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Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.

ABSTRACT: Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into the defect after ectopic preossification and prevascularization. The combination of SiHA, MSCs and BMP-2 resulted in the significant ectopic formation of bone tissue, which can easily be transferred by means of our custom-made titanium chamber. Implanted osteogenic MSCs survived in vivo for a total of 18 weeks. The use of SiHA alone did not lead to bone formation after ectopic implantation. Analysis of gene expression showed early osteoblast differentiation and a hypoxic and inflammatory environment in implanted constructs. Irradiation led to impaired bone healing, decreased vascularization and lower short-term survival of implanted cells. We conclude that our model is highly valuable for the investigation of bone healing and tissue engineering in pre-damaged tissue and that healing of bone defects can be substantially supported by combining SiHA, MSCs and BMP-2.

SUBMITTER: Rottensteiner-Brandl U

PROVIDER: S-EPMC8467400 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.

Rottensteiner-Brandl Ulrike U Bertram Ulf U Lingens Lara F LF Köhn Katrin K Distel Luitpold L Fey Tobias T Körner Carolin C Horch Raymund E RE Arkudas Andreas A

Cells 20210831 9

Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into th ...[more]

PMID: 34571907

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Project description:Bone regeneration poses a significant challenge in the field of tissue engineering, prompting ongoing research to explore innovative strategies for effective bone healing. The integration of stem cells and nanomaterial scaffolds has emerged as a promising approach, offering the potential to enhance regenerative outcomes. This study focuses on the application of a stem cell-laden nanomaterial scaffold designed for bone regeneration in rabbits. The in vivo study was conducted on thirty-six healthy skeletally mature New Zealand white rabbits that were randomly allocated into six groups. Group A was considered the control, wherein a 15 mm critical-sized defect was created and left as such without any treatment. In group B, this defect was filled with a polycaprolactone-hydroxyapatite (PCL + HAP) scaffold, whereas in group C, a PCL + HAP-carboxylated multiwalled carbon nanotube (PCL + HAP + MWCNT-COOH) scaffold was used. In group D, a PCL + HAP + MWCNT-COOH scaffold was used with local injection of bone morphogenetic protein-2 (BMP-2) on postoperative days 30, 45, and 60. The rabbit bone marrow-derived mesenchymal stem cells (rBMSCs) were seeded onto the PCL + HAP + MWCNT-COOH scaffold by the centrifugal method. In group E, an rBMSC-seeded PCL + HAP + MWCNT-COOH scaffold was used along with the local injection of rBMSC on postoperative days 7, 14, and 21. For group F, in addition to the treatment given to group E, BMP-2 was administered locally on postoperative days 30, 45, and 60. Gross observations, radiological observation, scanning electron microscopic assessment, and histological evaluation study showed that group F displayed the best healing properties, followed by group E, group D, group C, and B. Group A showed no healing with ends blunting minimal fibrous tissue. Incorporating growth factor BMP-2 in tissue-engineered rBMSC-loaded nanocomposite PCL + HAP + MWCNT-COOH construct can augment the osteoinductive and osteoconductive properties, thereby enhancing the healing in a critical-sized bone defect. This novel stem cell composite could prove worthy in the treatment of non-union and delayed union fractures in the near future.

Project description:BackgroundBone grafts simultaneously delivering therapeutic proteins and antibiotics may be valuable in orthopaedic trauma care. Previously, we developed a poly(2-hydroxyethyl methacrylate)-nanocrystalline hydroxyapatite (pHEMA-nHA) synthetic bone graft that, when preabsorbed with 400-ng rhBMP-2/7, facilitated the functional repair of critical-size rat femoral defects. Recently, we showed that pHEMA-nHA effectively retains/releases vancomycin and rhBMP-2 in vitro. The success of such a strategy requires that the incorporation of vancomycin does not compromise the structural integrity of the graft nor its ability to promote bone healing.Questions/purposes(1) To evaluate the ability of pHEMA-nHA-vancomycin composites in combination with 3-µg rhBMP-2 to repair 5 mm rat femoral segmental defects, and (2) To determine if the encapsulated vancomycin impairs the graft/rhBMP-2-assisted bone repair.MethodspHEMA-nHA-vancomycin, pHEMA-nHA, or collagen sponge control with/without 3-µg rhBMP-2 were press-fit in 5 mm femoral defects in SASCO-SD male rats (289-300 g). Histology, microcomputed tomography, and torsion testing were performed on 8- and 12-week explants to evaluate the extent and quality of repair. The effect of vancomycin on the temporal absorption of endogenous BMP-2 and stromal cell-derived factor-1 was evaluated by immunohistochemistry. These factors are important for bone healing initiation and stem cell recruitment, respectively.ResultsPartial bridging of the defect with bony callus by 12 weeks was observed with pHEMA-nHA-vancomycin without rhBMP-2 while full bridging with substantially mineralized callus and partial restoration of torsional strength was achieved with 3-µg rhBMP-2. The presence of vancomycin changed the absorption patterns of endogenous proteins on the grafts, but did not appear to substantially compromise graft healing.ConclusionsThe composite pHEMA-nHA-vancomycin preabsorbed with 3-µg rhBMP-2 promoted repair of 5 mm rat femoral segmental defects. With the sample sizes applied, vancomycin encapsulation did not appear to have a negative effect on bone healing.Clinical relevancepHEMA-nHA-vancomycin preabsorbed with rhBMP-2 may be useful in the repair of critical-size long bone defects prone to infections.

Project description:BackgroundSystemic administration of sclerostin neutralizing antibody has led to increased bone formation in animal models of osteoporosis. The purpose of this study was to determine if systemic administration of sclerostin neutralizing antibody could increase the healing response in a critical-sized femoral defect in rats.MethodsCritical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The sclerostin antibody (Scl-Ab) treatment groups included the continuous Scl-Ab group (twenty-one animals), the early Scl-Ab group (fifteen animals), and the delayed Scl-Ab group (fifteen animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0 through 12; weeks 0 through 2; and weeks 2 through 4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at zero, two, six, and twelve weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for twelve weeks (fifteen rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis.ResultsIn the primary study, four of fifteen defects in the continuous (zero to twelve-week) Scl-Ab group, three of fifteen defects in the early (zero to two-week) Scl-Ab group, and four of fifteen defects in the delayed (two to four-week) Scl-Ab group healed at twelve weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for twelve weeks demonstrated a significant increase in new bone formation (p < 0.05) compared with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls.ConclusionsAdministration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by twelve weeks.

Dataset Information

Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.

Publications

Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.

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