Research Overview

Over the past 20 years, our research has been funded by the National Institutes of Health (NIH), the National Aeronautics and Space Administration (NASA), the National Science Foundation (NSF) and other bodies.

Our researchers have worked to identify those mechanical factors embedded within exercise that can stimulate biological tissues like muscle and bone. Our work has shown that extremely low magnitude mechanical signals (such as low intensity vibrations) can build bone and muscle if applied at a high frequency (15 to 90 Hz, or cycles per second). To be considered "low magnitude" signals should be less than 1.0g in force. One-g is equivalent to Earth's gravitational field: 9.8 meters per second per second.

Similar to exercise, low intensity vibration (LIV) is able to exert beneficial effects to many physiological systems and our researchers have extensively studied HOW such small vibrations are able to achieve such substantial benefits.

From this work, we have recently established the efficacy of LIV to promote and maintain the health of the adult stem cell population with daily application of the non-invasive LIV signal. Further, LIV signals promotes the development of these stem cells into tissues such as bone and muscle, while reducing the percentage of cells that develop into fat tissue.

Our peer-reviewed studies have been reported in leading scientific journals, and have served as the foundation for building a safe and effective non-drug intervention for diseases as diverse as osteoporosis (lack of bone) and obesity (excess of fat).

HARNESSING BONE'S SENSITIVITY TO MECHANICAL SIGNALS - LIV INCREASES BONE DENSITY

3D recontructions of trabeculae
Figure 1. 3D reconstructions of 1cm3 of trabeculae from the medial femoral condyle of a control animal (left), as compared to an animal subject to 20 min/d of LMMS.  mCT images reflect the increases in trabecular density observed in the proximal femur determined by static and dynamic histo-morphometry, as well as improvements in trabecular connectivity and morphology.

Long-term animal studies show that the low magnitude mechanical signals (LMMS), as produced by the Marodyne device, increase bone density. The signal delivered whole body generates a force of 5 microstrain on the cortical shell (outer surface of the bone).

After one year, animals saw an increase in cancellous bone (spongy bone) volume fraction (Fig. 1), thicker trabeculae, increased trabecular number and enhanced bone stiffness and strength – factors which taken together equate to stronger, healthier bone.

In addition to studies done in otherwise healthy animals that show LIV as preventing age-induced bone loss, LMMS are effective in halting disuse osteoporosis.2 Our work has also shown that LMMS can enhance bony ingrowth into implants,5 and accelerate and augment the healing of fractures (Fig. 2).6

Radiographic assessment at ten-weeks post-op of a Control (left) and Experimental (right) animal (contrast controlled using step wedge) showed marked differences between the groups in the size and maturity of the callus. Also seen on the radiographs are the external fixation pins, and the accessory pins used for mounting the LVDT across the fracture gap. During the active stimulation of the fixator, 25µm of displacement was induced across the fracture gap. While there is some endochondral bone formation evident in both radiographs at ten weeks, the extent and maturity of the periosteal callus is much greater on the experimental animal, contributing to the increased functional stiffness of the fracture gap  
Figure 2. Radiographic assessment at ten-weeks post-op of a Control (left) and Experimental (right) animal (contrast controlled using step wedge) showed marked differences between the groups in the size and maturity of the callus.  Also seen on the radiographs are the external fixation pins, and the accessory pins used for mounting the LVDT across the fracture gap.  During the active stimulation of the fixator, 25µm of displacement was induced across the fracture gap.  While there is some endochondral bone formation evident in both radiographs at ten weeks, the extent and maturity of the periosteal callus is much greater on the experimental animal, contributing to the increased functional stiffness of the fracture gap.

LIV PROMOTES AND MAINTAINS THE BODY'S ADULT STEM CELL POPULATION

Studies in the mouse have shown that these low level mechanical signals, while anabolic to bone and muscle, are extremely complex in terms of their molecular regulators.3 HOW the signals work is an active area of research. Our research has recently indicated that a key mediator in the bone's response to mechanical signals is the bone marrow derived mesenchymal stem cell population.

Mesenchymal stem cells are an adult stem cell population can differentiate into a variety of cell types including bone cells (osteoblasts), cartilage cells (chondrocytes), and fat cells (adipocytes). While stem cells are theoretically a self-renewing population, it is known that injury, disease, and aging are associated with decreases in the number of stem cells.

It is believed that decreases in the number of stem cells can impair the normal repair and regenerative processes, as there are fewer cells that can be activated and mobilized.

We have recently shown that the Marodyne signal is capable of increasing the number of bone marrow derived stem cells after at little as 6 weeks of daily treatment. This signal is delivered non-invasively, and is designed to promote the body's own resident stem cell population. The ability of this increased stem cell pool to promote and accelerate wound healing is currently under study.

LIV REDUCES FAT MASS – PROTECTS AGAINST DIET INDUCED OBESITY

Very recent work indicates that these mechanical signals, by being able to preferentially promote stem cell differentation into musculoskeletal tissues, can subsequently reduce the development of fat tissue.

In animal models, it has been demonstrated that after 12 wks of daily treatment, animals exhibit on average 20-30% less total body fat mass than untreated animals.

To mimic human pathology where the development of obesity is often driven by a caloric excess and a diet high in fat, a study was designed testing the ability of LIV to counter this diet induced obesity – again showing an ~30% reduction in total body fat after 12 wks.

By suppressing adipogenesis (the development of stem cells into fat), we have shown in a 9 month long study that there is an improvement in health and the prevention of disease. In particular, we have reported that the reduced fat mass achieved and maintained by daily LIV can slow the development and incidence of Non-Alcoholic Fatty Liver Disease (in press, International Journal of Obesity).

TRANSLATING LMMS/LIV BASIC SCIENCE AND ENGINEERING INTO THE CLINIC

Ultimately, the principal mission of Marodyne Medical is to provide safe and effective treatments for human conditions through the maintenance of a healthy adult stem cell population and control of stem cell differentiation.

Towards that end, several clinical trials are underway (and others have been designed) to determine the clinical efficacy of LMMS for a number of disorders and clinical outcomes including:

  • Treatment for primary and secondary bone loss in diseases/pathologies such as spinal cord injury, cerebral palsy, Crohn's Disease, and cancer

  • Non-pharmacologic promotion of bone density in osteoporosis

  • Protection of musculoskeletal health in healthy individuals during aging

  • Pre-habilitation and post-habilitation to maximize and "prime" stem cell pool in surgical patients

  • Rehabilitation of patients undergoing the course of physical and/or occupational therapy

  • Treatment of childhood obesity, diabetes, and metabolic syndrome

HIGHLIGHTED HUMAN TRIALS, CLINICAL EFFICACY, AND ONGOING TRIALS

Post-menopausal Osteoporosis/Elderly Patients/Age-Induced Bone Loss

Funding Source: National Institutes of Health (NIH)

Study Location: Hebrew Rehabilitation Center for the Aged, Harvard Medical

Study Summary: A one year, double-blind, placebo controlled pilot study that involved seventy post-menopausal women, 50% subject to a 0.2g, 30Hz signal for two 10 minute periods per day, with the remaining women receiving placebo devices.11

A means of non-invasively inducing such strains into the skeleton was achieved through whole body vibration which, when delivered through the foot of the standing human9 can efficiently and effectively (Fig. 3) transmit mechanical information to the axial skeleton at frequencies of up to 90 Hz.10

As defined by accelerometers attached to Steinmann pins affixed to the greater trochanter and L3 (circled), approximately 80% of the 30Hz, 0.2g peak-to-peak acceleration of the top platen of the LMMS device (bottom of picture, solid line on left graph) was effectively transmitted to the femur (dashed) and spine (dotted).
Figure 3.  As defined by accelerometers attached to Steinmann pins affixed to the greater trochanter and L3 (circled), approximately 80% of the 30Hz, 0.2g peak-to-peak acceleration of the top platen of the LMMS device (bottom of picture, solid line on left graph) was effectively transmitted to the femur (dashed) and spine (dotted).

In the highest compliance quartile, the spines of lighter women (< 65 Kg) exhibited a relative benefit of treatment of 3.35% greater BMD (p=0.009) while for the mean compliance group a 2.73% benefit was measured (p=0.02).

A feasibility trial in the elderly showed that of the 24 women (mean 86y; range 79-92y) enrolled, 21 completed the study, with 93% compliance for daily treatment over 6 months.12

These data are the basis of a larger scale (200 subject) randomized study of osteopenic (t-scores of -1.0 to -2.5) women and men over the age of 70

Promotion of Bone Density in Adolescents with Cerebral Palsy

Funding Source: National Institutes of Health (NIH)

Study Location: Children's Hospital of Philadelphia (CHOP)

Study Summary: In the first LMMS study in an adolescent population, twenty children with cerebral palsy (4-19y) were randomized into treatment (0.3g, 90Hz, 10min·d-1) and placebo groups.13 After 6 months, bone mineral density of the proximal tibiae in the placebo group decreased by 11% while the treatment group gained 6.3%, a 17.7% "benefit" (p=0.003; Fig. 4).

Over the course of 6 months, the marked loss of volumetric BMD measured in the placebo group of cerebral palsy children (red bar, right graph) was reversed by LMMS, resulting in a bone gain in the proximal tibia (green bar), and a 17% “benefit” of treatment (p=0.003).
Figure 4. Over the course of 6 months, the marked loss of volumetric BMD measured in the placebo group of cerebral palsy children (red bar, right graph) was reversed by LMMS, resulting in a bone gain in the proximal tibia (green bar), and a 17% “benefit” of treatment (p=0.003).

Osteoporosis in Adolescents/Young Women

Funding Source: National Institutes of Health (NIH)

Study Location: Children's Hospital of Los Angeles

Study Summary: In a follow-on study of young women with osteoporosis, 48 women, 16-21y of age, and each in the lowest quartile of BMD, were randomized to receive one-year of LMMS (10min/d, 0.3g, 30Hz).14 At twelve months, those women subject to LMMS showed an increase in spinal bone density by 3.8mg/cm3 (p=0.03), as contrasted with those in the control group who showed no change. Further, the average area of paraspinous musculature at the mid-portion of the third lumbar vertebrae, which showed no change in the controls (+1.2cm2 ± s.e.1.9; p=0.52), was sharply elevated in the LMMS women (+10.1cm2 ± 2.5; p<0.001), indicating that LMMS promoted myogenesis in the human (Figure 5).

Young women subject to LMMS for one year (n=24; gray bars ± s.e.) realized significant increases in trabecular bone density and muscle area at the spine, changes paralleled by a non-significant increase in visceral adipose tissue (VAT). In contrast, controls (n=24; white bars), failed to increase either bone or muscle, but who realized a significant increase in VAT (p=0.015).
Figure 5. Young women subject to LMMS for one year (n=24; gray bars ± s.e.) realized significant increases in trabecular bone density and muscle area at the spine, changes paralleled by a non-significant increase in visceral adipose tissue (VAT).  In contrast, controls (n=24; white bars), failed to increase either bone or muscle, but who realized a significant increase in VAT (p=0.015).

Obesity in Young Adults

Funding Source: National Institutes of Health (NIH)

Study Location: Children's Hospital of Los Angeles

Study Summary: Following our observation on the influence of LMMS on the inverse relationship of adipogenesis and osteoblastogenesis,15 we returned to the data collected in the trial of young women with osteoporosis. An analysis of the study data and spinal CT scans found that in contrast to the increases relative to baseline in visceral abdominal fat (VAT) measured in control subjects (+5.6cm2 ± 2.4, p=0.015), that VAT in girls in the LMMS group increased by only 1.8cm2 ± 2.3, an amount not significantly different from baseline (p=0.22). These data, although retrospective, provide preliminary evidence that LMMS can indeed influence muscle mass as well as adiposity.

Low Back Pain and Postural Stability

Funding Source: National Aeronautics and Space Agency (NASA)

Study Location: Galveston, TX

Study Summary: In a study funded by NASA, the potential of LMMS to influence other phenotypic parameters of the musculoskeletal system is supported by early evidence of its ability to reduce low back pain and retain intervertebral disc morphology16 and postural stability (manuscript in review) in adult volunteers undergoing 90 days of restricted bedrest.

SUMMARY

Evidence in the animal and human indicates that brief exposure to low-magnitude, high frequency mechanical signals can benefit bone quantity and quality, and perhaps a benefit to the musculoskeletal "system." The Marodyne biomechanical intervention is self-targeting, endogenous to tissue, and auto-regulated, and provides promise towards a unique, non-pharmacogenic intervention for osteoporosis and obesity. By providing a surrogate for a diminished functional loading environment, the anabolic potential of mechanical stimuli indicates their potential to serve as a unique intervention for disorders and injuries of the musculoskeletal system… not "solely" by serving as an anabolic signal to bone, but by enabling the progenitor pool to become bone and higher order connective tissues.15

While high magnitude (>5g) whole body vibration has been shown to put the skeleton at grave risk,7,8 the bone strains which arise using our LMMS technology are far below (<1/1000th) those which may cause damage to bone or cartilage tissue.

REFERENCE LIST

  1. Rubin,C., Turner,A.S., Bain,S., Mallinckrodt,C. & McLeod,K. Anabolism: Low mechanical signals strengthen long bones. Nature 412, 603-604 (2001).
  2. Rubin,C., Xu,G. & Judex,S. The anabolic activity of bone tissue, suppressed by disuse, is normalized by brief exposure to extremely low-magnitude mechanical stimuli. FASEB J. 15, 2225-2229 (2001).
  3. Judex,S. et al. Mechanical modulation of molecular signals which regulate anabolic and catabolic activity in bone tissue. J. Cell Biochem. 94, 982-994 (2005).
  4. Rubin,C.T. et al. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc. Natl. Acad. Sci. U. S. A 104, 17879-17884 (2007).
  5. Rubin,C.T. & McLeod,K.J. Promotion of bony ingrowth by frequency-specific, low-amplitude mechanical strain. Clin. Orthop. 165-174 (1994).
  6. Goodship,A.E., Lawes,T.J. & Rubin,C.T. Low-magnitude high-frequency mechanical signals accelerate and augment endochondral bone repair: preliminary evidence of efficacy. J. Orthop. Res. 27, 922-930 (2009).
  7. Kiiski,J., Heinonen,A., Jarvinen,T.L., Kannus,P. & Sievanen,H. Transmission of vertical whole body vibration to the human body. J. Bone Miner. Res. 23, 1318-1325 (2008).
  8. Pel,J.J. et al. Platform accelerations of three different whole-body vibration devices and the transmission of vertical vibrations to the lower limbs. Med. Eng Phys. 31, 937-944 (2009).
  9. Fritton,J.C., Rubin,C.T., Qin,Y.X. & McLeod,K.J. Whole-body vibration in the skeleton: development of a resonance-based testing device. Ann. Biomed. Eng 25, 831-839 (1997).
  10. Rubin,C. et al. Transmissibility of 15-hertz to 35-hertz vibrations to the human hip and lumbar spine: determining the physiologic feasibility of delivering low-level anabolic mechanical stimuli to skeletal regions at greatest risk of fracture because of osteoporosis. Spine 28, 2621-2627 (2003).
  11. Rubin,C. et al. Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J. Bone Miner. Res. 19, 343-351 (2004).
  12. Hannan,M.T. et al. Establishing the compliance in elderly women for use of a low level mechanical stress device in a clinical osteoporosis study. Osteoporos. Int. 15, 918-926 (2004).
  13. Ward,K. et al. Low magnitude mechanical loading is osteogenic in children with disabling conditions. J. Bone Miner. Res. 19, 360-369 (2004).
  14. Gilsanz,V. et al. Low-Level, High-Frequency Mechanical Signals Enhance Musculoskeletal Development of Young Women With Low BMD. J. Bone Miner. Res. 21, 1464-1474 (2006).
  15. Luu,Y.K. et al. Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity. J. Bone Miner. Res. 24, 50-61 (2009).
  16. holguin,n., muir,j., Rubin,C. & Judex,S. Short applications of very low-magnitude vibrations attenuate expansion of the intervertebral disc during extended bed rest. Spine J. 9, 470-477 (2009). 
  17. ADD MUIR reference in Posture