Calcium Phosphate as a Key Material for Socially Responsible Tissue Engineering

Uskoković, Vuk; Wu, Victoria

doi:10.3390/ma9060434

Cited by 39 publications

(30 citation statements)

References 168 publications

(160 reference statements)

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“…This approach agrees with the fundamental nature of HAP, a material that is mediocre in terms of all its properties, yet a material that won the evolutionary battle for a place within the skeletal base of our bodies. 115 …”

Section: Discussionmentioning

confidence: 99%

Hydroxyapatite as a Vehicle for the Selective Effect of Superparamagnetic Iron Oxide Nanoparticles against Human Glioblastoma Cells

Pernal

Uskoković

2017

ACS Appl. Mater. Interfaces

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Despite the early promises of magnetic hyperthermia (MH) as a method for treating cancer, it has been stagnating in the past decade. Some of the reasons for the low effectiveness of superparamagnetic nanoparticles (SPIONs) in MH treatments include (a) low uptake in cancer cells; (b) generation of reactive oxygen species that cause harm to the healthy cells; (c) undeveloped targeting potential; and (d) lack of temperature sensitivity between cancer cells and healthy cells. Here we show that healthy cells, including human mesenchymal stem cells (MSCs) and primary mouse kidney and lung fibroblasts, display an unfavorably increased uptake of SPIONs compared to human brain cancer cells (E297 and U87) and mouse osteosarcomas cells (K7M2). Hydroxyapatite (HAP), the mineral component of our bones, may offer a solution to this unfavorably selective SPION delivery. HAP nanoparticles are commended not only for their exceptional biocompatibility but also for the convenience of their use as an intracellular delivery agent. Here we demonstrate that dispersing SPIONs in HAP using a wet synthesis method could increase the uptake in cancer cells and minimize the risk to healthy cells. Specifically, HAP/SPION nanocomposites retain the superparamagnetic nature of SPIONs, increase the uptake ratio between U87 human brain cancer cells and human MSCs versus their SPION counterparts, reduce migration in a primary brain cancer spheroid model compared to the control, reduce brain cancer cell viability compared to the treatment with SPIONs alone, and retain the viability of healthy human MSCs. A functional synergy between the two components of the nanocomposites was established; as a result, the cancer versus healthy cell (U87/MSC) selectivity in terms of both the uptake and the toxicity was higher for the composite than for SPIONs or HAP alone, allowing it to be damaging to cancer cells and harmless to the healthy ones. The analysis of actin cytoskeleton order at the microscale revealed that healthy MSCs and primary cancer cells after the uptake of SPIONs display reduced and increased anisotropy in their cytoskeletal arrangement, respectively. In contrast, the uptake of SPION/HAP nanocomposites increased the cytoskeletal anisotropy of both the healthy MSCs and the primary cancer cells. In spite of the moderate specific magnetization of HAP/SPION nanohybrids, reaching 15 emu/g for the 28.6 wt % SPION-containing composite, the cancer cell treatment in an alternating magnetic field resulted in an intense hyperthermia effect that increased the temperature by ca. 1 °C per minute of exposure and reduced the cell population treated for 30 min by more than 50%, while leaving the control populations unharmed. These findings on nanocomposites of HAP and SPIONs may open a new avenue for cancer therapies that utilize MH.

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Section: Discussionmentioning

confidence: 99%

Hydroxyapatite as a Vehicle for the Selective Effect of Superparamagnetic Iron Oxide Nanoparticles against Human Glioblastoma Cells

Pernal

Uskoković

2017

ACS Appl. Mater. Interfaces

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“…Tissue engineering constructs have been generally designed as composites containing a polymeric phase and HAp 1 , but thanks to its viscous properties in the cement form 2 , HAp has been often used alone as a bone graft in maxillofacial and orthopedic surgeries 3 . It has also been used as a support structure in scaffolds owing to its large compressive strength 4 as well as an osteoconductive component that promotes bone remodeling and regeneration 5 .…”

Section: Introductionmentioning

confidence: 99%

One ion to rule them all: the combined antibacterial, osteoinductive and anticancer properties of selenite-incorporated hydroxyapatite

Uskoković

Iyer

2017

J. Mater. Chem. B

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Although hydroxyapatite (HAp) has been doped with dozens of different ions, the quest for an ion imparting a combination of properties conducive to bone healing is still ongoing. Because of its protean potency and the similarity in size and shape to the phosphate tetrahedron, selenite ion presents a natural ionic substitute in HAp. The incorporation of selenite into synthetic HAp using two different methods – co-precipitation and ion-exchange sorption - was studied for its effect on crystal properties and on a triad of biological responses: antibacterial, anticancer and osteoinductive. Co-precipitation yielded HAp with higher selenite contents than sorption and the stoichiometry of HAp richest in selenite was represented as Ca9.75(PO4)5.75(SeO3)0.25(OH)1.75. Crystallinity of HAp decreased in direct proportion with the amount of selenite incorporated. Because of their lower selenite content, HAp powders prepared by ion-exchange exhibited a consistently higher crystallinity compared to the co-precipitated ones. Annealing partially recovered the crystallinity, yet the difference in crystallinity between powders prepared by co-precipitation and by ion-exchange remained, suggesting that the amorphization is mainly due to structural incorporation of selenite, not its effect on the crystal growth kinetics. The addition of selenite changed the morphology of HAp nanoparticles from acicular to rounded and affected the crystal lattice parameters in different ways depending on whether the powders were annealed or not. As for the annealed powders, the incorporation of selenite contracted the lattice in both a and c crystallographic directions. In the agar diffusion assay, the effectiveness of HAp was more dependent on the presence or absence of selenite in it than on its concentration and was highest against E. coli and S. aureus, moderately high against S. enteritidis and ineffective against P. aeruginosa. In liquid inoculation tests, on the other hand, the antibacterial activity of HAp was directly proportional to the amount of selenite contained in it. The viability of K7M2 osteosarcoma cells decreased in direct proportion with the amount of selenite in HAp and was significantly different from the untreated control and from pure HAp at contents equal to or higher than 1.9 wt.%. In contrast, no reduction was observed in the viability of primary fibroblasts treated with HAp incorporating different amounts of selenite ions, suggesting their potentially selective anticancer activity: lethal for the cancer cells and harmless for the healthy cells. Finally, mRNA expression of bone gamma-carboxyglutamate protein (BGLAP3) was higher in differentiated MC3T3-E1 osteoblastic cells treated with selenite-incorporated HAp particles than in cells treated with pure HAp. The osteoinductive effect was due to an overall higher metabolic activity of cells treated with the particles and not due to increased proliferation. In such a way, a triad of antibacterial, osteoinductive and anticancer activities was attributed to selenite-incorporated ...

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“…To fulfill this purpose, growth factors are often used as supplements in bone cements. However, they are associated with high cost [18] and with a range of undesired side effects [19–22], the reason for which ionic additives are often considered as viable alternatives to their use: not only are they considerably less expensive, but there is also a markedly lesser chance that their delivery would cause adverse effects. The third potentially positive effect achievable with the addition of copper ions is an increased solubility and resorption rate of TCP.…”

Section: Introductionmentioning

confidence: 99%

The Bone Building Blues: Self-hardening copper-doped calcium phosphate cement and its in vitro assessment against mammalian cells and bacteria

Rau

Graziani

et al. 2017

Materials Science and Engineering: C

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A blue calcium phosphate cement with optimal self-hardening properties was synthesized by doping whitlockite (β-TCP) with copper ions. The mechanism and the kinetics of the cement solidification process were studied using energy dispersive X-ray diffraction and it was found out that hardening was accompanied by the phase transition from TCP to brushite. Reduced lattice parameters in all crystallographic directions resulting from the rather low (1:180) substitution rate of copper for calcium was consistent with the higher ionic radius of the latter. The lower cationic hydration resulting from the partial Ca→Cu substitution facilitated the release of constitutive hydroxyls and lowered the energy of formation of TCP from the apatite precursor at elevated temperatures. Addition of copper thus effectively inhibited the formation of apatite as the secondary phase. The copper-doped cement exhibited an antibacterial effect, though exclusively against gram-negative bacteria, including E. coli, P. aeruginosa and S. enteritidis. This antibacterial effect was due to copper ions, as demonstrated by an almost negligible antibacterial effect of the pure, copper-free cement. Also, the antibacterial activity of the copper-containing cement was significantly higher than that of its precursor powder. Since there was no significant difference between the kinetics of the release of copper from the precursor TCP powder and from the final, brushite phase of the hardened cement, this has suggested that the antibacterial effect was not solely due to copper ions, but due to the synergy between cationic copper and a particular phase and aggregation state of calcium phosphate. Though inhibitory to bacteria, the copper-doped cement increased the viability of human glial E297 cells, murine osteoblastic K7M2 cells and especially human primary lung fibroblasts. That this effect was also due to copper ions was evidenced by the null effect on viability increase exhibited by the copper-free cements. The difference in the mechanism of protection of dehydratases in prokaryotes and eukaryotes was used as a rationale for explaining the hereby evidenced selectivity in biological response. It presents the basis for the consideration of copper as a dually effective ion when synergized with calcium phosphates: toxic for bacteria and beneficial for the healthy cells.

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Calcium Phosphate as a Key Material for Socially Responsible Tissue Engineering

Cited by 39 publications

References 168 publications

Hydroxyapatite as a Vehicle for the Selective Effect of Superparamagnetic Iron Oxide Nanoparticles against Human Glioblastoma Cells

Hydroxyapatite as a Vehicle for the Selective Effect of Superparamagnetic Iron Oxide Nanoparticles against Human Glioblastoma Cells

One ion to rule them all: the combined antibacterial, osteoinductive and anticancer properties of selenite-incorporated hydroxyapatite

The Bone Building Blues: Self-hardening copper-doped calcium phosphate cement and its in vitro assessment against mammalian cells and bacteria

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