scholarly journals Recapitulating bone development for tissue regeneration through engineered mesenchymal condensations and mechanical cues

2017 ◽  
Author(s):  
Anna M. McDermott ◽  
Samuel Herberg ◽  
Devon E. Mason ◽  
Hope B. Pearson ◽  
James H. Dawahare ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Bone Formation ◽  
Mechanical Loading ◽  
Endochondral Ossification ◽  
Bone Development ◽  
Bone Defects ◽  
Limb Bud ◽  
Large Bone ◽  
Large Bone Defects

ABSTRACTLarge bone defects cannot heal without intervention and have high complication rates even with the best treatments available. In contrast, bone fractures naturally healing with high success rates by recapitulating the process of bone development through endochondral ossification.1 Endochondral tissue engineering may represent a promising paradigm, but large bone defects are unable to naturally form a callus. We engineered mesenchymal condensations featuring local morphogen presentation (TGF-β1) to mimic the cellular organization and lineage progression of the early limb bud. As mechanical forces are 2,3 critical for proper endochondral ossification during bone morphogenesis2,3 and fracture healing, we hypothesized that mechanical cues would be important for endochondral regeneration.4,5 Here, using fixation plates that modulate ambulatory load transfer through dynamic tuning of axial compliance, we found that in vivo mechanical loading was necessary to restore bone function to large bone defects through endochondral ossification. Endochondral regeneration produced zonal cartilage and primary spongiosa mimetic of the native growth plate. Live human chondrocytes contributed to endochondral regeneration in vivo, while cell devitalization prior to condensation transplantation abrogated bone formation. Mechanical loading induced regeneration comparable to high-dose BMP-2 delivery, but without heterotopic bone formation and with order-of-magnitude greater mechanosensitivity.6–8In vitro, mechanical loading promoted chondrogenesis, and upregulated pericellular collagen 6 deposition and angiogenic gene expression. Consistently, in vivo mechanical loading regulated cartilage formation and neovascular invasion dependent on load timing. Together, this study represents the first demonstration of the effects of mechanical loading on transplanted cell-mediated bone defect regeneration, and provides a new template for recapitulating developmental programs for tissue engineering.

scholarly journals Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration

2019 ◽  
Vol 11 (495) ◽  
pp. eaav7756 ◽  
Author(s):  
Anna M. McDermott ◽  
Samuel Herberg ◽  
Devon E. Mason ◽  
Joseph M. Collins ◽  
Hope B. Pearson ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Bone Formation ◽  
Mechanical Loading ◽  
Bone Defect ◽  
Bone Development ◽  
Limb Bud ◽  
Mechanical Forces ◽  
Endochondral Bone ◽  
Large Bone

Large bone defects cannot form a callus and exhibit high complication rates even with the best treatment strategies available. Tissue engineering approaches often use scaffolds designed to match the properties of mature bone. However, natural fracture healing is most efficient when it recapitulates development, forming bone via a cartilage intermediate (endochondral ossification). Because mechanical forces are critical for proper endochondral bone development and fracture repair, we hypothesized that recapitulating developmental mechanical forces would be essential for large bone defect regeneration in rats. Here, we engineered mesenchymal condensations that mimic the cellular organization and lineage progression of the early limb bud in response to local transforming growth factor–β1 presentation from incorporated gelatin microspheres. We then controlled mechanical loading in vivo by dynamically tuning fixator compliance. Mechanical loading enhanced mesenchymal condensation–induced endochondral bone formation in vivo, restoring functional bone properties when load initiation was delayed to week 4 after defect formation. Live cell transplantation produced zonal human cartilage and primary spongiosa mimetic of the native growth plate, whereas condensation devitalization before transplantation abrogated bone formation. Mechanical loading induced regeneration comparable to high-dose bone morphogenetic protein-2 delivery, but without heterotopic bone formation and with order-of-magnitude greater mechanosensitivity. In vitro, mechanical loading promoted chondrogenesis and up-regulated pericellular matrix deposition and angiogenic gene expression. In vivo, mechanical loading regulated cartilage formation and neovascular invasion, dependent on load timing. This study establishes mechanical cues as key regulators of endochondral bone defect regeneration and provides a paradigm for recapitulating developmental programs for tissue engineering.

scholarly journals Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair

2019 ◽  
Author(s):  
S. Herberg ◽  
A. M. McDermott ◽  
P. N. Dang ◽  
D. S. Alt ◽  
R. Tang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Bone Formation ◽  
Mechanical Loading ◽  
Endochondral Ossification ◽  
Bone Development ◽  
Human Mesenchymal Stem Cell ◽  
Bone Defects ◽  
Mechanical Environment ◽  
Tgf Β1

AbstractEndochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation and is directed by local morphogen signals and mechanical cues. Here, we aimed to mimic these developmental conditions for regeneration of large bone defects. We hypothesized that engineered human mesenchymal stem cell (hMSC) condensations with in situ presentation of transforming growth factor-β1 (TGF-β1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles would promote endochondral regeneration of critical-sized rat femoral bone defects in a manner dependent on the in vivo mechanical environment. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with dual BMP-2 + TGF-β1 fully restoring mechanical bone function by week 12. In vivo ambulatory mechanical loading, initiated at week 4 by delayed unlocking of compliant fixation plates, significantly enhanced the bone formation rate in the four weeks after load initiation in the dual morphogen group. In vitro, local presentation of either BMP-2 alone or BMP-2 + TGF-β1 initiated endochondral lineage commitment of mesenchymal condensations, inducing both chondrogenic and osteogenic gene expression through SMAD3 and SMAD5 signaling. In vivo, however, endochondral cartilage formation was evident only in the BMP-2 + TGF-β1 group and was enhanced by mechanical loading. The degree of bone formation was comparable to BMP-2 soaked on collagen but without the ectopic bone formation that limits the clinical efficacy of BMP-2/collagen. In contrast, mechanical loading had no effect on autograft-mediated repair. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.One Sentence SummaryMimicking aspects of the cellular, biochemical, and mechanical environment during early limb development, chondrogenically-primed human mesenchymal stem cell condensations promoted functional healing of critical-sized femoral defects via endochondral ossification, and healing rate and extent was a function of the in vivo mechanical environment.

scholarly journals Heparin-mediated delivery of bone morphogenetic protein-2 improves spatial localization of bone regeneration

2020 ◽  
Vol 6 (1) ◽  
pp. eaay1240 ◽  
Author(s):  
Marian H. Hettiaratchi ◽  
Laxminarayanan Krishnan ◽  
Tel Rouse ◽  
Catherine Chou ◽  
Todd C. McDevitt ◽  
...  
Keyword(s):  
Bone Formation ◽  
Heterotopic Ossification ◽  
Bone Morphogenetic Protein ◽  
Spatial Localization ◽  
Bone Defects ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Large Bone ◽  
Large Bone Defects

Supraphysiologic doses of bone morphogenetic protein-2 (BMP-2) are used clinically to promote bone formation in fracture nonunions, large bone defects, and spinal fusion. However, abnormal bone formation (i.e., heterotopic ossification) caused by rapid BMP-2 release from conventional collagen sponge scaffolds is a serious complication. We leveraged the strong affinity interactions between heparin microparticles (HMPs) and BMP-2 to improve protein delivery to bone defects. We first developed a computational model to investigate BMP-2–HMP interactions and demonstrated improved in vivo BMP-2 retention using HMPs. We then evaluated BMP-2–loaded HMPs as a treatment strategy for healing critically sized femoral defects in a rat model that displays heterotopic ossification with clinical BMP-2 doses (0.12 mg/kg body weight). HMPs increased BMP-2 retention in vivo, improving spatial localization of bone formation in large bone defects and reducing heterotopic ossification. Thus, HMPs provide a promising opportunity to improve the safety profile of scaffold-based BMP-2 delivery.

scholarly journals Vascularization of Nanohydroxyapatite/Collagen/Poly(L-lactic acid) Composites by Implanting Intramuscularly In Vivo

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Hai Wang ◽  
Xiao Chang ◽  
Guixing Qiu ◽  
Fuzhai Cui ◽  
Xisheng Weng ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Orthopaedic Surgery ◽  
Bone Substitutes ◽  
Bone Defects ◽  
Large Defect ◽  
Natural Bone ◽  
Composition And Structure ◽  
Large Bone ◽  
Large Bone Defects

It still remains a major challenge to repair large bone defects in the orthopaedic surgery. In previous studies, a nanohydroxyapatite/collagen/poly(L-lactic acid) (nHAC/PLA) composite, similar to natural bone in both composition and structure, has been prepared. It could repair small sized bone defects, but they were restricted to repair a large defect due to the lack of oxygen and nutrition supply for cell survival without vascularization. The aim of the present study was to investigate whether nHAC/PLA composites could be vascularized in vivo. Composites were implanted intramuscularly in the groins of rabbits for 2, 6, or 10 weeks (n=5×3). After removing, the macroscopic results showed that there were lots of rich blood supply tissues embracing the composites, and the volumes of tissue were increasing as time goes on. In microscopic views, blood vessels and vascular sprouts could be observed, and microvessel density (MVD) of the composites trended to increase over time. It suggested that nHAC/PLA composites could be well vascularized by implanting in vivo. In the future, it would be possible to generate vascular pedicle bone substitutes with nHAC/PLA composites for grafting.

Hydroxyapatite scaffold pore architecture effects in large bone defects in vivo

2013 ◽  
Vol 28 (7) ◽  
pp. 1016-1027 ◽  
Author(s):  
Teja Guda ◽  
John A Walker ◽  
Brian Singleton ◽  
Jesus Hernandez ◽  
Daniel S Oh ◽  
...  
Keyword(s):  
Bone Defects ◽  
Pore Architecture ◽  
Hydroxyapatite Scaffold ◽  
Large Bone ◽  
Large Bone Defects

scholarly journals Poly(POG)n loaded with recombinant human bone morphogenetic protein-2 accelerates new bone formation in a critical-sized bone defect mouse model

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ryo Tazawa ◽  
Kentaro Uchida ◽  
Hiroaki Minehara ◽  
Terumasa Matsuura ◽  
Tadashi Kawamura ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bone Formation ◽  
Bone Morphogenetic Protein ◽  
Bone Defect ◽  
Bone Defects ◽  
Bone Morphogenetic Protein 2 ◽  
New Bone Formation ◽  
Morphogenetic Protein ◽  
Large Bone ◽  
Large Bone Defects

Abstract Background Delivery of bone morphogenetic protein-2 (BMP-2) via animal-derived absorbable collagen materials is used for the treatment of large bone defects. However, the administration of bovine proteins to humans is associated with the risk of zoonotic complications. We therefore examined the effect of combining BMP-2 with collagen-like peptides, poly(POG)n, in a critical-sized bone defect mouse model. Methods A 2-mm critical-sized bone defect was created in the femur of 9-week-old male C57/BL6J mice. Mice were randomly allocated into one of four treatment groups (n = 6 each): control (no treatment), poly(POG)n only, 0.2 μg, or 2.0 μg BMP-2 with poly(POG)n. New bone formation was monitored using soft X-ray radiographs, and bone formation at the bone defect site was examined using micro-computed tomography and histological examination at 4 weeks after surgery. Results Administration of 2.0 μg of BMP-2 with poly(POG)n promoted new bone formation and resulted in greater bone volume and bone mineral content than that observed in the control group and successfully achieved consolidation. In contrast, bone formation in all other groups was scarce. Conclusions Our findings suggest the potential of BMP-2 with poly(POG)n as a material, free from animal-derived collagen, for the treatment of large bone defects.

The reconstruction of large bone defects by novel functionalized polymers: an in vitro and in vivo experimental study

1993 ◽  
Vol 12 (13) ◽  
pp. 979-981 ◽  
Author(s):  
E. Dalas ◽  
P. Megas ◽  
M. Tyllianakis ◽  
D. Vynois ◽  
E. Lambiris
Keyword(s):  
Experimental Study ◽  
Bone Defects ◽  
Functionalized Polymers ◽  
Large Bone ◽  
Large Bone Defects

Strontium-calcium phosphate hybrid cement with enhanced osteogenic and angiogenic properties for vascularised bone regeneration

2021 ◽  
Author(s):  
Xiexing Wu ◽  
Ziniu Tang ◽  
Kang Wu ◽  
Yanjie Bai ◽  
X. LIN ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Calcium Phosphate ◽  
Bone Tissue Engineering ◽  
Bone Regeneration ◽  
Calcium Phosphate Cement ◽  
Treatment Options ◽  
Bone Defects ◽  
Large Bone ◽  
Large Bone Defects ◽  
Vascularized Bone

Vascularized bone tissue engineering is regarded as one of the optimal treatment options for large bone defects. The lack of angiogenic property and unsatisfactory physicochemical performance restricts calcium phosphate cement...

scholarly journals Effects of chondrogenic priming duration on mechanoregulation of engineered cartilage anlagen

2020 ◽  
Author(s):  
Anna M. McDermott ◽  
Emily A. Eastburn ◽  
Daniel J. Kelly ◽  
Joel D. Boerckel
Keyword(s):  
Dynamic Loading ◽  
Mechanical Loading ◽  
Endochondral Ossification ◽  
Bone Development ◽  
Mechanical Compression ◽  
Dynamic Mechanical ◽  
Matrix Deposition ◽  
Static Conditions

AbstractBone development and repair occur by endochondral ossification of a cartilage anlage, or template. Endochondral ossification is regulated by mechanical cues. Recently, we found that in vivo mechanical loading promoted regeneration of large bone defects through endochondral ossification, in a manner dependent on the timing of load initiation. Here, we have developed an in vitro model of the cartilage anlage to test whether the chondrogenic differentiation state alters the response to dynamic mechanical compression. We cultured human bone marrow stromal cells (hMSCs) at high cell density in fibrin hydrogels under chondrogenic priming conditions for periods of 0, 2, 4, or 6 weeks prior to two weeks of dynamic mechanical loading. Samples were evaluated by biomechanical testing, biochemical analysis of collagen and glycosaminoglycan (GAG) deposition, gene expression analysis, and immunohistological analysis, in comparison to time-matched controls cultured under static conditions. We found that dynamic loading increased the mechanical stiffness of engineered anlagen in a manner dependent on the duration of chondrogenic priming prior to load initiation. For chondrogenic priming times of 2 weeks or greater, dynamic loading enhanced the expression of type II collagen and aggrecan, although no significant changes in overall levels of matrix deposition was observed. For priming periods less than 4 weeks, dynamic loading generally supressed markers of hypertrophy and osteogenesis, although this was not observed if the priming period was extended to 6 weeks, where loading instead enhanced the expression of type X collagen. Taken together, these data demonstrate that the duration of chondrogenic priming regulates the endochondral response to dynamic mechanical compression in vitro, which may contribute to the effects of mechanical loading on endochondral bone development, repair, and regeneration in vivo.

Study of the Effect of Mechanical Loading on Cell Cultures in Bone Tissue Engineering

2012 ◽  
Author(s):  
Magali Cruel ◽  
Morad Bensidhoum ◽  
Laure Sudre ◽  
Guillaume Puel ◽  
Virginie Dumas ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Tissue Engineering ◽  
Bone Tissue ◽  
Bone Defects ◽  
Improved Design ◽  
Large Bone ◽  
Large Bone Defects

Bone tissue engineering currently represents one of the most interesting alternatives to autologous transplants and their drawbacks in the treatment of large bone defects. Mesenchymal stem cells are used to build new bone in vitro in a bioreactor. Their stimulation and our understanding of the mechanisms of mechanotransduction need to be improved in order to optimize the design of bioreactors. In this study, several geometries of bioreactor were analyzed experimentally and biological results were linked with numerical simulations of the flow inside the bioreactor. These results will constitute a base for an improved design of the existing bioreactor.

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