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Special Issue "Biomaterials for Hard Tissue Regeneration"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Nanochemistry".

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 21648

Special Issue Editor

Prof. Dr. Katrin Susanne Lips
E-Mail Website
Guest Editor
Experimental Trauma Surgery, Justus-Liebig-University Giessen, Aulweg 128, 35392 Giessen, Germany
Interests: regeneration; fracture healing; cartilage defects; cell–material interaction; neuronal and non-neuronal regulation of bone remodeling; cell differentiation; osteoporosis, drug delivery bone substitutes; nanoparticles; immunobone; musculoskeletal disorders

Special Issue Information

Dear Colleagues,

Biomaterials are of great clinical relevance because of their ability to stimulate the regeneration of hard tissues. Multiple cell–material interactions are involved in this process. New methods for manufacturing and modification of materials as well as the establishment of smart materials and biocompatible drug delivery substitutes can lead to adaptation of the already applicable materials as well to new biomaterials. The cellular suitability of new and modified biomaterials needs to be evaluated in preclinical in vitro and in vivo studies as well as clinical trials prior to clinical usage.

This Special Issue aims to provide new insight into the cellular compatibility of new or modified biomaterials that are designed for implantation into defects and fractures of hard tissues. Particularly, the molecular interactions of biomaterials and cells or their extracellular components will be in focus. Therefore, we welcome original research and review manuscripts that report molecular mechanisms of cells at the interface of biomaterials established for hard tissue regeneration.

Prof. Dr. Katrin Susanne Lips
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2300 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular mechanisms
  • cell–material interaction
  • biocompatibility
  • drug delivery bone substitutes
  • biomaterials

Published Papers (11 papers)

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Research

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Article
Porous 3D Scaffolds Enhance MSC Vitality and Reduce Osteoclast Activity
Molecules 2021, 26(20), 6258; https://doi.org/10.3390/molecules26206258 - 16 Oct 2021
Cited by 5 | Viewed by 1207
Abstract
In the context of an aging population, unhealthy Western lifestyle, and the lack of an optimal surgical treatment, deep osteochondral defects pose a great challenge for the public health system. Biodegradable, biomimetic scaffolds seem to be a promising solution. In this study we [...] Read more.
In the context of an aging population, unhealthy Western lifestyle, and the lack of an optimal surgical treatment, deep osteochondral defects pose a great challenge for the public health system. Biodegradable, biomimetic scaffolds seem to be a promising solution. In this study we investigated the biocompatibility of porous poly-((D,L)-lactide-ε-caprolactone)dimethacrylate (LCM) scaffolds in contrast to compact LCM scaffolds and blank cell culture plastic. Thus, morphology, cytotoxicity and metabolic activity of human mesenchymal stromal cells (MSC) seeded directly on the materials were analyzed after three and six days of culturing. Further, osteoclastogenesis and osteoclastic activity were assessed using reverse-transcriptase real-time PCR of osteoclast-specific genes, EIA and morphologic aspects after four, eight, and twelve days. LCM scaffolds did not display cytotoxic effects on MSC. After three days, metabolic activity of MSC was enhanced on 3D porous scaffolds (PS) compared to 2D compact scaffolds (CS). Osteoclast activity seemed to be reduced at PS compared to cell culture plastic at all time points, while no differences in osteoclastogenesis were detectable between the materials. These results indicate a good cytocompatibility of LCM scaffolds. Interestingly, porous 3D structure induced higher metabolic activity of MSC as well as reduced osteoclast activity. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Article
Protaetia brevitarsis seulensis Derived Protein Isolate with Enhanced Osteomodulatory and Antioxidative Property
Molecules 2020, 25(24), 6056; https://doi.org/10.3390/molecules25246056 - 21 Dec 2020
Cited by 7 | Viewed by 1640
Abstract
The osteogenic differentiation of stem cells is profoundly affected by their microenvironmental conditions. The differentiation behavior of stem cells can be tuned by changing the niche environments. The proteins or peptides that are derived by living organisms facilitate the osteogenic differentiation of stem [...] Read more.
The osteogenic differentiation of stem cells is profoundly affected by their microenvironmental conditions. The differentiation behavior of stem cells can be tuned by changing the niche environments. The proteins or peptides that are derived by living organisms facilitate the osteogenic differentiation of stem cells. Here, we have evaluated the osteoinductive and antioxidative potential of the Protaetia brevitarsis seulensis insect-derived protein for human bone marrow-derived mesenchymal stem cells (hBMSCs). The amino acid contents in the isolated protein were determined by an amino acid analyzer. Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) were used to analyze the extract’s functional groups and surface morphology. The extracted protein exhibited 51.08% β-sheet conformation. No adverse effects were observed in extract-treated cells, indicating their biocompatibility. The protein isolate showed an excellent antioxidative property. Besides this, an enhancement in the hBMSCs’ mineralization has been observed in the presence of treated protein isolates. Notably, osteogenic marker genes and proteins were effectively expressed in the treated cells. These results indicated that the P. brevitarsis-derived protein isolate can be used as a potential antioxidative biomaterial for bone tissue engineering applications. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Article
Gelatin-Modified Calcium/Strontium Hydrogen Phosphates Stimulate Bone Regeneration in Osteoblast/Osteoclast Co-Culture and in Osteoporotic Rat Femur Defects—In Vitro to In Vivo Translation
Molecules 2020, 25(21), 5103; https://doi.org/10.3390/molecules25215103 - 03 Nov 2020
Cited by 5 | Viewed by 1702
Abstract
The development and characterization of biomaterials for bone replacement in case of large defects in preconditioned bone (e.g., osteoporosis) require close cooperation of various disciplines. Of particular interest are effects observed in vitro at the cellular level and their in vivo representation in [...] Read more.
The development and characterization of biomaterials for bone replacement in case of large defects in preconditioned bone (e.g., osteoporosis) require close cooperation of various disciplines. Of particular interest are effects observed in vitro at the cellular level and their in vivo representation in animal experiments. In the present case, the material-based alteration of the ratio of osteoblasts to osteoclasts in vitro in the context of their co-cultivation was examined and showed equivalence to the material-based stimulation of bone regeneration in a bone defect of osteoporotic rats. Gelatin-modified calcium/strontium phosphates with a Ca:Sr ratio in their precipitation solutions of 5:5 and 3:7 caused a pro-osteogenic reaction on both levels in vitro and in vivo. Stimulation of osteoblasts and inhibition of osteoclast activity were proven during culture on materials with higher strontium content. The same material caused a decrease in osteoclast activity in vitro. In vivo, a positive effect of the material with increased strontium content was observed by immunohistochemistry, e.g., by significantly increased bone volume to tissue volume ratio, increased bone morphogenetic protein-2 (BMP2) expression, and significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. In addition, material degradation and bone regeneration were examined after 6 weeks using stage scans with ToF-SIMS and µ-CT imaging. The remaining material in the defects and strontium signals, which originate from areas exceeding the defect area, indicate the incorporation of strontium ions into the surrounding mineralized tissue. Thus, the material inherent properties (release of biologically active ions, solubility and degradability, mechanical strength) directly influenced the cellular reaction in vitro and also bone regeneration in vivo. Based on this, in the future, materials might be synthesized and specifically adapted to patient-specific needs and their bone status. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Article
GuttaFlow® Bioseal Cytotoxicity Assessment: In Vitro Study
Molecules 2020, 25(18), 4297; https://doi.org/10.3390/molecules25184297 - 19 Sep 2020
Cited by 3 | Viewed by 2082
Abstract
The sealers used for root canal treatment should be biocompatible for the peri-radicular tissues, to evaluate the cytotoxic effects of GuttaFlow® bioseal sealer and to compare them with AH26® epoxy resin. Culture media were conditioned with the GuttaFlow® bioseal and [...] Read more.
The sealers used for root canal treatment should be biocompatible for the peri-radicular tissues, to evaluate the cytotoxic effects of GuttaFlow® bioseal sealer and to compare them with AH26® epoxy resin. Culture media were conditioned with the GuttaFlow® bioseal and AH26® pellets. MDPC-23 odontoblast cell cultures were treated with conditioned medium and serial dilutions. To evaluate the metabolic activity and cellular viability, the MTT and SRB assays were performed. To determine the production of reactive oxygen species, the DHE and DCF-DA probes were used. Cell cycle and cell-death types were assessed by cytometry, and to evaluate the mineralization capacity, the Alizarin Red S coloration was used. Statistical analysis was performed using analysis of variance (ANOVA) when normality was found and Kruskal-Wallis on the opposite case. For the comparison with normality values, the Student t-test was used. Cells exposed to the GuttaFlow® bioseal conditioned medium maintained high metabolic activities, except at higher concentrations. Likewise, viability was maintained, but a significant decrease was observed after exposure to the highest concentration (p < 0.001), associated with cell death by late apoptosis and necrosis. When cell cultures were exposed to AH26®, metabolic activity was highly compromised, resulting in cell death. An imbalance in the production of peroxides and superoxide anion was observed. GuttaFlow® bioseal showed higher biocompatibility than AH26®. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Article
Effects of BDNF and PEC Nanoparticles on Osteocytes
Molecules 2020, 25(18), 4151; https://doi.org/10.3390/molecules25184151 - 10 Sep 2020
Cited by 3 | Viewed by 1598
Abstract
Bone substitute materials loaded with mediators that stimulate fracture healing are demanded in the clinical treatment in trauma surgery and orthopedics. Brain-derived neurotrophic factor (BDNF) enhances the proliferation and differentiation of mesenchymal stem cells into osteoblast. To load the implants with BDNF, a [...] Read more.
Bone substitute materials loaded with mediators that stimulate fracture healing are demanded in the clinical treatment in trauma surgery and orthopedics. Brain-derived neurotrophic factor (BDNF) enhances the proliferation and differentiation of mesenchymal stem cells into osteoblast. To load the implants with BDNF, a drug delivery system that allows the release of BDNF under spatiotemporal control would improve functionality. Polyelectrolyte complex nanoparticles (PECNP) have been reported as a suitable drug delivery system. The suitability of PECNP in contact with osteocytes as the main cell type of bone is not known so far. Thus, we aimed to verify that BDNF and PECNP loaded with BDNF (PECNP+BDNF) as well as pure PECNP have no negative effects on osteocytes in vitro. Therefore, the murine osteocyte cell line MLO-Y4 was treated with BDNF and PECNP+BDNF. The effects on proliferation were analyzed by the BrdU test (n = 5). The results demonstrated a significant increase in proliferation 24 h after BDNF application, whereas PECNP+BDNF did not lead to significant changes. Thus, we conclude that BDNF is an appropriate mediator to stimulate osteocytes. Since the addition of PECNP did not affect the viability of osteocytes, we conclude that PECNP are a suitable drug delivery system for bone implants. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Article
3D Bioprinted Osteogenic Tissue Models for In Vitro Drug Screening
Molecules 2020, 25(15), 3442; https://doi.org/10.3390/molecules25153442 - 29 Jul 2020
Cited by 6 | Viewed by 1751
Abstract
Metabolic bone disease affects hundreds of millions of people worldwide, and as a result, in vitro models of bone tissue have become essential tools to help analyze bone pathogenesis, develop drug screening, and test potential therapeutic strategies. Drugs that either promote or impair [...] Read more.
Metabolic bone disease affects hundreds of millions of people worldwide, and as a result, in vitro models of bone tissue have become essential tools to help analyze bone pathogenesis, develop drug screening, and test potential therapeutic strategies. Drugs that either promote or impair bone formation are in high demand for the treatment of metabolic bone diseases. These drugs work by targeting numerous signaling pathways responsible for regulating osteogenesis such as Hedgehog, Wnt/β-catenin, and PI3K-AKT. In this study, differentiated bone marrow-derived mesenchymal stem cell (BM-MSC) scaffold-free 3D bioprinted constructs and 2D monolayer cultures were utilized to screen four drugs predicted to either promote (Icariin and Purmorphamine) or impair osteogenesis (PD98059 and U0126). Osteogenic differentiation capacity was analyzed over a four week culture period by evaluating mineralization, alkaline phosphatase (ALP) activity, and osteogenesis related gene expression. Responses to drug treatment were observed in both 3D differentiated constructs and 2D monolayer cultures. After four weeks in culture, 3D differentiated constructs and 2D monolayer cultures treated with Icariin or Purmorphamine showed increased mineralization, ALP activity, and the gene expression of bone formation markers (BGLAP, SSP1, and COL1A1), signaling molecules (MAPK1, WNT1, and AKT1), and transcription factors (RUNX2 and GLI1) that regulate osteogenic differentiation relative to untreated. 3D differentiated constructs and 2D monolayer cultures treated with PD98059 or U0126 showed decreased mineralization, ALP activity, and the expression of the aforementioned genes BGLAP, SPP1, COL1A1, MAPK1, AKT1, RUNX2, and GLI1 relative to untreated. Differences in ALP activity and osteogenesis related gene expression relative to untreated cells cultured in a 2D monolayer were greater in 3D constructs compared to 2D monolayer cultures. These findings suggest that our bioprinted bone model system offers a more sensitive, biologically relevant drug screening platform than traditional 2D monolayer in vitro testing platforms. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Article
In Vitro and In Vivo Biocompatibility Studies of a Cast and Coated Titanium Alloy
Molecules 2020, 25(15), 3399; https://doi.org/10.3390/molecules25153399 - 27 Jul 2020
Cited by 6 | Viewed by 1592
Abstract
The biocompatibility of a cast porous and with a calcium titanate reaction layer functionalized titanium alloy (Ti-6Al-7Nb) was tested by means of cell culture, and a small (rat) and large animal (sheep) model. The uncoated titanium material served as a control. In-vitro tests [...] Read more.
The biocompatibility of a cast porous and with a calcium titanate reaction layer functionalized titanium alloy (Ti-6Al-7Nb) was tested by means of cell culture, and a small (rat) and large animal (sheep) model. The uncoated titanium material served as a control. In-vitro tests included the validation of osteoblast-like cells attached to the surface of the material with scanning electron microscopy and immunofluorescence of cytoskeletal actin as well as their osteogenic development, the ability to mineralize, and their vitality. Following the in-vitro tests a small animal (rat) and big animal (sheep) model were accomplished by inserting a cylindrical titanium implant into a drill hole defect in the femoral condyle. After 7, 14, and 30 days (rat) and 6 months (sheep) the condyles were studied regarding histological and histomorphometrical characteristics. Uncoated and coated material showed a good biocompatibility both in cell culture and animal models. While the defect area in the rat is well consolidated after 30 days, the sheep show only little bone inside the implant after 6 months, possibly due to stress shielding. None of the executed methods indicated a statistically significant difference between coated and uncoated material. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Review

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Review
The Role of Epigenetic Functionalization of Implants and Biomaterials in Osseointegration and Bone Regeneration—A Review
Molecules 2020, 25(24), 5879; https://doi.org/10.3390/molecules25245879 - 12 Dec 2020
Cited by 6 | Viewed by 2073
Abstract
The contribution of epigenetic mechanisms as a potential treatment model has been observed in cancer and autoimmune/inflammatory diseases. This review aims to put forward the epigenetic mechanisms as a promising strategy in implant surface functionalization and modification of biomaterials, to promote better osseointegration [...] Read more.
The contribution of epigenetic mechanisms as a potential treatment model has been observed in cancer and autoimmune/inflammatory diseases. This review aims to put forward the epigenetic mechanisms as a promising strategy in implant surface functionalization and modification of biomaterials, to promote better osseointegration and bone regeneration, and could be applicable for alveolar bone regeneration and osseointegration in the future. Materials and Methods: Electronic and manual searches of the literature in PubMed, MEDLINE, and EMBASE were conducted, using a specific search strategy limited to publications in the last 5 years to identify preclinical studies in order to address the following focused questions: (i) Which, if any, are the epigenetic mechanisms used to functionalize implant surfaces to achieve better osseointegration? (ii) Which, if any, are the epigenetic mechanisms used to functionalize biomaterials to achieve better bone regeneration? Results: Findings from several studies have emphasized the role of miRNAs in functionalizing implants surfaces and biomaterials to promote osseointegration and bone regeneration, respectively. However, there are scarce data on the role of DNA methylation and histone modifications for these specific applications, despite being commonly applied in cancer research. Conclusions: Studies over the past few years have demonstrated that biomaterials are immunomodulatory rather than inert materials. In this context, epigenetics can act as next generation of advanced treatment tools for future regenerative techniques. Yet, there is a need to evaluate the efficacy/cost effectiveness of these techniques in comparison to current standards of care. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Review
Autologous Materials in Regenerative Dentistry: Harvested Bone, Platelet Concentrates and Dentin Derivates
Molecules 2020, 25(22), 5330; https://doi.org/10.3390/molecules25225330 - 15 Nov 2020
Cited by 14 | Viewed by 1528
Abstract
The jawbone is a peculiar type of bone tissue, unique for its histological, anatomical and physiological characteristics. Therefore, a defect in the maxilla or in the mandible, because of pathological sequelae is difficult to prevent and to restore. Several biomaterials have been and [...] Read more.
The jawbone is a peculiar type of bone tissue, unique for its histological, anatomical and physiological characteristics. Therefore, a defect in the maxilla or in the mandible, because of pathological sequelae is difficult to prevent and to restore. Several biomaterials have been and are currently being developed to respond to the demands of regenerative medicine. A specific group of biomaterials used in regenerative dentistry is represented by the autologous materials. Platelet concentrates harvested bone and dentin derivates are indeed used in an attempt to minimise the alveolar resorption or in vertical ridge augmentation procedures or in sinus lift interventions. The aim of this review is to examine the properties of the above-listed materials, to compare them and to indicate eventual clinical applications. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Review
Tooth-Supporting Hard Tissue Regeneration Using Biopolymeric Material Fabrication Strategies
Molecules 2020, 25(20), 4802; https://doi.org/10.3390/molecules25204802 - 19 Oct 2020
Cited by 7 | Viewed by 3647
Abstract
The mineralized tissues (alveolar bone and cementum) are the major components of periodontal tissues and play a critical role to anchor periodontal ligament (PDL) to tooth-root surfaces. The integrated multiple tissues could generate biological or physiological responses to transmitted biomechanical forces by mastication [...] Read more.
The mineralized tissues (alveolar bone and cementum) are the major components of periodontal tissues and play a critical role to anchor periodontal ligament (PDL) to tooth-root surfaces. The integrated multiple tissues could generate biological or physiological responses to transmitted biomechanical forces by mastication or occlusion. However, due to periodontitis or traumatic injuries, affect destruction or progressive damage of periodontal hard tissues including PDL could be affected and consequently lead to tooth loss. Conventional tissue engineering approaches have been developed to regenerate or repair periodontium but, engineered periodontal tissue formation is still challenging because there are still limitations to control spatial compartmentalization for individual tissues and provide optimal 3D constructs for tooth-supporting tissue regeneration and maturation. Here, we present the recently developed strategies to induce osteogenesis and cementogenesis by the fabrication of 3D architectures or the chemical modifications of biopolymeric materials. These techniques in tooth-supporting hard tissue engineering are highly promising to promote the periodontal regeneration and advance the interfacial tissue formation for tissue integrations of PDL fibrous connective tissue bundles (alveolar bone-to-PDL or PDL-to-cementum) for functioning restorations of the periodontal complex. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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Review
Preparing the Bone Tissue Regeneration Ground by Exosomes: From Diagnosis to Therapy
Molecules 2020, 25(18), 4205; https://doi.org/10.3390/molecules25184205 - 14 Sep 2020
Cited by 12 | Viewed by 2163
Abstract
Bone tissue engineering employs acellular scaffolds or scaffolds, along with cells and growth factors, to provide the mechanical support needed, as well as serve as a delivery vehicle for bioactive molecules to the injury sites. As tissue engineering continues to evolve, it has [...] Read more.
Bone tissue engineering employs acellular scaffolds or scaffolds, along with cells and growth factors, to provide the mechanical support needed, as well as serve as a delivery vehicle for bioactive molecules to the injury sites. As tissue engineering continues to evolve, it has integrated two emerging fields: stem cells and nanotechnology. A paracrine factor that is found to be responsible for the major regenerative effect in stem cell transplantation is an extracellular vesicle called an ‘exosome’. Recent advances in nanotechnology have allowed the ‘exosome’ to be distinguished from other extracellular vesicles and be polymerized into a well-defined concept. Scientists are now investigating exosome uses in clinical applications. For bone-related diseases, exosomes are being explored as biomarkers for different bone pathologies. They are also being explored as a therapeutic agent where progenitor cell-derived exosomes are used to regenerate damaged bone tissue. In addition, exosomes are being tested as immune modulators for bone tissue inflammation, and finally as a delivery vehicle for therapeutic agents. This review discusses recently published literature on the clinical utilization of exosomes in bone-related applications and the correlated advantages. A particular focus will be placed on the potential utilization of regenerative cell-derived exosomes as a natural biomaterial for tissue regeneration. Full article
(This article belongs to the Special Issue Biomaterials for Hard Tissue Regeneration)
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