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Novel Biomaterials for 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 (31 July 2022) | Viewed by 70100

Special Issue Editor

Special Issue Information

Dear Colleagues,

Novel biomaterials are in the heart of regenerative medicine. The main goals for generating in vitro models for in vivo applications, include generating organs for transplantation and organ models for drug discovery. The focus is to generate organoids that will faithfully represent human organs. The composition of the biomaterials, their originality and suitability to each organ is very important for the functionality of the organoid/organ. In the area of drug discovery, iPSC-derived BBB organoid models, for example, will fasten the process of drug discovery by early selecting the drugs according to their BBB penetrance. The success in formation heart organoid that will represent the complexity of heart tissue, is dependent, for example, on the biomaterials used including peptides cross-linked to the scaffolds. Success in future heart scar replacement will involve those biomaterial that will create environment that promote tissue regeneration and will not activate the immune response and lead to graft rejection.

Dr. Rivka Ofir
Collection Editor

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Keywords

  • biomaterials
  • organoid
  • scaffold
  • in vitro drug discovery
  • tissue engineering
  • cell transplantation
  • immune modulation

Published Papers (22 papers)

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12 pages, 2879 KiB  
Article
Addition of Synthetic Biomaterials to Deproteinized Bovine Bone Mineral (DBBM) for Bone Augmentation—A Preclinical In Vivo Study
by Masako Fujioka-Kobayashi, Hiroki Katagiri, Niklaus P. Lang, Jean-Claude Imber, Benoit Schaller and Nikola Saulacic
Int. J. Mol. Sci. 2022, 23(18), 10516; https://doi.org/10.3390/ijms231810516 - 10 Sep 2022
Viewed by 1469
Abstract
(1) Aim: To investigate the effect of synthetic bone substitutes, α-tricalcium phosphate (α-TCP) or bi-layered biphasic calcium-phosphate (BBCP) combined with deproteinized bovine bone mineral (DBBM), on bone formation. (2) Methods: Thirty critical size defects were randomly treated with the following five different treatment [...] Read more.
(1) Aim: To investigate the effect of synthetic bone substitutes, α-tricalcium phosphate (α-TCP) or bi-layered biphasic calcium-phosphate (BBCP) combined with deproteinized bovine bone mineral (DBBM), on bone formation. (2) Methods: Thirty critical size defects were randomly treated with the following five different treatment modalities: (1) negative control (NC, empty), (2) DBBM, (3) α-TCP + DBBM (1:1), (4) BBCP 3%HA/97%α-TCP + DBBM (1:1), and (5) BBCP 6%HA/94%α-TCP + DBBM (1:1). The samples, at four weeks post-surgery, were investigated by micro-CT and histological analysis. (3) Results: A similar level of new bone formation was demonstrated in the DBBM with α-TCP bone substitute groups when compared to the negative control by histomorphometry. DBBM alone showed significantly lower new bone area than the negative control (p = 0.0252). In contrast to DBBM, the micro-CT analysis revealed resorption of the α-TCP + DBBM, BBCP 3%HA/97%α-TCP + DBBM and BBCP 6%HA/94%α-TCP + DBBM, as evidenced by a decrease of material density (p = 0.0083, p = 0.0050 and p = 0.0191, respectively), without changing their volume. (4) Conclusions: New bone formation was evident in all defects augmented with biomaterials, proving the osteoconductive properties of the tested material combinations. There was little impact of the HA coating degree on α-TCP in bone augmentation potential and material resorption for four weeks when mixed with DBBM. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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24 pages, 7733 KiB  
Article
Functionalized Nanogels with Endothelin-1 and Bradykinin Receptor Antagonist Peptides Decrease Inflammatory and Cartilage Degradation Markers of Osteoarthritis in a Horse Organoid Model of Cartilage
by Aurélie Cullier, Frédéric Cassé, Seng Manivong, Romain Contentin, Florence Legendre, Aracéli Garcia Ac, Pierre Sirois, Gaëlle Roullin, Xavier Banquy, Florina Moldovan, Lélia Bertoni, Fabrice Audigié, Philippe Galéra and Magali Demoor
Int. J. Mol. Sci. 2022, 23(16), 8949; https://doi.org/10.3390/ijms23168949 - 11 Aug 2022
Cited by 8 | Viewed by 2154
Abstract
Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat [...] Read more.
Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat OA is the use of drug delivery systems (DDS) to release bioactive molecules over a long period of time directly into the joint to limit inflammation, control pain, and reduce cartilage degradation. Two vasoactive peptides, endothelin-1 and bradykinin, play important roles in OA pathogenesis. In this study, we investigated the effects of two functionalized nanogels as DDS. We assessed the effect of chitosan functionalized with a type A endothelin receptor antagonist (BQ-123-CHI) and/or hyaluronic acid functionalized with a type B1 bradykinin receptor antagonist (R-954-HA). The biocompatibility of these nanogels, alone or in combination, was first validated on equine articular chondrocytes cultured under different oxic conditions. Further, in an OA equine organoid model via induction with interleukin-1 beta (IL-1β), a combination of BQ-123-CHI and R-954-HA (BR5) triggered the greatest decrease in inflammatory and catabolic markers. In basal and OA conditions, BQ-123-CHI alone or in equimolar combinations with R-954-HA had weak pro-anabolic effects on collagens synthesis. These new nanogels, as part of a composite DDS, show promising attributes for treating OA. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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19 pages, 3065 KiB  
Article
Poly-Alanine-ε-Caprolacton-Methacrylate as Scaffold Material with Tuneable Biomechanical Properties for Osteochondral Implants
by Nicole Hauptmann, Johanna Ludolph, Holger Rothe, Jürgen Rost, Alexander Krupp, Jörg Lechner, Svenja Kohlhaas, Manuela Winkler, Benedikt Stender, Gerhard Hildebrand and Klaus Liefeith
Int. J. Mol. Sci. 2022, 23(6), 3115; https://doi.org/10.3390/ijms23063115 - 14 Mar 2022
Cited by 3 | Viewed by 2787
Abstract
An aging population and injury-related damage of the bone substance lead to an increasing need of innovative materials for the regeneration of osteochondral defects. Biodegradable polymers form the basis for suitable artificial implants intended for bone replacement or bone augmentation. The great advantage [...] Read more.
An aging population and injury-related damage of the bone substance lead to an increasing need of innovative materials for the regeneration of osteochondral defects. Biodegradable polymers form the basis for suitable artificial implants intended for bone replacement or bone augmentation. The great advantage of these structures is the site-specific implant design, which leads to a considerable improvement in patient outcomes and significantly reduced post-operative regeneration times. Thus, biomechanical and biochemical parameters as well as the rate of degradation can be set by the selection of the polymer system and the processing technology. Within this study, we developed a polymer platform based on the amino acid Alanine and ε-Caprolacton for use as raw material for osteochondral implants. The biomechanical and degradation properties of these Poly-(Alanine-co-ε-Caprolacton)-Methacrylate (ACM) copolymers can be adjusted by changing the ratio of the monomers. Fabrication of artificial structures for musculo-skeletal tissue engineering was done by Two-Photon-Polymerization (2PP), which represents an innovative technique for generating defined scaffolds with tailor-made mechanical and structural properties. Here we show the synthesis, physicochemical characterization, as well as first results for structuring ACM using 2PP technology. The data demonstrate the high potential of ACM copolymers as precursors for the fabrication of biomimetic implants for bone-cartilage reconstruction. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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16 pages, 22179 KiB  
Article
Mesenchymal Stem-Cell Remodeling of Adsorbed Type-I Collagen—The Effect of Collagen Oxidation
by Regina Komsa-Penkova, Galya Stavreva, Kalina Belemezova, Stanimir Kyurkchiev, Svetla Todinova and George Altankov
Int. J. Mol. Sci. 2022, 23(6), 3058; https://doi.org/10.3390/ijms23063058 - 11 Mar 2022
Cited by 4 | Viewed by 2116
Abstract
This study describes the effect of collagen type I (Col I) oxidation on its physiological remodeling by adipose tissue-derived mesenchymal stem cells (ADMSCs), both mechanical and proteolytic, as an in vitro model for the acute oxidative stress that may occur in vivo upon [...] Read more.
This study describes the effect of collagen type I (Col I) oxidation on its physiological remodeling by adipose tissue-derived mesenchymal stem cells (ADMSCs), both mechanical and proteolytic, as an in vitro model for the acute oxidative stress that may occur in vivo upon distinct environmental changes. Morphologically, remodeling was interpreted as the mechanical rearrangement of adsorbed FITC-labelled Col I into a fibril-like pattern. This process was strongly abrogated in cells cultured on oxidized Col I albeit without visible changes in cell morphology. Proteolytic activity was quantified utilizing fluorescence de-quenching (FRET effect). The presence of ADMSCs caused a significant increase in native FITC-Col I fluorescence, which was almost absent in the oxidized samples. Parallel studies in a cell-free system confirmed the enzymatic de-quenching of native FITC-Col I by Clostridial collagenase with statistically significant inhibition occurring in the oxidized samples. Structural changes to the oxidized Col I were further studied by differential scanning calorimetry. In the oxidized samples, an additional endotherm with sustained enthalpy (∆H) was observed at 33.6 °C along with Col I’s typical one at 40.5 °C. Collectively, these data support that the remodeling of Col I by ADMSCs is altered upon oxidation due to intrinsic changes to the protein’s structure, which represents a novel mechanism for the control of stem cell behavior. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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16 pages, 2721 KiB  
Article
Activin A Promotes Osteoblastic Differentiation of Human Preosteoblasts through the ALK1-Smad1/5/9 Pathway
by Hideki Sugii, Mhd Safwan Albougha, Orie Adachi, Hiroka Tomita, Atsushi Tomokiyo, Sayuri Hamano, Daigaku Hasegawa, Shinichiro Yoshida, Tomohiro Itoyama and Hidefumi Maeda
Int. J. Mol. Sci. 2021, 22(24), 13491; https://doi.org/10.3390/ijms222413491 - 16 Dec 2021
Cited by 2 | Viewed by 3044
Abstract
Activin A, a member of transforming growth factor-β superfamily, is involved in the regulation of cellular differentiation and promotes tissue healing. Previously, we reported that expression of activin A was upregulated around the damaged periodontal tissue including periodontal ligament (PDL) tissue and alveolar [...] Read more.
Activin A, a member of transforming growth factor-β superfamily, is involved in the regulation of cellular differentiation and promotes tissue healing. Previously, we reported that expression of activin A was upregulated around the damaged periodontal tissue including periodontal ligament (PDL) tissue and alveolar bone, and activin A promoted PDL-related gene expression of human PDL cells (HPDLCs). However, little is known about the biological function of activin A in alveolar bone. Thus, this study analyzed activin A-induced biological functions in preosteoblasts (Saos2 cells). Activin A promoted osteoblastic differentiation of Saos2 cells. Activin receptor-like kinase (ALK) 1, an activin type I receptor, was more strongly expressed in Saos2 cells than in HPDLCs, and knockdown of ALK1 inhibited activin A-induced osteoblastic differentiation of Saos2 cells. Expression of ALK1 was upregulated in alveolar bone around damaged periodontal tissue when compared with a nondamaged site. Furthermore, activin A promoted phosphorylation of Smad1/5/9 during osteoblastic differentiation of Saos2 cells and knockdown of ALK1 inhibited activin A-induced phosphorylation of Smad1/5/9 in Saos2 cells. Collectively, these findings suggest that activin A promotes osteoblastic differentiation of preosteoblasts through the ALK1-Smad1/5/9 pathway and could be used as a therapeutic product for the healing of alveolar bone as well as PDL tissue. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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15 pages, 4732 KiB  
Article
Nano-Sized Extracellular Matrix Particles Lead to Therapeutic Improvement for Cutaneous Wound and Hindlimb Ischemia
by Sang Su Ha, Jung-Hyun Kim, Cininta Savitri, Donghoon Choi and Kwideok Park
Int. J. Mol. Sci. 2021, 22(24), 13265; https://doi.org/10.3390/ijms222413265 - 9 Dec 2021
Cited by 2 | Viewed by 2518
Abstract
Cell-derived matrix (CDM) has proven its therapeutic potential and been utilized as a promising resource in tissue regeneration. In this study, we prepared a human fibroblast-derived matrix (FDM) by decellularization of in vitro cultured cells and transformed the FDM into a nano-sized suspended [...] Read more.
Cell-derived matrix (CDM) has proven its therapeutic potential and been utilized as a promising resource in tissue regeneration. In this study, we prepared a human fibroblast-derived matrix (FDM) by decellularization of in vitro cultured cells and transformed the FDM into a nano-sized suspended formulation (sFDM) using ultrasonication. The sFDM was then homogeneously mixed with Pluronic F127 and hyaluronic acid (HA), to effectively administer sFDM into target sites. Both sFDM and sFDM containing hydrogel (PH/sFDM) were characterized via immunofluorescence, sol–gel transition, rheological analysis, and biochemical factors array. We found that PH/sFDM hydrogel has biocompatible, mechanically stable, injectable properties and can be easily administered into the external and internal target regions. sFDM itself holds diverse bioactive molecules. Interestingly, sFDM-containing serum-free media helped maintain the metabolic activity of endothelial cells significantly better than those in serum-free condition. PH/sFDM also promoted vascular endothelial growth factor (VEGF) secretion from monocytes in vitro. Moreover, when we evaluated therapeutic effects of PH/sFDM via the murine full-thickness skin wound model, regenerative potential of PH/sFDM was supported by epidermal thickness, significantly more neovessel formation, and enhanced mature collagen deposition. The hindlimb ischemia model also found some therapeutic improvements, as assessed by accelerated blood reperfusion and substantially diminished necrosis and fibrosis in the gastrocnemius and tibialis muscles. Together, based on sFDM holding a strong therapeutic potential, our engineered hydrogel (PH/sFDM) should be a promising candidate in tissue engineering and regenerative medicine. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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14 pages, 7304 KiB  
Article
Suppression of Bone Necrosis around Tooth Extraction Socket in a MRONJ-like Mouse Model by E-rhBMP-2 Containing Artificial Bone Graft Administration
by Yukie Tanaka, Kyaw Thu Aung, Mitsuaki Ono, Akihiro Mikai, Anh Tuan Dang, Emilio Satoshi Hara, Ikue Tosa, Kei Ishibashi, Aya Ono-Kimura, Kumiko Nawachi, Takuo Kuboki and Toshitaka Oohashi
Int. J. Mol. Sci. 2021, 22(23), 12823; https://doi.org/10.3390/ijms222312823 - 26 Nov 2021
Cited by 2 | Viewed by 2902
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is related to impaired bone healing conditions in the maxillomandibular bone region as a complication of bisphosphonate intake. Although there are several hypotheses for the onset of MRONJ symptoms, one of the possible causes is the inhibition [...] Read more.
Medication-related osteonecrosis of the jaw (MRONJ) is related to impaired bone healing conditions in the maxillomandibular bone region as a complication of bisphosphonate intake. Although there are several hypotheses for the onset of MRONJ symptoms, one of the possible causes is the inhibition of bone turnover and blood supply leading to bone necrosis. The optimal treatment strategy for MRONJ has not been established either. BMP-2, a member of the TGF-β superfamily, is well known for regulating bone remodeling and homeostasis prenatally and postnatally. Therefore, the objectives of this study were to evaluate whether cyclophosphamide/zoledronate (CY/ZA) induces necrosis of the bone surrounding the tooth extraction socket, and to examine the therapeutic potential of BMP-2 in combination with the hard osteoinductive biomaterial, β-tricalcium phosphate (β-TCP), in the prevention and treatment of alveolar bone loss around the tooth extraction socket in MRONJ-like mice models. First, CY/ZA was intraperitoneally administered for three weeks, and alveolar bone necrosis was evaluated before and after tooth extraction. Next, the effect of BMP-2/β-TCP was investigated in both MRONJ-like prevention and treatment models. In the prevention model, CY/ZA was continuously administered for four weeks after BMP-2/β-TCP transplantation. In the treatment model, CY/ZA administration was suspended after transplantation of BMP-2/β-TCP. The results showed that CY/ZA induced a significant decrease in the number of empty lacunae, a sign of bone necrosis, in the alveolar bone around the tooth extraction socket after tooth extraction. Histological analysis showed a significant decrease in the necrotic alveolar bone around tooth extraction sockets in the BMP-2/β-TCP transplantation group compared to the non-transplanted control group in both MRONJ-like prevention and treatment models. However, bone mineral density, determined by micro-CT analysis, was significantly higher in the BMP-2/β-TCP transplanted group than in the control group in the prevention model only. These results clarified that alveolar bone necrosis around tooth extraction sockets can be induced after surgical intervention under CY/ZA administration. In addition, transplantation of BMP-2/β-TCP reduced the necrotic alveolar bone around the tooth extraction socket. Therefore, a combination of BMP-2/β-TCP could be an alternative approach for both prevention and treatment of MRONJ-like symptoms. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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20 pages, 4020 KiB  
Article
Extracellular Matrix Hydrogels Originated from Different Organs Mediate Tissue-Specific Properties and Function
by Tzila Davidov, Yael Efraim, Rotem Hayam, Jacopo Oieni, Limor Baruch and Marcelle Machluf
Int. J. Mol. Sci. 2021, 22(21), 11624; https://doi.org/10.3390/ijms222111624 - 27 Oct 2021
Cited by 18 | Viewed by 3216
Abstract
Porcine extracellular matrix (pECM)-derived hydrogels were introduced, in recent years, aiming to benefit the pECM’s microstructure and bioactivity, while controlling the biomaterial’s physical and mechanical properties. The use of pECM from different tissues, however, offers tissue-specific features that can better serve different applications. [...] Read more.
Porcine extracellular matrix (pECM)-derived hydrogels were introduced, in recent years, aiming to benefit the pECM’s microstructure and bioactivity, while controlling the biomaterial’s physical and mechanical properties. The use of pECM from different tissues, however, offers tissue-specific features that can better serve different applications. In this study, pECM hydrogels derived from cardiac, artery, pancreas, and adipose tissues were compared in terms of composition, structure, and mechanical properties. While major similarities were demonstrated between all the pECM hydrogels, their distinctive attributes were also identified, and their substantial effects on cell-ECM interactions were revealed. Furthermore, through comprehensive protein and gene expression analyses, we show, for the first time, that each pECM hydrogel supports the spontaneous differentiation of induced pluripotent stem cells towards the resident cells of its origin tissue. These findings imply that the origin of ECM should be carefully considered when designing a biomedical platform, to achieve a maximal bioactive impact. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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27 pages, 9913 KiB  
Article
From Primary MSC Culture of Adipose Tissue to Immortalized Cell Line Producing Cytokines for Potential Use in Regenerative Medicine Therapy or Immunotherapy
by Maria Paprocka, Honorata Kraskiewicz, Aleksandra Bielawska-Pohl, Agnieszka Krawczenko, Leszek Masłowski, Agnieszka Czyżewska-Buczyńska, Wojciech Witkiewicz, Danuta Dus and Anna Czarnecka
Int. J. Mol. Sci. 2021, 22(21), 11439; https://doi.org/10.3390/ijms222111439 - 23 Oct 2021
Cited by 7 | Viewed by 2044
Abstract
For twenty-five years, attempts have been made to use MSCs in the treatment of various diseases due to their regenerative and immunomodulatory properties. However, the results are not satisfactory. Assuming that MSCs can be replaced in some therapies by the active factors they [...] Read more.
For twenty-five years, attempts have been made to use MSCs in the treatment of various diseases due to their regenerative and immunomodulatory properties. However, the results are not satisfactory. Assuming that MSCs can be replaced in some therapies by the active factors they produce, the immortalized MSCs line was established from human adipose tissue (HATMSC1) to produce conditioned media and test its regenerative potential in vitro in terms of possible clinical application. The production of biologically active factors by primary MSCs was lower compared to the HATMSC1 cell line and several factors were produced only by the cell line. It has been shown that an HATMSC1-conditioned medium increases the proliferation of various cell types, augments the adhesion of cells and improves endothelial cell function. It was found that hypoxia during culture resulted in an augmentation in the pro-angiogenic factors production, such as VEGF, IL-8, Angiogenin and MCP-1. The immunomodulatory factors caused an increase in the production of GM-CSF, IL-5, IL-6, MCP-1, RANTES and IL-8. These data suggest that these factors, produced under different culture conditions, could be used for different medical conditions, such as in regenerative medicine, when an increased concentration of pro-angiogenic factors may be beneficial, or in inflammatory diseases with conditioned media with a high concentration of immunomodulatory factors. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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13 pages, 2186 KiB  
Communication
Kinases of the Focal Adhesion Complex Contribute to Cardiomyocyte Specification
by Sacha Robert, Marcus Flowers and Brenda M. Ogle
Int. J. Mol. Sci. 2021, 22(19), 10430; https://doi.org/10.3390/ijms221910430 - 28 Sep 2021
Cited by 4 | Viewed by 1685
Abstract
Differentiation of pluripotent stem cells to cardiomyocytes is influenced by culture conditions including the extracellular matrices or similar synthetic scaffolds on which they are grown. However, the molecular mechanisms that link the scaffold with differentiation outcomes are not fully known. Here, we determined [...] Read more.
Differentiation of pluripotent stem cells to cardiomyocytes is influenced by culture conditions including the extracellular matrices or similar synthetic scaffolds on which they are grown. However, the molecular mechanisms that link the scaffold with differentiation outcomes are not fully known. Here, we determined by immunofluorescence staining and mass spectrometry approaches that extracellular matrix (ECM) engagement by mouse pluripotent stem cells activates critical components of canonical wingless/integrated (Wnt) signaling pathways via kinases of the focal adhesion to drive cardiomyogenesis. These kinases were found to be differentially activated depending on type of ECM engaged. These outcomes begin to explain how varied ECM composition of in vivo tissues with development and in vitro model systems gives rise to different mature cell types, having broad practical applicability for the design of engineered tissues. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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15 pages, 4808 KiB  
Article
Myogenic Potential of Extracellular Matrix Derived from Decellularized Bovine Pericardium
by Flavia Carton, Dalila Di Francesco, Luca Fusaro, Emma Zanella, Claudio Apostolo, Francesca Oltolina, Diego Cotella, Maria Prat and Francesca Boccafoschi
Int. J. Mol. Sci. 2021, 22(17), 9406; https://doi.org/10.3390/ijms22179406 - 30 Aug 2021
Cited by 12 | Viewed by 2686
Abstract
Skeletal muscles represent 40% of body mass and its native regenerative capacity can be permanently lost after a traumatic injury, congenital diseases, or tumor ablation. The absence of physiological regeneration can hinder muscle repair preventing normal muscle tissue functions. To date, tissue engineering [...] Read more.
Skeletal muscles represent 40% of body mass and its native regenerative capacity can be permanently lost after a traumatic injury, congenital diseases, or tumor ablation. The absence of physiological regeneration can hinder muscle repair preventing normal muscle tissue functions. To date, tissue engineering (TE) represents one promising option for treating muscle injuries and wasting. In particular, hydrogels derived from the decellularized extracellular matrix (dECM) are widely investigated in tissue engineering applications thanks to their essential role in guiding muscle regeneration. In this work, the myogenic potential of dECM substrate, obtained from decellularized bovine pericardium (Tissuegraft Srl), was evaluated in vitro using C2C12 murine muscle cells. To assess myotubes formation, the width, length, and fusion indexes were measured during the differentiation time course. Additionally, the ability of dECM to support myogenesis was assessed by measuring the expression of specific myogenic markers: α-smooth muscle actin (α-sma), myogenin, and myosin heavy chain (MHC). The results obtained suggest that the dECM niche was able to support and enhance the myogenic potential of C2C12 cells in comparison of those grown on a plastic standard surface. Thus, the use of extracellular matrix proteins, as biomaterial supports, could represent a promising therapeutic strategy for skeletal muscle tissue engineering. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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19 pages, 4292 KiB  
Article
Analysis of CGF Biomolecules, Structure and Cell Population: Characterization of the Stemness Features of CGF Cells and Osteogenic Potential
by Eleonora Stanca, Nadia Calabriso, Laura Giannotti, Paola Nitti, Fabrizio Damiano, Benedetta Di Chiara Stanca, Maria Annunziata Carluccio, Giuseppe Egidio De Benedetto, Christian Demitri, Andrea Palermo, Franco Ferrante, Luisa Siculella and Alessio Rochira
Int. J. Mol. Sci. 2021, 22(16), 8867; https://doi.org/10.3390/ijms22168867 - 18 Aug 2021
Cited by 32 | Viewed by 3037
Abstract
Concentrated Growth Factors (CGF) represent new autologous (blood-derived biomaterial), attracting growing interest in the field of regenerative medicine. In this study, the chemical, structural, and biological characterization of CGF was carried out. CGF molecular characterization was performed by GC/MS to quantify small metabolites [...] Read more.
Concentrated Growth Factors (CGF) represent new autologous (blood-derived biomaterial), attracting growing interest in the field of regenerative medicine. In this study, the chemical, structural, and biological characterization of CGF was carried out. CGF molecular characterization was performed by GC/MS to quantify small metabolites and by ELISA to measure growth factors and matrix metalloproteinases (MMPs) release; structural CGF characterization was carried out by SEM analysis and immunohistochemistry; CGF has been cultured, and its primary cells were isolated for the identification of their surface markers by flow cytometry, Western blot, and real-time PCR; finally, the osteogenic differentiation of CGF primary cells was evaluated through matrix mineralization by alizarin red staining and through mRNA quantification of osteogenic differentiation markers by real-time PCR. We found that CGF has a complex inner structure capable of influencing the release of growth factors, metabolites, and cells. These cells, which could regulate the production and release of the CGF growth factors, show stem features and are able to differentiate into osteoblasts producing a mineralized matrix. These data, taken together, highlight interesting new perspectives for the use of CGF in regenerative medicine. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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18 pages, 5618 KiB  
Article
Synthesis and Characterization of Novel Quaternary Ammonium Urethane-Dimethacrylate Monomers—A Pilot Study
by Marta W. Chrószcz and Izabela M. Barszczewska-Rybarek
Int. J. Mol. Sci. 2021, 22(16), 8842; https://doi.org/10.3390/ijms22168842 - 17 Aug 2021
Cited by 12 | Viewed by 2121
Abstract
Six novel urethane-dimethacrylate analogues (QAUDMAs) were synthesized and characterized. They consisted of the 2,4,4,-trimethylhexamethylene diisocyanate (TMDI) core and two methacrylate-terminated wings containing quaternary ammonium groups substituted with alkyl chains of 8, 10, 12, 14, 16, or 18 carbon atoms. QAUDMAs, due to the [...] Read more.
Six novel urethane-dimethacrylate analogues (QAUDMAs) were synthesized and characterized. They consisted of the 2,4,4,-trimethylhexamethylene diisocyanate (TMDI) core and two methacrylate-terminated wings containing quaternary ammonium groups substituted with alkyl chains of 8, 10, 12, 14, 16, or 18 carbon atoms. QAUDMAs, due to the presence of quaternary ammonium groups, may have possible antibacterial effects. Since they showed satisfactory physicochemical properties, they will be subjected to further research towards the development of dental composites with a capacity to reduce secondary caries. The synthesis of QAUDMAs included three stages: (i) transesterification of methyl methacrylate (MMA) with N-methyldiethanolamine (MDEA), (ii) N-alkylation of the tertiary amino group with alkyl bromide, and (iii) addition of TMDI to the intermediate achieved in the second stage. The formation of QAUDMAs was confirmed by 1H and 13C NMR. They were characterized for density (dm), viscosity (η), refractive index (RI), glass transition temperature (Tg), polymerization shrinkage (S), and degree of conversion (DC). QAUDMAs were yellow, viscous resins (the η values ranged from 1.28 × 103 to 1.39 × 104 Pa·s, at 50 °C). Their RI ranged from 1.50 to 1.52, Tg from −31 to −15 °C, DC from 53 to 78%, and S from 1.24 to 2.99%, which is appropriate for dental applications. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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16 pages, 3924 KiB  
Article
Decellularised Human Umbilical Artery as a Vascular Graft Elicits Minimal Pro-Inflammatory Host Response Ex Vivo and In Vivo
by Alexander Høgsted Ahlmann, Shu Fang, Sussi Bagge Mortensen, Line Weis Andersen, Pernille Gejl Pedersen, Johanne Juel Callesen, Sara Thornby Bak, Kate Lykke Lambertsen and Ditte Caroline Andersen
Int. J. Mol. Sci. 2021, 22(15), 7981; https://doi.org/10.3390/ijms22157981 - 26 Jul 2021
Cited by 4 | Viewed by 2348
Abstract
Small diameter (<6 mm) vessel grafts still pose a challenge for scientists worldwide. Decellularised umbilical artery (dUA) remains promising as small diameter tissue engineered vascular graft (TEVG), yet their immunogenicity remains unknown. Herein, we evaluated the host immune responses, with a focus on [...] Read more.
Small diameter (<6 mm) vessel grafts still pose a challenge for scientists worldwide. Decellularised umbilical artery (dUA) remains promising as small diameter tissue engineered vascular graft (TEVG), yet their immunogenicity remains unknown. Herein, we evaluated the host immune responses, with a focus on the innate part, towards human dUA implantation in mice, and confirmed our findings in an ex vivo allogeneic human setup. Overall, we did not observe any differences in the number of circulating white blood cells nor the number of monocytes among three groups of mice (1) dUA patch; (2) Sham; and (3) Mock throughout the study (day −7 to 28). Likewise, we found no difference in systemic inflammatory and anti-inflammatory cytokine levels between groups. However, a massive local remodelling response with M2 macrophages were observed in the dUA at day 28, whereas M1 macrophages were less frequent. Moreover, human monocytes from allogeneic individuals were differentiated into macrophages and exposed to lyophilised dUA to maximize an eventual M1 response. Yet, dUA did not elicit any immediate M1 response as determined by the absence of CCR7 and CXCL10. Together this suggests that human dUA elicits a minimal pro-inflammatory response further supporting its use as a TEVG in an allogeneic setup. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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Review

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23 pages, 2778 KiB  
Review
The Role of Biomaterials in Peripheral Nerve and Spinal Cord Injury: A Review
by Ben Kaplan and Shulamit Levenberg
Int. J. Mol. Sci. 2022, 23(3), 1244; https://doi.org/10.3390/ijms23031244 - 23 Jan 2022
Cited by 27 | Viewed by 7130
Abstract
Peripheral nerve and spinal cord injuries are potentially devastating traumatic conditions with major consequences for patients’ lives. Severe cases of these conditions are currently incurable. In both the peripheral nerves and the spinal cord, disruption and degeneration of axons is the main cause [...] Read more.
Peripheral nerve and spinal cord injuries are potentially devastating traumatic conditions with major consequences for patients’ lives. Severe cases of these conditions are currently incurable. In both the peripheral nerves and the spinal cord, disruption and degeneration of axons is the main cause of neurological deficits. Biomaterials offer experimental solutions to improve these conditions. They can be engineered as scaffolds that mimic the nerve tissue extracellular matrix and, upon implantation, encourage axonal regeneration. Furthermore, biomaterial scaffolds can be designed to deliver therapeutic agents to the lesion site. This article presents the principles and recent advances in the use of biomaterials for axonal regeneration and nervous system repair. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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11 pages, 253 KiB  
Review
Adipose Tissue Uses in Peripheral Nerve Surgery
by Allison Podsednik, Raysa Cabrejo and Joseph Rosen
Int. J. Mol. Sci. 2022, 23(2), 644; https://doi.org/10.3390/ijms23020644 - 7 Jan 2022
Cited by 11 | Viewed by 2187
Abstract
Currently, many different techniques exist for the surgical repair of peripheral nerves. The degree of injury dictates the repair and, depending on the defect or injury of the peripheral nerve, plastic surgeons can perform nerve repairs, grafts, and transfers. All the previously listed [...] Read more.
Currently, many different techniques exist for the surgical repair of peripheral nerves. The degree of injury dictates the repair and, depending on the defect or injury of the peripheral nerve, plastic surgeons can perform nerve repairs, grafts, and transfers. All the previously listed techniques are routinely performed in human patients, but a novel addition to these peripheral nerve surgeries involves concomitant fat grafting to the repair site at the time of surgery. Fat grafting provides adipose-derived stem cells to the injury site. Though fat grafting is performed as an adjunct to some peripheral nerve surgeries, there is no clear evidence as to which procedures have improved outcomes resultant from concomitant fat grafting. This review explores the evidence presented in various animal studies regarding outcomes of fat grafting at the time of various types of peripheral nerve surgery. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
27 pages, 12234 KiB  
Review
Application of Graphene in Tissue Engineering of the Nervous System
by Karolina Ławkowska, Marta Pokrywczyńska, Krzysztof Koper, Luis Alex Kluth, Tomasz Drewa and Jan Adamowicz
Int. J. Mol. Sci. 2022, 23(1), 33; https://doi.org/10.3390/ijms23010033 - 21 Dec 2021
Cited by 17 | Viewed by 5331
Abstract
Graphene is the thinnest two-dimensional (2D), only one carbon atom thick, but one of the strongest biomaterials. Due to its unique structure, it has many unique properties used in tissue engineering of the nervous system, such as high strength, flexibility, adequate softness, electrical [...] Read more.
Graphene is the thinnest two-dimensional (2D), only one carbon atom thick, but one of the strongest biomaterials. Due to its unique structure, it has many unique properties used in tissue engineering of the nervous system, such as high strength, flexibility, adequate softness, electrical conductivity, antibacterial effect, and the ability to penetrate the blood–brain barrier (BBB). Graphene is also characterized by the possibility of modifications that allow for even wider application and adaptation to cell cultures of specific cells and tissues, both in vitro and in vivo. Moreover, by using the patient’s own cells for cell culture, it will be possible to produce tissues and organs that can be re-transplanted without transplant rejection, the negative effects of taking immunosuppressive drugs, and waiting for an appropriate organ donor. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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38 pages, 1091 KiB  
Review
Therapeutic Acellular Scaffolds for Limiting Left Ventricular Remodelling-Current Status and Future Directions
by Sadia Perveen, Daniela Rossin, Emanuela Vitale, Rachele Rosso, Roberto Vanni, Caterina Cristallini, Raffaella Rastaldo and Claudia Giachino
Int. J. Mol. Sci. 2021, 22(23), 13054; https://doi.org/10.3390/ijms222313054 - 2 Dec 2021
Cited by 5 | Viewed by 2873
Abstract
Myocardial infarction (MI) is one of the leading causes of heart-related deaths worldwide. Following MI, the hypoxic microenvironment triggers apoptosis, disrupts the extracellular matrix and forms a non-functional scar that leads towards adverse left ventricular (LV) remodelling. If left untreated this eventually leads [...] Read more.
Myocardial infarction (MI) is one of the leading causes of heart-related deaths worldwide. Following MI, the hypoxic microenvironment triggers apoptosis, disrupts the extracellular matrix and forms a non-functional scar that leads towards adverse left ventricular (LV) remodelling. If left untreated this eventually leads to heart failure. Besides extensive advancement in medical therapy, complete functional recovery is never accomplished, as the heart possesses limited regenerative ability. In recent decades, the focus has shifted towards tissue engineering and regenerative strategies that provide an attractive option to improve cardiac regeneration, limit adverse LV remodelling and restore function in an infarcted heart. Acellular scaffolds possess attractive features that have made them a promising therapeutic candidate. Their application in infarcted areas has been shown to improve LV remodelling and enhance functional recovery in post-MI hearts. This review will summarise the updates on acellular scaffolds developed and tested in pre-clinical and clinical scenarios in the past five years with a focus on their ability to overcome damage caused by MI. It will also describe how acellular scaffolds alone or in combination with biomolecules have been employed for MI treatment. A better understanding of acellular scaffolds potentialities may guide the development of customised and optimised therapeutic strategies for MI treatment. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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24 pages, 4472 KiB  
Review
The Significance of Biomechanics and Scaffold Structure for Bladder Tissue Engineering
by Marta Hanczar, Mehran Moazen and Richard Day
Int. J. Mol. Sci. 2021, 22(23), 12657; https://doi.org/10.3390/ijms222312657 - 23 Nov 2021
Cited by 10 | Viewed by 4214
Abstract
Current approaches for bladder reconstruction surgery are associated with many morbidities. Tissue engineering is considered an ideal approach to create constructs capable of restoring the function of the bladder wall. However, many constructs to date have failed to create a sufficient improvement in [...] Read more.
Current approaches for bladder reconstruction surgery are associated with many morbidities. Tissue engineering is considered an ideal approach to create constructs capable of restoring the function of the bladder wall. However, many constructs to date have failed to create a sufficient improvement in bladder capacity due to insufficient neobladder compliance. This review evaluates the biomechanical properties of the bladder wall and how the current reconstructive materials aim to meet this need. To date, limited data from mechanical testing and tissue anisotropy make it challenging to reach a consensus on the native properties of the bladder wall. Many of the materials whose mechanical properties have been quantified do not fall within the range of mechanical properties measured for native bladder wall tissue. Many promising new materials have yet to be mechanically quantified, which makes it difficult to ascertain their likely effectiveness. The impact of scaffold structures and the long-term effect of implanting these materials on their inherent mechanical properties are areas yet to be widely investigated that could provide important insight into the likely longevity of the neobladder construct. In conclusion, there are many opportunities for further investigation into novel materials for bladder reconstruction. Currently, the field would benefit from a consensus on the target values of key mechanical parameters for bladder wall scaffolds. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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13 pages, 1713 KiB  
Review
Towards Biomanufacturing of Cell-Derived Matrices
by Weng Wan Chan, Fang Yu, Quang Bach Le, Sixun Chen, Marcus Yee and Deepak Choudhury
Int. J. Mol. Sci. 2021, 22(21), 11929; https://doi.org/10.3390/ijms222111929 - 3 Nov 2021
Cited by 11 | Viewed by 3254
Abstract
Cell-derived matrices (CDM) are the decellularised extracellular matrices (ECM) of tissues obtained by the laboratory culture process. CDM is developed to mimic, to a certain extent, the properties of the needed natural tissue and thus to obviate the use of animals. The composition [...] Read more.
Cell-derived matrices (CDM) are the decellularised extracellular matrices (ECM) of tissues obtained by the laboratory culture process. CDM is developed to mimic, to a certain extent, the properties of the needed natural tissue and thus to obviate the use of animals. The composition of CDM can be tailored for intended applications by carefully optimising the cell sources, culturing conditions and decellularising methods. This unique advantage has inspired the increasing use of CDM for biomedical research, ranging from stem cell niches to disease modelling and regenerative medicine. However, while much effort is spent on extracting different types of CDM and exploring their utilisation, little is spent on the scale-up aspect of CDM production. The ability to scale up CDM production is essential, as the materials are due for clinical trials and regulatory approval, and in fact, this ability to scale up should be an important factor from the early stages. In this review, we first introduce the current CDM production and characterisation methods. We then describe the existing scale-up technologies for cell culture and highlight the key considerations in scaling-up CDM manufacturing. Finally, we discuss the considerations and challenges faced while converting a laboratory protocol into a full industrial process. Scaling-up CDM manufacturing is a challenging task since it may be hindered by technologies that are not yet available. The early identification of these gaps will not only quicken CDM based product development but also help drive the advancement in scale-up cell culture and ECM extraction. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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25 pages, 5571 KiB  
Review
Isotropic and Anisotropic Scaffolds for Tissue Engineering: Collagen, Conventional, and Textile Fabrication Technologies and Properties
by Robert Tonndorf, Dilbar Aibibu and Chokri Cherif
Int. J. Mol. Sci. 2021, 22(17), 9561; https://doi.org/10.3390/ijms22179561 - 3 Sep 2021
Cited by 14 | Viewed by 5235
Abstract
In this review article, tissue engineering and regenerative medicine are briefly explained and the importance of scaffolds is highlighted. Furthermore, the requirements of scaffolds and how they can be fulfilled by using specific biomaterials and fabrication methods are presented. Detailed insight is given [...] Read more.
In this review article, tissue engineering and regenerative medicine are briefly explained and the importance of scaffolds is highlighted. Furthermore, the requirements of scaffolds and how they can be fulfilled by using specific biomaterials and fabrication methods are presented. Detailed insight is given into the two biopolymers chitosan and collagen. The fabrication methods are divided into two categories: isotropic and anisotropic scaffold fabrication methods. Processable biomaterials and achievable pore sizes are assigned to each method. In addition, fiber spinning methods and textile fabrication methods used to produce anisotropic scaffolds are described in detail and the advantages of anisotropic scaffolds for tissue engineering and regenerative medicine are highlighted. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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17 pages, 1476 KiB  
Review
Intrinsically Conductive Polymers for Striated Cardiac Muscle Repair
by Arsalan Ul Haq, Felicia Carotenuto, Fabio De Matteis, Paolo Prosposito, Roberto Francini, Laura Teodori, Alessandra Pasquo and Paolo Di Nardo
Int. J. Mol. Sci. 2021, 22(16), 8550; https://doi.org/10.3390/ijms22168550 - 9 Aug 2021
Cited by 18 | Viewed by 3320
Abstract
One of the most important features of striated cardiac muscle is the excitability that turns on the excitation-contraction coupling cycle, resulting in the heart blood pumping function. The function of the heart pump may be impaired by events such as myocardial infarction, the [...] Read more.
One of the most important features of striated cardiac muscle is the excitability that turns on the excitation-contraction coupling cycle, resulting in the heart blood pumping function. The function of the heart pump may be impaired by events such as myocardial infarction, the consequence of coronary artery thrombosis due to blood clots or plaques. This results in the death of billions of cardiomyocytes, the formation of scar tissue, and consequently impaired contractility. A whole heart transplant remains the gold standard so far and the current pharmacological approaches tend to stop further myocardium deterioration, but this is not a long-term solution. Electrically conductive, scaffold-based cardiac tissue engineering provides a promising solution to repair the injured myocardium. The non-conductive component of the scaffold provides a biocompatible microenvironment to the cultured cells while the conductive component improves intercellular coupling as well as electrical signal propagation through the scar tissue when implanted at the infarcted site. The in vivo electrical coupling of the cells leads to a better regeneration of the infarcted myocardium, reducing arrhythmias, QRS/QT intervals, and scar size and promoting cardiac cell maturation. This review presents the emerging applications of intrinsically conductive polymers in cardiac tissue engineering to repair post-ischemic myocardial insult. Full article
(This article belongs to the Special Issue Novel Biomaterials for Regenerative Medicine)
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