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1.
Acta Biomater ; 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35988660

RESUMO

Understanding the optimal conditions required for bone healing can have a substantial impact to target the problem of non-unions and large bone defects. The combination of bioactive factors, regenerative progenitor cells and biomaterials to form a tissue engineered (TE) complex is a promising solution but translation to the clinic has been slow. We hypothesized the typical material testing algorithm used is insufficient and leads to materials being mischaracterized as promising. In the first part of this study, human bone marrow - derived mesenchymal stromal cells (hBM-MSCs) were embedded in three commonly used biomaterials (hyaluronic acid methacrylate, gelatin methacrylate and fibrin) and combined with relevant bioactive osteogenesis factors (dexamethasone microparticles and polyphosphate nanoparticles) to form a TE construct that underwent in vitro osteogenic differentiation for 28 days. Gene expression of relevant transcription factors and osteogenic markers, and von Kossa staining were performed. In the second and third part of this study, the same combination of TE constructs were implanted subcutaneously (cell containing) in T cell-deficient athymic Crl:NIH-Foxn1rnu rats for 8 weeks or cell free in an immunocompetent New Zealand white rabbit calvarial model for 6 weeks, respectively. Osteogenic performance was investigated via MicroCT imaging and histology staining. The in vitro study showed enhanced upregulation of relevant genes and significant mineral deposition within the three biomaterials, generally considered as a positive result. Subcutaneous implantation indicates none to minor ectopic bone formation. No enhanced calvarial bone healing was detected in implanted biomaterials compared to the empty defect. The reasons for the poor correlation of in vitro and in vivo outcomes are unclear and needs further investigation. This study highlights the discrepancy between in vitro and in vivo outcomes, demonstrating that in vitro data should be interpreted with extreme caution. In vitro models with higher complexity are necessary to increase value for translational studies. STATEMENT OF SIGNIFICANCE: Preclinical testing of newly developed biomaterials is a crucial element of the development cycle. Despite this, there is still significant discrepancy between in vitro and in vivo test results. Within this study we investigate multiple combinations of materials and osteogenic stimulants and demonstrate a poor correlation between the in vitro and in vivo data. We propose rationale for why this may be the case and suggest a modified testing algorithm.

2.
Sci Rep ; 12(1): 5094, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332169

RESUMO

Tissue engineering (TE) combines cells and biomaterials to treat orthopedic pathologies. Maturation of de novo tissue is highly dependent on local mechanical environments. Mechanical stimulation influences stem cell differentiation, however, the role of various mechanical loads remains unclear. While bioreactors simplify the complexity of the human body, the potential combination of mechanical loads that can be applied make it difficult to assess how different factors interact. Human bone marrow-derived mesenchymal stromal cells were seeded within a fibrin-polyurethane scaffold and exposed to joint-mimicking motion. We applied a full factorial design of experiment to investigate the effect that the interaction between different mechanical loading parameters has on biological markers. Additionally, we employed planned contrasts to analyze differences between loading protocols and a linear mixed model with donor as random effect. Our approach enables screening of multiple mechanical loading combinations and identification of significant interactions that could not have been studied using classical mechanobiology studies. This is useful to screen the effect of various loading protocols and could also be used for TE experiments with small sample sizes and further combinatorial medication studies.


Assuntos
Células-Tronco Mesenquimais , Engenharia Tecidual , Materiais Biocompatíveis , Reatores Biológicos , Diferenciação Celular/fisiologia , Humanos , Estresse Mecânico , Engenharia Tecidual/métodos , Tecidos Suporte
3.
Clin Transl Med ; 12(2): e690, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35170248

RESUMO

Bone tissue engineering is a rapidly developing field with potential for the regeneration of craniomaxillofacial (CMF) bones, with 3D printing being a suitable fabrication tool for patient-specific implants. The CMF region includes a variety of different bones with distinct functions. The clinical implementation of tissue engineering concepts is currently poor, likely due to multiple reasons including the complexity of the CMF anatomy and biology, and the limited relevance of the currently used preclinical models. The 'recapitulation of a human disease' is a core requisite of preclinical animal models, but this aspect is often neglected, with a vast majority of studies failing to identify the specific clinical indication they are targeting and/or the rationale for choosing one animal model over another. Currently, there are no suitable guidelines that propose the most appropriate animal model to address a specific CMF pathology and no standards are established to test the efficacy of biomaterials or tissue engineered constructs in the CMF field. This review reports the current clinical scenario of CMF reconstruction, then discusses the numerous limitations of currently used preclinical animal models employed for validating 3D-printed tissue engineered constructs and the need to reduce animal work that does not address a specific clinical question. We will highlight critical research aspects to consider, to pave a clinically driven path for the development of new tissue engineered materials for CMF reconstruction.


Assuntos
Materiais Biocompatíveis , Traumatismos Maxilofaciais , Modelos Animais , Impressão Tridimensional , Animais , Mandíbula/anormalidades , Mandíbula/cirurgia , Traumatismos Maxilofaciais/cirurgia , Engenharia Tecidual
4.
Stem Cell Rev Rep ; 17(5): 1647-1665, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33954877

RESUMO

Cartilage injuries following trauma create a puzzling clinical scenario. The finite reparative potential of articular cartilage is well known, and injuries are associated with an increased risk of osteoarthritis. Cell-based therapies have spotlighted chondrocytes and mesenchymal stromal cells (MSCs) as the functional unit of articular cartilage and the progenitor cells, respectively. The available clinical treatments cannot reproduce the biomechanical properties of articular cartilage and call for continuous investigations into alternative approaches. Co-cultures of chondrocytes and MSCs are an attractive in vitro system to step closer to the in vivo multicellular environment's complexity. Research on the mechanisms of interaction between both cell types will reveal essential cues to understand cartilage regeneration. This review describes the latest discoveries on these interactions, along with advantages and main challenges in vitro and in vivo. The successful clinical translation of in vitro studies requires establishing rigorous standards and clinically relevant research models and an organ-targeting therapeutic strategy.


Assuntos
Condrócitos , Células-Tronco Mesenquimais , Cartilagem
5.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807323

RESUMO

A continuing challenge in cartilage tissue engineering for cartilage regeneration is the creation of a suitable synthetic microenvironment for chondrocytes and tissue regeneration. The aim of this study was to develop a highly tunable hybrid scaffold based on a silk fibroin matrix (SM) and a hyaluronic acid (HA) hydrogel. Human articular chondrocytes were embedded in a porous 3-dimensional SM, before infiltration with tyramine modified HA hydrogel. Scaffolds were cultured in chondropermissive medium with and without TGF-ß1. Cell viability and cell distribution were assessed using CellTiter-Blue assay and Live/Dead staining. Chondrogenic marker expression was detected using qPCR. Biosynthesis of matrix compounds was analyzed by dimethylmethylene blue assay and immuno-histology. Differences in biomaterial stiffness and stress relaxation were characterized using a one-step unconfined compression test. Cell morphology was investigated by scanning electron microscopy. Hybrid scaffold revealed superior chondro-inductive and biomechanical properties compared to sole SM. The presence of HA and TGF-ß1 increased chondrogenic marker gene expression and matrix deposition. Hybrid scaffolds offer cytocompatible and highly tunable properties as cell-carrier systems, as well as favorable biomechanical properties.


Assuntos
Cartilagem Articular/metabolismo , Fibroínas/farmacologia , Engenharia Tecidual/métodos , Idoso , Materiais Biocompatíveis/metabolismo , Cartilagem/citologia , Cartilagem/metabolismo , Cartilagem Articular/citologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Condrócitos/metabolismo , Condrogênese , Fibroínas/metabolismo , Humanos , Ácido Hialurônico/farmacologia , Hidrogéis/metabolismo , Hidrogéis/farmacologia , Pessoa de Meia-Idade , Porosidade , Seda/metabolismo , Tecidos Suporte/química
6.
Adv Drug Deliv Rev ; 146: 289-305, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30605736

RESUMO

Once damaged, articular cartilage has a limited potential to repair. Clinically, a repair tissue is formed, yet, it is often mechanically inferior fibrocartilage. The use of monolayer expanded versus naïve cells may explain one of the biggest discrepancies in mesenchymal stromal/stem cell (MSC) based cartilage regeneration. Namely, studies utilizing monolayer expanded MSCs, as indicated by numerous in vitro studies, report as a main limitation the induction of type X collagen and hypertrophy, a phenotype associated with endochondral bone formation. However, marrow stimulation and transfer studies report a mechanically inferior collagen I/II fibrocartilage as the main outcome. Therefore, this review will highlight the collagen species produced during the different therapeutic approaches. New developments in scaffold design and delivery of therapeutic molecules will be described. Potential future directions towards clinical translation will be discussed. New delivery mechanisms are being developed and they offer new hope in targeted therapeutic delivery.


Assuntos
Fibrocartilagem , Cartilagem Hialina , Animais , Humanos
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