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Special Issue "Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials"

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 (29 February 2020).

Special Issue Editors

Special Issue Information

Dear Colleagues,

Regenerative medicine is a growing area of the medical sciences that has the unique peculiarity of involving both the biological pathways and the clinical applications. Currently, the main actors of tissue regeneration are stem cells and biomaterials: The proper combination of these factors is the key to successfully treating damaged or lost tissues, to promoting tissue formation, and to restoring, at the same time, aesthetics and function. Future regenerative strategies will be aimed at developing innovative biologically-friendly and smart biomaterials, as well as at triggering stem cells towards specific lineages in clinical-grade conditions, also through the use of MSC-derived conditioned medium, exosomes or small molecules. The next approaches should overcome the current biological and clinical limitations and be able to use those autologous factors that can naïvely induce and promote the biological conditions that could guide and improve any kind of tissue regeneration. The biomedical applications of innovative coatings or functionalized surfaces have recently boosted the theranostic use of novel biomaterials. This Special Issue will highlight the most promising applications of tissue engineering in the future diagnostic and therapeutic procedures applied to the medical sciences.

Dr. Marco Tatullo
Prof. Dr. Adriano Piattelli
Prof. Dr. Barbara Zavan
Guest Editors

Manuscript Submission Information

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Keywords

  • Regenerative medicine
  • Biomaterials
  • Scaffolds
  • Stem cells
  • Smart materials
  • Exosomes
  • Functionalized surfaces
  • Coatings
  • Bioactive surfaces
  • Theranostics

Published Papers (10 papers)

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Research

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Article
Participation of Somatic Stem Cells, Labeled by a Unique Antibody (A3) Recognizing Both N-glycan and Peptide, to Hair Follicle Cycle and Cutaneous Wound Healing in Rats
Int. J. Mol. Sci. 2020, 21(11), 3806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113806 - 27 May 2020
Cited by 1 | Viewed by 942
Abstract
A monoclonal antibody (A3) was generated by using rat malignant fibrous histiocytoma (MFH) cells as the antigen. Generally, MFH is considered to be a sarcoma derived from undifferentiated mesenchymal cells. Molecular biological analyses using the lysate of rat MFH cells revealed that A3 [...] Read more.
A monoclonal antibody (A3) was generated by using rat malignant fibrous histiocytoma (MFH) cells as the antigen. Generally, MFH is considered to be a sarcoma derived from undifferentiated mesenchymal cells. Molecular biological analyses using the lysate of rat MFH cells revealed that A3 is a conformation specific antibody recognizing both N-glycan and peptide. A3-labeled cells in bone marrow were regarded as somatic stem cells, because the cells partly coexpressed CD90 and CD105 (both immature mesenchymal markers). In the hair follicle cycle, particularly the anagen, the immature epithelial cells (suprabasal cells) near the bulge and some immature mesenchymal cells in the disassembling dermal papilla and regenerating connective tissue sheath/hair papilla reacted to A3. In the cutaneous wound-healing process, A3-labeled epithelial cells participated in re-epithelialization in the wound bed, and apparently, the labeled cells were derived from the hair bulge; in addition, A3-labeled immature mesenchymal cells in the connective tissue sheath of hair follicles at the wound edge showed the expansion of the A3 immunolabeling. A3-labeled immature epithelial and mesenchymal cells contributed to morphogenesis in the hair cycle and tissue repair after a cutaneous wound. A3 could become a unique antibody to identify somatic stem cells capable of differentiating both epithelial and mesenchymal cells in rat tissues. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Article
In Vitro Characterization of Adipose Stem Cells Non-Enzymatically Extracted from the Thigh and Abdomen
Int. J. Mol. Sci. 2020, 21(9), 3081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093081 - 27 Apr 2020
Cited by 10 | Viewed by 1344
Abstract
Autologous fat grafting is a surgical technique in which adipose tissue is transferred from one area of the body to another, in order to reconstruct or regenerate damaged or injured tissues. Before reinjection, adipose tissue needs to be purified from blood and cellular [...] Read more.
Autologous fat grafting is a surgical technique in which adipose tissue is transferred from one area of the body to another, in order to reconstruct or regenerate damaged or injured tissues. Before reinjection, adipose tissue needs to be purified from blood and cellular debris to avoid inflammation and preserve the graft viability. To perform this purification, different enzymatic and mechanical methods can be used. In this study, we characterized in vitro the product of a closed automatic device based on mechanical disaggregation, named Rigenera®, focusing on two sites of adipose tissue harvesting. At first, we optimized the Rigenera® operating timing, demonstrating that 60 s of treatment allows a higher cellular yield, in terms of the cell number and growth rate. This result optimizes the mechanical disaggregation and it can increase the clinical efficiency of the final product. When comparing the extracted adipose samples from the thigh and abdomen, our results showed that the thigh provides a higher number of mesenchymal-like cells, with a faster replication rate and a higher ability to form colonies. We can conclude that by collecting adipose tissue from the thigh and treating it with the Rigenera® device for 60 s, it is possible to obtain the most efficient product. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Article
Immediate or Delayed Transplantation of a Vein Conduit Filled with Nasal Olfactory Stem Cells Improves Locomotion and Axogenesis in Rats after a Peroneal Nerve Loss of Substance
Int. J. Mol. Sci. 2020, 21(8), 2670; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082670 - 11 Apr 2020
Cited by 2 | Viewed by 944
Abstract
Over the recent years, several methods have been experienced to repair injured peripheral nerves. Among investigated strategies, the use of natural or synthetic conduits was validated for clinical application. In this study, we assessed the therapeutic potential of vein guides, transplanted immediately or [...] Read more.
Over the recent years, several methods have been experienced to repair injured peripheral nerves. Among investigated strategies, the use of natural or synthetic conduits was validated for clinical application. In this study, we assessed the therapeutic potential of vein guides, transplanted immediately or two weeks after a peroneal nerve injury and filled with olfactory ecto-mesenchymal stem cells (OEMSC). Rats were randomly allocated to five groups. A3 mm peroneal nerve loss was bridged, acutely or chronically, with a 1 cm long femoral vein and with/without OEMSCs. These four groups were compared to unoperated rats (Control group). OEMSCs were purified from male olfactory mucosae and grafted into female hosts. Three months after surgery, nerve repair was analyzed by measuring locomotor function, mechanical muscle properties, muscle mass, axon number, and myelination. We observed that stem cells significantly (i) increased locomotor recovery, (ii) partially maintained the contractile phenotype of the target muscle, and (iii) augmented the number of growing axons. OEMSCs remained in the nerve and did not migrate in other organs. These results open the way for a phase I/IIa clinical trial based on the autologous engraftment of OEMSCs in patients with a nerve injury, especially those with neglected wounds. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Article
Efficient Cardiac Differentiation of Human Amniotic Fluid-Derived Stem Cells into Induced Pluripotent Stem Cells and Their Potential Immune Privilege
Int. J. Mol. Sci. 2020, 21(7), 2359; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072359 - 29 Mar 2020
Cited by 3 | Viewed by 1312
Abstract
Mature mammalian hearts possess very limited regenerative potential. The irreversible cardiomyocyte loss after heart injury can lead to heart failure and death. Pluripotent stem cells (PSCs) can differentiate into cardiomyocytes for cardiac repair, but there are obstacles to their clinical application. Among these [...] Read more.
Mature mammalian hearts possess very limited regenerative potential. The irreversible cardiomyocyte loss after heart injury can lead to heart failure and death. Pluripotent stem cells (PSCs) can differentiate into cardiomyocytes for cardiac repair, but there are obstacles to their clinical application. Among these obstacles is their potential for post-transplant rejection. Although human amniotic fluid-derived stem cells (hAFSCs) are immune privileged, they cannot induce cardiac differentiation. Thus, we generated hAFSC-derived induced PSCs (hAFSC-iPSCs) and used a Wnt-modulating differentiation protocol for the cardiac differentiation of hAFSC-iPSCs. In vitro studies using flow cytometry, immunofluorescence staining, and patch-clamp electrophysiological study, were performed to identify the characteristics of hAFSC-iPSC-derived cardiomyocytes (hAFSC-iPSC-CMs). We injected hAFSC-iPSC-CMs intramuscularly into rat infarcted hearts to evaluate the therapeutic potential of hAFSC-iPSC-CM transplantation. At day 21 of differentiation, the hAFSC-iPSC-CMs expressed cardiac-specific marker (cardiac troponin T), presented cardiomyocyte-specific electrophysiological properties, and contracted spontaneously. Importantly, these hAFSC-iPSC-CMs demonstrated low major histocompatibility complex (MHC) class I antigen expression and the absence of MHC class II antigens, indicating their low immunogenicity. The intramyocardial transplantation of hAFSC-iPSC-CMs restored cardiac function, partially remuscularized the injured region, and reduced fibrosis in the rat infarcted hearts. Therefore, hAFSC-iPSCs are potential candidates for the repair of infarcted myocardium. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Article
Proteomic and Ultrastructural Analysis of Cellulite—New Findings on an Old Topic
Int. J. Mol. Sci. 2020, 21(6), 2077; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062077 - 18 Mar 2020
Cited by 4 | Viewed by 1865
Abstract
Background: Cellulite is a condition in which the skin has a dimpled lumpy appearance. The main causes of cellulite development, studied until now, comprehends modified sensitivity to estrogens, the damage of microvasculature present among dermis and hypodermis. The differences of adipose tissue architecture [...] Read more.
Background: Cellulite is a condition in which the skin has a dimpled lumpy appearance. The main causes of cellulite development, studied until now, comprehends modified sensitivity to estrogens, the damage of microvasculature present among dermis and hypodermis. The differences of adipose tissue architecture between male and female might make female more susceptible to cellulite. Adipose tissue is seen to be deeply modified during cellulite development. Our study tried to understand the overall features within and surrounding cellulite to apply the best therapeutic approach. Methods: Samples of gluteal femoral area were collected from cadavers and women who had undergone surgical treatment to remove orange peel characteristics on the skin. Samples from cadavers were employed for an accurate study of cellulite using magnetic resonance imaging at 7 Tesla and for light microscopy. Specimens from patients were employed for the proteomic analysis, which was performed using high resolution mass spectroscopy (MS). Stromal vascular fraction (SVF) was obtained from the samples, which was studied using MS and flow cytometry. Results: light and electron microscopy of the cellulite affected area showed a morphology completely different from the other usual adipose depots. In cellulite affected tissues, sweat glands associated with adipocytes were found. In particular, there were vesicles in the extracellular matrix, indicating a crosstalk between the two different components. Proteomic analysis showed that adipose tissue affected by cellulite is characterized by high degree of oxidative stress and by remodeling phenomena. Conclusions: The novel aspects of this study are the peculiar morphology of adipose tissue affected by cellulite, which could influence the surgical procedures finalized to the reduction of dimpling, based on the collagen fibers cutting. The second novel aspect is the role played by the mesenchymal stem cells isolated from stromal vascular fraction of adipose tissue affected by cellulite. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Article
Osteogenic Potential of Bovine Bone Graft in Combination with Laser Photobiomodulation: An Ex Vivo Demonstrative Study in Wistar Rats by Cross-Linked Studies Based on Synchrotron Microtomography and Histology
Int. J. Mol. Sci. 2020, 21(3), 778; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030778 - 25 Jan 2020
Cited by 10 | Viewed by 1342
Abstract
Background: Alveolar bone defects are usually the main concern when planning implant treatments for the appropriate oral rehabilitation of patients. To improve local conditions and achieve implant treatments, there are several methods used for increasing bone volume, among which one of the most [...] Read more.
Background: Alveolar bone defects are usually the main concern when planning implant treatments for the appropriate oral rehabilitation of patients. To improve local conditions and achieve implant treatments, there are several methods used for increasing bone volume, among which one of the most successful, versatile, and effective is considered to be guided bone regeneration. The aim of this demonstrative study was to propose an innovative analysis protocol for the evaluation of the effect of photobiomodulation on the bone regeneration process, using rat calvarial defects of 5 mm in diameter, filled with xenograft, covered with collagen membrane, and then exposed to laser radiation. Methods: The animals were sacrificed at different points in time (i.e., after 14, 21, and 30 days). Samples of identical dimensions were harvested in order to compare the results obtained after different periods of healing. The analysis was performed by cross-linking the information obtained using histology and high-resolution synchrotron-based tomography on the same samples. A comparison was made with both the negative control (NC) group (with a bone defect which was left for spontaneous healing), and the positive control (PC) group (in which the bone defects were filled with xenografts and collagen membrane without receiving laser treatment). Results: We demonstrated that using photobiomodulation provides a better healing effect than when receiving only the support of the biomaterial. This effect has been evident for short times treatments, i.e., during the first 14 days after surgery. Conclusion: The proposed analysis protocol was effective in detecting the presence of higher quantities of bone volumes under remodeling after photobiomodulation with respect to the exclusive bone regeneration guided by the xenograft. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Article
Titania Nanofiber Scaffolds with Enhanced Biointegration Activity—Preliminary In Vitro Studies
Int. J. Mol. Sci. 2019, 20(22), 5642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225642 - 11 Nov 2019
Cited by 5 | Viewed by 1079
Abstract
The increasing need for novel bone replacement materials has been driving numerous studies on modifying their surface to stimulate osteogenic cells expansion and to accelerate bone tissue regeneration. The goal of the presented study was to optimize the production of titania-based bioactive materials [...] Read more.
The increasing need for novel bone replacement materials has been driving numerous studies on modifying their surface to stimulate osteogenic cells expansion and to accelerate bone tissue regeneration. The goal of the presented study was to optimize the production of titania-based bioactive materials with high porosity and defined nanostructure, which supports the cell viability and growth. We have chosen to our experiments TiO2 nanofibers, produced by chemical oxidation of Ti6Al4V alloy. Fibrous nanocoatings were characterized structurally (X-ray diffraction (XRD)) and morphologically (scanning electron microscopy (SEM)). The wettability of the coatings and their mechanical properties were also evaluated. We have investigated the direct influence of the modified titanium alloy surfaces on the survival and proliferation of mesenchymal stem cells derived from adipose tissue (ADSCs). In parallel, proliferation of bone tissue cells—human osteoblasts MG-63 and connective tissue cells - mouse fibroblasts L929, as well as cell viability in co-cultures (osteoblasts/ADSCs and fibroblasts/ADSCs has been studied. The results of our experiments proved that among all tested nanofibrous coatings, the amorphous titania-based ones were the most optimal scaffolds for the integration and proliferation of ADSCs, fibroblasts, and osteoblasts. Thus, we postulated these scaffolds to have the osteopromotional potential. However, from the co-culture experiments it can be concluded that ADSCs have the ability to functionalize the initially unfavorable surface, and make it suitable for more specialized and demanding cells. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Review

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Review
Bone Marrow Aspirate Concentrate: Its Uses in Osteoarthritis
Int. J. Mol. Sci. 2020, 21(9), 3224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093224 - 02 May 2020
Cited by 11 | Viewed by 1513
Abstract
Human bone marrow (BM) is a kind of source of mesenchymal stem cells (MSCs) as well as growth factors and cytokines that may aid anti-inflammation and regeneration for various tissues, including cartilage and bone. However, since MSCs in BM usually occupy only a [...] Read more.
Human bone marrow (BM) is a kind of source of mesenchymal stem cells (MSCs) as well as growth factors and cytokines that may aid anti-inflammation and regeneration for various tissues, including cartilage and bone. However, since MSCs in BM usually occupy only a small fraction (0.001%) of nucleated cells, bone marrow aspirate concentrate (BMAC) for cartilage pathologies, such as cartilage degeneration, defect, and osteoarthritis, have gained considerable recognition in the last few years due to its potential benefits including disease modifying and regenerative capacity. Although further research with well-designed, randomized, controlled clinical trials is needed to elucidate the exact mechanism of BMAC, this may have the most noteworthy effect in patients with osteoarthritis. The purpose of this article is to review the general characteristics of BMAC, including its constituent, action mechanisms, and related issues. Moreover, this article aims to summarize the clinical outcomes of BMAC reported to date. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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Review
Clinical-Grade Human Pluripotent Stem Cells for Cell Therapy: Characterization Strategy
Int. J. Mol. Sci. 2020, 21(7), 2435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072435 - 31 Mar 2020
Cited by 4 | Viewed by 1594
Abstract
Human pluripotent stem cells have the potential to change the way in which human diseases are cured. Clinical-grade human embryonic stem cells and human induced pluripotent stem cells have to be created according to current good manufacturing practices and regulations. Quality and safety [...] Read more.
Human pluripotent stem cells have the potential to change the way in which human diseases are cured. Clinical-grade human embryonic stem cells and human induced pluripotent stem cells have to be created according to current good manufacturing practices and regulations. Quality and safety must be of the highest importance when humans’ lives are at stake. With the rising number of clinical trials, there is a need for a consensus on hPSCs characterization. Here, we summarize mandatory and ′for information only′ characterization methods with release criteria for the establishment of clinical-grade hPSC lines. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
Review
Synthetic Blocks for Bone Regeneration: A Systematic Review and Meta-Analysis
Int. J. Mol. Sci. 2019, 20(17), 4221; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174221 - 28 Aug 2019
Cited by 16 | Viewed by 1525
Abstract
This systematic review is aimed at evaluating the effectiveness of synthetic block materials for bone augmentation in preclinical in vivo studies. An electronic search was performed on Pubmed, Scopus, EMBASE. Articles selected underwent risk-of-bias assessment. The outcomes were: new bone formation and residual [...] Read more.
This systematic review is aimed at evaluating the effectiveness of synthetic block materials for bone augmentation in preclinical in vivo studies. An electronic search was performed on Pubmed, Scopus, EMBASE. Articles selected underwent risk-of-bias assessment. The outcomes were: new bone formation and residual graft with histomorphometry, radiographic bone density, soft tissue parameters, complications. Meta-analysis was performed to compare new bone formation in test (synthetic blocks) vs. control group (autogenous blocks or spontaneous healing). The search yielded 214 articles. After screening, 39 studies were included, all performed on animal models: rabbits (n = 18 studies), dogs (n = 4), rats (n = 7), minipigs (n = 4), goats (n = 4), and sheep (n = 2). The meta-analysis on rabbit studies showed significantly higher new bone formation for synthetic blocks with respect to autogenous blocks both at four-week (mean difference (MD): 5.91%, 95% confidence intervals (CI): 1.04, 10.79%, p = 0.02) and at eight-week healing (MD: 4.44%, 95% CI: 0.71, 8.17%, p = 0.02). Other animal models evidenced a trend for better outcomes with synthetic blocks, though only based on qualitative analysis. Synthetic blocks may represent a viable resource in bone regenerative surgery for achieving new bone formation. Differences in the animal models, the design of included studies, and the bone defects treated should be considered when generalizing the results. Clinical studies are needed to confirm the effectiveness of synthetic blocks in bone augmentation procedures. Full article
(This article belongs to the Special Issue Regenerative Medicine: Role of Stem Cells and Innovative Biomaterials)
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