Ectopic bone formation associated with mesenchymal stem cells in a resorbable calcium deficient hydroxyapatite carrier

Kasten, Philip; Vogel, J.; Luginbühl, Reto; Niemeyer, P; Tonak, Marcus; Lorenz, Helga; Helbig, Lars; Weiß, Stefan; Fellenberg, Jörg; Leo, Albrecht; Simank, H.-G.; Richter, Wiltrud

doi:10.1016/j.biomaterials.2005.03.001

Cited by 151 publications

(155 citation statements)

References 35 publications

(83 reference statements)

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“…Nuclei were counterstained with hematoxylin and permanently mounted with Aquatex (Merck, Rahway, NJ). Untreated sections or type II collagen-immunostained sections were further processed for in situ hybridization for human Alu genomic repeats, as described previously (29).…”

mentioning

confidence: 99%

Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice

Pelttari¹,

Winter²,

Steck³

et al. 2006

Arthritis & Rheumatism

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726

669

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Objective. Functional suitability and phenotypic stability of ectopic transplants are crucial factors in the clinical application of mesenchymal stem cells (MSCs) for articular cartilage repair, and might require a stringent control of chondrogenic differentiation. This study evaluated whether human bone marrow-derived MSCs adopt natural differentiation stages during induction of chondrogenesis in vitro, and whether they can form ectopic stable cartilage that is resistant to vascular invasion and calcification in vivo.Methods. During in vitro chondrogenesis of MSCs, the expression of 44 cartilage-, stem cell-, and bone-related genes and the deposition of aggrecan and types II and X collagen were determined. Similarly treated, expanded articular chondrocytes served as controls. MSC pellets were allowed to differentiate in chondrogenic medium for 3-7 weeks, after which the chondrocytes were implanted subcutaneously into SCID mice; after 4 weeks in vivo, samples were evaluated by histology.Results. The 3-stage chondrogenic differentiation cascade initiated in MSCs was primarily characterized by sequential up-regulation of common cartilage genes. Premature induction of hypertrophy-related molecules (type X collagen and matrix metalloproteinase 13) occurred before production of type II collagen and was followed by up-regulation of alkaline phosphatase activity. In contrast, hypertrophy-associated genes were not induced in chondrocyte controls. Whereas control chondrocyte pellets resisted calcification and vascular invasion in vivo, most MSC pellets mineralized, in spite of persisting proteoglycan and type II collagen content.Conclusion. An unnatural pathway of differentiation to chondrocyte-like cells was induced in MSCs by common in vitro protocols. MSC pellets transplanted to ectopic sites in SCID mice underwent alterations related to endochondral ossification rather than adopting a stable chondrogenic phenotype. Further studies are needed to evaluate whether a more stringent control of MSC differentiation to chondrocytes can be achieved during cartilage repair in a natural joint environment.

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confidence: 99%

Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice

Pelttari¹,

Winter²,

Steck³

et al. 2006

Arthritis & Rheumatism

Self Cite

726

669

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“…Previous studies also reported no bone formation in MSCseeded porous ceramics at 4 weeks 47,48 and might suggest evaluation at longer time period for bone formation. However, there was mineralization on the nanofibers, which were seeded with MSCs on both groups, which would suggest that the calcium/phosphate ratio observed in the MSCseeded constructs was due to the mineralized ECM produced by seeded MSCs.…”

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confidence: 99%

Bone Tissue Engineering with Multilayered Scaffolds—Part I: An Approach for Vascularizing Engineered Constructs In Vivo

Sathy

Mony

Menon

et al. 2015

Tissue Engineering Part A

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Obtaining functional capillaries through the bulk has been identified as a major challenge in tissue engineering, particularly for critical-sized defects. In the present study, a multilayered scaffold system was developed for bone tissue regeneration, designed for through-the-thickness vascularization of the construct. The basic principle of this approach was to alternately layer mesenchymal stem cell-seeded nanofibers (osteogenic layer) with microfibers or porous ceramics (osteoconductive layer), with an intercalating angiogenic zone between the two and with each individual layer in the microscale dimension (100-400 mm). Such a design can create a scaffold system potentially capable of spatially distributed vascularization in the overall bulk tissue. In the cellular approach, the angiogenic zone consisted of collagen/fibronectin gel with endothelial cells and pericytes, while in the acellular approach, cells were omitted from the zone without altering the gel composition. The cells incorporated into the construct were analyzed for viability, distribution, and organization of cells on the layers and vessel development in vitro. Furthermore, the layered constructs were implanted in the subcutaneous space of nude mice and the processes of vascularization and bone tissue regeneration were followed by histological and energy-dispersive X-ray spectroscopy (EDS) analysis. The results indicated that the microenvironment in the angiogenic zone, microscale size of the layers, and the continuously channeled architecture at the interface were adequate for infiltrating host vessels through the bulk and vascularizing the construct. Through-thethickness vascularization and mineralization were accomplished in the construct, suggesting that a suitably bioengineered layered construct may be a useful design for regeneration of large bone defects.

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“…We showed that HHA had been well-recognized by osteoclasts for a long period after implantation, and mild biodegradability and good substitution for newly formed bone were detected in animal experiments. Previously, calcium-deficient HA was introduced in biological analyses [17], but the purity and uniformity of the material were uncertain. Biodegradation of HHA by osteoclasts during the experimental period showed that molar ratio of Ca/P directly affected osteoclast activity, even though the organic components in bone tissue might also affect osteoclast activity.…”

Section: Discussionmentioning

confidence: 99%

Calcium Deficient Hydroxyapatite for Medical Application Prepared by Hydrothermal Method

Ioku

Kamitakahara

Ikeda

2010

AIP Conference Proceedings

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Abstract. Hydrothermal processing plays a key role in the synthesis of biomaterials with excellent biocompatibility in the physiological environment. Especially, calcium phosphates are paid to much attention for the regenerative medicine. Two kinds of porous materials of hydroxyapatite with 70% porosity were prepared. One of them is a newly developed calcium-deficient hydroxyapatite composed of rod-shaped particles of about 20 m in length synthesized hydrothermally (HHA) and the other one is the stoichiometric hydroxyapatite (SHA) synthesized by the conventional sintering method. These materials were used for animal implantation tests to compare these biological responses. In the rabbit femur, implanted HHA was slowly resorbed and then most of the implanted HHA was resorbed after 72 weeks. The implanted SHA was unresorbed throughout the experimental period. The volume of newly formed bone and the number of osteoclasts in the implanted region were significantly larger in HHA than in SHA after 24 weeks. Results in the present research suggested that the activity of osteoclasts correlated to the bone forming activity of osteoblasts. The method to synthesize biodegradable pure calcium-deficient HA is expected to provide adequate biodegradability and bone replaceability.

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Ectopic bone formation associated with mesenchymal stem cells in a resorbable calcium deficient hydroxyapatite carrier

Cited by 151 publications

References 35 publications

Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice

Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice

Bone Tissue Engineering with Multilayered Scaffolds—Part I: An Approach for Vascularizing Engineered Constructs In Vivo

Calcium Deficient Hydroxyapatite for Medical Application Prepared by Hydrothermal Method

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