly with Guerkov et al (51) that such treatment stimulates differentiation of mesenchymal cells derived from marrow elements into chondrocytes and induces the proliferation of existing chondrocytes at the wound margins. There have been several studies testing the incorporation of calcium and its relation to various electric and or magnetic field stimulation (13,52). For example, Norton and Rovetti (53)hypothesized that the incorporation of Ca in the extracellular matrix of cartilage is influenced by electromagnetic field stimulation. They proved that the largest biologic response in chondrocytes occurred after 24 hours of this stimulation, as defined by autoradiography data. The effect of low-energy, combined AC and DC (unipolar) magnetic fields on the metabolism of articular cartilage was studied by Grande D et al (13).
After 30 minutes of such unipolar magnetic field exposure, there was a significant increase in radioactive calcium uptake. This uptake was insignificant with exposures of only 1 and 2 minutes and also after 24 hours. The authors concluded that the metabolism of articular cartilage can be stimulated by low-energy pulsating-unipolar, effective DC, magnetic fields, and this unipolar effect is associated with an increase in calcium ion uptake by the cells.
How, and at what level, do various electric, magnetic, electromagnetic, and pulsed EM field devices initiate changes in cell behavior? For the time being, answers to these questions remain to be accurately determined. Notwithstanding the limitations of currently accepted insights into the exact mechanism by which electrical field stimulation works, it is clear that it has a potentially beneficial role to play in clinical practice. The problems in accurately delineating the electromagnetic mechanisms are not only complicated by cellular complexities, but also by the complexities inherent in properly defining the electric, magnetic, and pulsed combinations of these energy fields.
Further research should be directed at establishing the parameters of high-frequency electromagnetic, PEMF, PG, PC, and both static Gauss and static Coulomb field transduction. All related phenomena need to be considered in order to provide a viable foundation for interpreting biologic interactions of the different energy fields with living systems. The literature dealing with electric and magnetic energy stimuli is full of a bewildering array of model systems, clinical situations, signal configurations, and stimulation devices. From these data, one can tentatively propose concepts of energy and tissue specificity. Electronic signal specificity involves a very wide range of pulse repetition rates, electric and magnetic waveforms, frequencies energy amplitudes, dose regimens, and other parameters of a particular electromedicine application that result in a favorable biologic response. The concept of tissue specificity refers to the nature of the biological response to the applied energy.
The complexity of tissue and energy specificity should not be unexpected; rather, it should help illuminate the wide variety of synthetic and clinical responses presently reported. As the energy responses become better understood, one can anticipate increasingly efficacious techniques for electronic energy stimulation of tissue repair.
REFERENCES
1. Burr HS, Taffel M, Harvey SC. An electrometric study of the healing wound in man. Yale J Bio Med 12, 483-485, 1940.
2. Fukada E, Yasuda I. On the piezoelectric effect of bone. J Physiol Soc Jpn 12, 1957;1158-1162.
3. Becker RO. The biolelectric factors in amphibian limb regeneration. J Bone Joint Surg Am 1961;43:643-656.
4. Barker AT, Jaffee LF, Vanable JW, Jr. The glabrous epidermis of cavies contains a powerful battery. Am J Physiol 1982;242:R358-R366.
5. Akai M, Hayashi K. Effect of electrical stimulation on musculoskeletal systems; a meta-analysis of controlled clinical trials. Bioelectromagnetics 2002;23:132-143.
6. Luden RA, Cain CD, Chen MC-Y, et al. Effects of electromagnetic stimuli on bone and bone cells in vivo: Inhibition of responses to parathyroid hormone by low- energy, low-frequency fields. Proc Natl Acad Sci USA 1982;79:4180-4184.
7. Cain CD, Adey WR, Luben RA. Evidence that pulsed electromagnetic fields inhibit coupling of adenylate cyclase by parathyroid hormone in bone cells. J Bone Miner Res 1987; 2:437-441.
8. Brighton CT, McCluskey W. Response of cultured bone cells to a capacitively coupled electric field: Inhibition of cAMP response to parathyroid hormone. J Orthop Res 1988;6:567-571.
9. Cho MR, Thatte HS, Lee RC, et al. Induced redistribution of cell surface receptors by alternating current electric fields. FASEB J 1994;8:771-776.
10. Varani K, Gessi S, Merighi S, et al. Effect of low frequency electromagnetic fields on A2A adenosine receptors in human neutrophils. Br J Pharmacol 2002;136:57-66.
11. Brighton CT. Treatment of nonunion of the tibia with constant direct current. J Trauma 1981;21:3-11.
12. Goodman R, Shirley-Henderson A. A transcription and translation in cells exposed to extremely low frequency electromagnetic fields. Bioelectrochem Bioenerget 1991;25:335-355.
13. Grande D, Magee F, Weinstein A. The effect of low energy combined AC and DC magnetic fields on articular cartilage metabolism. Ann NY Acad Sci 1983;31:18-22.
14. Fukuda E, Yasuda I. On the piezoelectric affect of bone. J Physiol Soc Jpn 1957;12:1158-1164.
15. Anglen J. The clinical use of bone stimulators. J South Orthop Assoc 2003;12:46-54.
16. Abeed RI, Naseer M, Abel EW. Capacitively coupled electrical stimulation treatment: Results from patients with failed long bone fracture unions. J Orthop Trauma 1998;12:510-513.
17. Zamora-Navas P, Borras VA, Antelo LR, et al. Electrical stimulation of bone nonunion with the presence of a gap. Acta Orthop Belg 1995;61:169-176.
18. Kleczynski S. Electrical stimulation to promote the union of fractures. Int Orthop 1988;12:83-87.
19. Ahl T, Anderson G, Herberts P, Kalen R. Electrical treatment of nonunited fractures. Acta Orthop Scand 1984;55:585-588.
20. Rettig AC, Shelbourne KD, McCarroll JR. The natural history and treatment of delayed union stress fractures of the anterior cortex of the tibia. Am J Sports Med 1988;16:250-255.
21. Breighton CT. Fracture healing in the rabbit fibula when subjected to various capacitively coupled electrical fields. J Orthop Res 1985;3:331-340.
22. Masureik C, Ericksson C. Preliminary clinical evaluation of the effect of small electrical currents on the healing of jaw fractures. Clin Orthop 1977;84-91.
23. Dejardin LM, Kahanovitz N, Arnocyzky SP, Simon BJ. The effect of varied electrical current densities on lumbar spinal fusions in dogs. Spine J 2001;1:341-347.
24. Akai M, Kawashima N, Kimura T, Hayashi K. Electrical stimulation as an adjunct to spinal fusion: A meta-analysis of controlled clinical trials. Bioelectromagnetics 2002;23:496-504.
25. Toth JM, Seim HB 3rd, Schwardt JD, et al. Direct current electrical stimulation increases the fusion rate of spinal fusion cages. Spine 2000;25:2580-2587.
26. Haupt HA. Electrical stimulation of osteogenesis. South Med 1984;77:56-64.
27. Schubert T, Kleditzsch J, Wolf E. Results of fluorescense microscopy studies of bone healing by direct stimulation with bipolar impulse currents and with the interference current procedure in the animal experiment. Z Orthop Ihre Grenzgeb 1986;124:6-12. 28. Reger SI, Hyodo A, Negami S, Kambic HE, Sahgal V. Experimental wound healing with electrical stimulation. Artif Organs 1999;23:460-462. 29. Naegele RJ, Lipari J, Chakkalakal D, et al. Electric field stimulation of human osteosarcoma-derived cells: A dose-response study. Cancer Biochem Biophys 1991;12:95-101.
30. Goodman R, Shirley-Henderson A. A transcription and translation in cells exposed to extremely low frequency electromagnetic fields. Bioelectrochem Bioenerget 1991;25:335-355.
31. Zhuang H, Wang W, Seldes R, et al. Electrical stimulation induces the level of TGF-beta1 mRNA in osteoblastic cells by a mechanism involving calcium/camodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
32. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Relat Res 2001;384:265-279. 33. Aaron RK, Ciombor DM, Keeping HS. Power frequency fields promote cell differentiation coincident with an increase in transforming TGF-1 expression. Biolelectromagnetics 1999; 10:453-458.
34. Aoran RK, Wang S, Ciombor DM. Upregulation of basal TGF1 levels by EMF coincident with chondrogenesis: Implications for skeletal repair and tissue engineering. J Orthop Res 2002;20:233-240.
35. Bodamyali T, Bhatt B, Highes FJ, et al. Pulsed electromagnetic fields simultaneously induce osteogenesis and upregulate transcription of bone morphogenetic proteins 2 ad 4 in rat osteoblasts in vitro. Biophys Biochem Res Commun 1998;250:458-461.
36. Aaron RK, Boyan BD, Ciombor DM, et al. Stimulation of growth factor synthesis by electric and electromagnetic fields. Clin Orthop 2004;419:30-37.
37. Aaron RK, Ciombor D, Jones AR. Bone induction by decalcified bone matrix and mRNA of TGFB and IGF-1 are increased by ELF field stimulation. Trans Orthop Res Soc 1997;22:548-564.
38. Zhuang H, Wang W, Seldes R, et al. Electrical stimulation induces the level of TGF-beta1 mRNA in osteoblastic cells by a mechanism involving calcium/camodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
39. Guerkov HH, Lohmann CH, Liu Y, et al. Pulsed electromagnetic fields increase growth factor release by nonunion cells. Clin Orthop Relat Res 2001;384:265-279.
40. Fitzsimmons R, Farley J, Adey W, Baylink D. Embryonic bone matrix formation is increased after exposure to a low amplitude capacitively coupled electric field in vitro. Biochem Biophys Acta 1986;882:51-56.
41. Aaron RK, Ciombor D. Stimulation of chondrogenesis in experimental endochondral ossification by pulsing electromagnetic fields. Trans Bioelectric Repair Growth Soc 1987;737A.
42. Zhuang H, Wang W, Seldes RM, et al. Electrical stimulation induces the level of TGF-1 MRNA in osteoblastic cells by a mechanism involving calcium calmodulin pathway. Biochem Biophys Res Commun 1997;237:225-229.
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About the Author:
Dr. Jack Haddad, MD, MBA is the founder and owner of King of Home Care, an independently owned non-medical In-home care agency. In addition to his compassion and dedication to the home care industry, Dr. Haddad's expertise and knowledge with In-Home Care is evident by the clinical research trials that he has conducted over the years.
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