In-Silico Models as a Tool for the Design of Specific Treatments: Applications in Bone Regeneration

  • Esther Reina-Romo
  • María José Gómez-Benito
  • Libardo Andrés González-Torres
  • Jaime Domínguez
  • José Manuel García-Aznar
Chapter
Part of the Lecture Notes in Computational Vision and Biomechanics book series (LNCVB, volume 1)

Abstract

Numerous pathologies related to bone regeneration such as bone healing or distraction osteogenesis are focus of intense research nowadays since there are many cues not well understood yet. Intense activity is performed in both experimental and computational fields. However, in silico models may play a relevant role since computer simulations allow to consider and control factors that cannot be easily controlled or measured in experimental tests. In addition, experiments can be time-consuming, expensive and with a high difficulty to control all the parameters. This review addresses some of the main problems of in-silico models and focus on bone healing and distraction osteogenesis as mechanical based pathologies extensively investigated in the last decades.

Keywords

Fracture Healing Bone Regeneration Distraction Osteogenesis Endochondral Ossification Fracture Callus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors gratefully acknowledge the research support of the project part financed by the European Union (European Regional Development Fund) through the grant DPI 2009-14115-C03-01.

References

  1. 1.
    Al Ruhaimi KA (2001) Comparison of different distraction rates in the mandible: an experimental investigation. Int J Oral Maxillofac Surg 30:220–227Google Scholar
  2. 2.
    Andreykiv A, van Keulen F, Prendergast PJ (2007) Simulation of fracture healing incorporating mechanoregulation of tissue differentiation and dispersal/proliferation of cells. Biomech Model Mechanobiol 7:443–461Google Scholar
  3. 3.
    Aronson J (1993) Temporal and spatial increases in blood flow during distraction osteogenesis. Clin Orthop Relat Res 301:124–131Google Scholar
  4. 4.
    Bailón-Plaza A, van der Meulen MC (2001) A mathematical framework to study the effects of growth factor influences on fracture healing. J Theor Biol 212:191–209Google Scholar
  5. 5.
    Boccaccio A, Lamberti L, Pappalettere C, Carano A, Cozzani M (2006) Mechanical behavior of an osteotomized mandible with distraction orthodontic devices. J Biomech 39:2907–2918Google Scholar
  6. 6.
    Boccaccio A, Pappalettere C, Kelly DJ (2007) The influence of expansion rates on mandibular distraction osteogenesis: a computational analysis. Ann Biomed Eng 35:1940–1960Google Scholar
  7. 7.
    Boccaccio A, Prendergast PJ, Pappalettere C, Kelly DJ (2008) Tissue differentiation and bone regeneration in an osteotomized mandible: a computational analysis of the latency period. Med Biol Eng Comput 46:283–298Google Scholar
  8. 8.
    Boccaccio A, Kelly DJ, Pappalettere C (2011) A mechano-regulation model of fracture repair in vertebral bodies. J Orthop Res 29:433–443Google Scholar
  9. 9.
    Brunner UH, Cordey J, Schweiberer L, Perren SM (1994) Force required for bone segment transport in the treatment of large bone defects using medullary nail fixation. Clin Orthop Relat Res 301:147–155Google Scholar
  10. 10.
    Byrne DP (2008) Computational modelling of bone regeneration using a three-dimensional lattice approach. PhD thesis, Trinity College Dublin, (Ireland)Google Scholar
  11. 11.
    Byrne H (2010) Dissecting cancer through mathematics: from the cell to the animal model. Nat Rev Cancer 10:221–230Google Scholar
  12. 12.
    Carter DR (1987) Mechanical loading history and skeletal biology. J Biomech 20:1095–1109Google Scholar
  13. 13.
    Cattaneo PM, Kofod T, Dalstra M, Melsen B (2005) Using the Finite Element Method to model the biomechanics of the asymmetric mandible before, during and after skeletal correction by distraction osteogenesis. Comput Method Biomech Biomed Eng 8:157–165Google Scholar
  14. 14.
    Choi IH, Shim JS, Seong SC, Lee MC, Song KY, Park SC, Chung CY, Cho TJ, Lee DY (1997) Effect of the distraction rate on the activity of the osteoblast lineage in distraction osteogenesis of rat’s tibia. Immunostaining study of the proliferating cell nuclear antigen, osteocalcin, and transglutaminase C. Bull Hosp Jt Dis 56:34–40Google Scholar
  15. 15.
    Choi P, Ogilvie C, Thompson T, Miclau T, Helms JH (2004) Cellular and molecular characterization of a murine non-union model. J Orthop Res 22:1100–1107Google Scholar
  16. 16.
    Claes LE, Heigele CA (1999) Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 32:255–266Google Scholar
  17. 17.
    Cope JB, Samchukov ML, Cherkashin AM (1999) Mandibular distraction osteogenesis: a historic perspective and future directions. Am J Orthod Dentofac Orthop 115:448–460Google Scholar
  18. 18.
    Delloye C, Delefortrie G, Coutelier L, Vincent A (1990) Bone regenerate formation in cortical bone during distraction lengthening: an experimental study. Clin Orthop 250:34–42Google Scholar
  19. 19.
    Einhorn TA (1998) The cell and molecular biology of fracture healing. Clin Orthop Rel Res 355:S7–S21Google Scholar
  20. 20.
    Farhadieh RH, Gianoutsos MP, Dickinson R, Walsh WR (2000) Effect of distraction rate on biomechanical, mineralization, and histologic properties of an ovine mandible model. Plast Reconstr Surg 105:889–895Google Scholar
  21. 21.
    Fischgrund J, Paley D, Suter C (1994) Variables affecting time to bone healing during limb lengthening. Clin Orthop Relat Res 301:31–37Google Scholar
  22. 22.
    Frost HM (1989) The biology of fracture healing an overview for clinicicians. part i and ii. Clin Orthop 289:283–309Google Scholar
  23. 23.
    García-Aznar JM, Kuiper JH, Gómez-Benito MJ, Doblaré M, Richardson JB (2007) Computational simulation of fracture healing: influence of interfragmentary movement on the callus growth. J Biomech 40:1467–1476Google Scholar
  24. 24.
    Geris L, Van Oosterwyck H, Vander Sloten J, Duyck J, Naert I (2003) Assessment of mechanobiological models for the numerical simulation of tissue differentiation around immediately loaded implants. Comput Method Biomech Biomed Eng 6:277–88Google Scholar
  25. 25.
    Geris L, Andreykiv A, Van Oosterwyck H, Vander Sloten J, van Keulen F, Duyck J, Naert I (2004) Numerical simulation of tissue differentiation around loaded titanium implants in a bone chamber. J Biomech 37:763–769Google Scholar
  26. 26.
    Geris L, Vandamme K, Naert I, Vander Sloten J, Duyck J, Van Oosterwyck H (2009) Numerical simulation of bone regeneration in a bone chamber. J Dent Res 88:158–163Google Scholar
  27. 27.
    Geris L, Schugart R, Van Oosterwyck H (2010) In silico design of treatment strategies in wound healing and bone fracture healing. Philos Trans A Math Phys Eng Sci 368:2683–2706Google Scholar
  28. 28.
    Gómez-Benito MJ, García-Aznar JM, Kuiper JH, Doblaré M (2005) Influence of fracture gap size on the pattern of long bone healing: a computational study. J Theor Biol 235:105–119Google Scholar
  29. 29.
    Gómez-Benito MJ, García-Aznar JM, Kuiper JH, Doblaré M (2006) A 3D computational simulation of fracture callus formation: influence of the stiffness of the external fixator. J Biomech Eng 128:290–299Google Scholar
  30. 30.
    Gómez-Benito MJ, González-Torres LA, Reina-Romo E, Grasa J, Seral B, García-Aznar JM (2011) Influence of high frequency cyclical stimulation on bone fracture healing process: mathematical and experimental models. Philos Transact A Math Phys Eng Sci-2pc]Please check if inserted year, volume number and page range for Ref. [30] are okay. 369:4278–4294.Google Scholar
  31. 31.
    González-Torres LA, Gómez-Benito MJ, Doblaré M, García-Aznar JM (2010) Influence of the frequency of the external mechanical stimulus on bone healing: a computational study. Med Eng Phys 32:363–371Google Scholar
  32. 32.
    Goodship AE, Kenwright J (1985) The influence of induced micromovement upon the healing of experimental tibial fractures. J Bone Jt Surg Br 67:650–655Google Scholar
  33. 33.
    Grasa J, Gómez-Benito MJ, González-Torres LA, Asiaín D, Quero F, García-Aznar JM (2010) Monitoring in vivo load transmission through an external fixator. Ann Biomed Eng 38:605–612Google Scholar
  34. 34.
    Ilizarov GA (1989) The tension-stress effect on the genesis and growth of tissues. Part I: the influence of stability of fixation and soft-tissue preservation. Clin Orthop 238:249–281Google Scholar
  35. 35.
    Ilizarov GA (1989) The tension-stress effect on the genesis and growth of tissues. Part II: the influence of the rate and frequency of distraction. Clin Orthop 239:263–285Google Scholar
  36. 36.
    Ilizarov GA (1990) Clinical application of the tension–stress effect for limb lengthening. Clin Orthop Relat Res 250:8–26Google Scholar
  37. 37.
    Ilizarov GA, Ledyaev VI (1992) The replacement of long tubular bone defects by lengthening distraction osteotomy of one of the fragments. 1969. Clin Orthop Relat Res 280:7–10Google Scholar
  38. 38.
    Isaksson H, Comas O, Van Donkelaar CC, Mediavilla J, Wilson W, Huiskes R, Ito K (2007) Bone regeneration during distraction osteogenesis: mechano-regulation by shear strain and fluid velocity. J Biomech 40:2002–2011Google Scholar
  39. 39.
    Isaksson H, van Donkelaar CC, Huiskes R, Ito K (2008) A mechanoregulatory bone-healing model incorporating cell-phenotype specific activity. J Theor Biol 252:230–246Google Scholar
  40. 40.
    Judex S, Lei X, Han D, Rubin C (2007) Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. J Biomech 40:1333–1339Google Scholar
  41. 41.
    Kelly DJ, Prendergast PJ (2005) Mechano-regulation of stem cell differentiation and tissue regeneration in osteochondral defects. J Biomech 38:1413–1422Google Scholar
  42. 42.
    King NS, Liu ZJ, Wang LL, Chiu IY, Whelan MF, Huang GJ (2003) Effect of distraction rate and consolidation period on bone density following mandibular osteodistraction in rats. Arch Oral Biol 48:299–308Google Scholar
  43. 43.
    Kluess D, Mittelmeier W, Bader R (2010) From theory to practice: transfer of fea results into clinical applications. J Biomech 43S1:S3–S14Google Scholar
  44. 44.
    Kofod T, Cattaneo PM, Melsen B (2005) Three-dimensional finite element analysis of the mandible and temporomandibular joint on simulated occlusal forces before and after vertical ramus elongation by distraction osteogenesis. J Craniofac Surg 16:421–429Google Scholar
  45. 45.
    Kojimoto H, Yasui N, Goto T, Matsuda S, Shimomura Y (1988) Bone lengthening in rabbits by callus distraction. J Bone Jt Surg Br 70-B:543–549Google Scholar
  46. 46.
    Lacroix D, Prendergast PJ (2002) A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J Biomech 35:1163–1171Google Scholar
  47. 47.
    Li G, Simpson HRW, Kenwright J, Triffitt JT (1997) Assessment of cell proliferation in regenerating bone during distraction osteogenesis at different distraction rates. J Orthop Res 15:765–772Google Scholar
  48. 48.
    Li G, Simpson HRW, Kenwright J, Triffitt JT (2000) Tissues formed during distraction osteogenesis in the rabbit are determined by the distraction rate: localization of the cells that express the mRNAs and the distribution of types I and II collagens. Cell Biol Int 24:25–33Google Scholar
  49. 49.
    Loboa EG, Fang TD, Parker DW, Warren SM, Fong KD, Longaker MT, Carter DR (2005) Mechanobiology of mandibular distraction osteogenesis: finite element analyses with a rat model. J Orthop Res 23:663–670Google Scholar
  50. 50.
    Marieb EN (2004) Bone and skeletal tissues part A. Human anatomy and physiology. Power point lecture slide presentation by Vicen Austin, University of Kentchucky, 6th edn. Pearson education, New York, publishing as Benjamin CummingsGoogle Scholar
  51. 51.
    McCarthy JG, Schreiber J, Karp N, Thorne CH, Grayson BH (1992) Lengthening the human mandible by gradual distraction. Plast Reconstr Surg 89:1–8Google Scholar
  52. 52.
    Ohyama M, Miyasaka Y, Sakurai M, Yokobori AJ, Sasaki S (1994) The mechanical behavior and morphological structure of callus in experimental callotasis. Biomed Mater Eng 4:273–281Google Scholar
  53. 53.
    Perren SM (1979) Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthop 138:175–195Google Scholar
  54. 54.
    Prendergast PJ, Huiskes R, Soballe K (1997) Biophysical stimuli on cells during tissue differentiation at implant interfaces. ESB Research Award 1996. J Biomech 30:539–548Google Scholar
  55. 55.
    Prendergast PJ, Lally C, Lennon AB (2009) Finite element modelling of medical devices. Med Eng Phys 31:419Google Scholar
  56. 56.
    Reina-Romo E, Gómez-Benito MJ, García-Aznar JM, Domínguez J, Doblaré M (2009) Modeling distraction osteogenesis: analysis of the distraction rate. Biomech Model Mechanobiol 8:323–335Google Scholar
  57. 57.
    Reina-Romo E, Gómez-Benito MJ, García-Aznar JM, Domínguez J, Doblaré M (2010) Growth mixture model of distraction osteogenesis: effect of pre-traction stresses. Biomech Model Mechanobiol 9:103–115Google Scholar
  58. 58.
    Reina-Romo E, Gómez-Benito MJ, García-Aznar JM, Domínguez J, Doblaré M (2010) An interspecies computational study on limb lengthening. Proc Inst Mech Eng H 224:245–1256Google Scholar
  59. 59.
    Reina-Romo E, Sampietro-Fuentes A, Gómez-Benito MJ, Domínguez J, Doblaré M, García-Aznar JM (2010) Biomechanical response of a mandible in a patient affected with hemifacial microsomia before and after distraction osteogenesis. Med Eng Phys 32:860–866Google Scholar
  60. 60.
    Reina-Romo E, Gómez-Benito MJ, Sampietro-Fuentes A, Domínguez J, García-Aznar JM (2011) Three-dimensional simulation of mandibular distraction osteogenesis: mechanobiological analysis. Ann Biomed Eng 39:35–43Google Scholar
  61. 61.
    Richards M, Goulet JA, Weiss JA, Waanders NA, Schaffler MB, Goldstein SA (1998) Bone regeneration and fracture healing: experience with distraction osteogenesis model. Clin Orthop Relat Res 355S:S191–S204Google Scholar
  62. 62.
    Roder I (2003) Dynamical modeling of hematopoietic stem cell organization. PhD thesis, University of Leipzig, LeipzigGoogle Scholar
  63. 63.
    Samchukov ML, Cope JB, Cherkashin Mosby AM (2001) Craniofacial distraction osteogenesis. Springer, Heidelberg, pp 22–23. Mosby, St. LouisGoogle Scholar
  64. 64.
    Tajana GF, Morandi M, Zembo M (1989). The structure and development of osteogenic repair tissue according to Ilizarov technique in man. Characterization of extracellular matrix. Orthop 12:515–523Google Scholar
  65. 65.
    van der Meulen MC, Huiskes R (2002) Why mechanobiology? A survey article. J Biomech 35:401–414Google Scholar
  66. 66.
    White SH, Kenwright J (1990) The timing of distraction of an osteotomy. J Bone Jt Surg Br 72:356–361Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Esther Reina-Romo
    • 1
  • María José Gómez-Benito
    • 2
  • Libardo Andrés González-Torres
    • 2
  • Jaime Domínguez
    • 1
  • José Manuel García-Aznar
    • 2
  1. 1.Department of Mechanical EngineeringUniversity of SevilleSevilleSpain
  2. 2.Aragon Institute of Engineering Research (I3A)University of ZaragozaZaragozaSpain

Personalised recommendations