Purpose: Despite many scientific advances, Regenerative Medicine is still in the preclinical stages in many areas. In this article, we intend to discuss the role of microsurgery in the bench-to-bedside transition of such primary findings. Method: By searching the papers related to the history of Regenerative Medicine (RM) and the news of Tissue Engineering (TE) in orthopedics in Pubmed, Scopus, and Google Scholar databases, we accessed a complete archive of various topics related to this field. Result: We first assessed the history and achievements of regenerative medicine, then we realized the importance of translational medical sciences and the role of animal models in this incipient phenomenon. Finally, after mastering the capabilities of microsurgery and the useful contribution of this technique to the advancement of clinical applications of regenerative medicine in various branches such as skin, skeletal system, nerves, and blood vessels, we decided to express the gist of our studies through this article. Conclusion: Considering the widespread use of small animals in regenerative medicine projects and the inevitable role of microsurgery in performing the best intervention on these animal models, the significant progress of regenerative medicine clinical application requires special attention to microsurgery in associated research.
References
[1]
Blundell, J. (1818) Experiments on the Transfusion of Blood by the Syringe. Medico-Chirurgical Transactions, 9, 56-92. https://doi.org/10.1177/09595287180090P107
[2]
Murray, J.E., Merrill, J.P. and Harrison, J.H. (1958) Kidney Transplantation between Seven Pairs of Identical Twins. Annals of Surgery, 148, 343-359. https://doi.org/10.1097/00000658-195809000-00004
[3]
Jadlowiec, C.C. and Taner, T. (2016) Liver Transplantation: Current Status and Challenges. World Journal of Gastroenterology, 22, 4438-4445. https://doi.org/10.3748/wjg.v22.i18.4438
[4]
Kobayashi, E. and Haga, J. (2016) Translational Microsurgery. A New Platform for Transplantation Research. Acta Cirúrgica Brasileira, 31, 212-217. https://doi.org/10.1590/S0102-865020160030000010
[5]
Hoffman, T., Khademhosseini, A. and Langer, R. (2019) Chasing the Paradigm: Clinical Translation of 25 Years of Tissue Engineering. Tissue Engineering Part A, 25, 679-687. https://doi.org/10.1089/ten.tea.2019.0032
[6]
Mason, C. and Dunnill, P. (2008) A Brief Definition of Regenerative Medicine. Regenerative Medicine, 3, 1-5. https://doi.org/10.2217/17460751.3.1.1
[7]
Orlando, G., et al. (2011) Regenerative Medicine as Applied to Solid Organ Transplantation: Current Status and Future Challenges. Transplant International, 24, 223-232. https://doi.org/10.1111/j.1432-2277.2010.01182.x
[8]
Orlando, G., et al. (2011) Regenerative Medicine and Organ Transplantation: Past, Present, and Future. Transplantation, 91, 1310-1317. https://doi.org/10.1097/TP.0b013e318219ebb5
[9]
Jacques, E. and Suuronen, E.J. (2020) The Progression of Regenerative Medicine and Its Impact on Therapy Translation. Clinical and Translational Science, 13, 440-450. https://doi.org/10.1111/cts.12736
[10]
Daar, A.S. and Greenwood, H.L. (2007) A Proposed Definition of Regenerative Medicine. Journal of Tissue Engineering and Regenerative Medicine, 1, 179-184. https://doi.org/10.1002/term.20
[11]
Plotner, A.N. and Mostow, E.N. (2010) A Review of Bioactive Materials and Chronic Wounds. Cutis, 85, 259-266.
[12]
Goodarzi, P., et al. (2018) Tissue Engineered Skin Substitutes. Advances in Experimental Medicine and Biology, 1107, 143-188. https://doi.org/10.1007/5584_2018_226
[13]
Sommer, F., Brandl, F. and Göpferich, A. (2006) Ocular Tissue Engineering. Advances in Experimental Medicine and Biology, 585, 413-429. https://doi.org/10.1007/978-0-387-34133-0_27
[14]
Shimmura, S. and Tsubota, K. (2003) Regeneration of the Cornea. Nihon Rinsho, 61, 475-479.
[15]
Sohier, J., et al. (2008) Critical Factors in the Design of Growth Factor Releasing Scaffolds for Cartilage Tissue Engineering. Expert Opinion on Drug Delivery, 5, 543-566. https://doi.org/10.1517/17425247.5.5.543
[16]
Risbud, M.V. and Sittinger, M. (2002) Tissue Engineering: Advances in in Vitro Cartilage Generation. Trends in Biotechnology, 20, 351-356. https://doi.org/10.1016/S0167-7799(02)02016-4
[17]
Yang, Z., Xie, H. and Li, T. (2000) Tissue Engineering of the Musculo-Skeletal System—Basic Research and Clinical Applications. Journal of Hand Surgery 5, 49-55. https://doi.org/10.1142/S0218810400000132
[18]
Kessler, M.W. and Grande, D.A. (2008) Tissue Engineering and Cartilage. Organogenesis, 4, 28-32. https://doi.org/10.4161/org.6116
[19]
Atala, A., et al. (2006) Tissue-Engineered Autologous Bladders for Patients Needing Cystoplasty. The Lancet, 367, 1241-1246. https://doi.org/10.1016/S0140-6736(06)68438-9
[20]
Raya-Rivera, A., et al. (2011) Tissue-Engineered Autologous Urethras for Patients Who Need Reconstruction: An Observational Study. The Lancet, 377, 1175-1182. https://doi.org/10.1016/S0140-6736(10)62354-9
[21]
Baiguera, S., Birchall, M.A. and Macchiarini, P. (2010) Tissue-Engineered Tracheal Transplantation. Transplantation, 89, 485-491. https://doi.org/10.1097/TP.0b013e3181cd4ad3
[22]
Macchiarini, P., et al. (2008) Clinical Transplantation of a Tissue-Engineered Airway. The Lancet, 372, 2023-2030. https://doi.org/10.1016/S0140-6736(08)61598-6
[23]
Ott, H.C., et al. (2010) Regeneration and Orthotopic Transplantation of a Bioartificial Lung. Nature Medicine, 16, 927-933. https://doi.org/10.1038/nm.2193
[24]
Petersen, T.H., et al. (2010) Tissue-Engineered Lungs for in Vivo Implantation. Science, 329, 538-541. https://doi.org/10.1126/science.1189345
[25]
Orive, G., et al. (2009) Biomaterials for Promoting Brain Protection, Repair and Regeneration. Nature Reviews Neuroscience, 10, 682-692. https://doi.org/10.1038/nrn2685
[26]
Pfister, B.J., et al. (2007) Neural Engineering to Produce in Vitro Nerve Constructs and Neurointerface. Neurosurgery, 60, 137-141. https://doi.org/10.1227/01.NEU.0000249197.61280.1D
[27]
Okano, H. (2001) Neural Stem Cells: The Basic Biology and Prospects for Brain Repair. Rinsho Shinkeigaku, 41, 1036-1040.
[28]
Sacks, M.S., Schoen, F.J. and Mayer, J.E. (2009) Bioengineering Challenges for Heart Valve Tissue Engineering. Annual Review of Biomedical Engineering, 11, 289-313. https://doi.org/10.1146/annurev-bioeng-061008-124903
[29]
Sarraf, C.E., et al. (2002) Tissue Engineering of Biological Cardiovascular System Surrogates. Heart, Lung and Circulation, 11, 142-150. https://doi.org/10.1046/j.1444-2892.2002.00150.x
[30]
Zimmermann, W.H. and Eschenhagen, T. (2003) Cardiac Tissue Engineering for Replacement Therapy. Heart Failure Reviews, 8, 259-269. https://doi.org/10.1023/A:1024725818835
[31]
Ott, H.C., et al. (2008) Perfusion-Decellularized Matrix: Using Nature’s Platform to Engineer a Bioartificial Heart. Nature Medicine, 14, 213-221. https://doi.org/10.1038/nm1684
[32]
Hibino, N., et al. (2010) Late-Term Results of Tissue-Engineered Vascular Grafts in Humans. The Journal of Thoracic and Cardiovascular Surgery, 139, 431-436.e1-2. https://doi.org/10.1016/j.jtcvs.2009.09.057
[33]
Matsumura, G., et al. (2003) Successful Application of Tissue Engineered Vascular Autografts: Clinical Experience. Biomaterials, 24, 2303-2308. https://doi.org/10.1016/S0142-9612(03)00043-7
[34]
Shinoka, T., Imai, Y. and Ikada, Y. (2001) Transplantation of a Tissue-Engineered Pulmonary Artery. The New England Journal of Medicine, 344, 532-533. https://doi.org/10.1056/NEJM200102153440717
[35]
Shinoka, T., et al. (2005) Midterm Clinical Result of Tissue-Engineered Vascular Autografts Seeded with Autologous Bone Marrow Cells. The Journal of Thoracic and Cardiovascular Surgery, 129, 1330-1338. https://doi.org/10.1016/j.jtcvs.2004.12.047
Chen, Y. and Wang, Y. (2003) Progress in Scaffolding Materials of Bioartificial Liver. Journal of Biomedical Engineering, 20, 153-156.
[38]
Allen, J.W. and Bhatia, S.N. (2002) Engineering Liver Therapies for the Future. Tissue Engineering, 8, 725-737. https://doi.org/10.1089/10763270260424097
[39]
Baptista, P.M., et al. (2009) Whole Organ Decellularization—A Tool for Bioscaffold Fabrication and Organ Bioengineering. 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Minneapolis, 3-6 September 2009, 6526-6529. https://doi.org/10.1109/IEMBS.2009.5333145
[40]
Uygun, B.E., et al. (2010) Organ Reengineering through Development of a Transplantable Recellularized Liver Graft Using Decellularized Liver Matrix. Nature Medicine, 16, 814-820. https://doi.org/10.1038/nm.2170
[41]
Kobayashi, N. (2008) Bioartificial Pancreas for the Treatment of Diabetes. Cell Transplantation, 17, 11-17. https://doi.org/10.3727/000000008783907107
[42]
Soria, B., et al. (2000) Engineering Pancreatic Islets. Pflügers Archiv, 440, 1-18. https://doi.org/10.1007/s004240000251
[43]
Colton, C.K. and Avgoustiniatos, E.S. (1991) Bioengineering in Development of the Hybrid Artificial Pancreas. Journal of Biomechanical Engineering, 113, 152-170. https://doi.org/10.1115/1.2891229
[44]
Han, F., et al. (2020) Tissue Engineering and Regenerative Medicine: Achievements, Future, and Sustainability in Asia. Frontiers in Bioengineering and Biotechnology, 8, 83-83. https://doi.org/10.3389/fbioe.2020.00083
[45]
Clarke, G., et al. (2018) Bench to Bedside: Current Advances in Regenerative Medicine. Current Opinion in Cell Biology, 55, 59-66. https://doi.org/10.1016/j.ceb.2018.05.006
[46]
McRae, D., Matthews, R. and Matthews, R. (2007) Every Second Counts: The Race to Transplant the First Human Heart. Journal of Nuclear Medicine, 48, 1571-1572. https://doi.org/10.2967/jnumed.107.042549
[47]
Squifflet, J.P., Gruessner, R.W. and Sutherland, D.E. (2008) The History of Pancreas Transplantation: Past, Present and Future. Acta Chirurgica Belgica, 108, 367-378. https://doi.org/10.1080/00015458.2008.11680243
[48]
Zarrinpar, A. and Busuttil, R.W. (2013) Liver Transplantation: Past, Present and Future. Nature Reviews Gastroenterology & Hepatology, 10, 434-440. https://doi.org/10.1038/nrgastro.2013.88
[49]
Walker, D.A., Wilder, F.G. and Bush, E.L. (2020) What Is the Current Status of Lung Transplantation? Advances in Surgery, 54, 103-127. https://doi.org/10.1016/j.yasu.2020.05.004
[50]
National Research Council (US) and Institute of Medicine (US) Committee on the Use of Laboratory Animals in Biomedical and Behavioral Research (1988) Use of Laboratory Animals in Biomedical and Behavioral Research. National Academies Press (US), Washington DC. https://www.ncbi.nlm.nih.gov/books/NBK218267
[51]
Siddiqui, E.A., et al. (2016) Relevance of Small Laboratory Animals as Models in Translational Research: Challenges and Road Ahead. Journal of Applied Pharmaceutical Science, 6, 198-209. https://doi.org/10.7324/JAPS.2016.60531
[52]
Isselhard, W.H. and Kusche, J. (1986) Animal Experimentation. In: Troidl, H., et al., Eds., Principles and Practice of Research: Strategies for Surgical Investigators, Springer, Berlin, 149-161. https://doi.org/10.1007/978-3-642-96942-3_16
[53]
Muschler, G.F., et al. (2010) The Design and Use of Animal Models for Translational Research in Bone Tissue Engineering and Regenerative Medicine. Tissue Engineering Part B: Reviews, 16, 123-145. https://doi.org/10.1089/ten.teb.2009.0658
[54]
Russell, W.M.S. and Burch, R.L. (1959) The Principles of Humane Experimental Technique. Methuen Publishing, North Yorkshire.
[55]
Sah, R.L. and Ratcliffe, A. (2010) Translational Models for Musculoskeletal Tissue Engineering and Regenerative Medicine. Tissue Engineering Part B: Reviews, 16, 1-3. https://doi.org/10.1089/ten.teb.2009.0726
[56]
Mavrogenis, A.F., et al. (2019) The History of Microsurgery. European Journal of Orthopaedic Surgery & Traumatology, 29, 247-254. https://doi.org/10.1007/s00590-019-02378-7
[57]
Shores, J.T., Gabriel, A. and Gupta, S. (2007) Skin Substitutes and Alternatives: A Review. Advances in Skin & Wound Care, 20, 493-508. https://doi.org/10.1097/01.ASW.0000288217.83128.f3
[58]
Huang, Z., et al. (2010) Embryonic Porcine Skin Precursors Can Successfully Develop into Integrated Skin without Teratoma Formation Posttransplantation in Nude Mouse Model. PLOS ONE, 5, e8717. https://doi.org/10.1371/journal.pone.0008717
[59]
Ikada, Y. (2006) Challenges in Tissue Engineering. Journal of the Royal Society Interface, 3, 589-601. https://doi.org/10.1098/rsif.2006.0124
[60]
Blackwood, K.A., et al. (2008) Development of Biodegradable Electrospun Scaffolds for Dermal Replacement. Biomaterials, 29, 3091-3104. https://doi.org/10.1016/j.biomaterials.2008.03.037
[61]
Tremblay, P.-L., et al. (2005) Inosculation of Tissue-Engineered Capillaries with the Host’s Vasculature in A Reconstructed Skin Transplanted on Mice. American Journal of Transplantation, 5, 1002-1010. https://doi.org/10.1111/j.1600-6143.2005.00790.x
[62]
Karageorgiou, V. and Kaplan, D. (2005) Porosity of 3D Biomaterial Scaffolds and Osteogenesis. Biomaterials, 26, 5474-5491. https://doi.org/10.1016/j.biomaterials.2005.02.002
[63]
Standard, A. (2008) Standard Guide for Preclinical in Vivo Evaluation in Critical Size Segmental Bone Defects. ASTM International, West Conshohocken.
[64]
Poser, L., et al. (2014) A Standardized Critical Size Defect Model in Normal and Osteoporotic Rats to Evaluate Bone Tissue Engineered Constructs. BioMed Research International, 2014, Article ID: 348635. https://doi.org/10.1155/2014/348635
[65]
Khairallah, M. and Almeshaly, H. (2016) Present Strategies for Critical Bone Defects Regeneration. Oral Health Case Reports, 2, 3. https://doi.org/10.4172/2471-8726.1000127
[66]
Fan, W., Crawford, R. and Xiao, Y. (2010) Enhancing in Vivo Vascularized Bone Formation by Cobalt Chloride-Treated Bone Marrow Stromal Cells in a Tissue Engineered Periosteum Model. Biomaterials, 31, 3580-3589. https://doi.org/10.1016/j.biomaterials.2010.01.083
[67]
Parizi, A.M., et al. (2012) Human Platelet Rich Plasma plus Persian Gulf Coral Effects on Experimental Bone Healing in Rabbit Model: Radiological, Histological, Macroscopical and Biomechanical Evaluation. Journal of Materials Science: Materials in Medicine, 23, 473-483. https://doi.org/10.1007/s10856-011-4478-1
[68]
Dodwell, E.R. and Kelley, S.P. (2011) Physeal Fractures: Basic Science, Assessment and Acute Management. Orthopaedics and Trauma, 25, 377-391. https://doi.org/10.1016/j.mporth.2011.08.001
[69]
Erickson, C.B., et al. (2017) A Rat Tibial Growth Plate Injury Model to Characterize Repair Mechanisms and Evaluate Growth Plate Regeneration Strategies. Journal of Visualized Experiments, 125, e55571. https://doi.org/10.3791/55571-v
[70]
Chung, R., et al. (2006) Roles of Neutrophil-Mediated Inflammatory Response in the Bony Repair of Injured Growth Plate Cartilage in Young Rats. Journal of Leukocyte Biology, 80, 1272-1280. https://doi.org/10.1189/jlb.0606365
[71]
Chung, R., et al. (2013) Roles of Wnt/β-Catenin Signalling Pathway in the Bony Repair of Injured Growth Plate Cartilage in Young Rats. Bone, 52, 651-658. https://doi.org/10.1016/j.bone.2012.10.035
[72]
Zhou, F.H., et al. (2006) TNF-α Mediates p38 MAP Kinase Activation and Negatively Regulates Bone Formation at the Injured Growth Plate in Rats. Journal of Bone and Mineral Research, 21, 1075-1088. https://doi.org/10.1359/jbmr.060410
[73]
Lee, S.-U., et al. (2016) Transplantation of a Scaffold-Free Cartilage Tissue Analogue for the Treatment of Physeal Cartilage Injury of the Proximal Tibia in Rabbits. Yonsei Medical Journal, 57, 441-448. https://doi.org/10.3349/ymj.2016.57.2.441
[74]
Ribeiro-Resende, V.T., et al. (2009) Strategies for Inducing the Formation of Bands of Büngner in Peripheral Nerve Regeneration. Biomaterials, 30, 5251-5259. https://doi.org/10.1016/j.biomaterials.2009.07.007
[75]
McGrath, A.M., et al. (2016) Proximal versus Distal Nerve Transfer for Biceps Reinnervation—A Comparative Study in a Rat’s Brachial Plexus Injury Model. Plastic and Reconstructive Surgery Global Open, 4, e1130. https://doi.org/10.1097/GOX.0000000000001130
[76]
Sinis, N., et al. (2005) Nerve Regeneration across a 2-cm Gap in the Rat Median Nerve Using a Resorbable Nerve Conduit Filled with Schwann Cells. Journal of Neurosurgery, 103, 1067-1076. https://doi.org/10.3171/jns.2005.103.6.1067
[77]
Lietz, M., et al. (2006) Neuro Tissue Engineering of Glial Nerve Guides and the Impact of Different Cell Types. Biomaterials, 27, 1425-1436. https://doi.org/10.1016/j.biomaterials.2005.08.007
[78]
Sinis, N., et al. (2006) Cross-Chest Median Nerve Transfer: A New Model for the Evaluation of Nerve Regeneration across a 40 mm Gap in the Rat. Journal of Neuroscience Methods, 156, 166-172. https://doi.org/10.1016/j.jneumeth.2006.02.022
[79]
Kemp, S.W., et al. (2009) Collagen Nerve Conduits Promote Enhanced Axonal Regeneration, Schwann Cell Association, and Neovascularization Compared to Silicone Conduits. Tissue Engineering Part A, 15, 1975-1988. https://doi.org/10.1089/ten.tea.2008.0338
[80]
Chuang, D.C. (2018) Distal Nerve Transfers: A Perspective on the Future of Reconstructive Microsurgery. Journal of Reconstructive Microsurgery, 34, 669-671. https://doi.org/10.1055/s-0038-1656719
[81]
Cassel, W.S., et al. (1989) An Animal Model for Small-Diameter Arterial Grafts. Journal of Investigative Surgery, 2, 181-186. https://doi.org/10.3109/08941938909015349
[82]
Chaouat, M., et al. (2006) The Evaluation of a Small-Diameter Polysaccharide-Based Arterial Graft in Rats. Biomaterials, 27, 5546-5553. https://doi.org/10.1016/j.biomaterials.2006.06.032
[83]
Wu, W., Allen, R.A. and Wang, Y. (2012) Fast-Degrading Elastomer Enables Rapid Remodeling of a Cell-Free Synthetic Graft into a Neoartery. Nature Medicine, 18, 1148-1153. https://doi.org/10.1038/nm.2821
[84]
Rouwkema, J., Rivron, N.C. and van Blitterswijk, C.A. (2008) Vascularization in Tissue Engineering. Trends in Biotechnology, 26, 434-441. https://doi.org/10.1016/j.tibtech.2008.04.009
[85]
Bigham, A., et al. (2011) Evaluation of Osteoinduction Properties of the Demineralized Bovine Foetal Growth Plate Powder as a New Xenogenic Biomaterial in Rat. Research in Veterinary Science, 91, 306-310. https://doi.org/10.1016/j.rvsc.2010.12.001
[86]
Kujala, S., et al. (2003) Effect of Porosity on the Osteointegration and Bone Ingrowth of a Weight-Bearing Nickel-Titanium Bone Graft Substitute. Biomaterials, 24, 4691-4697. https://doi.org/10.1016/S0142-9612(03)00359-4
[87]
Kasper, F.K., et al. (2017) Tissue Engineered Prevascularized Bone and Soft Tissue Flaps. Oral and Maxillofacial Surgery Clinics, 29, 63-73. https://doi.org/10.1016/j.coms.2016.08.005
