TECHNOLOGY AND OUTCOMES

To learn more about the #1 bone stimulator in Europe,1 click here

Growth factors

Osteoconductive scaffolds

Osteogenic cells

Mechanical environment

EXOGEN complements surgical intervention Four factors contribute to the process of bone restoration.2 These form the Diamond Model of bone healing. Any deficit of the four factors alters the physiological sequence of fracture healing and predisposes to complications.2

Fracture healing managed through surgical intervention

Bone healing stimulated through EXOGEN’s mechanism of action

The Diamond Model2

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

EXOGEN Treatment Pathways

References and Indications

EXOGEN sends ultrasound through soft tissue to the fracture site, resulting in nanomotion of osteoblasts.

Integrins cluster on the cell surface, triggering a biological cascade inculding:

• Greater expression of COX-27

• Greater production of PGE2

Cell stimulus leads to clinical responses:

• Increased number of osteoblasts3-5 through conversion of stem cells

• Improved blood supply3,6 resulting from stimulation of VEGF

• New bone formation7,8 by increased levels of BMP’s (-2, -4, -6 and -7)

• Enhanced mineralization3,10

EXOGEN promotes bone healing by stimulating biological processes9

Nanomotion at the Fracture Site

Detection by Integrins

Reaction of CellsFocal Adhesion

Beam is for illustrative purposes only. Actual beam size is 45 mm wide and penetrates soft tissue at a depth of more than 250 mm.11

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

EXOGEN Treatment Pathways

References and Indications

Risk factors and bone healing

While most fractures heal uneventfully, fracture-healing complications such as delayed union, nonunion, and malunion do occur.12

• Nonunion rate in long bones: 5%-10%13

• Nonunion rate in tibial shaft fractures: 10%-20%12

• Nonunion rate in foot and ankle fusions: ± 12%14

Several risk factors may affect bone healing:12-14

• Fracture-related factors: - Open fracture - High-energy trauma - Multiple fractures

• Patient-related factors: - Diabetes - Smoking - Chronic opiod use - Osteoporosis - Osteoarthritis +/- rheumatoid arthritis - Anticoagulant prescription

EXOGEN helps to mitigate patient-related risk factors.

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

Diabetes

Smoking

EXOGEN Treatment Pathways

References and Indications

Risk factors and bone healing - diabetes

Diabetics:6

• are known to have compromised healing in both soft tissue and bone. • showed 63% slower time to heal than normal in closed fractures. • 87% slower fracture healing in cases that required open reduction.

EXOGEN mitigates the effects of diabetes:

Diabetes: The problems6 EXOGEN: The benefits

Electrolyte and endocrine imbalances

Vascular insufficiency and microvascular pathology*

Compromised immune responses and infection

Not Applicable

Improved bloodsupply (angiogenesis); ± 100-fold increase in VEGF3,6

Non-invasive treatment; no risk of post surgical infections

*Diabetic rats produced substantially lower levels of VEGF and healed more slowly compared to nondiabetic controls6

EXOGEN heal rates in diabetics:

Heal rates All Diabetics

Zura16† 96.2% 95.3%

Post-market Data 84.4% 84.2%

†Study of fresh fracture heal rates

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

Diabetes

Smoking

EXOGEN Treatment Pathways

References and Indications

Risk factors and bone healing - smoking

Smokers:15

• are 3 times more likely to have impaired bone healing. • are 6-fold more likely to develop deep infections after surgery. • were significantly more likely to develop delayed and nonunions (p=0.0007) in tibial shaft fracture patients.

EXOGEN mitigates the effects of smoking:

Smoking: The problems17

Impaired perfusion of the extremities (due to chronic vasoconstriction associated with nicotine)

Inhibition of osteoblast differentiation

Higher risk of developing deep infections post-surgery (6-fold higher risk)

EXOGEN: The benefits

Improved blood-supply (angiogenesis); ± 100-fold increase in VEGF3,6

Promotes conversion of stem cells to osteoblasts3-5

Non-invasive treatment; no risk of post surgical infections

EXOGEN accelerates healing in smokers:17

EXOGEN heal rates in smokers:

Heal rates All SmokersZura16* 96.2% 94.9%Gebauer18 85.0% 79.2%Scaphoid nonunions19 92.0% 100.0%

*Study of fresh fracture heal rates

Tibi

al fr

actu

res

175 days +/- 27.0

103 days +/- 8.3

EXOGEN Control

n = 7

n = 14

p < 0.006

% faster58

Values are mean +/- standard error

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

Diabetes

Smoking

EXOGEN Treatment Pathways

References and Indications

EXOGEN Treatment Pathways

EXOGEN complements surgical intervention.

Initial treatment

Surgery

Acute Fracture Follow Up

My patient is not progressing

as expected. What can I do?

Consider EXOGEN as an alternative treatment to stimulate bone biology.

Consider EXOGEN as an adjunctive treatment to stimulate bone biology.

Healing uncertain

Healed

EXOGEN offers a safe, noninvasive treatment with equivalent heal rates to surgery.

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

EXOGEN Treatment Pathways

References and Indications

References and Indications

References: 1. iData (EUTRA17 report, issued Jan 2018). 2. Giannoudis PV, Einhorn TA, March D. Fracture healing: The diamond concept. Injury, Int.J.Care Injured. 2007:38S4;S3-S6. 3. Leung KS, Cheung WH, Zhang C, Lee KM, Lo HK. Low intensity pulsed ultrasound stimulates osteogenic activity of human periosteal cells. Clin Orthop Relat Res. 2004;418:253-9.4. Lai CH, Chen SC, Chiu LH, et al. Effects of low-intensity pulsed ultrasound, dexamethasone/TGF-ß1 and/or BMP-2 on the transcriptional expression of genes in human mesenchymal

stem cells: chondrogenic vs. osteogenic differentiation. Ultrasound Med Biol. 2010;36(6):1022-33.5. Ebisawa K, Hata K, Okada K, et al. Ultrasound enhances transforming growth factor β-mediated Chondrocyte differentiation of human mesenchymal stem cells. Tissue Engineering.

2004; 10(5-6); 921-929.6. Coords M, Breitbart E, Paglia D, et al. The effects of low-intensity pulsed ultrasound upon diabetic fracture healing. J Orthop Res. 2011;29(2):181-8.7. Naruse K, Sekiya H, Harada Y, et al. Prolonged endochondral bone healing in senescence is shortened by low-intensity pulsed ultrasound in a manner dependent on COX-2.

Ultrasound Med Biol. 2010;36(7):1098-108.8. Sant’Anna EF, Leven RM, Virdi AS, Sumner DR. Effect of low intensity pulsed ultrasound and BMP-2 on rat bone marrow stromal cell gene expression. J Orthop Res.

2005;23(3):646-52.9. Harrison A, Lin S, Pounder N, Mikuni-Takagaki Y. Mode & mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair. Ultrasonics. 2016:70;45–52. 10. Schofer MD, Block JE, Aigner J, Schmelz A. Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled

trial. BMC Musculoskelet Disord. 2010;11(1):229. doi: 10.1186/1471-2474-11-229.11. Data on file. RPT-00036812. Hermandez RK, Do TP, Critchlow CW, Dent RE. Patient-related risk factors for fracture-healing complications in the United Kingdom General Practice Research Database. Acta

Orthopeadica. 2012;83 (6):653-660. 13. Zura R, Mehta S, Della Rocca GJ, Steen RG. Biological risk factors for nonunion of bone fracture. JBJS Reviews. 2016;4(1):1-1214. Thevedran G, Shah K, Pinney SJ, Younger AS. Perceived risk factors for nonunion following foot and ankle arthrodesis. J of Orthopedic Surgery. 2017;25(I):1-6. 15. Della Rocca G, Brodie C, Harrison A. The impact of Low-Intensity Pulsed Ultrasound (LIPUS) on Risk Factors for Fracture Nonunion. ORS Connect. 2018:xxx16. Zura R, Mehta S, Della Rocca GJ, Jones J. A cohort study of 4,190 patients treated with low-intensity pulsed ultrasound (LIPUS): findings in the elderly versus all patients. BMC

Muscoskeletal Disorders. 2015;16:1-10. 17. Cook SD, Ryaby JP, McCabe J, Frey JJ, Heckman JD, Kristiansen TK. Acceleration of tibia and distal radius fracture healing in patients who smoke. Clin Orthop Relat Res. 1997; 337:

198-207.18. Gebauer D, Mayr E, Orthner E, RyabyJ P. Low-intensity pulsed ultrasound: effects on nonunions. Ultrasound Med Biol. 005;31(10):1391−1402.19. Data on file. RPT-00039020. Data on file. RPT-000351

Summary of Indications for Use: EXOGEN is indicated for the non-invasive treatment of osseous defects (excluding vertebra and skull) that includes the treatment of delayed unions, nonunions,† stress fractures and joint fusion. EXOGEN is also indicated for the acceleration of fresh fracture heal time, repair following osteotomy, repair in bone transport procedures and repair in distraction osteogenesis procedures.†A nonunion is considered to be established when the fracture site shows no visibly progressive signs of healing.

There are no known contraindications for the EXOGEN device. Safety and effectiveness have not been established for individuals lacking skeletal maturity, pregnant or nursing women, patients with cardiac pacemakers, on fractures due to bone cancer, or on patients with poor blood circulation or clotting problems. Some patients may be sensitive to the ultrasound gel.

Full prescribing information can be found in product labeling, at www.exogen.com.

Bioventus, the Bioventus logo, and EXOGEN are registered trademarks of Bioventus LLC. © 2018 Bioventus LLC. All rights reserved. SMK-002623 10/18

EXOGEN Complements Surgical Intervention

EXOGEN Promotes Bone Healing

Risk Factors and Bone Healing

EXOGEN Treatment Pathways

References and Indications