Standard in vitro evaluations of engineered bone substitutes are not sufficient to predict in vivo preclinical model outcomes

Hatt, Luan Phelipe; Armiento, Angela R.; Mys, Karen; Thompson, Keith; Hildebrand, Maria; Nehrbass, Dirk; Müller, Werner; Zeiter, Stephan; Eglin, David; Stoddart, Martin J.

doi:10.1016/j.actbio.2022.08.021

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…When studying new biomaterials/surfaces for bone regeneration, promising in vitro results do not often correlate with the outcome obtained from the in vivo experiments. 17 Nevertheless, new regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that can reduce the burden on animal testing by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

“…There is a considerable need for proven in vitro assays that can reduce the burden on animal testing by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. 17 Our group has been working in developing new in vitro test to characterize the biocompatibility 18,19 and regenerative potential 20 of different types of biomaterials based on proteomic evaluations. This technique was previously employed to evaluate the effect of Ca 2+ on protein adsorption onto dental implant surfaces.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing the correlation between in vitro and in vivo experiments in dental implant osseointegration: investigating the role of Ca ions

Romero Gavilán,

Cerqueira,

Anitua

et al. 2024

J. Mater. Chem. B

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing the correlation between in vitro and in vivo experiments in dental implant osseointegration: investigating the role of Ca ions

Romero Gavilán,

Cerqueira,

Anitua

et al. 2024

J. Mater. Chem. B

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“…In vitro evaluation of scaffolds is subjected to several limitations arising from the reduced complexity of the in vitro culture models, the absence of immune or inflammatory response as well as the impossibility to reproduce the complex cascade of events occurring after in vivo implantation [ 11 , 12 ]. These include the interaction with body fluids (e.g.…”

Section: Introductionmentioning

confidence: 99%

Integrating bioprinting, cell therapies and drug delivery towards in vivo regeneration of cartilage, bone and osteochondral tissue

Abbadessa,

Ronca,

Salerno

2023

Drug Deliv. and Transl. Res.

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The biological and biomechanical functions of cartilage, bone and osteochondral tissue are naturally orchestrated by a complex crosstalk between zonally dependent cells and extracellular matrix components. In fact, this crosstalk involves biomechanical signals and the release of biochemical cues that direct cell fate and regulate tissue morphogenesis and remodelling in vivo. Three-dimensional bioprinting introduced a paradigm shift in tissue engineering and regenerative medicine, since it allows to mimic native tissue anisotropy introducing compositional and architectural gradients. Moreover, the growing synergy between bioprinting and drug delivery may enable to replicate cell/extracellular matrix reciprocity and dynamics by the careful control of the spatial and temporal patterning of bioactive cues. Although significant advances have been made in this direction, unmet challenges and open research questions persist. These include, among others, the optimization of scaffold zonality and architectural features; the preservation of the bioactivity of loaded active molecules, as well as their spatio-temporal release; the in vitro scaffold maturation prior to implantation; the pros and cons of each animal model and the graft-defect mismatch; and the in vivo non-invasive monitoring of new tissue formation. This work critically reviews these aspects and reveals the state of the art of using three-dimensional bioprinting, and its synergy with drug delivery technologies, to pattern the distribution of cells and/or active molecules in cartilage, bone and osteochondral engineered tissues. Most notably, this work focuses on approaches, technologies and biomaterials that are currently under in vivo investigations, as these give important insights on scaffold performance at the implantation site and its interaction/integration with surrounding tissues. Graphical Abstract

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“…In vitro osteogenesis of MSCs serves as initial step in this validation process ( Bongio et al, 2015 ). The traditional in vitro induction of osteogenesis requires medium supplementation with a differentiation cocktail that includes dexamethasone, ascorbic acid and organic β-glycerophosphate (BGP) ( Hatt et al, 2022b ). This osteogenic cocktail induces cell morphology changes, increases alkaline phosphatase (ALP) activity, the expression of osteogenic gene markers and secretion of matrix minerals ( Langenbach and Handschel, 2013 ; Zha et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

β-TCP from 3D-printed composite scaffolds acts as an effective phosphate source during osteogenic differentiation of human mesenchymal stromal cells

Hatt,

van der Heide,

Armiento

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are often combined with calcium phosphate (CaP)—based 3D-printed scaffolds with the goal of creating a bone substitute that can repair segmental bone defects. In vitro, the induction of osteogenic differentiation traditionally requires, among other supplements, the addition of β-glycerophosphate (BGP), which acts as a phosphate source. The aim of this study is to investigate whether phosphate contained within the 3D-printed scaffolds can effectively be used as a phosphate source during hBM-MSC in vitro osteogenesis.Methods: hBM-MSCs are cultured on 3D-printed discs composed of poly (lactic-co-glycolic acid) (PLGA) and β-tricalcium phosphate (β-TCP) for 28 days under osteogenic conditions, with and without the supplementation of BGP. The effects of BGP removal on various cellular parameters, including cell metabolic activity, alkaline phosphatase (ALP) presence and activity, proliferation, osteogenic gene expression, levels of free phosphate in the media and mineralisation, are assessed.Results: The removal of exogenous BGP increases cell metabolic activity, ALP activity, proliferation, and gene expression of matrix-related (COL1A1, IBSP, SPP1), transcriptional (SP7, RUNX2/SOX9, PPARγ) and phosphate-related (ALPL, ENPP1, ANKH, PHOSPHO1) markers in a donor dependent manner. BGP removal leads to decreased free phosphate concentration in the media and maintained of mineral deposition staining.Discussion: Our findings demonstrate the detrimental impact of exogenous BGP on hBM-MSCs cultured on a phosphate-based material and propose β-TCP embedded within 3D-printed scaffold as a sufficient phosphate source for hBM-MSCs during osteogenesis. The presented study provides novel insights into the interaction of hBM-MSCs with 3D-printed CaP based materials, an essential aspect for the advancement of bone tissue engineering strategies aimed at repairing segmental defects.

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Standard in vitro evaluations of engineered bone substitutes are not sufficient to predict in vivo preclinical model outcomes

Cited by 7 publications

References 48 publications

Enhancing the correlation between in vitro and in vivo experiments in dental implant osseointegration: investigating the role of Ca ions

Enhancing the correlation between in vitro and in vivo experiments in dental implant osseointegration: investigating the role of Ca ions

Integrating bioprinting, cell therapies and drug delivery towards in vivo regeneration of cartilage, bone and osteochondral tissue

β-TCP from 3D-printed composite scaffolds acts as an effective phosphate source during osteogenic differentiation of human mesenchymal stromal cells

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