Outcomes of Vascularized Bone Allotransplantation with Surgically Induced Autogenous Angiogenesis in a Large Animal Model: Bone Healing, Remodeling, and Material Properties

Rudolph H. Houben; Dimitra Kotsougiani; Patricia F. Friedrich; Alexander Y. Shin; Allen T. Bishop

doi:10.1055/s-0039-1695052

Journal of Reconstructive Microsurgery, Table of Contents

J Reconstr Microsurg 2020; 36(02): 082-092
DOI: 10.1055/s-0039-1695052

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Outcomes of Vascularized Bone Allotransplantation with Surgically Induced Autogenous Angiogenesis in a Large Animal Model: Bone Healing, Remodeling, and Material Properties

Rudolph H. Houben

¹Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota

,

Dimitra Kotsougiani

²Clinic for Hand, Plastic, and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Germany

³Department of Plastic Surgery, University of Heidelberg, Germany

,

Patricia F. Friedrich

¹Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota

,

Alexander Y. Shin

¹Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota

,

Allen T. Bishop

¹Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota

› Author Affiliations

Abstract

Background Bone vascularized composite allotransplantation (VCA) is a possible alternative for the treatment of large bone defects. Clinical application of VCAs is limited by the need for life-long immunosuppression (IS). We report an alternative method to maintain bone allotransplant viability in a large animal model without the need for life-long IS by using autogenous vessel implantation.

Methods Fourteen bone only VCAs were transplanted in a porcine tibia defect model with short-term IS. Two groups were used to evaluate the effect of the implantation of an autogenous arteriovenous (AV)-bundle, therefore the only difference between the groups was the patency of the AV-bundle. We radiographically evaluated bone healing and allogenic pedicle patency. AV-bundle patency and union were evaluated with micro-CT. Bone remodeling was assessed with histomorphometry and material properties were evaluated with axial compression testing and cyclic reference point indentation.

Results Two subjects did not reach the final time point. Twelve tibiae healed proximally, and nine at the distal transplant–bone interface. Bone allotransplants showed their viability in the first 4 to 6 weeks by significant periosteal bridging arising from the transplant and maintained pedicle patency. Bone material properties were not affected by the implantation of an AV-bundle when compared with ligated AV-bundle controls, but diminished compared with normal bone. Significantly higher bone formation rates resulted from the implantation of a patent AV-bundle.

Conclusion New periosteal bone formation and subsequent bone healing result from blood flow through the microsurgically repaired nutrient blood supply, demonstrated by maintained allogenic pedicle patency. The implantation of a patent autogenous AV-bundle has no adverse effect on material properties, but a positive effect on bone remodeling of endosteal surfaces despite thrombosis of the allogenic pedicle. Bone material properties change after transplantation compared with normal bone, although 20-weeks survival time is relatively short for the final evaluation of bone material properties.

Keywords

vascularized composite allotransplantation - bone - neoangiogenesis - reconstruction

Full Text

References

References
1 Mankin HJ, Doppelt S, Tomford W. Clinical experience with allograft implantation. The first ten years. Clin Orthop Relat Res 1983; (174) 69-86
2 Moran SL, Shin AY, Bishop AT. The use of massive bone allograft with intramedullary free fibular flap for limb salvage in a pediatric and adolescent population. Plast Reconstr Surg 2006; 118 (02) 413-419
3 Li J, Wang Z, Guo Z, Chen GJ, Li SW, Pei GX. The use of massive allograft with intramedullary fibular graft for intercalary reconstruction after resection of tibial malignancy. J Reconstr Microsurg 2011; 27 (01) 37-46
4 Berrey Jr BH, Lord CF, Gebhardt MC, Mankin HJ. Fractures of allografts. Frequency, treatment, and end-results. J Bone Joint Surg Am 1990; 72 (06) 825-833
5 Enneking WF, Mindell ER. Observations on massive retrieved human allografts. J Bone Joint Surg Am 1991; 73 (08) 1123-1142
6 Dick HM, Strauch RJ. Infection of massive bone allografts. Clin OrthopRelat Res 1994; (306) 46-53
7 de Boer HH, Wood MB. Bone changes in the vascularised fibular graft. J Bone Joint Surg Br 1989; 71 (03) 374-378
8 Moran CG, Wood MB. Vascularized bone autografts. Orthop Rev 1993; 22 (02) 187-197
9 Weiland AJ, Phillips TW, Randolph MA. Bone grafts: a radiologic, histologic, and biomechanical model comparing autografts, allografts, and free vascularized bone grafts. Plast Reconstr Surg 1984; 74 (03) 368-379
10 Arata MA, Wood MB, Cooney III WP. Revascularized segmental diaphyseal bone transfers in the canine. An analysis of viability. J Reconstr Microsurg 1984; 1 (01) 11-19
11 Larsen M, Pelzer M, Friedrich PF, Wood CM, Bishop AT. Living bone allotransplants survive by surgical angiogenesis alone: development of a novel method of composite tissue allotransplantation. J Bone Joint Surg Am 2011; 93 (03) 261-273
12 Giessler GA, Zobitz M, Friedrich PF, Bishop AT. Host-derived neoangiogenesis with short-term immunosuppression allows incorporation and remodeling of vascularized diaphyseal allogeneic rabbit femur transplants. J Orthop Res 2009; 27 (06) 763-770
13 Pelzer M, Larsen M, Chung YG. , et al. Short-term immunosuppression and surgical neoangiogenesis with host vessels maintains long-term viability of vascularized bone allografts. J Orthop Res 2007; 25 (03) 370-377
14 Larsen M, Willems WF, Pelzer M, Friedrich PF, Yaszemski MJ, Bishop AT. Augmentation of surgical angiogenesis in vascularized bone allotransplants with host-derived a/v bundle implantation, fibroblast growth factor-2, and vascular endothelial growth factor administration. J Orthop Res 2010; 28 (08) 1015-1021
15 Pelzer M, Larsen M, Friedrich PF, Aleff RA, Bishop AT. Repopulation of vascularized bone allotransplants with recipient-derived cells: detection by laser capture microdissection and real-time PCR. J Orthop Res 2009; 27 (11) 1514-1520
16 Kotsougiani D, Hundepool CA, Bulstra LF, Friedrich PF, Shin AY, Bishop AT. Recipient-derived angiogenesis with short term immunosuppression increases bone remodeling in bone vascularized composite allotransplantation: a pilot study in a swine tibial defect model. J Orthop Res 2017; 35 (06) 1242-1249
17 Kotsougiani D, Hundepool CA, Willems JI, Friedrich P, Shin AY, Bishop AT. Surgical angiogenesis in porcine tibial allotransplantation: a new large animal bone vascularized composite allotransplantation model. J Vis Exp 2017; (126) xx
18 Giessler GA, Zobitz M, Friedrich PF, Bishop AT. Transplantation of a vascularized rabbit femoral diaphyseal segment: mechanical and histologic properties of a new living bone transplantation model. Microsurgery 2008; 28 (04) 291-299
19 Kremer T, Giessler GA, Friedrich PF, Willems WF, Giusti G, Bishop AT. Surgical angiogenesis with short-term immunosuppression maintains bone viability in rabbit allogenic knee joint transplantation. Plast Reconstr Surg 2013; 131 (02) 148e-157e
20 Kremer T, Giusti G, Friedrich PF, Willems W, Bishop AT, Giessler GA. Knee joint transplantation combined with surgical angiogenesis in rabbits—a new experimental model. Microsurgery 2012; 32 (02) 118-127
21 Kotsougiani D, Hundepool CA, Willems JI, Friedrich P, Shin AY, Bishop AT. Surgical angiogenesis in porcine tibial allotransplantation: a new large animal bone vascularized composite allotransplantation model. J Vis Exp 2017; 126 (126) 13
22 Taira H, Moreno J, Ripalda P, Forriol F. Radiological and histological analysis of cortical allografts: an experimental study in sheep femora. Arch Orthop Trauma Surg 2004; 124 (05) 320-325
23 Reilly DT, Burstein AH, Frankel VH. The elastic modulus for bone. J Biomech 1974; 7 (03) 271-275
24 Pelker RR, Friedlaender GE, Markham TC, Panjabi MM, Moen CJ. Effects of freezing and freeze-drying on the biomechanical properties of rat bone. J Orthop Res 1984; 1 (04) 405-411
25 Gallant MA, Brown DM, Organ JM, Allen MR, Burr DB. Reference-point indentation correlates with bone toughness assessed using whole-bone traditional mechanical testing. Bone 2013; 53 (01) 301-305
26 Aberg M, Rydholm A, Holmberg J, Wieslander JB. Reconstruction with a free vascularized fibular graft for malignant bone tumor. Acta Orthop Scand 1988; 59 (04) 430-437
27 Fujimaki A, Suda H. Experimental study and clinical observations on hypertrophy of vascularized bone grafts. Microsurgery 1994; 15 (10) 726-732
28 Mathes DW, Randolph MA, Bourget JL. , et al. Recipient bone marrow engraftment in donor tissue after long-term tolerance to a composite tissue allograft. Transplantation 2002; 73 (12) 1880-1885
29 Ren X, Shirbacheh MV, Ustüner ET. , et al. Osteomyocutaneous flap as a preclinical composite tissue allograft: swine model. Microsurgery 2000; 20 (03) 143-149
30 Ustüner ET, Zdichavsky M, Ren X. , et al. Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy. Transplantation 1998; 66 (12) 1581-1587
31 Kuo YR, Sacks JM, Lee WP. , et al. Porcine heterotopic composite tissue allograft transplantation using a large animal model for preclinical studies. Chang Gung Med J 2006; 29 (03) 268-274
32 Vossen M, Edelstein J, Majzoub RK. , et al. Bone quality and healing in a swine vascularized bone allotransplantation model using cyclosporine-based immunosuppression therapy. Plast Reconstr Surg 2005; 115 (02) 529-538
33 de Boer HH. Vascularized Fibular Transfer. Leiden: University of Leiden; 1988
34 Weiland AJ, Moore JR, Daniel RK. Vascularized bone autografts. Experience with 41 cases. Clin Orthop Relat Res 1983; (174) 87-95
35 Diefenbeck M, Nerlich A, Schneeberger S, Wagner F, Hofmann GO. Allograft vasculopathy after allogeneic vascularized knee transplantation. Transpl Int 2011; 24 (01) e1-e5
36 Issa F. Vascularized composite allograft-specific characteristics of immune responses. Transpl Int 2016; 29 (06) 672-681
37 Siemionow M, Klimczak A. Basics of immune responses in transplantation in preparation for application of composite tissue allografts in plastic and reconstructive surgery: part I. Plast Reconstr Surg 2008; 121 (01) 4e-12e
38 Muramatsu K, Bishop AT. Cell repopulation in vascularized bone grafts. J Orthop Res 2002; 20 (04) 772-778
39 Muramatsu K, Bishop AT. Microchimerism following vascularized bone allotransplantation. Transpl Proc 2002; 34 (07) 2722-2724
40 Muramatsu K, Bishop AT, Sunagawa T, Valenzuela RG. Fate of donor cells in vascularized bone grafts: identification of systemic chimerism by the polymerase chain reaction. Plast Reconstr Surg 2003; 111 (02) 763-72 ; discussion 773–774
41 Akoglu B, Kriener S, Martens S. , et al. Interleukin-2 in CD8+ T cells correlates with Banff score during organ rejection in liver transplant recipients. Clin Exp Med 2009; 9 (04) 259-262
42 Hofmann GO, Kirschner MH, Wagner FD, Brauns L, Gonschorek O, Bühren V. Allogeneic vascularized transplantation of human femoral diaphyses and total knee joints—first clinical experiences. Transpl Proc 1998; 30 (06) 2754-2761
43 Hofmann GO, Falk C, Wangemann T. Immunological transformations in the recipient of grafted allogeneic human bone. Arch Orthop Trauma Surg 1997; 116 (03) 143-150
44 Hofmann GO, Kirschner MH. Clinical experience in allogeneic vascularized bone and joint allografting. Microsurgery 2000; 20 (08) 375-383
45 Hofmann GO, Kirschner MH, Brauns L, Wagner FD, Land W, Bühren V. Vascularized knee joint transplantation in man: a report on the first cases. Transpl Int 1998; 11 (Suppl. 01) S487-S490
46 Hofmann GO, Kirschner MH, Bühren V, Land W. Allogenic vascularized transplantation of a human femoral diaphysis under cyclosporin A immunosuppression. Transpl Int 1995; 8 (05) 418-419
47 Hofmann GO, Kirschner MH, Wangemann T, Falk C, Mempel W, Hammer C. Infections and immunological hazards of allogeneic bone transplantation. Arch Orthop Trauma Surg 1995; 114 (03) 159-166
48 Doi K, Kawai S, Shigetomi M. Congenital tibial pseudoarthrosis treated with vascularised bone allograft. Lancet 1996; 347 (9006): 970-971
49 Diefenbeck M, Wagner F, Kirschner MH, Nerlich A, Mückley T, Hofmann GO. Outcome of allogeneic vascularized knee transplants. Transpl Int 2007; 20 (05) 410-418