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      Vascularized pulp regeneration via injecting simvastatin functionalized GelMA cryogel microspheres loaded with stem cells from human exfoliated deciduous teeth

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          Abstract

          Dental pulp necrosis are serious pathologic entities that causes tooth nutrition deficiency and abnormal root development, while regeneration of functional pulp tissue is of paramount importance to regain tooth vitality. However, existing clinical treatments, which focus on replacing the necrotic pulp tissue with inactive filling materials, fail to restore pulp vitality and functions, thus resulting in a devitalized and weakened tooth. Currently, dental pulp regeneration via stem cell-based therapy for pulpless teeth has raised enormous attention to restore the functional pulp. Here, a novel design of injectable simvastatin (SIM) functionalized gelatin methacrylate (GelMA) cryogel microspheres (SMS) loaded with stem cells from human exfoliated deciduous teeth (SHEDs) was established to refine SHEDs biological behaviors and promote in vivo vascularized pulp-like tissue regeneration. In this system, SIM encapsulated poly (lactide- co-glycolide) (PLGA) nanoparticles were incorporated into GelMA cryogel microspheres via cryogelation and O 1/W/O 2 emulsion method. SMS with sustained release of SIM promoted SHEDs adhesion, proliferation and exhibited cell protection properties during the injection process. Furthermore, SMS enhanced SHEDs odontogenic differentiation and angiogenic potential, and SHEDs loaded SMS (SHEDs/SMS) are beneficial for human umbilical vein endothelial cells (HUVECs) migration and angiogenesis, demonstrating their potential for use in promoting vascularized tissue regeneration. SHEDs/SMS complexes were injected into cleaned human tooth root segments for subcutaneous implantation in nude mice. Our results demonstrated that SHEDs/SMS could induce vessel-rich pulp-like tissue regeneration in vivo and that such an injectable nano-in-micro multistage system for the controlled delivery of bioactive reagents would be suitable for clinical application in endodontic regenerative dentistry.

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          Highlights

          • •

            Simvastatin functionalized cryogel microspheres (SMS) protect SHEDs during the injection process.

          • •

            SMS enhance SHEDs biological behaviors.

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            SHEDs loaded SMS promote vascularized pulp like tissue regeneration in tooth root segments.

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          Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels.

          Kan Yue, Grissel Trujillo-de Santiago, Mario Moisés Alvarez … (2015)
          Gelatin methacryloyl (GelMA) hydrogels have been widely used for various biomedical applications due to their suitable biological properties and tunable physical characteristics. GelMA hydrogels closely resemble some essential properties of native extracellular matrix (ECM) due to the presence of cell-attaching and matrix metalloproteinase responsive peptide motifs, which allow cells to proliferate and spread in GelMA-based scaffolds. GelMA is also versatile from a processing perspective. It crosslinks when exposed to light irradiation to form hydrogels with tunable mechanical properties. It can also be microfabricated using different methodologies including micromolding, photomasking, bioprinting, self-assembly, and microfluidic techniques to generate constructs with controlled architectures. Hybrid hydrogel systems can also be formed by mixing GelMA with nanoparticles such as carbon nanotubes and graphene oxide, and other polymers to form networks with desired combined properties and characteristics for specific biological applications. Recent research has demonstrated the proficiency of GelMA-based hydrogels in a wide range of tissue engineering applications including engineering of bone, cartilage, cardiac, and vascular tissues, among others. Other applications of GelMA hydrogels, besides tissue engineering, include fundamental cell research, cell signaling, drug and gene delivery, and bio-sensing.
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            SHED: stem cells from human exfoliated deciduous teeth.

            M. Miura, S Gronthos, M. Zhao … (2003)
            To isolate high-quality human postnatal stem cells from accessible resources is an important goal for stem-cell research. In this study we found that exfoliated human deciduous tooth contains multipotent stem cells [stem cells from human exfoliated deciduous teeth (SHED)]. SHED were identified to be a population of highly proliferative, clonogenic cells capable of differentiating into a variety of cell types including neural cells, adipocytes, and odontoblasts. After in vivo transplantation, SHED were found to be able to induce bone formation, generate dentin, and survive in mouse brain along with expression of neural markers. Here we show that a naturally exfoliated human organ contains a population of stem cells that are completely different from previously identified stem cells. SHED are not only derived from a very accessible tissue resource but are also capable of providing enough cells for potential clinical application. Thus, exfoliated teeth may be an unexpected unique resource for stem-cell therapies including autologous stem-cell transplantation and tissue engineering.
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              Protein therapeutics: a summary and pharmacological classification.

              Benjamin Leader, Quentin J Baca, David Golan (2008)
              Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.
              Article 0 comments Cited 253 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaojing Yuan
                Chunyang Xiong
                Lihong Ge
                Yuming Zhao
                Journal
                Journal ID (nlm-ta): Mater Today Bio
                Journal ID (iso-abbrev): Mater Today Bio
                Title: Materials Today Bio
                Publisher: Elsevier
                ISSN (Electronic): 2590-0064
                Publication date PMC-release: 31 January 2022
                Publication date Collection: January 2022
                Publication date (Electronic): 31 January 2022
                Volume: 13
                Electronic Location Identifier: 100209
                Affiliations
                [a ]Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China
                [b ]Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, 100871, China
                [c ]State Key Laboratory of Organic-Inorganic Composites; Beijing Laboratory of Biomedical Materials; Beijing University of Chemical Technology, Beijing, 100029, China
                [d ]Department of Emergency, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China
                [e ]Dental Medical Devices Testing Center, Dental Materials Laboratory, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China
                [f ]Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
                Author notes
                [∗ ]Corresponding author. Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, 100871, China. cyxiong@ 123456pku.edu.cn
                [∗∗ ]Corresponding author. Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. gelihong0919@ 123456163.com
                [∗∗∗ ]Corresponding author. Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. yumingzhao70@ 123456sina.com
                [1]

                These two authors contribute equally.

                Article
                Publisher Item ID: S2590-0064(22)00007-2 Publisher ID: 100209
                DOI: 10.1016/j.mtbio.2022.100209
                PMC ID: 8841886
                SO-VID: 337f3c9f-9fc8-4491-94f5-8908cf6ae339
                Copyright © © 2022 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 30 November 2021
                Date revision received : 20 January 2022
                Date accepted : 27 January 2022
                Categories
                Subject: Full Length Article

                Keywords: pulp regeneration,stem cells from human exfoliated deciduous teeth,simvastatin,controlled delivery,cryogel microspheres
                Data availability:
                Keywords: pulp regeneration, stem cells from human exfoliated deciduous teeth, simvastatin, controlled delivery, cryogel microspheres

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