Full Text:   <3504>

CLC number: R684.7

On-line Access: 2012-12-07

Received: 2012-05-04

Revision Accepted: 2012-08-05

Crosschecked: 2012-10-30

Cited: 5

Clicked: 6713

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2012 Vol.13 No.12 P.955-963


Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing

Author(s):  Zhi-min Ying, Tiao Lin, Shi-gui Yan

Affiliation(s):  Department of Orthopaedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; more

Corresponding email(s):   zrjwsj@zju.edu.cn

Key Words:  Low-intensity pulsed ultrasound, ACL reconstruction, Ultrasound, Anterior cruciate ligament reconstruction, LIPUS, Tendon-bone interface healing, Fracture healing

Share this article to: More |Next Article >>>

Zhi-min Ying, Tiao Lin, Shi-gui Yan. Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing[J]. Journal of Zhejiang University Science B, 2012, 13(12): 955-963.

@article{title="Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing",
author="Zhi-min Ying, Tiao Lin, Shi-gui Yan",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing
%A Zhi-min Ying
%A Tiao Lin
%A Shi-gui Yan
%J Journal of Zhejiang University SCIENCE B
%V 13
%N 12
%P 955-963
%@ 1673-1581
%D 2012
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1200129

T1 - Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing
A1 - Zhi-min Ying
A1 - Tiao Lin
A1 - Shi-gui Yan
J0 - Journal of Zhejiang University Science B
VL - 13
IS - 12
SP - 955
EP - 963
%@ 1673-1581
Y1 - 2012
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1200129

Incorporation of a tendon graft within the bone tunnel represents a challenging clinical problem. Successful anterior cruciate ligament (ACL) reconstruction requires solid healing of the tendon graft in the bone tunnel. Enhancement of graft healing to bone is important to facilitate early aggressive rehabilitation and a rapid return to pre-injury activity levels. No convenient, effective or inexpensive procedures exist to enhance tendon-bone (T-B) healing after surgery. ultrasound%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>low-intensity pulsed ultrasound (LIPUS) improves local blood perfusion and angiogenesis, stimulates cartilage maturation, enhances differentiation and proliferation of osteoblasts, and motivates osteogenic differentiation of mesenchymal stem cells (MSCs), and therefore, appears to be a potential non-invasive tool for T-B healing in early stage of rehabilitation of ACL reconstruction. It is conceivable that LIPUS could be used to stimulate T-B tunnel healing in the home, with the aim of accelerating rehabilitation and an earlier return to normal activities in the near future. The purpose of this review is to demonstrate how LIPUS stimulates T-B healing at the cellular and molecular levels, describe studies in animal models, and provide a future direction for research.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Angle, S.R., Sena, K., Sumner, D.R., Virdi, A.S., 2011. Osteogenic differentiation of rat bone marrow stromal cells by various intensities of low-intensity pulsed ultrasound. Ultrasonics, 51(3):281-288.

[2]Bar, R., 1988. Ultrasound-enhanced bioprocesses: cholesterol oxidation by Rhodococcus erythropolis. Biotechnol. Bioeng., 32(5):655-663.

[3]Bolander, M.E., 1992. Regulation of fracture repair by growth factors. Proc. Soc. Exp. Biol. Med., 200(2):165-170.

[4]Busse, J.W., Kaur, J., Mollon, B., Bhandari, M., Tornetta, P.,3rd, Schunemann, H.J., Guyatt, G.H., 2009. Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials. BMJ, 338:b351.

[5]Cai, X.Z., Yan, S.G., Wu, H.B., He, R.X., Dai, X.S., Chen, H.X., Yan, R.J., Zhao, X.H., 2007. Effect of delayed pulsed-wave ultrasound on local pharmacokinetics and pharmacodynamics of vancomycin-loaded acrylic bone cement in vivo. Antimicrob. Agents Chemother., 51(9):3199-3204.

[6]Chen, C.H., 2009. Strategies to enhance tendon graft-bone healing in anterior cruciate ligament reconstruction. Chang Gung Med. J., 32(5):483-493.

[7]Chung, B., Wiley, J.P., 2002. Extracorporeal shockwave therapy: a review. Sports Med., 32(13):851-865.

[8]Clark, J., Stechschulte, D.J., 1998. The interface between bone and tendon at an insertion site: a study of the quadriceps tendon insertion. J. Anat., 192(4):605-616.

[9]Cui, J.H., Park, S.R., Park, K., Choi, B.H., Min, B.H., 2007. Preconditioning of mesenchymal stem cells with low-intensity ultrasound for cartilage formation in vivo. Tissue Eng., 13(2):351-360.

[10]Demirag, B., Sarisozen, B., Ozer, O., Kaplan, T., Ozturk, C., 2005. Enhancement of tendon-bone healing of anterior cruciate ligament grafts by blockage of matrix metalloproteinases. J. Bone Joint Surg. Am., 87(11):2401-2410.

[11]Doan, N., Reher, P., Meghji, S., Harris, M., 1999. In vitro effects of therapeutic ultrasound on cell proliferation, protein synthesis, and cytokine production by human fibroblasts, osteoblasts, and monocytes. J. Oral. Maxillofac. Surg., 57(4):409-419.

[12]Doktycz, S.J., Suslick, K.S., 1990. Interparticle collisions driven by ultrasound. Science, 247(4946):1067-1069.

[13]Einhorn, T.A., 1995. Enhancement of fracture-healing. J. Bone Joint Surg. Am., 77(6):940-956.

[14]El-Mowafi, H., Mohsen, M., 2005. The effect of low-intensity pulsed ultrasound on callus maturation in tibial distraction osteogenesis. Int. Orthop., 29(2):121-124.

[15]Feril, L.B.Jr., Kondo, T., 2004. Biological effects of low intensity ultrasound: the mechanism involved, and its implications on therapy and on biosafety of ultrasound. J. Radiat. Res., 45(4):479-489.

[16]George, M.S., Dunn, W.R., Spindler, K.P., 2006. Current concepts review: revision anterior cruciate ligament reconstruction. Am. J. Sports Med., 34(12):2026-2037.

[17]Gulotta, L.V., Kovacevic, D., Ying, L., Ehteshami, J.R., Montgomery, S., Rodeo, S.A., 2008. Augmentation of tendon-to-bone healing with a magnesium-based bone adhesive. Am. J. Sports Med., 36(7):1290-1297.

[18]Hadjiargyrou, M., McLeod, K., Ryaby, J.P., Rubin, C., 1998. Enhancement of fracture healing by low intensity ultrasound. Clin. Orthop. Relat. Res., 355(Suppl.):S216-S229.

[19]Hashimoto, Y., Yoshida, G., Toyoda, H., Takaoka, K., 2007. Generation of tendon-to-bone interface “enthesis” with use of recombinant BMP-2 in a rabbit model. J. Orthop. Res., 25(11):1415-1424.

[20]Huangfu, X., Zhao, J., 2007. Tendon-bone healing enhancement using injectable tricalcium phosphate in a dog anterior cruciate ligament reconstruction model. Arthroscopy, 23(5):455-462.

[21]Ju, Y.J., Muneta, T., Yoshimura, H., Koga, H., Sekiya, I., 2008. Synovial mesenchymal stem cells accelerate early remodeling of tendon-bone healing. Cell Tissue Res., 332(3):469-478.

[22]Juffermans, L.J., Kamp, O., Dijkmans, P.A., Visser, C.A., Musters, R.J., 2008. Low-intensity ultrasound-exposed microbubbles provoke local hyperpolarization of the cell membrane via activation of BK (Ca) channels. Ultrasound Med., Biol., 34(3):502-508.

[23]Kanazawa, T., Soejima, T., Murakami, H., Inoue, T., Katouda, M., Nagata, K., 2006. An immunohistological study of the integration at the bone-tendon interface after reconstruction of the anterior cruciate ligament in rabbits. J. Bone Joint Surg. Br., 88(5):682-687.

[24]Karaoglu, S., Celik, C., Korkusuz, P., 2009. The effects of bone marrow or periosteum on tendon-to-bone tunnel healing in a rabbit model. Knee Surg. Sports Traumatol. Arthrosc., 17(2):170-178.

[25]Karshafian, R., Bevan, P.D., Williams, R., Samac, S., Burns, P.N., 2009. Sonoporation by ultrasound-activated microbubble contrast agents: effect of acoustic exposure parameters on cell membrane permeability and cell viability. Ultrasound Med. Biol., 35(5):847-860.

[26]Kokubu, T., Matsui, N., Fujioka, H., Tsunoda, M., Mizuno, K., 1999. Low intensity pulsed ultrasound exposure increases prostaglandin E2 production via the induction of cyclooxygenase-2 mRNA in mouse osteoblasts. Biochem. Biophys. Res. Commun., 256(2):284-287.

[27]Korstjens, C.M., Nolte, P.A., Burger, E.H., Albers, G.H., Semeins, C.M., Aartman, I.H., Goei, S.W., Klein-Nulend, J., 2004. Stimulation of bone cell differentiation by low-intensity ultrasound: a histomorphometric in vitro study. J. Orthop. Res., 22(3):495-500.

[28]Kovacevic, D., Fox, A.J., Bedi, A., Ying, L., Deng, X.H., Warren, R.F., Rodeo, S.A., 2011. Calcium-phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair. Am. J. Sports Med., 39(4):811-819.

[29]Lee, H.J., Choi, B.H., Min, B.H., Son, Y.S., Park, S.R., 2006. Low-intensity ultrasound stimulation enhances chondrogenic differentiation in alginate culture of mesenchymal stem cells. Artif. Organs, 30(9):707-715.

[30]Leung, K.S., Qin, L., Fu, L.K., Chan, C.W., 2002. A comparative study of bone to bone repair and bone to tendon healing in patella-patellar tendon complex in rabbits. Clin. Biomech., 17(8):594-602.

[31]Leung, K.S., Lee, W.S., Tsui, H.F., Liu, P.P., Cheung, W.H., 2004. Complex tibial fracture outcomes following treatment with low-intensity pulsed ultrasound. Ultrasound Med. Biol., 30(3):389-395.

[32]Lim, J.K., Hui, J., Li, L., Thambyah, A., Goh, J., Lee, E.H., 2004. Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy, 20(9):899-910.

[33]Liu, X., Yin, C., Gong, X., Cao, W., 2010. Theoretical and experimental study on temperature elevation behind ribs caused by weakly focused ultrasound. Ultrasound Med. Biol., 36(10):1704-1712.

[34]Liu, Y., Miyoshi, H., Nakamura, M., 2006. Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. J. Control. Release, 114(1):89-99.

[35]Lovric, V., Ledger, M., Goldberg, J., Harper, W., Bertollo, N., Pelletier, M.H., Oliver, R.A., Yu, Y., Walsh, W.R., 2012. The effects of low-intensity pulsed ultrasound on tendon-bone healing in a transosseous-equivalent sheep rotator cuff model. Knee Surg. Sports Traumatol. Arthrosc., Epub ahead of print.

[36]Lu, C.C., Liu, Y.C., Cheng, Y.M., Chih, T.T., Tien, Y.C., 2009. Augmentation of tendon-bone interface healing with low-intensity pulsed ultrasound. Orthopedics, 32(3):173.

[37]Lu, H., Qin, L., Fok, P., Cheung, W., Lee, K., Guo, X., Wong, W., Leung, K., 2006. Low-intensity pulsed ultrasound accelerates bone-tendon junction healing: a partial patellectomy model in rabbits. Am. J. Sports Med., 34(8):1287-1296.

[38]Lu, H., Qin, L., Cheung, W., Lee, K., Wong, W., Leung, K., 2008. Low-intensity pulsed ultrasound accelerated bone-tendon junction healing through regulation of vascular endothelial growth factor expression and cartilage formation. Ultrasound Med. Biol., 34(8):1248-1260.

[39]Lu, M.H., Zheng, Y.P., Huang, Q.H., Lu, H.B., Qin, L., 2009. Low Intensity Pulsed Ultrasound Increases the Mechanical Properties of the Healing Tissues at Bone-Tendon Junction. Engineering in Medicine and Biology Society, 2009. EMBC 2009. Annual International Conference of the IEEE, p.2141-2144.

[40]Mutsuzaki, H., Sakane, M., Fujie, H., Hattori, S., Kobayashi, H., Ochiai, N., 2011. Effect of calcium phosphate-hybridized tendon graft on biomechanical behavior in anterior cruciate ligament reconstruction in a goat model: novel technique for improving tendon-bone healing. Am. J. Sports Med., 39(5):1059-1066.

[41]Nolte, P.A., van der Krans, A., Patka, P., Janssen, I.M., Ryaby, J.P., Albers, G.H., 2001. Low-intensity pulsed ultrasound in the treatment of nonunions. J. Trauma., 51(4):693-702; discussion 702-703.

[42]Ohl, C.D., Arora, M., Ikink, R., de Jong, N., Versluis, M., Delius, M., Lohse, D., 2006. Sonoporation from jetting cavitation bubbles. Biophys. J., 91(11):4285-4295.

[43]Petersen, W., Laprell, H., 2000. Insertion of autologous tendon grafts to the bone: a histological and immunohistochemical study of hamstring and patellar tendon grafts. Knee Surg. Sports Traumatol. Arthrosc., 8(1):26-31.

[44]Pitt, W.G., Ross, S.A., 2003. Ultrasound increases the rate of bacterial cell growth. Biotechnol. Prog., 19(3):1038-1044.

[45]Prozorov, T., Prozorov, R., Suslick, K.S., 2004. High velocity interparticle collisions driven by ultrasound. J. Am. Chem. Soc., 126(43):13890-13891.

[46]Qin, L., Leung, K.S., Chan, C.W., Fu, L.K., Rosier, R., 1999. Enlargement of remaining patella after partial patellectomy in rabbits. Med. Sci. Sports Exerc., 31(4):502-506.

[47]Qin, L., Fok, P., Lu, H., Shi, S., Leng, Y., Leung, K., 2006a. Low intensity pulsed ultrasound increases the matrix hardness of the healing tissues at bone-tendon insertion-a partial patellectomy model in rabbits. Clin. Biomech., 21(4):387-394.

[48]Qin, L., Lu, H., Fok, P., Cheung, W., Zheng, Y., Lee, K., Leung, K., 2006b. Low-intensity pulsed ultrasound accelerates osteogenesis at bone-tendon healing junction. Ultrasound Med. Biol., 32(12):1905-1911.

[49]Reher, P., Doan, N., Bradnock, B., Meghji, S., Harris, M., 1999. Effect of ultrasound on the production of IL-8, basic FGF and VEGF. Cytokine, 11(6):416-423.

[50]Reher, P., Harris, M., Whiteman, M., Hai, H.K., Meghji, S., 2002. Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts. Bone, 31(1):236-241.

[51]Robert, H., Es-Sayeh, J., Heymann, D., Passuti, N., Eloit, S., Vaneenoge, E., 2003. Hamstring insertion site healing after anterior cruciate ligament reconstruction in patients with symptomatic hardware or repeat rupture: a histologic study in 12 patients. Arthroscopy, 19(9):948-954.

[52]Rodeo, S.A., Arnoczky, S.P., Torzilli, P.A., Hidaka, C., Warren, R.F., 1993. Tendon-healing in a bone tunnel. A biomechanical and histological study in the dog. J. Bone Joint Surg. Am., 75(12):1795-1803.

[53]Rubin, C., Bolander, M., Ryaby, J.P., Hadjiargyrou, M., 2001. The use of low-intensity ultrasound to accelerate the healing of fractures. J. Bone Joint Surg. Am., 83A(2):259-270.

[54]Sasaki, K., Kuroda, R., Ishida, K., Kubo, S., Matsumoto, T., Mifune, Y., Kinoshita, K., Tei, K., Akisue, T., Tabata, Y., Kurosaka, M., 2008. Enhancement of tendon-bone osteointegration of anterior cruciate ligament graft using granulocyte colony-stimulating factor. Am. J. Sports Med., 36(8):1519-1527.

[55]Shimazaki, A., Inui, K., Azuma, Y., Nishimura, N., Yamano, Y., 2000. Low-intensity pulsed ultrasound accelerates bone maturation in distraction osteogenesis in rabbits. J. Bone Joint Surg. Br., 82(7):1077-1082.

[56]Sivakumar, M., Tachibana, K., Pandit, A.B., Yasui, K., Tuziuti, T., Towata, A., Iida, Y., 2005. Transdermal drug delivery using ultrasound-theory, understanding and critical analysis. Cell Mol. Biol., 51(Suppl.):OL767-OL784.

[57]Soon, M.Y., Hassan, A., Hui, J.H., Goh, J.C., Lee, E.H., 2007. An analysis of soft tissue allograft anterior cruciate ligament reconstruction in a rabbit model: a short-term study of the use of mesenchymal stem cells to enhance tendon osteointegration. Am. J. Sports Med., 35(6):962-971.

[58]Sun, J.S., Hong, R.C., Chang, W.H., Chen, L.T., Lin, F.H., Liu, H.C., 2001. In vitro effects of low-intensity ultrasound stimulation on the bone cells. J. Biomed. Mater. Res., 57(3):449-456.

[59]Walsh, W.R., Stephens, P., Vizesi, F., Bruce, W., Huckle, J., Yu, Y., 2007. Effects of low-intensity pulsed ultrasound on tendon-bone healing in an intra-articular sheep knee model. Arthroscopy, 23(2):197-204.

[60]Wang, C.J., Weng, L.H., Chou, W.Y., Hsu, S.L., Ko, J.Y., Ko, S.F., Huang, C.C., 2011. Extracorporeal shock wave therapy enhances early tendon-bone healing and reduces bone tunnel enlargement in hamstring autograft anterior cruciate ligament reconstruction. Am. J. Sports Med., 40(7):NP14.

[61]Wang, F.S., Kuo, Y.R., Wang, C.J., Yang, K.D., Chang, P.R., Huang, Y.T., Huang, H.C., Sun, Y.C., Yang, Y.J., Chen, Y.J., 2004. Nitric oxide mediates ultrasound-induced hypoxia-inducible factor-1alpha activation and vascular endothelial growth factor-an expression in human osteoblasts. Bone, 35(1):114-123.

[62]Warden, S.J., Bennell, K.L., McMeeken, J.M., Wark, J.D., 2000. Acceleration of fresh fracture repair using the sonic accelerated fracture healing system (SAFHS): a review. Calcif. Tissue Int., 66(2):157-163.

[63]Welgus, H.G., Jeffrey, J.J., Eisen, A.Z., 1981. Human skin fibroblast collagenase. Assessment of activation energy and deuterium isotope effect with collagenous substrates. J. Biol. Chem., 256:9516-9521.

[64]Wen, C.Y., Qin, L., Lee, K.M., Chan, K.M., 2009. The use of brushite calcium phosphate cement for enhancement of bone-tendon integration in an anterior cruciate ligament reconstruction rabbit model. J. Biomed. Mater. Res. B Appl. Biomater., 89B(2):466-474.

[65]Wong, N.W., Qin, L., Lee, K.M., Tai, K.O., Chong, W.S., Leung, K.S., Chan, K.M., 2003. Healing of bone tendon junction in a bone trough: a goat partial patellectomy model. Clin. Orthop. Relat. Res., 413:291-302.

[66]Yan,S.G., Huang, L.Y., Cai, X.Z., 2011. Low-intensity pulsed ultrasound: a potential non-invasive therapy for femoral head osteonecrosis. Med. Hypotheses, 76(1):4-7.

[67]Yoichiro, M., John, S., Allen, Shin, Y., Teiichiro, I., Yukio, K., 2005. Medical ultrasound with microbubbles. Exp. Therm. Fluid Sci., 29(3):255-265.

[68]Young, S.R., Dyson, M., 1990. The effect of therapeutic ultrasound on angiogenesis. Ultrasound Med. Biol., 16(3):261-269.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE