Intro 

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Bone fractures are a common medical condition, with approximately 7.9 million cases occurring annually  in the United States. While the human body has a natural ability to heal fractures, approximately 8–10%  of cases fail to heal properly, leading to delayed healing, nonunion, or other complications. Traditional  approaches to fracture treatment rely on immobilization, surgical intervention, and, in some cases,  biological or mechanical stimulation to accelerate healing. One such stimulation technique is Low Intensity Pulsed Ultrasound (LIPUS), a non-invasive therapy that has been FDA-approved for over 30 years to enhance fracture healing by promoting bone formation and mineralization. Despite its long standing clinical use, research continues to explore ways to improve upon LIPUS technology and develop  more effective bone healing therapies. 

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A novel LIPUS approach, referenced herein as “Bimodal Acoustic Signal” (BMAS) therapy, introduces an  additional shear stress component to ultrasound stimulation. Unlike the traditional LIPUS signal, which  relies solely on longitudinal ultrasound waves, Sonogen’s BMAS LIPUS signal is rich in shear wave content, which Sonogen theorized would represent a stronger mechanical stimulus for bone  regeneration. Given that bone is a mechanosensitive organ that responds to mechanical and  biochemical stimuli, the hope was that the introduction of shear stress could provide greater stimulation  to osteoblasts and extracellular matrix proteins, ultimately accelerating and strengthening bone repair. 

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A recent study¹ published in IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control set  out to compare the effectiveness of BMAS LIPUS versus traditional LIPUS signals in promoting fracture  healing. The study aimed to determine whether BMAS LIPUS could outperform traditional LIPUS in  terms of generating bone strength, bone stiffness, and overall quality of healing. This white paper  summarizes the study’s findings and explores the implications for the future of non-invasive fracture  treatment. 

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Methodology 

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The IACUC-approved study, designed to comply with all federal, state, and ethical requires related to  animal welfare, was conducted using thirty mature New Zealand white rabbits – selected for their non weight-bearing fibula bones, which provide an ideal model for controlled fracture healing experiments.  A similar model has been used for decades to assess the efficacy of bone fracture healing technologies.  Each rabbit underwent a bilateral fibular osteotomy, meaning that both fibulae were surgically fractured  under sterile conditions. This approach allowed each rabbit to serve as its own control, with one leg  

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Following surgery, each leg received a daily 20-minute ultrasound treatment for 18 consecutive days.  The traditional LIPUS system used in the study was the FDA-approved EXOGEN device, which emits  longitudinal ultrasound waves at a frequency of 1.5 MHz with a spatial average temporal intensity  (ISATA) of 30 mW/cm². The BMAS LIPUS device, by contrast, was designed to apply both longitudinal  and shear wave ultrasound stimulation at a slightly higher ISATA of 40 mW/cm². 

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Throughout the study, fracture healing was monitored using X-ray imaging and Power Doppler Imaging  (PDI) at specific time points: Days 0, 2, 4, 7, 11, 14, 18, and 21. These imaging techniques allowed  researchers to assess bone callus formation, mineralization, and local blood flow at the fracture site. At  the conclusion of the study on Day 21, the rabbits were euthanized, and their fibulae were subjected to  mechanical strength testing to measure torsional stiffness, maximum torque, and angular displacement  at failure. 

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Statistical analysis was performed using ANOVA and paired t-tests to compare the effects of BMAS LIPUS  and traditional LIPUS within individual rabbits, ensuring that biological variability was minimized. 

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^{1 Machado P, Li J, Blackman R, Liu J-B, Kepler CK, Fang T, Muratore R, Winder JH, Winder AA,  Forsberg F, “Comparison between Clinically Available LIPUS and a Novel Bimodal Acoustic Signal  System for Accelerating Fracture Healing,” IEEE UFFC, Vol.69, No. 2, Feb. 2022, 629-636. randomly assigned to receive BMAS LIPUS treatment and the other receiving traditional LIPUS  treatment.} 

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Results and Findings 

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The study produced compelling evidence that BMAS LIPUS therapy led to stronger and stiffer bones  compared to traditional LIPUS. The mechanical testing results revealed that the fibulae treated with  BMAS LIPUS exhibited higher torsional stiffness (0.21 ± 0.19 N·cm/degree) than those treated with  traditional LIPUS (0.16 ± 0.19 N·cm/degree). This difference, which approached statistical significance (p  = 0.050), suggests that BMAS LIPUS-treated bones had a more rigid and stable structure following  healing. 

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Additionally, the maximum torque at failure—a critical indicator of bone strength—was significantly  higher for BMAS LIPUS-treated bones (7.84 ± 5.55 N·cm) compared to those treated with traditional  LIPUS (6.26 ± 3.46 N·cm). The p-value of 0.022 confirmed statistical significance, meaning that BMAS  LIPUS treatment resulted in bones that could withstand greater forces before fracturing. 

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Interestingly, Power Doppler Imaging (PDI) assessments showed that traditional LIPUS-treated bones  exhibited higher vascularity on Days 4 and 18 (p < 0.04). Increased blood flow is typically associated with  enhanced angiogenesis and inflammatory response, which are critical in the early stages of fracture  healing. However, despite LIPUS demonstrating greater blood flow, BMAS LIPUS still resulted in  stronger, stiffer bones by Day 21, suggesting that shear stress stimulation plays a more significant role in  bone strength than vascular response alone. 

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X-Ray imaging did not reveal substantial qualitative differences between BMAS LIPUS and traditional  LIPUS treatments in terms of bone callus formation or fracture bridging. However, the mechanical  testing data clearly indicated that BMAS LIPUS-treated bones were structurally superior to those treated  with traditional LIPUS.

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Discussion and Implications 

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The study’s findings support the hypothesis that BMAS LIPUS therapy enhances fracture healing more  effectively than traditional LIPUS. While LIPUS has long been used to accelerate healing, its reliance  solely on longitudinal ultrasound waves may limit its effectiveness in stimulating the full range of  biomechanical and biochemical processes involved in bone repair. By introducing shear stress waves,  BMAS LIPUS appears to more effectively engage bone-forming cells and extracellular matrix proteins,  leading to stronger and more resilient bones. 

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One possible explanation for the superior mechanical properties observed in BMAS LIPUS-treated bones  is the effect of shear waves on osteoblast activity. Previous research has shown that shear stress  stimulates integrin signaling pathways and enhances extracellular matrix remodeling, both of which  contribute to accelerated and more robust bone formation. The BMAS LIPUS system's ability to generate  both shear and longitudinal waves likely improves mechano-biochemical conversion efficiency, making it  a more potent stimulus for bone regeneration. 

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Despite these promising results, the study had several limitations that warrant further investigation. The  sample size was relatively small, with only 17 rabbits completing the study, which limits the  generalizability of the findings. Additionally, the 21-day follow-up period may not have been long  enough to fully capture long-term differences in healing outcomes. Future studies should incorporate  larger sample sizes, longer observation periods, and human clinical trials to validate the effectiveness of  BMAS LIPUS in a clinical setting. 

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Another area for further exploration is the microvascular response to BMAS LIPUS therapy. While PDI  imaging showed lower vascularity in BMAS LIPUS-treated fractures, this does not necessarily indicate a  weaker healing response. It is possible that BMAS LIPUS promotes microvascular changes that are  undetectable with PDI, and future research using contrast-enhanced ultrasound or other high-resolution  imaging techniques could provide deeper insights. 

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Conclusion

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This study provides strong evidence that BMAS LIPUS therapy offers significant advantages over  traditional LIPUS in promoting bone fracture healing. By incorporating shear wave stimulation, BMAS LIPUS effectively enhances bone stiffness, strength, and overall structural integrity, suggesting that it  may be a superior alternative for non-invasive fracture treatment. While traditional LIPUS remains a  valuable and widely used tool, the findings indicate that BMAS LIPUS technology has the potential to  revolutionize bone healing protocols. 

As research continues to explore new frontiers in ultrasound therapy, BMAS LIPUS represents a  promising advancement that could lead to faster, stronger, and more reliable bone repair solutions.  Future clinical trials will be crucial in determining whether this novel approach can replace or  complement existing treatments for fracture healing in human patients. For orthopedic specialists,  rehabilitation professionals, and medical device manufacturers, BMAS LIPUS presents an exciting  opportunity to improve patient outcomes and set a new standard for bone healing therapies.

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