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Special Issue "Cells and Materials for Disease Modeling and Regenerative Medicine"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (30 July 2020) | Viewed by 22788

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Special Issue Editors

Dr. Ander Abarrategi
E-Mail Website
Guest Editor
CICbiomaGUNE
Interests: Regenerative medicine; Biomaterials; Tissue Engineering; Adult Stem Cells; Cancer Stem Cells; Mesenchymal Stem Cells; Hematopoietic Stem Cells; Bone; Cartilage
Prof. Dr. Senentxu Lanceros-Mendez
E-Mail Website
Guest Editor
BCMaterials, Basque Center for Materials, Applications and Nanostructures, UPV/EHU Science Park, 48940 Leioa, Spain
Interests: smart and multifunctional materials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Materials science and engineering are continuously developing tools that are potentially useful in biological and biomedical applications. Interestingly, concepts related to molecular and cellular biology are now being used to yield approaches with biological rationale, biocompatible and/or bioactive, and useful for novel in vitro testing strategies and in vivo regenerative advanced therapies (gene therapy, cell therapy, and tissue engineering).

This Special Issue of IJMS will compile original scientific experimental articles and comprehensive reviews focused on using “Cells and Materials for Disease Modeling and Regenerative Medicine” purposes. It will cover in vitro and in vivo strategies based on cell-material interactions, targeting any tissue and aiming to respond to any physiological and/or pathological question relevant to the field.

Dr. Ander Abarrategi
Prof. Dr. Senentxu Lanceros-Mendez
Guest Editors

Manuscript Submission Information

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Keywords

  • materials
  • biomaterials
  • cells
  • stem cells
  • Ipsc
  • organoids
  • microenvironment
  • niche
  • biocompatibility
  • bioactivity
  • 3D printing
  • tissue engineering
  • regenerative medicine
  • cell therapy
  • advanced therapies

Published Papers (12 papers)

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Research

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Article
Patterned Piezoelectric Scaffolds for Osteogenic Differentiation
Int. J. Mol. Sci. 2020, 21(21), 8352; https://doi.org/10.3390/ijms21218352 - 07 Nov 2020
Cited by 3 | Viewed by 986
Abstract
The morphological clues of scaffolds can determine cell behavior and, therefore, the patterning of electroactive polymers can be a suitable strategy for bone tissue engineering. In this way, this work reports on the influence of poly(vinylidene fluoride-co-trifluoroethylene) (P(VDF-TrFE)) electroactive micropatterned scaffolds on the [...] Read more.
The morphological clues of scaffolds can determine cell behavior and, therefore, the patterning of electroactive polymers can be a suitable strategy for bone tissue engineering. In this way, this work reports on the influence of poly(vinylidene fluoride-co-trifluoroethylene) (P(VDF-TrFE)) electroactive micropatterned scaffolds on the proliferation and differentiation of bone cells. For that, micropatterned P(VDF-TrFE) scaffolds were produced by lithography in the form of arrays of lines and hexagons and then tested for cell proliferation and differentiation of pre-osteoblast cell line. Results show that more anisotropic surface microstructures promote bone differentiation without the need of further biochemical stimulation. Thus, the combination of specific patterns with the inherent electroactivity of materials provides a promising platform for bone regeneration. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Article
Multilineage Differentiation Potential of Human Dental Pulp Stem Cells—Impact of 3D and Hypoxic Environment on Osteogenesis In Vitro
Int. J. Mol. Sci. 2020, 21(17), 6172; https://doi.org/10.3390/ijms21176172 - 26 Aug 2020
Cited by 11 | Viewed by 1913
Abstract
Human dental pulp harbours unique stem cell population exhibiting mesenchymal stem/stromal cell (MSC) characteristics. This study aimed to analyse the differentiation potential and other essential functional and morphological features of dental pulp stem cells (DPSCs) in comparison with Wharton’s jelly-derived MSCs from the [...] Read more.
Human dental pulp harbours unique stem cell population exhibiting mesenchymal stem/stromal cell (MSC) characteristics. This study aimed to analyse the differentiation potential and other essential functional and morphological features of dental pulp stem cells (DPSCs) in comparison with Wharton’s jelly-derived MSCs from the umbilical cord (UC-MSCs), and to evaluate the osteogenic differentiation of DPSCs in 3D culture with a hypoxic microenvironment resembling the stem cell niche. Human DPSCs as well as UC-MSCs were isolated from primary human tissues and were subjected to a series of experiments. We established a multiantigenic profile of DPSCs with CD45/CD14/CD34/CD29+/CD44+/CD73+/CD90+/CD105+/Stro-1+/HLA-DR (using flow cytometry) and confirmed their tri-lineage osteogenic, chondrogenic, and adipogenic differentiation potential (using qRT-PCR and histochemical staining) in comparison with the UC-MSCs. The results also demonstrated the potency of DPSCs to differentiate into osteoblasts in vitro. Moreover, we showed that the DPSCs exhibit limited cardiomyogenic and endothelial differentiation potential. Decreased proliferation and metabolic activity as well as increased osteogenic differentiation of DPSCs in vitro, attributed to 3D cell encapsulation and low oxygen concentration, were also observed. DPSCs exhibiting elevated osteogenic potential may serve as potential candidates for a cell-based product for advanced therapy, particularly for bone repair. Novel tissue engineering approaches combining DPSCs, 3D biomaterial scaffolds, and other stimulating chemical factors may represent innovative strategies for pro-regenerative therapies. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Article
The Specific Molecular Composition and Structural Arrangement of Eleutherodactylus Coqui Gular Skin Tissue Provide Its High Mechanical Compliance
Int. J. Mol. Sci. 2020, 21(16), 5593; https://doi.org/10.3390/ijms21165593 - 05 Aug 2020
Cited by 2 | Viewed by 931
Abstract
A male Eleutherodactylus Coqui (EC, a frog) expands and contracts its gular skin to a great extent during mating calls, displaying its extraordinarily compliant organ. There are striking similarities between frog gular skin and the human bladder as both organs expand [...] Read more.
A male Eleutherodactylus Coqui (EC, a frog) expands and contracts its gular skin to a great extent during mating calls, displaying its extraordinarily compliant organ. There are striking similarities between frog gular skin and the human bladder as both organs expand and contract significantly. While the high extensibility of the urinary bladder is attributed to the unique helical ultrastructure of collagen type III, the mechanism behind the gular skin of EC is unknown. We therefore aim to understand the structure–property relationship of gular skin tissues of EC. Our findings demonstrate that the male EC gular tissue can elongate up to 400%, with an ultimate tensile strength (UTS) of 1.7 MPa. Species without vocal sacs, Xenopus Laevis (XL) and Xenopus Muelleri (XM), elongate only up to 80% and 350% with UTS~6.3 MPa and ~4.5 MPa, respectively. Transmission electron microscopy (TEM) and histological staining further show that EC tissues’ collagen fibers exhibit a layer-by-layer arrangement with an uninterrupted, knot-free, and continuous structure. The collagen bundles alternate between a circular and longitudinal shape, suggesting an out-of-plane zig-zag structure, which likely provides the tissue with greater extensibility. In contrast, control species contain a nearly linear collagen structure interrupted by thicker muscle bundles and mucous glands. Meanwhile, in the rat bladder, the collagen is arranged in a helical structure. The bladder-like high extensibility of EC gular skin tissue arises despite it having eight-fold lesser elastin and five times more collagen than the rat bladder. To our knowledge, this is the first study to report the structural and molecular mechanisms behind the high compliance of EC gular skin. We believe that these findings can lead us to develop more compliant biomaterials for applications in regenerative medicine. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Article
A Tissue-Engineered Human Psoriatic Skin Model to Investigate the Implication of cAMP in Psoriasis: Differential Impacts of Cholera Toxin and Isoproterenol on cAMP Levels of the Epidermis
Int. J. Mol. Sci. 2020, 21(15), 5215; https://doi.org/10.3390/ijms21155215 - 23 Jul 2020
Cited by 4 | Viewed by 1480
Abstract
Pathological and healthy skin models were reconstructed using similar culture conditions according to well-known tissue engineering protocols. For both models, cyclic nucleotide enhancers were used as additives to promote keratinocytes’ proliferation. Cholera toxin (CT) and isoproterenol (ISO), a beta-adrenergic agonist, are the most [...] Read more.
Pathological and healthy skin models were reconstructed using similar culture conditions according to well-known tissue engineering protocols. For both models, cyclic nucleotide enhancers were used as additives to promote keratinocytes’ proliferation. Cholera toxin (CT) and isoproterenol (ISO), a beta-adrenergic agonist, are the most common cAMP stimulators recommended for cell culture. The aim of this study was to evaluate the impact of either CT or ISO on the pathological characteristics of the dermatosis while producing a psoriatic skin model. Healthy and psoriatic skin substitutes were produced according to the self-assembly method of tissue engineering, using culture media supplemented with either CT (10−10 M) or ISO (10−6 M). Psoriatic substitutes produced with CT exhibited a more pronounced psoriatic phenotype than those produced with ISO. Indeed, the psoriatic substitutes produced with CT had the thickest epidermis, as well as contained the most proliferating cells and the most altered expression of involucrin, filaggrin, and keratin 10. Of the four conditions under study, psoriatic substitutes produced with CT had the highest levels of cAMP and enhanced expression of adenylate cyclase 9. Taken together, these results suggest that high levels of cAMP are linked to a stronger psoriatic phenotype. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Article
Devitalizing Effect of High Hydrostatic Pressure on Human Cells—Influence on Cell Death in Osteoblasts and Chondrocytes
Int. J. Mol. Sci. 2020, 21(11), 3836; https://doi.org/10.3390/ijms21113836 - 28 May 2020
Cited by 7 | Viewed by 1226
Abstract
Chemical and physical processing of allografts is associated with a significant reduction in biomechanics. Therefore, treatment of tissue with high hydrostatic pressure (HHP) offers the possibility to devitalize tissue gently without changing biomechanical properties. To obtain an initial assessment of the effectiveness of [...] Read more.
Chemical and physical processing of allografts is associated with a significant reduction in biomechanics. Therefore, treatment of tissue with high hydrostatic pressure (HHP) offers the possibility to devitalize tissue gently without changing biomechanical properties. To obtain an initial assessment of the effectiveness of HHP treatment, human osteoblasts and chondrocytes were treated with different HHPs (100–150 MPa, 250–300 MPa, 450–500 MPa). Devitalization efficiency was determined by analyzing the metabolic activity via WST-1(water-soluble tetrazolium salt) assay. The type of cell death was detected with an apoptosis/necrosis ELISA (enzyme-linked immune sorbent assay) and flow cytometry. Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) were carried out to detect the degree of cell destruction. After HHP treatment, the metabolic activities of both cell types decreased, whereas HHP of 250 MPa and higher resulted in metabolic inactivation. Further, the highest HHP range induced mostly necrosis while the lower HHP ranges induced apoptosis and necrosis equally. FESEM and TEM analyses of treated osteoblasts revealed pressure-dependent cell damage. In the present study, it could be proven that a pressure range of 250–300 MPa can be used for cell devitalization. However, in order to treat bone and cartilage tissue gently with HHP, the results of our cell experiments must be verified for tissue samples in future studies. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Article
Mitochondrial Dysfunction and Calcium Dysregulation in Leigh Syndrome Induced Pluripotent Stem Cell Derived Neurons
Int. J. Mol. Sci. 2020, 21(9), 3191; https://doi.org/10.3390/ijms21093191 - 30 Apr 2020
Cited by 9 | Viewed by 1492
Abstract
Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS [...] Read more.
Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Review

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Review
Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Proximity
Int. J. Mol. Sci. 2020, 21(21), 7916; https://doi.org/10.3390/ijms21217916 - 25 Oct 2020
Cited by 7 | Viewed by 1828
Abstract
Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that affects the connective tissue and primarily the joints. If not treated, RA ultimately leads to progressive cartilage and bone degeneration. The etiology of the pathogenesis of RA is unknown, demonstrating heterogeneity [...] Read more.
Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that affects the connective tissue and primarily the joints. If not treated, RA ultimately leads to progressive cartilage and bone degeneration. The etiology of the pathogenesis of RA is unknown, demonstrating heterogeneity in its clinical presentation, and is associated with autoantibodies directed against modified self-epitopes. Although many models already exist for RA for preclinical research, many current model systems of arthritis have limited predictive value because they are either based on animals of phylogenetically distant origin or suffer from overly simplified in vitro culture conditions. These limitations pose considerable challenges for preclinical research and therefore clinical translation. Thus, a sophisticated experimental human-based in vitro approach mimicking RA is essential to (i) investigate key mechanisms in the pathogenesis of human RA, (ii) identify targets for new therapeutic approaches, (iii) test these approaches, (iv) facilitate the clinical transferability of results, and (v) reduce the use of laboratory animals. Here, we summarize the most commonly used in vitro models of RA and discuss their experimental feasibility and physiological proximity to the pathophysiology of human RA to highlight new human-based avenues in RA research to increase our knowledge on human pathophysiology and develop effective targeted therapies. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Review
Adipose Tissue Fibrosis: Mechanisms, Models, and Importance
Int. J. Mol. Sci. 2020, 21(17), 6030; https://doi.org/10.3390/ijms21176030 - 21 Aug 2020
Cited by 15 | Viewed by 3853
Abstract
Increases in adipocyte volume and tissue mass due to obesity can result in inflammation, further dysregulation in adipose tissue function, and eventually adipose tissue fibrosis. Like other fibrotic diseases, adipose tissue fibrosis is the accumulation and increased production of extracellular matrix (ECM) proteins. [...] Read more.
Increases in adipocyte volume and tissue mass due to obesity can result in inflammation, further dysregulation in adipose tissue function, and eventually adipose tissue fibrosis. Like other fibrotic diseases, adipose tissue fibrosis is the accumulation and increased production of extracellular matrix (ECM) proteins. Adipose tissue fibrosis has been linked to decreased insulin sensitivity, poor bariatric surgery outcomes, and difficulty in weight loss. With the rising rates of obesity, it is important to create accurate models for adipose tissue fibrosis to gain mechanistic insights and develop targeted treatments. This article discusses recent research in modeling adipose tissue fibrosis using in vivo and in vitro (2D and 3D) methods with considerations for biomaterial selections. Additionally, this article outlines the importance of adipose tissue in treating other fibrotic diseases and methods used to detect and characterize adipose tissue fibrosis. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Review
Biomaterials Loaded with Growth Factors/Cytokines and Stem Cells for Cardiac Tissue Regeneration
Int. J. Mol. Sci. 2020, 21(17), 5952; https://doi.org/10.3390/ijms21175952 - 19 Aug 2020
Cited by 11 | Viewed by 1404
Abstract
Myocardial infarction causes cardiac tissue damage and the release of damage-associated molecular patterns leads to activation of the immune system, production of inflammatory mediators, and migration of various cells to the site of infarction. This complex response further aggravates tissue damage by generating [...] Read more.
Myocardial infarction causes cardiac tissue damage and the release of damage-associated molecular patterns leads to activation of the immune system, production of inflammatory mediators, and migration of various cells to the site of infarction. This complex response further aggravates tissue damage by generating oxidative stress, but it eventually heals the infarction site with the formation of fibrotic tissue and left ventricle remodeling. However, the limited self-renewal capability of cardiomyocytes cannot support sufficient cardiac tissue regeneration after extensive myocardial injury, thus, leading to an irreversible decline in heart function. Approaches to improve cardiac tissue regeneration include transplantation of stem cells and delivery of inflammation modulatory and wound healing factors. Nevertheless, the harsh environment at the site of infarction, which consists of, but is not limited to, oxidative stress, hypoxia, and deficiency of nutrients, is detrimental to stem cell survival and the bioactivity of the delivered factors. The use of biomaterials represents a unique and innovative approach for protecting the loaded factors from degradation, decreasing side effects by reducing the used dosage, and increasing the retention and survival rate of the loaded cells. Biomaterials with loaded stem cells and immunomodulating and tissue-regenerating factors can be used to ameliorate inflammation, improve angiogenesis, reduce fibrosis, and generate functional cardiac tissue. In this review, we discuss recent findings in the utilization of biomaterials to enhance cytokine/growth factor and stem cell therapy for cardiac tissue regeneration in small animals with myocardial infarction. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Review
In Vitro Modeling of Non-Solid Tumors: How Far Can Tissue Engineering Go?
Int. J. Mol. Sci. 2020, 21(16), 5747; https://doi.org/10.3390/ijms21165747 - 11 Aug 2020
Cited by 5 | Viewed by 1418
Abstract
In hematological malignancies, leukemias or myelomas, malignant cells present bone marrow (BM) homing, in which the niche contributes to tumor development and drug resistance. BM architecture, cellular and molecular composition and interactions define differential microenvironments that govern cell fate under physiological and pathological [...] Read more.
In hematological malignancies, leukemias or myelomas, malignant cells present bone marrow (BM) homing, in which the niche contributes to tumor development and drug resistance. BM architecture, cellular and molecular composition and interactions define differential microenvironments that govern cell fate under physiological and pathological conditions and serve as a reference for the native biological landscape to be replicated in engineered platforms attempting to reproduce blood cancer behavior. This review summarizes the different models used to efficiently reproduce certain aspects of BM in vitro; however, they still lack the complexity of this tissue, which is relevant for fundamental aspects such as drug resistance development in multiple myeloma. Extracellular matrix composition, material topography, vascularization, cellular composition or stemness vs. differentiation balance are discussed as variables that could be rationally defined in tissue engineering approaches for achieving more relevant in vitro models. Fully humanized platforms closely resembling natural interactions still remain challenging and the question of to what extent accurate tissue complexity reproduction is essential to reliably predict drug responses is controversial. However, the contributions of these approaches to the fundamental knowledge of non-solid tumor biology, its regulation by niches, and the advance of personalized medicine are unquestionable. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Review
Tissue-Specific Decellularization Methods: Rationale and Strategies to Achieve Regenerative Compounds
Int. J. Mol. Sci. 2020, 21(15), 5447; https://doi.org/10.3390/ijms21155447 - 30 Jul 2020
Cited by 46 | Viewed by 2692
Abstract
The extracellular matrix (ECM) is a complex network with multiple functions, including specific functions during tissue regeneration. Precisely, the properties of the ECM have been thoroughly used in tissue engineering and regenerative medicine research, aiming to restore the function of damaged or dysfunctional [...] Read more.
The extracellular matrix (ECM) is a complex network with multiple functions, including specific functions during tissue regeneration. Precisely, the properties of the ECM have been thoroughly used in tissue engineering and regenerative medicine research, aiming to restore the function of damaged or dysfunctional tissues. Tissue decellularization is gaining momentum as a technique to obtain potentially implantable decellularized extracellular matrix (dECM) with well-preserved key components. Interestingly, the tissue-specific dECM is becoming a feasible option to carry out regenerative medicine research, with multiple advantages compared to other approaches. This review provides an overview of the most common methods used to obtain the dECM and summarizes the strategies adopted to decellularize specific tissues, aiming to provide a helpful guide for future research development. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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Review
Tooth Formation: Are the Hardest Tissues of Human Body Hard to Regenerate?
Int. J. Mol. Sci. 2020, 21(11), 4031; https://doi.org/10.3390/ijms21114031 - 04 Jun 2020
Cited by 14 | Viewed by 2802
Abstract
With increasing life expectancy, demands for dental tissue and whole-tooth regeneration are becoming more significant. Despite great progress in medicine, including regenerative therapies, the complex structure of dental tissues introduces several challenges to the field of regenerative dentistry. Interdisciplinary efforts from cellular biologists, [...] Read more.
With increasing life expectancy, demands for dental tissue and whole-tooth regeneration are becoming more significant. Despite great progress in medicine, including regenerative therapies, the complex structure of dental tissues introduces several challenges to the field of regenerative dentistry. Interdisciplinary efforts from cellular biologists, material scientists, and clinical odontologists are being made to establish strategies and find the solutions for dental tissue regeneration and/or whole-tooth regeneration. In recent years, many significant discoveries were done regarding signaling pathways and factors shaping calcified tissue genesis, including those of tooth. Novel biocompatible scaffolds and polymer-based drug release systems are under development and may soon result in clinically applicable biomaterials with the potential to modulate signaling cascades involved in dental tissue genesis and regeneration. Approaches for whole-tooth regeneration utilizing adult stem cells, induced pluripotent stem cells, or tooth germ cells transplantation are emerging as promising alternatives to overcome existing in vitro tissue generation hurdles. In this interdisciplinary review, most recent advances in cellular signaling guiding dental tissue genesis, novel functionalized scaffolds and drug release material, various odontogenic cell sources, and methods for tooth regeneration are discussed thus providing a multi-faceted, up-to-date, and illustrative overview on the tooth regeneration matter, alongside hints for future directions in the challenging field of regenerative dentistry. Full article
(This article belongs to the Special Issue Cells and Materials for Disease Modeling and Regenerative Medicine)
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