Living bone allotransplants survive by surgical angiogenesis alone: Development of a novel method of composite tissue allotransplantation

Mikko Larsen, Michael Pelzer, Patricia F. Friedrich, Christina M. Wood, Allen Thorp Bishop

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Segmental bone defects pose reconstructive challenges. Composite tissue allotransplantation offers a potential solution but requires long-term immunosuppression with attendant health risks. This study demonstrates a novel method of composite-tissue allotransplantation, permitting long-term drug-free survival, with use of therapeutic angiogenesis of autogenous vessels to maintain circulation. Methods: Ninety-three rats underwent femoral allotransplantation, isotransplantation, or allografting. Group-1 femora were transplanted across a major histocompatibility complex barrier, with microsurgical pedicle anastomoses. The contralateral saphenous artery and vein (termed the AV bundle) of the recipient animal were implanted within the medullary canal to allow development of an autogenous circulation. In Group 2, allotransplantation was also performed, but with AV bundle ligation. Group 3 bones were frozen allografts rather than composite-tissue allotransplantation femora, and Group 4 bones were isotransplants. Paired comparison allowed evaluation of AV bundle effect, bone allogenicity (isogeneic or allogeneic), and initial circulation and viability (allotransplant versus allograft). Two weeks of immunosuppression therapy maintained blood flow initially, during development of a neoangiogenic autogenous blood supply from the AV bundle in patent groups. At eighteen weeks, skin grafts from donor, recipient, and third-party rats were tested for immunocompetence and donor-specific tolerance. At twenty-one weeks, bone circulation was quantified and new bone formation was measured. Results: Final circulatory status depended on both the initial viability of the graft and the successful development of neoangiogenic circulation. Median cortical blood flow was highest in Group 1 (4.6 mL/min/100 g), intermediate in Group 4 isotransplants (0.4 mL/min/100 g), and absent in others. Capillary proliferation and new bone formation were generally highest in allotransplants (15.0%, 6.4 μm3/μm2/yr) and isotransplants with patent AV bundles (16.6%, 50.3 μm3/μm2/yr) and less in allotransplants with ligated AV bundles (4.4%, 0.0 μm3/μm 2/yr) or allografts (8.1%, 24.1 μm3/μm 2/yr). Donor and third-party-type skin grafts were rejected, indicating immunocompetence without donor-specific tolerance. Conclusions: In the rat model, microvascular allogeneic bone transplantation in combination with short-term immunosuppression and AV bundle implantation creates an autogenous neoangiogenic circulation, permitting long-term allotransplant survival with measurable blood flow. Clinical Relevance: These methods may allow future composite-tissue allotransplantation of bone without the appreciable health risks that are associated with long-term immunosuppression or immune tolerance induction.

Original languageEnglish (US)
Pages (from-to)261-273
Number of pages13
JournalJournal of Bone and Joint Surgery - Series A
Volume93
Issue number3
DOIs
StatePublished - Feb 2 2011

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Vascularized Composite Allotransplantation
Isografts
Bone and Bones
Immunosuppression
Allografts
Immunocompetence
Homologous Transplantation
Transplants
Osteogenesis
Femur
Matched-Pair Analysis
Immune Tolerance
Skin
Bone Transplantation
Saphenous Vein
Health
Therapeutic Uses
Thigh
Major Histocompatibility Complex
Ligation

ASJC Scopus subject areas

  • Surgery
  • Orthopedics and Sports Medicine

Cite this

Living bone allotransplants survive by surgical angiogenesis alone : Development of a novel method of composite tissue allotransplantation. / Larsen, Mikko; Pelzer, Michael; Friedrich, Patricia F.; Wood, Christina M.; Bishop, Allen Thorp.

In: Journal of Bone and Joint Surgery - Series A, Vol. 93, No. 3, 02.02.2011, p. 261-273.

Research output: Contribution to journalArticle

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abstract = "Background: Segmental bone defects pose reconstructive challenges. Composite tissue allotransplantation offers a potential solution but requires long-term immunosuppression with attendant health risks. This study demonstrates a novel method of composite-tissue allotransplantation, permitting long-term drug-free survival, with use of therapeutic angiogenesis of autogenous vessels to maintain circulation. Methods: Ninety-three rats underwent femoral allotransplantation, isotransplantation, or allografting. Group-1 femora were transplanted across a major histocompatibility complex barrier, with microsurgical pedicle anastomoses. The contralateral saphenous artery and vein (termed the AV bundle) of the recipient animal were implanted within the medullary canal to allow development of an autogenous circulation. In Group 2, allotransplantation was also performed, but with AV bundle ligation. Group 3 bones were frozen allografts rather than composite-tissue allotransplantation femora, and Group 4 bones were isotransplants. Paired comparison allowed evaluation of AV bundle effect, bone allogenicity (isogeneic or allogeneic), and initial circulation and viability (allotransplant versus allograft). Two weeks of immunosuppression therapy maintained blood flow initially, during development of a neoangiogenic autogenous blood supply from the AV bundle in patent groups. At eighteen weeks, skin grafts from donor, recipient, and third-party rats were tested for immunocompetence and donor-specific tolerance. At twenty-one weeks, bone circulation was quantified and new bone formation was measured. Results: Final circulatory status depended on both the initial viability of the graft and the successful development of neoangiogenic circulation. Median cortical blood flow was highest in Group 1 (4.6 mL/min/100 g), intermediate in Group 4 isotransplants (0.4 mL/min/100 g), and absent in others. Capillary proliferation and new bone formation were generally highest in allotransplants (15.0{\%}, 6.4 μm3/μm2/yr) and isotransplants with patent AV bundles (16.6{\%}, 50.3 μm3/μm2/yr) and less in allotransplants with ligated AV bundles (4.4{\%}, 0.0 μm3/μm 2/yr) or allografts (8.1{\%}, 24.1 μm3/μm 2/yr). Donor and third-party-type skin grafts were rejected, indicating immunocompetence without donor-specific tolerance. Conclusions: In the rat model, microvascular allogeneic bone transplantation in combination with short-term immunosuppression and AV bundle implantation creates an autogenous neoangiogenic circulation, permitting long-term allotransplant survival with measurable blood flow. Clinical Relevance: These methods may allow future composite-tissue allotransplantation of bone without the appreciable health risks that are associated with long-term immunosuppression or immune tolerance induction.",
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N2 - Background: Segmental bone defects pose reconstructive challenges. Composite tissue allotransplantation offers a potential solution but requires long-term immunosuppression with attendant health risks. This study demonstrates a novel method of composite-tissue allotransplantation, permitting long-term drug-free survival, with use of therapeutic angiogenesis of autogenous vessels to maintain circulation. Methods: Ninety-three rats underwent femoral allotransplantation, isotransplantation, or allografting. Group-1 femora were transplanted across a major histocompatibility complex barrier, with microsurgical pedicle anastomoses. The contralateral saphenous artery and vein (termed the AV bundle) of the recipient animal were implanted within the medullary canal to allow development of an autogenous circulation. In Group 2, allotransplantation was also performed, but with AV bundle ligation. Group 3 bones were frozen allografts rather than composite-tissue allotransplantation femora, and Group 4 bones were isotransplants. Paired comparison allowed evaluation of AV bundle effect, bone allogenicity (isogeneic or allogeneic), and initial circulation and viability (allotransplant versus allograft). Two weeks of immunosuppression therapy maintained blood flow initially, during development of a neoangiogenic autogenous blood supply from the AV bundle in patent groups. At eighteen weeks, skin grafts from donor, recipient, and third-party rats were tested for immunocompetence and donor-specific tolerance. At twenty-one weeks, bone circulation was quantified and new bone formation was measured. Results: Final circulatory status depended on both the initial viability of the graft and the successful development of neoangiogenic circulation. Median cortical blood flow was highest in Group 1 (4.6 mL/min/100 g), intermediate in Group 4 isotransplants (0.4 mL/min/100 g), and absent in others. Capillary proliferation and new bone formation were generally highest in allotransplants (15.0%, 6.4 μm3/μm2/yr) and isotransplants with patent AV bundles (16.6%, 50.3 μm3/μm2/yr) and less in allotransplants with ligated AV bundles (4.4%, 0.0 μm3/μm 2/yr) or allografts (8.1%, 24.1 μm3/μm 2/yr). Donor and third-party-type skin grafts were rejected, indicating immunocompetence without donor-specific tolerance. Conclusions: In the rat model, microvascular allogeneic bone transplantation in combination with short-term immunosuppression and AV bundle implantation creates an autogenous neoangiogenic circulation, permitting long-term allotransplant survival with measurable blood flow. Clinical Relevance: These methods may allow future composite-tissue allotransplantation of bone without the appreciable health risks that are associated with long-term immunosuppression or immune tolerance induction.

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