scholarly journals Construction of developmentally inspired periosteum-like tissue for bone regeneration

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Kai Dai ◽  
Shunshu Deng ◽  
Yuanman Yu ◽  
Fuwei Zhu ◽  
Jing Wang ◽  
...  
Keyword(s):  
Endochondral Ossification ◽  
Bone Development ◽  
Autologous Transplantation ◽  
Tumor Resection ◽  
Bone Morphogenetic Protein 2 ◽  
Long Bone ◽  
Defect Repair ◽  
Novel Strategy ◽  
Bone Tumor Resection

AbstractThe periosteum, a highly vascularized thin tissue, has excellent osteogenic and bone regenerative abilities. The generation of periosteum-mimicking tissue has become a novel strategy for bone defect repair and regeneration, especially in critical-sized bone defects caused by trauma and bone tumor resection. Here, we utilized a bone morphogenetic protein-2 (BMP-2)-loaded scaffold to create periosteum-like tissue (PT) in vivo, mimicking the mesenchymal condensation during native long bone development. We found that BMP-2-induced endochondral ossification plays an indispensable role in the construction of PTs. Moreover, we confirmed that BMP-2-induced PTs exhibit a similar architecture to the periosteum and harbor abundant functional periosteum-like tissue-derived cells (PTDCs), blood vessels, and osteochondral progenitor cells. Interestingly, we found that the addition of chondroitin sulfate (CS), an essential component of the extracellular matrix (ECM), could further increase the abundance and enhance the function of recruited PTDCs from the PTs and finally increase the regenerative capacity of the PTs in autologous transplantation assays, even in old mice. This novel biomimetic strategy for generating PT through in vivo endochondral ossification deserves further clinical translation.

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

2019 ◽  
Vol 5 (8) ◽  
pp. eaax2476 ◽  
Author(s):  
S. Herberg ◽  
A. M. McDermott ◽  
P. N. Dang ◽  
D. S. Alt ◽  
R. Tang ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transforming Growth Factor ◽  
Bone Development ◽  
Formation Rate ◽  
Natural Fracture ◽  
Bone Morphogenetic Protein 2 ◽  
Long Bone ◽  
Bone Formation Rate ◽  
Tgf Β1

Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor–β1 (TGF-β1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-β1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-β1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-β1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

scholarly journals Rac signaling in osteoblastic cells is required for normal bone development but is dispensable for hematopoietic development

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 736-744 ◽  
Author(s):  
Steven W. Lane ◽  
Serena De Vita ◽  
Kylie A. Alexander ◽  
Ruchan Karaman ◽  
Michael D. Milsom ◽  
...  
Keyword(s):  
Bone Growth ◽  
Bone Development ◽  
Long Bone ◽  
Perivascular Niche ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Rac1 Gtpase

Abstract Hematopoietic stem cells (HSCs) interact with osteoblastic, stromal, and vascular components of the BM hematopoietic microenvironment (HM) that are required for the maintenance of long-term self-renewal in vivo. Osteoblasts have been reported to be a critical cell type making up the HSC niche in vivo. Rac1 GTPase has been implicated in adhesion, spreading, and differentiation of osteoblast cell lines and is critical for HSC engraftment and retention. Recent data suggest a differential role of GTPases in endosteal/osteoblastic versus perivascular niche function. However, whether Rac signaling pathways are also necessary in the cell-extrinsic control of HSC function within the HM has not been examined. In the present study, genetic and inducible models of Rac deletion were used to demonstrate that Rac depletion causes impaired proliferation and induction of apoptosis in the OP9 cell line and in primary BM stromal cells. Deletion of Rac proteins caused reduced trabecular and cortical long bone growth in vivo. Surprisingly, HSC function and maintenance of hematopoiesis in vivo was preserved despite these substantial cell-extrinsic changes. These data have implications for therapeutic strategies to target Rac signaling in HSC mobilization and in the treatment of leukemia and provide clarification to our evolving concepts of HSC-HM interactions.

scholarly journals Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2993
Author(s):  
Arbi Aghali
Keyword(s):  
Tissue Engineering ◽  
Growth Factors ◽  
Bone Tissue ◽  
Stromal Cells ◽  
Critical Size ◽  
Tumor Resection ◽  
Bone Morphogenetic Protein 2 ◽  
Craniofacial Bone

Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in tissue engineering and regenerative medicine use innovative techniques to address these challenges. The use of biomaterials, stromal cells, and growth factors have demonstrated promising outcomes in vitro and in vivo. Natural and synthetic bone grafts combined with Mesenchymal Stromal Cells (MSCs) and growth factors have shown encouraging results in regenerating critical-size cranial defects. One of prevalent growth factors is Bone Morphogenetic Protein-2 (BMP-2). BMP-2 is defined as a gold standard growth factor that enhances new bone formation in vitro and in vivo. Recently, emerging evidence suggested that Megakaryocytes (MKs), induced by Thrombopoietin (TPO), show an increase in osteoblast proliferation in vitro and bone mass in vivo. Furthermore, a co-culture study shows mature MKs enhance MSC survival rate while maintaining their phenotype. Therefore, MKs can provide an insight as a potential therapy offering a safe and effective approach to regenerating critical-size cranial defects.

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.

Bone marrow concentrate for autologous transplantation in minipigs

2013 ◽  
Vol 26 (01) ◽  
pp. 34-41 ◽  
Author(s):  
M. Herten ◽  
M. Sager ◽  
L. Benga ◽  
J. C. Fischer ◽  
M. Jäger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Autologous Transplantation ◽  
Tendon Healing ◽  
Autologous Bone Marrow ◽  
Long Bone ◽  
Osteogenic Potential ◽  
Differentiation Potential ◽  
Bone Marrow Concentrate

SummaryAutologous bone marrow plays an increasing role in the treatment of bone, cartilage and tendon healing disorders. Cell-based therapies display promising results in the support of local regeneration, especially therapies using intra-operative one-step treatments with autologous progenitor cells. In the present study, bone marrow-derived cells were concentrated in a point-of-care device and investigated for their mesenchymal stem cell (MSC) characteristics and their osteogenic potential.Bone marrow was harvested from the iliac crest of 16 minipigs. The mononucleated cells (MNC) were concentrated by gradient density centrifugation, cultivated, characterized by flow cytometry and stimulated into osteoblasts, adipocytes, and chondrocytes. Cell differentiation was investigated by histological and immunohistological staining of relevant lineage markers. The proliferation capacity was determined via colony forming units of fibroblast and of osteogenic alkaline-phosphatase-positive-cells.The MNC could be enriched 3.5-fold in nucleated cell concentrate in comparison to bone marrow. Flow cytometry analysis revealed a positive signal for the MSC markers. Cells could be differentiated into the three lines confirming the MSC character. The cellular osteogenic potential correlated significantly with the percentage of newly formed bone in vivo in a porcine metaphyseal long-bone defect model.This study demonstrates that bone marrow concentrate from minipigs display cells with MSC character and their osteogenic differentiation potential can be used for osseous defect repair in autologous transplantations.

scholarly journals Newly Designed Human-Like Collagen to Maximize Sensitive Release of BMP-2 for Remarkable Repairing of Bone Defects

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 450 ◽  
Author(s):  
Chen ◽  
Zhang ◽  
Ma ◽  
Duan ◽  
Hui ◽  
...  
Keyword(s):  
Sustained Release ◽  
Mechanical Strength ◽  
Bone Repair ◽  
Low Dose ◽  
Collagen Matrix ◽  
Bone Morphogenetic Protein 2 ◽  
Release Time ◽  
Hydrogel Matrix ◽  
Defect Repair

Designing the “ideal” hydrogel/matrix which can load bone morphogenetic protein-2 (BMP-2) in a low dose and with a sustained release is the key for its successful therapeutic application to enhance osteogenesis. The current use of natural collagen sponges as hydrogel/matrix is limited due to the collagen matrix showing weak mechanical strength and unmanageable biodegradability. Furthermore, the efficiency and safe dose usage of the BMP-2 has never been seriously considered other than purely chasing the lowest dose usage and extended-release time. In this paper, we customized a novel enzymatically cross-linked recombinant human-like collagen (HLC) sponge with low immunogenicity, little risk from hidden viruses, and easy production. We obtained a unique vertical pore structure and the porosity of the HLC, which are beneficial for Mesenchymal stem cells (MSCs) migration into the HLC sponge and angiopoiesis. This HLC sponge loading with low dose BMP-2 (1 µg) possessed high mechanical strength along with a burst and a sustained release profile. These merits overcome previous limitations of HLC in bone repair and are safer and more sensitive than commercial collagens. For the first time, we identified that a 5 µg dose of BMP-2 can bring about the side effect of bone overgrowth through this sensitive delivery system. Osteoinduction of the HLC-BMP sponges was proved by an in vivo mouse ectopic bone model and a rat cranial defect repair model. The method and the HLC-BMP sponge have the potential to release other growth factors and aid other tissue regeneration. Additionally, the ability to mass-produce HLC in our study overcomes the current supply shortage, which limits bone repair in the clinic.

scholarly journals CaMKII Signaling Stimulates Mef2c Activity In Vitro but Only Minimally Affects Murine Long Bone Development in vivo

2017 ◽  
Vol 5 ◽  
Author(s):  
Chandra S. Amara ◽  
Christine Fabritius ◽  
Astrid Houben ◽  
Lena I. Wolff ◽  
Christine Hartmann
Keyword(s):  
Bone Development ◽  
Long Bone

scholarly journals Wireless Implantable Sensor for Noninvasive, Longitudinal Quantification of Axial Strain Across Rodent Long Bone Defects

2017 ◽  
Vol 139 (11) ◽  
Author(s):  
Brett S. Klosterhoff ◽  
Keat Ghee Ong ◽  
Laxminarayanan Krishnan ◽  
Kevin M. Hetzendorfer ◽  
Young-Hui Chang ◽  
...  
Keyword(s):  
Bone Repair ◽  
Ex Vivo ◽  
Bone Development ◽  
Axial Strain ◽  
Tissue Level ◽  
Tissue Mechanics ◽  
Long Bone ◽  
Segmental Defect ◽  
Transient Nature

Bone development, maintenance, and regeneration are remarkably sensitive to mechanical cues. Consequently, mechanical stimulation has long been sought as a putative target to promote endogenous healing after fracture. Given the transient nature of bone repair, tissue-level mechanical cues evolve rapidly over time after injury and are challenging to measure noninvasively. The objective of this work was to develop and characterize an implantable strain sensor for noninvasive monitoring of axial strain across a rodent femoral defect during functional activity. Herein, we present the design, characterization, and in vivo demonstration of the device’s capabilities for quantitatively interrogating physiological dynamic strains during bone regeneration. Ex vivo experimental characterization of the device showed that it possessed promising sensitivity, signal resolution, and electromechanical stability for in vivo applications. The digital telemetry minimized power consumption, enabling extended intermittent data collection. Devices were implanted in a rat 6 mm femoral segmental defect model, and after three days, data were acquired wirelessly during ambulation and synchronized to corresponding radiographic videos, validating the ability of the sensor to noninvasively measure strain in real-time. Together, these data indicate the sensor is a promising technology to quantify tissue mechanics in a specimen specific manner, facilitating more detailed investigations into the role of the mechanical environment in dynamic bone healing and remodeling processes.

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.

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