Tissue-engineered bone constructed in a bioreactor for repairing critical-sized bone defects in sheep

Li, Deqiang; Li, Ming; Liu, Peilai; Yuankai, Zhang; Lu, Jianxi; Li, Jianmin

doi:10.1007/s00264-014-2389-8

Cited by 18 publications

(12 citation statements)

References 30 publications

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“…Bioreactors have been widely utilized in tissue engineering applications, especially for bone regeneration due to their ability to provide a dynamic culturing environment, a preferred condition during osteogenic differentiation of hMPCs (Fan et al, ; Grayson et al, ; Li et al, ; Sikavitsas et al, ). Specifically, the TPS bioreactor increases oxygen and nutrient supply to cells encapsulated in hydrogel scaffolds, but also applies fluid flow forces that lead to molecular changes in cells as surface receptors trigger molecular pathways downstream (Yeatts and Fisher, ).…”

Section: Discussionmentioning

confidence: 99%

Tunable osteogenic differentiation of hMPCs in tubular perfusion system bioreactor

Nguyen

Fisher

2016

Biotech & Bioengineering

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The use of bioreactors for bone tissue engineering has been widely investigated. While the benefits of shear stress on osteogenic differentiation are well known, the underlying effects of dynamic culture on subpopulations within a bioreactor are less evident. In this work, we explore the influence of applied flow in the tubular perfusion system (TPS) bioreactor on the osteogenic differentiation of human mesenchymal progenitor cells (hMPCs), specifically analyzing the effects of axial position along the growth chamber. TPS bioreactor experiments conducted with unidirectional flow demonstrated enhanced expression of osteogenic markers in cells cultured downstream from the inlet flow. We utilized computational fluid dynamic modeling to confirm uniform shear stress distribution on the surface of the scaffolds and along the length of the growth chamber. The concept of paracrine signaling between cell populations was validated with the use of alternating flow, which diminished the differences in osteogenic differentiation between cells cultured at the inlet and outlet of the growth chamber. After the addition of controlled release of bone morphogenic protein-2 (BMP-2) into the system, osteogenic differentiation among subpopulations along the growth chamber was augmented, yet remained homogenous. These results allow for greater understanding of axial bioreactor cultures, their microenvironment, and how well-established parameters of osteogenic differentiation affect bone tissue development. With this work, we have demonstrated the capability of tuning osteogenic differentiation of hMPCs through the application of fluid flow and the addition of exogenous growth factors. Such precise control allows for the culture of distinct subpopulation within one dynamic system for the use of complex engineered tissue constructs. Biotechnol. Bioeng. 2016;113: 1805-1813. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Tunable osteogenic differentiation of hMPCs in tubular perfusion system bioreactor

Nguyen

Fisher

2016

Biotech & Bioengineering

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“…We have previously demonstrated the benefits of the tubular perfusion system (TPS) bioreactor on osteogenic differentiation of hMSCs due to the applied shear flow and the increased oxygen and nutrient supply to the cultured cells . Although these systems have been utilized to create bone tissue constructs of large sizes, the leap from in vitro bench top applications to clinical reality will require the presence of ECs within the construct to allow for the establishment of preexisting vasculature.…”

Section: Introductionmentioning

confidence: 99%

Collagen hydrogel scaffold promotes mesenchymal stem cell and endothelial cell coculture for bone tissue engineering

Nguyen

Moriarty

Kamalitdinov

et al. 2017

J Biomedical Materials Res

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The generation of functional, vascularized tissues is a key challenge for the field of tissue engineering. Before clinical implantations of such tissue engineered bone constructs can succeed, tactics to promote neovascularization need to be strengthened. We have previously demonstrated that the tubular perfusion system (TPS) bioreactor is an effective culturing method to augment osteogenic differentiation and maintain viability of human mesenchymal stem cells (hMSC). Here, we devised a strategy to address the need for a functional microvasculature by designing an in vitro coculture system that simultaneously cultures osteogenic differentiating hMSCs with endothelial cells (ECs). We utilized the TPS bioreactor as a dynamic coculture environment, which we hypothesize will encourage prevascularization of endothelial cells and early formation of bone tissue and could aid in anastomosis of the graft with the host vasculature after patient implantation. To evaluate the effect of different natural scaffolds for this coculture system, the cells were encapsulated in alginate and/or collagen hydrogel scaffolds. We discovered the necessity of cell-to-cell proximity between the two cell types as well as preference for the natural cell binding capabilities of hydrogels like collagen. We discovered increased osteogenic and angiogenic potential as seen by amplified gene and protein expression of ALP, BMP-2, VEGF, and PECAM. The TPS bioreactor further augmented these expressions, indicating a synergistic effect between coculture and applied shear stress. The development of this dynamic coculture platform for the prevascularization of engineered bone, emphasizing the importance of the construct microenvironments and will advance the clinical use of tissue engineered constructs.

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“…Bone defects, especially critical size defects, have always been a complex problem in orthopaedics (Li et al, ). The high incidence of such injuries results in a high fracture non‐union rate, and this problem has attracted the attention of orthopaedic researchers (Fernandes et al, ).…”

Section: Discussionmentioning

confidence: 99%

Novel standardized massive bone defect model in rats employing an internal eight‐hole stainless steel plate for bone tissue engineering

Jiang

Cheng

et al. 2018

J Tissue Eng Regen Med

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Massive bone defects are a challenge in orthopaedic research. Defective regeneration leads to bone atrophy, non-union of bone, and physical morbidity. Large animals are important models, however, production costs are high, nursing is complex, and evaluation methods are limited. A suitable laboratory animal model is required to explore the underlying molecular mechanism and cellular process of bone tissue engineering. We designed a stainless steel plate with 8 holes; the middle 2 holes were used as a guide to create a standardized critical size defect in the femur of anaesthetized rats. The plate was fixed to the bone using 6 screws, serving as an inner fixed bracket to secure a tricalcium phosphate implant seeded with green fluorescent protein-positive rat bone marrow mesenchymal stem cells within the defect. In some animals, we also grafted a vessel bundle into the lateral side of the implant, to promote vascularized bone tissue engineering. X-ray, microcomputed tomography, and histological analyses demonstrated the stainless steel plate resulted in a stable large segmental defect model in the rat femur. Vascularization significantly increased bone formation and implant degradation. Moreover, survival and expansion of green fluorescent protein-positive seeded cells could be clearly monitored in vivo at 1, 4, and 8 weeks postoperation via fluorescent microscopy. This standardized large segmental defect model in a small animal may help to advance the study of bone tissue engineering. Furthermore, availability of antibodies and genetically modified rats could help to dissect the precise cellular and molecular mechanisms of bone repair.

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Tissue-engineered bone constructed in a bioreactor for repairing critical-sized bone defects in sheep

Abstract: Tissue-engineered bone improved osteogenesis in vivo and enhanced the ability to repair critical-sized bone defects in large animals.

Cited by 18 publications

References 30 publications

Tunable osteogenic differentiation of hMPCs in tubular perfusion system bioreactor

Tunable osteogenic differentiation of hMPCs in tubular perfusion system bioreactor

Collagen hydrogel scaffold promotes mesenchymal stem cell and endothelial cell coculture for bone tissue engineering

Novel standardized massive bone defect model in rats employing an internal eight‐hole stainless steel plate for bone tissue engineering

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