Research on the nature of micromovement and the biomechanical staging of fracture healing_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

SHI Jinyou ,  XIAO Yuzhou , WU Min , GUAN Jianzhong

Department of Orthopaedics, the First Affiliated Hospital, Bengbu Medical College, Bengbu Anhui, 233000, P.R.China;

Corresponding?author：

XIAO Yuzhou, Email: XiaoYuzhou1@aliyun.com

Keywords：

Micromovement; strain; biomechanics; callus; fracture healing

DOI：

10.7507/1002-1892.202103050

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To explore the nature of micromovement and the biomechanical staging of fracture healing.Methods Through literature review and theoretical analysis, the difference in micromovement research was taken as the breakthrough point to try to provide a new understanding of the role of micromovement and the mechanical working mode in the process of fracture healing.Results The process of fracture healing is the process of callus generation and connection. The micromovement is the key to start the growth of callus, and the total amount of callus should be matched with the size of the fracture space. The strain at the fracture end is the key to determine the callus connection. The strain that can be tolerated by different tissues in the fracture healing process will limit the micromovement. According to this, the fracture healing process can be divided into the initiation period, perfusion period, contradiction period, connection period, and physiological period, i.e., the biomechanical staging of fracture healing.Conclusion Biomechanical staging of fracture healing incorporates important mechanical parameters affecting fracture healing and introduces the concepts of time and space, which helps to understand the role of biomechanics, and its significance needs further clinical test and exploration.

Citation： SHI Jinyou, XIAO Yuzhou, WU Min, GUAN Jianzhong. Research on the nature of micromovement and the biomechanical staging of fracture healing. Chinese Journal of Reparative and Reconstructive Surgery, 2021, 35(9): 1205-1211. doi: 10.7507/1002-1892.202103050 Copy

1.	Steiner M, Claes L, Ignatius A, et al. Disadvantages of interfragmentary shear on fracture healing—mechanical insights through numerical simulation. J Orthop Res, 2014, 32(7): 865-872.
2.	Sellei RM, Garrison RL, Kobbe P, et al. Effects of near cortical slotted holes in locking plate constructs. J Orthop Trauma, 2011, 25 Suppl 1: S35-S40.
3.	高哲辰, 周方, 田耘, 等. 鎖定接骨板內固定治療股骨遠端骨折. 中華創傷骨科雜志, 2016, 18(11): 965-969.
4.	Lujan TJ, Henderson CE, Madey SM, et al. Locked plating of distal femur fractures leads to inconsistent and asymmetric callus formation. J Orthop Trauma, 2010, 24(3): 156-162.
5.	M?rdian S, Schaser KD, Duda GN, et al. Working length of locking plates determines interfragmentary movement in distal femur fractures under physiological loading. Clin Biomech (Bristol, Avon), 2015, 30(4): 391-396.
6.	Wang J, Zhang X, Li S, et al. Plating system design determines mechanical environment in long bone mid-shaft fractures: a finite element analysis. J Invest Surg, 2020, 33(8): 699-708.
7.	張宏軍, 許緯洲, 賀長青, 等. 自控微動帶鎖髓內釘對山羊骨折愈合的生物化學研究. 中國臨床解剖學雜志, 2008, 26(4): 423-425.
8.	Bottlang M, Doornink J, Fitzpatrick DC, et al. Far cortical locking can reduce stiffness of locked plating constructs while retaining construct strength. J Bone Joint Surg (Am), 2009, 91(8): 1985-1994.
9.	Epari DR, Gurung R, Hofmann-Fliri L, et al. Biphasic plating improves the mechanical performance of locked plating for distal femur fractures. J Biomech, 2021, 115: 110192. doi: 10.1016/j.jbiomech.2020.110192.
10.	向明, 胡曉川, 林硯銘, 等. 可控性微動時間對骨折愈合影響的實驗研究. 中華骨科雜志, 2019, 39(21): 1333-1343.
11.	Elkins J, Marsh JL, Lujan T, et al. Motion predicts clinical callus formation: construct-specific finite element analysis of supracondylar femoral fractures. J Bone Joint Surg (Am), 2016, 98(4): 276-284.
12.	Epari DR, Duda GN, Thompson MS. Mechanobiology of bone healing and regeneration: in vivo models. Proc Inst Mech Eng H, 2010, 224(12): 1543-1553.
13.	Goodship AE, Cunningham JL, Kenwright J. Strain rate and timing of stimulation in mechanical modulation of fracture healing. Clin Orthop Relat Res, 1998, (355 Suppl): S105-S115.
14.	Glatt V, Evans CH, Tetsworth K. A Concert between biology and biomechanics: the influence of the mechanical environment on bone healing. Front Physiol, 2017, 7: 678. doi: 10.3389/fphys.2016.00678.
15.	Perren SM. Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthop Relat Res, 1979, (138): 175-196.
16.	劉振東. 骨痂的形成與分類. 中國矯形外科雜志, 2016, 24(4): 332-337.
17.	Ueno M, Urabe K, Naruse K, et al. Influence of internal fixator stiffness on murine fracture healing: two types of fracture healing lead to two distinct cellular events and FGF-2 expressions. Exp Anim, 2011, 60(1): 79-87.
18.	喬林, 侯樹勛, 李文峰, 等. 微動對骨折端微循環及血管內皮生長因子(VEGF) 表達的影響. 中華創傷骨科雜志, 2005, 7(1): 52-54.
19.	Claes LE, Meyers N. The direction of tissue strain affects the neovascularization in the fracture-healing zone. Med Hypotheses, 2020, 137: 109537. doi: 10.1016/j.mehy.2019.109537.
20.	Chen X, Yan J, He F, et al. Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway. Free Radic Biol Med, 2018, 126: 187-201.
21.	McKibbin B. The biology of fracture healing in long bones. J Bone Joint Surg (Br), 1978, 60-B(2): 150-162.
22.	Hulth A. Current concepts of fracture healing. Clin Orthop Relat Res, 1989, (249): 265-284.
23.	Joslin CC, Eastaugh-Waring SJ, Hardy JR, et al. Weight bearing after tibial fracture as a guide to healing. Clin Biomech (Bristol, Avon), 2008, 23(3): 329-333.
24.	Augat P, Merk J, Ignatius A, et al. Early, full weightbearing with flexible fixation delays fracture healing. Clin Orthop Relat Res, 1996, (328): 194-202.
25.	喻鑫罡, 張先龍, 曾炳芳. 低頻可控性微動影響長骨骨折愈合的實驗研究. 中華創傷骨科雜志, 2005, 7(8): 744-748.
26.	Kim IS, Song YM, Lee B, et al. Human mesenchymal stromal cells are mechanosensitive to vibration stimuli. J Dent Res, 2012, 91(12): 1135-1140.
27.	Augat P, Merk J, Wolf S, et al. Mechanical stimulation by external application of cyclic tensile strains does not effectively enhance bone healing. J Orthop Trauma, 2001, 15(1): 54-60.
28.	Vaughn JE, Shah RV, Samman T, et al. Systematic review of dynamization vs exchange nailing for delayed/non-union femoral fractures. World J Orthop, 2018, 9(7): 92-99.
29.	Loboa EG, Beaupré GS, Carter DR. Mechanobiology of initial pseudarthrosis formation with oblique fractures. J Orthop Res, 2001, 19(6): 1067-1072.
30.	Uzer G, Pongkitwitoon S, Ete Chan M, et al. Vibration induced osteogenic commitment of mesenchymal stem cells is enhanced by cytoskeletal remodeling but not fluid shear. J Biomech, 2013, 46(13): 2296-2302.
31.	Bishop NE, van Rhijn M, Tami I, et al. Shear does not necessarily inhibit bone healing. Clin Orthop Relat Res, 2006, 443: 307-314.
32.	MacLeod AR, Serrancoli G, Fregly BJ, et al. The effect of plate design, bridging span, and fracture healing on the performance of high tibial osteotomy plates: An experimental and finite element study. Bone Joint Res, 2019, 7(12): 639-649.
33.	Steiner M, Claes L, Ignatius A, et al. Numerical simulation of callus healing for optimization of fracture fixation stiffness. PLoS One, 2014, 9(7): e101370. doi: 10.1371/journal.pone.0101370.
34.	Park SH, O’Connor K, McKellop H, et al. The influence of active shear or compressive motion on fracture-healing. J Bone Joint Surg (Am), 1998, 80(6): 868-878.
35.	Augat P, Hollensteiner M, von Rüden C. The role of mechanical stimulation in the enhancement of bone healing. Injury, 2021, 52 Suppl 2: S78-S83.
36.	Ramesh S, Zaman F, Madhuri V, et al. Radial extracorporeal shock wave treatment promotes bone growth and chondrogenesis in cultured fetal rat metatarsal bones. Clin Orthop Relat Res, 2020, 478(3): 668-678.
37.	Leighton R, Watson JT, Giannoudis P, et al. Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): A systematic review and meta-analysis. Injury, 2017, 48(7): 1339-1347.
38.	Ribeiro FO, Folgado J, Garcia-Aznar JM, et al. Is the callus shape an optimal response to a mechanobiological stimulus? Med Eng Phys, 2014, 36(11): 1508-1514.
39.	Claes L. Mechanobiology of fracture healing part 1: Principles. Unfallchirurg, 2017, 120(1): 14-22.
40.	Willie BM, Blakytny R, Gl?ckelmann M, et al. Temporal variation in fixation stiffness affects healing by differential cartilage formation in a rat osteotomy model. Clin Orthop Relat Res, 2011, 469(11): 3094-3101.
41.	Ghiasi MS, Chen JE, Rodriguez EK, et al. Computational modeling of human bone fracture healing affected by different conditions of initial healing stage. BMC Musculoskelet Disord, 2019, 20(1): 562. doi: 10.1186/s12891-019-2854-z.
42.	Houston J, Armitage L, Sedgwick PM, et al. Defining the mean angle of diaphyseal long bone non-unions—Does shear prevail? J Orthop Trauma, 2020. doi: 10.1097/BOT.0000000000002050.
43.	Kiyono M, Noda T, Nagano H, et al. Clinical outcomes of treatment with locking compression plates for distal femoral fractures in a retrospective cohort. J Orthop Surg Res, 2019, 14(1): 384.
44.	Rosa N, Marta M, Vaz M, et al. Recent developments on intramedullary nailing: a biomechanical perspective. Ann N Y Acad Sci, 2017, 1408(1): 20-31.
45.	Fu R, Feng Y, Liu Y, et al. The combined effects of dynamization time and degree on bone healing. J Orthop Res, 2021: 29. doi: 10.1002/jor.25060.
46.	程建崗, 袁志, 劉建, 等. 鎖定接骨板動力化治療股骨遠端骨折經鎖定接骨板內固定術后骨不連的效果. 國際骨科學雜志, 2019, 40(1): 57-59.
47.	Popkov AV, Kononovich NA, Filimonova GN, et al. Bone formation and adaptive morphology of the anterior tibial muscle in 3-mm daily lengthening using high-fractional automated distraction and osteosynthesis with the Ilizarov apparatus combined with intramedullary hydroxyapatite-coated wire. Biomed Res Int, 2019, 2019: 3241263. doi: 10.1155/2019/3241263.
48.	Bakhsh K, Atiq-Ur-Rehman None, Zimri FK, et al. Presentation and management outcome of tibial infected non-union with Ilizarov technique. Pak J Med Sci, 2019, 35(1): 136-140.
49.	Bottlang M, Feist F. Biomechanics of far cortical locking. J Orthop Trauma, 2011, 25 Suppl 1(Suppl 1): S21-S28.
50.	Siddiqui JA, Partridge NC. Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology (Bethesda), 2016, 31(3): 233-245.
51.	裴國獻. 數字骨科: 骨科領域的第三次技術浪潮. 中華創傷骨科雜志, 2019, 21(1): 3-5.
52.	Pietsch M, Niemeyer F, Simon U, et al. Modelling the fracture-healing process as a moving-interface problem using an interface-capturing approach. Comput Methods Biomech Biomed Engin, 2018, 21(8): 512-520.
53.	Ghimire S, Miramini S, Edwards G, et al. The investigation of bone fracture healing under intramembranous and endochondral ossification. Bone Rep, 2020, 14: 100740. doi: 10.1016/j.bonr.2020.100740.
54.	Henderson CE, Bottlang M, Marsh JL, et al. Does locked plating of periprosthetic supracondylar femur fractures promote bone healing by callus formation? Two cases with opposite outcomes. Iowa Orthop J, 2008, 28: 73-76.
55.	Perumal R, Shankar V, Basha R, et al. Is nail dynamization beneficial after twelve weeks—An analysis of 37 cases. J Clin Orthop Trauma, 2018, 9(4): 322-326.
56.	Oh JK, Hwang JH, Lee SJ, et al. Dynamization of locked plating on distal femur fracture. Arch Orthop Trauma Surg, 2011, 131(4): 535-539.
57.	潘志軍. 非感染性骨不連的再認識-AO 的觀點. 中華創傷骨科雜志, 2020, 22(2): 112-115.

1. Steiner M, Claes L, Ignatius A, et al. Disadvantages of interfragmentary shear on fracture healing—mechanical insights through numerical simulation. J Orthop Res, 2014, 32(7): 865-872.
2. Sellei RM, Garrison RL, Kobbe P, et al. Effects of near cortical slotted holes in locking plate constructs. J Orthop Trauma, 2011, 25 Suppl 1: S35-S40.
3. 高哲辰, 周方, 田耘, 等. 鎖定接骨板內固定治療股骨遠端骨折. 中華創傷骨科雜志, 2016, 18(11): 965-969.
4. Lujan TJ, Henderson CE, Madey SM, et al. Locked plating of distal femur fractures leads to inconsistent and asymmetric callus formation. J Orthop Trauma, 2010, 24(3): 156-162.
5. M?rdian S, Schaser KD, Duda GN, et al. Working length of locking plates determines interfragmentary movement in distal femur fractures under physiological loading. Clin Biomech (Bristol, Avon), 2015, 30(4): 391-396.
6. Wang J, Zhang X, Li S, et al. Plating system design determines mechanical environment in long bone mid-shaft fractures: a finite element analysis. J Invest Surg, 2020, 33(8): 699-708.
7. 張宏軍, 許緯洲, 賀長青, 等. 自控微動帶鎖髓內釘對山羊骨折愈合的生物化學研究. 中國臨床解剖學雜志, 2008, 26(4): 423-425.
8. Bottlang M, Doornink J, Fitzpatrick DC, et al. Far cortical locking can reduce stiffness of locked plating constructs while retaining construct strength. J Bone Joint Surg (Am), 2009, 91(8): 1985-1994.
9. Epari DR, Gurung R, Hofmann-Fliri L, et al. Biphasic plating improves the mechanical performance of locked plating for distal femur fractures. J Biomech, 2021, 115: 110192. doi: 10.1016/j.jbiomech.2020.110192.
10. 向明, 胡曉川, 林硯銘, 等. 可控性微動時間對骨折愈合影響的實驗研究. 中華骨科雜志, 2019, 39(21): 1333-1343.
11. Elkins J, Marsh JL, Lujan T, et al. Motion predicts clinical callus formation: construct-specific finite element analysis of supracondylar femoral fractures. J Bone Joint Surg (Am), 2016, 98(4): 276-284.
12. Epari DR, Duda GN, Thompson MS. Mechanobiology of bone healing and regeneration: in vivo models. Proc Inst Mech Eng H, 2010, 224(12): 1543-1553.
13. Goodship AE, Cunningham JL, Kenwright J. Strain rate and timing of stimulation in mechanical modulation of fracture healing. Clin Orthop Relat Res, 1998, (355 Suppl): S105-S115.
14. Glatt V, Evans CH, Tetsworth K. A Concert between biology and biomechanics: the influence of the mechanical environment on bone healing. Front Physiol, 2017, 7: 678. doi: 10.3389/fphys.2016.00678.
15. Perren SM. Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthop Relat Res, 1979, (138): 175-196.
16. 劉振東. 骨痂的形成與分類. 中國矯形外科雜志, 2016, 24(4): 332-337.
17. Ueno M, Urabe K, Naruse K, et al. Influence of internal fixator stiffness on murine fracture healing: two types of fracture healing lead to two distinct cellular events and FGF-2 expressions. Exp Anim, 2011, 60(1): 79-87.
18. 喬林, 侯樹勛, 李文峰, 等. 微動對骨折端微循環及血管內皮生長因子(VEGF) 表達的影響. 中華創傷骨科雜志, 2005, 7(1): 52-54.
19. Claes LE, Meyers N. The direction of tissue strain affects the neovascularization in the fracture-healing zone. Med Hypotheses, 2020, 137: 109537. doi: 10.1016/j.mehy.2019.109537.
20. Chen X, Yan J, He F, et al. Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway. Free Radic Biol Med, 2018, 126: 187-201.
21. McKibbin B. The biology of fracture healing in long bones. J Bone Joint Surg (Br), 1978, 60-B(2): 150-162.
22. Hulth A. Current concepts of fracture healing. Clin Orthop Relat Res, 1989, (249): 265-284.
23. Joslin CC, Eastaugh-Waring SJ, Hardy JR, et al. Weight bearing after tibial fracture as a guide to healing. Clin Biomech (Bristol, Avon), 2008, 23(3): 329-333.
24. Augat P, Merk J, Ignatius A, et al. Early, full weightbearing with flexible fixation delays fracture healing. Clin Orthop Relat Res, 1996, (328): 194-202.
25. 喻鑫罡, 張先龍, 曾炳芳. 低頻可控性微動影響長骨骨折愈合的實驗研究. 中華創傷骨科雜志, 2005, 7(8): 744-748.
26. Kim IS, Song YM, Lee B, et al. Human mesenchymal stromal cells are mechanosensitive to vibration stimuli. J Dent Res, 2012, 91(12): 1135-1140.
27. Augat P, Merk J, Wolf S, et al. Mechanical stimulation by external application of cyclic tensile strains does not effectively enhance bone healing. J Orthop Trauma, 2001, 15(1): 54-60.
28. Vaughn JE, Shah RV, Samman T, et al. Systematic review of dynamization vs exchange nailing for delayed/non-union femoral fractures. World J Orthop, 2018, 9(7): 92-99.
29. Loboa EG, Beaupré GS, Carter DR. Mechanobiology of initial pseudarthrosis formation with oblique fractures. J Orthop Res, 2001, 19(6): 1067-1072.
30. Uzer G, Pongkitwitoon S, Ete Chan M, et al. Vibration induced osteogenic commitment of mesenchymal stem cells is enhanced by cytoskeletal remodeling but not fluid shear. J Biomech, 2013, 46(13): 2296-2302.
31. Bishop NE, van Rhijn M, Tami I, et al. Shear does not necessarily inhibit bone healing. Clin Orthop Relat Res, 2006, 443: 307-314.
32. MacLeod AR, Serrancoli G, Fregly BJ, et al. The effect of plate design, bridging span, and fracture healing on the performance of high tibial osteotomy plates: An experimental and finite element study. Bone Joint Res, 2019, 7(12): 639-649.
33. Steiner M, Claes L, Ignatius A, et al. Numerical simulation of callus healing for optimization of fracture fixation stiffness. PLoS One, 2014, 9(7): e101370. doi: 10.1371/journal.pone.0101370.
34. Park SH, O’Connor K, McKellop H, et al. The influence of active shear or compressive motion on fracture-healing. J Bone Joint Surg (Am), 1998, 80(6): 868-878.
35. Augat P, Hollensteiner M, von Rüden C. The role of mechanical stimulation in the enhancement of bone healing. Injury, 2021, 52 Suppl 2: S78-S83.
36. Ramesh S, Zaman F, Madhuri V, et al. Radial extracorporeal shock wave treatment promotes bone growth and chondrogenesis in cultured fetal rat metatarsal bones. Clin Orthop Relat Res, 2020, 478(3): 668-678.
37. Leighton R, Watson JT, Giannoudis P, et al. Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): A systematic review and meta-analysis. Injury, 2017, 48(7): 1339-1347.
38. Ribeiro FO, Folgado J, Garcia-Aznar JM, et al. Is the callus shape an optimal response to a mechanobiological stimulus? Med Eng Phys, 2014, 36(11): 1508-1514.
39. Claes L. Mechanobiology of fracture healing part 1: Principles. Unfallchirurg, 2017, 120(1): 14-22.
40. Willie BM, Blakytny R, Gl?ckelmann M, et al. Temporal variation in fixation stiffness affects healing by differential cartilage formation in a rat osteotomy model. Clin Orthop Relat Res, 2011, 469(11): 3094-3101.
41. Ghiasi MS, Chen JE, Rodriguez EK, et al. Computational modeling of human bone fracture healing affected by different conditions of initial healing stage. BMC Musculoskelet Disord, 2019, 20(1): 562. doi: 10.1186/s12891-019-2854-z.
42. Houston J, Armitage L, Sedgwick PM, et al. Defining the mean angle of diaphyseal long bone non-unions—Does shear prevail? J Orthop Trauma, 2020. doi: 10.1097/BOT.0000000000002050.
43. Kiyono M, Noda T, Nagano H, et al. Clinical outcomes of treatment with locking compression plates for distal femoral fractures in a retrospective cohort. J Orthop Surg Res, 2019, 14(1): 384.
44. Rosa N, Marta M, Vaz M, et al. Recent developments on intramedullary nailing: a biomechanical perspective. Ann N Y Acad Sci, 2017, 1408(1): 20-31.
45. Fu R, Feng Y, Liu Y, et al. The combined effects of dynamization time and degree on bone healing. J Orthop Res, 2021: 29. doi: 10.1002/jor.25060.
46. 程建崗, 袁志, 劉建, 等. 鎖定接骨板動力化治療股骨遠端骨折經鎖定接骨板內固定術后骨不連的效果. 國際骨科學雜志, 2019, 40(1): 57-59.
47. Popkov AV, Kononovich NA, Filimonova GN, et al. Bone formation and adaptive morphology of the anterior tibial muscle in 3-mm daily lengthening using high-fractional automated distraction and osteosynthesis with the Ilizarov apparatus combined with intramedullary hydroxyapatite-coated wire. Biomed Res Int, 2019, 2019: 3241263. doi: 10.1155/2019/3241263.
48. Bakhsh K, Atiq-Ur-Rehman None, Zimri FK, et al. Presentation and management outcome of tibial infected non-union with Ilizarov technique. Pak J Med Sci, 2019, 35(1): 136-140.
49. Bottlang M, Feist F. Biomechanics of far cortical locking. J Orthop Trauma, 2011, 25 Suppl 1(Suppl 1): S21-S28.
50. Siddiqui JA, Partridge NC. Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology (Bethesda), 2016, 31(3): 233-245.
51. 裴國獻. 數字骨科: 骨科領域的第三次技術浪潮. 中華創傷骨科雜志, 2019, 21(1): 3-5.
52. Pietsch M, Niemeyer F, Simon U, et al. Modelling the fracture-healing process as a moving-interface problem using an interface-capturing approach. Comput Methods Biomech Biomed Engin, 2018, 21(8): 512-520.
53. Ghimire S, Miramini S, Edwards G, et al. The investigation of bone fracture healing under intramembranous and endochondral ossification. Bone Rep, 2020, 14: 100740. doi: 10.1016/j.bonr.2020.100740.
54. Henderson CE, Bottlang M, Marsh JL, et al. Does locked plating of periprosthetic supracondylar femur fractures promote bone healing by callus formation? Two cases with opposite outcomes. Iowa Orthop J, 2008, 28: 73-76.
55. Perumal R, Shankar V, Basha R, et al. Is nail dynamization beneficial after twelve weeks—An analysis of 37 cases. J Clin Orthop Trauma, 2018, 9(4): 322-326.
56. Oh JK, Hwang JH, Lee SJ, et al. Dynamization of locked plating on distal femur fracture. Arch Orthop Trauma Surg, 2011, 131(4): 535-539.
57. 潘志軍. 非感染性骨不連的再認識-AO 的觀點. 中華創傷骨科雜志, 2020, 22(2): 112-115.

Chinese Journal of Reparative and Reconstructive Surgery

Research on the nature of micromovement and the biomechanical staging of fracture healing

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