Abstract
Bone defect will not undergo any process of healing when not treated. Tissue engineering is currently exploring alternatives for generating new bone tissue. The base triad for bone tissue engineering is manipulation of osteogenic cells, growth factors, and bio scaffolds. Diamond concept includes mechanical environment and this base triad. Provided constant stream of pluripotent stem cells and biomolecular signals that is necessary for bone formation are some advantages of this in vivo bioreactor. Thus, we conducted article searches by using computerized database of PUBMED and Google Scholar. After sorting and selecting, 14 articles were finally obtained. Several things are considered upon designing an in vivo bioreactor. Before conception, it is necessary to measure the size and geometry of the defect. Afterwards, the materials for bioreactor construction must be determined. These include the scaffold material, cell seeding, and growth factors. Method of prefabrications follows to be decided, including site for implantation and time until transfer. Lastly, additional strategies to improve angiogenesis and osseointegration can be considered and added, until the graft is clinically applied. Some issues still need to be covered on this new trending discovery. Study comparing prefabrication sites to find the most optimal site is needed, as well as the optimal time to harvest. Further development regarding technique to produce large volume of bone tissue must be considered. Moreover, further studies in human subjects with larger samples followed by evaluation after clinical implantation would be necessary to examine the applicability and feasibility in human population.
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References
Day SM, Ostrum RF, Chao EY, Rubin CT, Aro H, Einhorn TA. Bone injury, regeneration and repair. In: Einhorn TA, Simon SR, American Academy of Orthopaedic Surgeons, editors. Orthopaedic basic science: biology and biomechanics of the musculoskeletal system. 2nd ed. Rosemont: American Academy of Orthopaedic Surgeons; 2000. p. 377–82.
Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. 1998;(355 Suppl):S7–21.
Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551–5.
Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury. 2007;38(Suppl 4):S3–6.
Nadra R, Grover L, Porter K. Fracture non union epidemiology and treatment. Trauma. 2016;18(1):3–11.
Nauth A, McKee MD, Einhorn TA, Watson JT, Li R, Schemitsch EH. Managing bone defects. J Orthop Trauma. 2011;25(8):462–6.
Calori GM, Mazza E, Colombo M, Ripamonti C. The use of bone-graft substitutes in large bone defects: any specific needs? Injury. 2011;42(Suppl 2):S56–63.
van der Stok J, Van Lieshout E, El-Massoudi Y, Van Kralingen G, Patka P. Bone substitutes in the Netherlands—a systematic literature review. Acta Biomater. 2011;7(2):739–50.
Mauffrey C, Barlow BT, Smith W. Management of segmental bone defects. J Am Acad Orthop Surg. 2015;23(3):143–53.
Kanakaris NK, Paliobeis C, Nlanidakis N, Giannoudis PV. Biological enhancement of tibial diaphyseal aseptic non-unions: the efficacy of autologous bone grafting, BMPs and reaming by-products. Injury. 2007;38(Suppl 2):S65–75.
Hertel R, Gerber A, Schlegel U, Cordey J, Ruegsegger P, Rahn BA. Cancellous bone graft for skeletal reconstruction. Muscular versus periosteal bed—preliminary report. Injury. 1994;25(Suppl 1):A59–70.
Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA. Complications of iliac crest bone graft harvesting. Clin Orthop Relat Res. 1996;329:300–9.
Liu G, Zhao L, Zhang W, Cui L, Liu W, Cao Y. Repair of goat tibial defects with bone marrow stromal cells and beta-tricalcium phosphate. J Mater Sci Mater Med. 2008;19(6):2367–76.
Belthur MV, Conway JD, Jindal G, Ranade A, Herzenberg JE. Bone graft harvest using a new intramedullary system. Clin Orthop Relat Res. 2008;466(12):2973–80.
Sagi HC, Young ML, Gerstenfeld L, Einhorn TA, Tornetta P. Qualitative and quantitative differences between bone graft obtained from the medullary canal (with a reamer/irrigator/aspirator) and the iliac crest of the same patient. J Bone Joint Surg Am. 2012;94(23):2128–35.
Dimitriou R, Mataliotakis GI, Angoules AG, Kanakaris NK, Giannoudis PV. Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review. Injury. 2011;42(Suppl 2):S3–15.
McCoy RJ, O'Brien FJ. Influence of shear stress in perfusion bioreactor cultures for the development of three-dimensional bone tissue constructs: a review. Tissue Eng B Rev. 2010;16(6):587–601.
Huang C, Ogawa R. Mechanotransduction in bone repair and regeneration. FASEB J. 2010;24(10):3625–32.
Rauh J, Milan F, Gunther KP, Stiehler M. Bioreactor systems for bone tissue engineering. Tissue Eng B Rev. 2011;17(4):263–80.
Sladkova M, de Peppo GM. Bioreactor systems for human bone tissue engineering. PRO. 2014;2:494–525.
Warnke PH. In-vivo tissue engineering of biological joint replacements. Lancet. 2010;376(9739):394–6.
Huang RL, Liu K, Li Q. Bone regeneration following the in vivo bioreactor principle: is in vitro manipulation of exogenous elements still needed? Regen Med. 2016;11(5):475–81.
Warnke PH, Springer IN, Wiltfang J, Acil Y, Eufinger H, Wehmoller M, et al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet. 2004;364(9436):766–70.
Liu Y, Moller B, Wiltfang J, Warnke PH, Terheyden H. Tissue engineering of a vascularized bone graft of critical size with an osteogenic and angiogenic factor-based in vivo bioreactor. Tissue Eng A. 2014;20(23–24):3189–97.
Kokemueller H, Spalthoff S, Nolff M, Tavassol F, Essig H, Stuehmer C, et al. Prefabrication of vascularized bioartificial bone grafts in vivo for segmental mandibular reconstruction: experimental pilot study in sheep and first clinical application. Int J Oral Maxillofac Surg. 2010;39(4):379–87.
Spalthoff S, Jehn P, Zimmerer R, Mollmann U, Gellrich NC, Kokemueller H. Heterotopic bone formation in the musculus latissimus dorsi of sheep using beta-tricalcium phosphate scaffolds: evaluation of an extended prefabrication time on bone formation and matrix degeneration. Int J Oral Maxillofac Surg. 2015;44(6):791–7.
Zhi W, Zhang C, Duan K, Li X, Qu S, Wang J, et al. A novel porous bioceramics scaffold by accumulating hydroxyapatite spherulites for large bone tissue engineering in vivo. II. Construct large volume of bone grafts. J Biomed Mater Res A. 2014;102(8):2491–501.
Han D, Dai K. Prefabrication of a vascularized bone graft with Beta tricalcium phosphate using an in vivo bioreactor. Artif Organs. 2013;37(10):884–93.
Tatara AM, Wong ME, Mikos AG. In vivo bioreactors for mandibular reconstruction. J Dent Res. 2014;93(12):1196–202.
Glass GE, Chan JK, Freidin A, Feldmann M, Horwood NJ, Nanchahal J. TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proc Natl Acad Sci U S A. 2011;108(4):1585–90.
Lu C, Miclau T, Hu D, Marcucio RS. Ischemia leads to delayed union during fracture healing: a mouse model. J Orthop Res. 2007;25(1):51–61.
Warnke PH, Wiltfang J, Springer I, Acil Y, Bolte H, Kosmahl M, et al. Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. Biomaterials. 2006;27(17):3163–7.
Augustin G, Antabak A, Davila S. The periosteum. Part 1: anatomy, histology and molecular biology. Injury. 2007;38(10):1115–30.
Stevens MM, Marini RP, Schaefer D, Aronson J, Langer R, Shastri VP. In vivo engineering of organs: the bone bioreactor. Proc Natl Acad Sci U S A. 2005;102(32):11450–5.
Hunziker EB, Driesang IM. Functional barrier principle for growth-factor-based articular cartilage repair. Osteoarthr Cartil. 2003;11(5):320–7.
Cheng MH, Brey EM, Allori AC, Gassman A, Chang DW, Patrick CW Jr, et al. Periosteum-guided prefabrication of vascularized bone of clinical shape and volume. Plast Reconstr Surg. 2009;124(3):787–95.
Tatara AM, Shah SR, Demian N, Ho T, Shum J, van den Beucken JJ, et al. Reconstruction of large mandibular defects using autologous tissues generated from in vivo bioreactors. Acta Biomater. 2016;45:72–84.
Bigham-Sadegh A, Oryan A, Mirshokraei P, Shadkhast M, Basiri E. Bone tissue engineering with periosteal-free graft and pedicle omentum. ANZ J Surg. 2013;83(4):255–61.
Sadegh AB, Basiri E, Oryan A, Mirshokraei P. Wrapped omentum with periosteum concurrent with adipose derived adult stem cells for bone tissue engineering in dog model. Cell Tissue Bank. 2014;15(1):127–37.
Wiltfang J, Rohnen M, Egberts JH, Lutzen U, Wieker H, Acil Y, et al. Man as a living bioreactor: prefabrication of a custom vascularized bone graft in the gastrocolic omentum. Tissue Eng Part C Methods. 2016;22(8):740–6.
Holt GE, Halpern JL, Dovan TT, Hamming D, Schwartz HS. Evolution of an in vivo bioreactor. J Orthop Res. 2005;23(4):916–23.
Patel JJ, Modes JE, Flanagan CL, Krebsbach PH, Edwards SP, Hollister SJ. Dual delivery of EPO and BMP2 from a novel modular poly-varepsilon-caprolactone construct to increase the bone formation in prefabricated bone flaps. Tissue Eng Part C Methods. 2015;21(9):889–97.
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Rahyussalim, A.J., Marsetio, A.F. & Kurniawati, T. Bioreactor as a New Resource of Autologous Bone Graft to Overcome Bone Defect In Vivo. Clinic Rev Bone Miner Metab 15, 139–150 (2017). https://doi.org/10.1007/s12018-017-9237-5
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DOI: https://doi.org/10.1007/s12018-017-9237-5
Keywords
- Bone defect
- Bioreactor
- Osteoconductive
- Osteoinductive
- Bio scaffolds