Protocol for the systematic review of the immunomodulatory properties of hydrogels added with osteogenically differentiated mesenchymal stem cells
Creators: name: Ramírez Sánchez, Jazmín Ivonne
Publisher: name: Zenodo
Year: 2021
Subjects: Hydrogel
immunomodulatory
Immunomodulation
immune stimulation
surface modification
Biomedical engineering
Nanomedicine

description: <strong>Background</strong> According to data from the World Health Organization, approximately 1710 million people in the world suffer from musculoskeletal disorders, and affected people are found in all age groups [1]. In addition, skeletal muscle, representing 40% of body mass, is highly exposed to injuries during clinical practices or due to accidents due to automobiles, work, war or sports [2]. Studies have been carried out involving the use of hydrogels containing mesenchymal stem cells (MSC) to give rise to immunosuppression and favor the applied treatment. In 2015, a polyethylene glycol-based hydrogel was prepared and stem cells were cultured from murine bone marrow. The results showed that the MSCs modulate the immune response when they are encapsulated in the hydrogel by changing the inflammatory response that regularly occurs due to the response to foreign bodies, this due to the partial or total suppression of the IL-6 gene, which It takes place in the activation of the inflammation process. Having this, it can be incorporated into synthetic scaffolds in order to improve tissue regeneration [3]. Additionally, a multifunctional system was developed to encapsulate and culture MSCs obtained directly from bone marrow to improve their immunomodulatory properties. Results were obtained in which, by biomimicking an extracellular matrix of collagen, chemically modified alginate and cytokine-loaded heparin-coated beads, it was possible to increase the expression of immunomodulatory genes (IDO1, GAL9 and PTGS2) while cell proliferation was suppressed. T[4]. In another study, work was done to develop a system composed of a MSC-loaded hydroxypropyl chitin hydrogel combined with a three-dimensionally printed poly(ε-caprolactone)/nanohydroxyapatite scaffold for bone defect repair. It was obtained that, as the cells were encapsulated in the hydrogel, the expression of genes such as OCN, OPN and Runx2 was increased, as well as for Runx1 and Runx2, which are related to chondrogenesis. Likewise, subcutaneous implantation in murine animals indicated the activation of M2 macrophages, responsible for anti-inflammatory effects; turning out to be a useful tool for bone and cartilage tissue engineering [5]. In addition, there is evidence of SDF-1 chemokine membranes loaded with polylactic acid and hydroxyapatite that promote cell recruitment (in this case, MSCs), immunomodulation, angiogenesis, and osteogenesis for bone regeneration. Genetic expression was measured based on the quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) technique, observing a high expression of osteocalcin (OCN) and osteopontin (OPN), directly related to osteogenesis [6]. Recently, Zou, Sun and Xiang worked on a hydrogel of carboxymethyl chitosan and polyethylene glycol diacrylate, added with graphene oxide for the adhesion and proliferation of bone marrow MSCs with the purpose of inducing the polarization of M2 macrophages through the cytokine IL-4 . After 7 and 14 days of culture, all the genetic material (RNA) content was extracted and gene expression for ALP, Runx2, COL1A1 and OCN was detected by RT-qPCR. [7]. With this context, it is intended to report on the importance of the study of hydrogels currently in tissue engineering, since they play a leading role, together with different types of cells, in tissue healing and regeneration. <strong>Research Question</strong> For all of the above, it is evident that the composition of hydrogels is too heterogeneous in recent research and it is observed that the polymers have an influence on immunomodulation, which is evaluated by genetic expression and proliferation of immune cells; For this reason, we have posed the following research question: How do the polymers present in hydrogels act, together with mesenchymal stem cells, to modulate the immune response and affect gene expression? <strong>Inclusion criteria</strong><br> • The record was published from 2015<br> • The registry deals with the use of hydrogels in combination with mesenchymal stem cells.<br> • The registry shows results that include quantification of expression of at least one gene.<br> • The registry deals with experimental studies in vitro or in vivo between the hydrogel and regeneration of bone tissue. <strong>Exclusion criteria</strong><br> • The registration does not mention the composition of the hydrogel or the composition does not include at least one natural or synthetic polymer<br> • Texts that are not written in the English language.<br> • Studies that cannot be fully accessed.<br> • Registries dealing with other types of stem cells that are not mesenchymal.<br> • Review articles, conferences or comments. <strong>Overall objective</strong><br> • Identify the effect of immunological modulation on gene expression when using hydrogels with mesenchymal stem cells. <strong>Specific objectives</strong><br> • Understand the body's defense mechanism against a tissue injury that requires healing.<br> • Study compositions of different hydrogels that serve as support for tissue repair and regeneration.<br> • Identify the variables directly related to immune modulation when hydrogels are used.<br> • Expose the fundamental role of hydrogels in potential in vivo applications for the regeneration of bone tissue in humans.<br> • Determine the areas with the greatest scope currently within tissue engineering in where applications for bone tissue are involved using hydrogels combined with differentiated mesenchymal stem cells. Injuries to the musculoskeletal system occur with high frequency in the global population, affecting people of all ages; For this reason, it is necessary to be at the forefront of techniques and treatments that facilitate recovery. Tissue engineering has been a tool explored in recent years to provide a better quality of life for living beings, however, this area of medicine continues to face challenges.<br> The importance of this work lies in the analysis of various studies in the area of regenerative medicine where hydrogels with mesenchymal stem cells are used to evaluate the effectiveness of natural or synthetic materials, in order to determine the polymeric material that promotes the conditions in which the hydrogel-MSC system successfully reaches the site of action, suppresses the action of immune cells when required (evaluating gene expression) and exerts the therapeutic effect. In this way, the information collected can support future research and, in the not too distant future, this will be categorized as a primary treatment and not an adjuvant therapy. <strong>Proposed methodology</strong> Information search in three databases: Science Direct, EBSCO Host and PubMed. Selection of search terms with booleans to find the bibliography on the subject: (hydrogel) AND (immunomodulation) AND ("mesenchymal stem cell") AND ("regenerative medicine" OR "tissue engineering") AND ("cell differentiation" OR bone). Choice of articles according to the established inclusion and exclusion criteria. Extraction and elaboration of synthesis of important data of each article: polymer used, genes expressed and quantification, target cell and immunosuppressive effect. Analysis and conclusion on data collected regarding the composition of the hydrogel, the immunomodulatory properties it exerted and the genes expressed.
description: {"references": ["[1] Organizaci\u00f3n Mundial de la Salud, \"OMS, Serie de lnformes Tecnicos. Enfermedades Reumaticas. lnforme de un Grupo Cientifico de la OMS,\" p. 66, 1992, [Online]. Available: https://apps.who.int/iris/bitstream/handle/10665/39682/9243208160_spa.pdf?sequence=1&amp;isAllowed=y.", "[2] J. M. Grasman, M. J. Zayas, R. L. Page, and G. D. Pins, \"Biomimetic scaffolds for regeneration of volumetric muscle loss in skeletal muscle injuries,\" Acta Biomater., vol. 25, pp. 2\u201315, 2015, doi: 10.1016/j.actbio.2015.07.038.", "[3] M. D. Swartzlander, A. K. Blakney, L. D. Amer, K. D. Hankenson, T. R. Kyriakides, and S. J. Bryant, \"Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels,\" Biomaterials, vol. 41, pp. 79\u201388, 2015, doi: 10.1016/j.biomaterials.2014.11.020.", "[4] A. Gonzalez-Pujana et al., \"Multifunctional biomimetic hydrogel systems to boost the immunomodulatory potential of mesenchymal stromal cells,\" Biomaterials, vol. 257, no. July, p. 120266, 2020, doi: 10.1016/j.biomaterials.2020.120266.", "[5] X. Ji et al., \"Mesenchymal stem cell-loaded thermosensitive hydroxypropyl chitin hydrogel combined with a three-dimensional-printed poly(\u03b5-caprolactone) /nano-hydroxyapatite scaffold to repair bone defects via osteogenesis, angiogenesis and immunomodulation,\" Theranostics, vol. 10, no. 2, pp. 725\u2013740, 2020, doi: 10.7150/thno.39167.", "[6] X. Li et al., \"Multifunctional SDF-1-loaded hydroxyapatite/polylactic acid membranes promote cell recruitment, immunomodulation, angiogenesis, and osteogenesis for biomimetic bone regeneration,\" Appl. Mater. Today, vol. 22, p. 100942, 2021, doi: 10.1016/j.apmt.2021.100942.", "[7] M. Zou, J. Sun, and Z. Xiang, \"Induction of M2-Type Macrophage Differentiation for Bone Defect Repair via an Interpenetration Network Hydrogel with a GO-Based Controlled Release System,\" Adv. Healthc. Mater., vol. 10, no. 6, 2021, doi: 10.1002/adhm.202001502."]}