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Bioengineering
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Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive...
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Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials

A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Regenerative Engineering".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 22734

Special Issue Editors

Dr. Elena A. Jones

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Guest Editor
Leeds Institute of Molecular Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
Interests: mesenchymal stem cells/multipotential stromal cells (MSCs); bone regeneration; cartilage regeneration; osteoarthritis; regenerative medicine; regenerative orthopedics; MSC senescence
Special Issues, Collections and Topics in MDPI journals
Dr. Jehan J. El-Jawhari

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Guest Editor
Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
Interests: cellular biology; mesenchymal stem cells; bone marrow microenvironment; cancer immunology
Special Issues, Collections and Topics in MDPI journals
Dr. Dimitrios Kouroupis

E-Mail Website
Guest Editor
Department of Orthopaedics, Division of Sports Medicine, Diabetes Research Institute, Cell Transplant Center, University of Miami, Miller School of Medicine, 1450NW 10th Ave, Room 3012, Miami, FL 33136, USA
Interests: mesenchymal stem cells/multipotential stromal cells (MSCs); MSC trophic and immunomodulatory actions; MSC functionalization ex vivo; inflammation and fibrosis reversal; synovitis; osteoarthritis; regenerative sports medicine; regenerative orthopaedics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The regeneration of large bone defects and fractures at risk of non-union is a serious clinical problem. Bone biological augmentation with autologous multipotential stromal/mesenchymal stem cells (MSCs) is beneficial. However, clinical approaches vary considerably regarding MSC tissue source, MSC isolation, the degree of MSC culture expansion and priming ex vivo, and the use of biomaterial scaffolds. This Special Issue aims to present a state-of-the-art update on using MSCs for bone regeneration. We welcome original research articles, comprehensive reviews, methods, mini-reviews, and perspectives, including (but not limited to) the following topics:

  • the benefits and limitations of using minimally manipulated autologous MSC isolates versus culture-expanded MSCs for bone repair;
  • phenotype-based MSC isolation and/or priming, including the use of growth factors from autologous platelet concentrates;
  • MSC and biomaterial functionalization, including gene-activated matrices;
  • engineering of MSCs and immune cells for bone regeneration;
  • personalized implants and therapies for patients with co-morbidities, including metabolic bone diseases;
  • novel approaches to in vitro analysis of MSC–scaffold interactions in three-dimensional (3D) conditions;
  • sensors and novel live imaging techniques for the assessment of bone regeneration in weight-bearing and non-weight-bearing bones

Dr. Elena A. Jones
Dr. Jehan J. El-Jawhari
Dr. Dimitrios Kouroupis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Bioengineering is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

  • multipotential stromal/mesenchymal stem cells (MSCs)
  • bone regeneration
  • cell engineering
  • activated matrices
  • sensors and imaging
  • scaffolds and biomaterials

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Published Papers (7 papers)

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Research

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12 pages, 5452 KiB  
Article
Enhancing Bone Formation Through bFGF-Loaded Mesenchymal Stromal Cell Spheroids During Fracture Healing in Mice
by Kugo Takeda, Hiroki Saito, Shintaro Shoji, Hiroyuki Sekiguchi, Mitsuyoshi Matsumoto, Masanobu Ujihira, Masayuki Miyagi, Gen Inoue, Masashi Takaso and Kentaro Uchida
Bioengineering 2024, 11(10), 1041; https://doi.org/10.3390/bioengineering11101041 - 18 Oct 2024
Viewed by 678
Abstract
This study aimed to evaluate the osteogenic potential of mesenchymal stromal cell (MSC) spheroids combined with the basic fibroblast growth factor (bFGF) in a mouse femur fracture model. To begin, MSC spheroids were generated, and the expression of key trophic factors (bFGF Bmp2 [...] Read more.
This study aimed to evaluate the osteogenic potential of mesenchymal stromal cell (MSC) spheroids combined with the basic fibroblast growth factor (bFGF) in a mouse femur fracture model. To begin, MSC spheroids were generated, and the expression of key trophic factors (bFGF Bmp2, and Vegfa) was assessed using quantitative PCR (qPCR). A binding assay confirmed the interaction between the bFGF and the spheroids’ extracellular matrix. The spheroid cultures significantly upregulated bFGF, Bmp2, and Vegfa expression compared to the monolayers (p < 0.001), and the binding assay demonstrated effective bFGF binding to the MSC spheroids. Following these in vitro assessments, the mice were divided into five groups for the in vivo study: (1) no treatment (control), (2) spheroids alone, (3) bFGF alone, (4) bFGF-loaded spheroids (bFGF-spheroids), and (5) non-viable (frozen) bFGF-loaded spheroids (bFGF-dSpheroids). Bone formation was analyzed by a micro-CT, measuring the bone volume (BV) and bone mineral content (BMC) of the mice four weeks post-fracture. A high dose of the bFGF (10 µg) significantly promoted bone formation regardless of the presence of spheroids, as evidenced by the increases in BV (bFGF, p = 0.010; bFGF-spheroids, p = 0.006; bFGF-dSpheroids, p = 0.032) and BMC (bFGF, p = 0.023; bFGF-spheroids, p = 0.004; bFGF-dSpheroids, p = 0.014), compared to the controls. In contrast, a low dose of the bFGF (1 µg) combined with the MSC spheroids significantly increased BV and BMC compared to the control (BV, p = 0.012; BMC, p = 0.015), bFGF alone (BV, p = 0.012; BMC, p = 0.008), and spheroid (BV, p < 0.001; BMC, p < 0.001) groups. A low dose of the bFGF alone did not significantly promote bone formation (p > 0.05). The non-viable (frozen) spheroids loaded with a low dose of the bFGF resulted in a higher BV and BMC compared to the spheroids alone (BV, p = 0.003; BMC, p = 0.017), though the effect was less pronounced than in the viable spheroids. These findings demonstrate the synergistic effect of the bFGF and MSC spheroids on bone regeneration. The increased expression of the BMP-2 and VEGF observed in the initial experiments, coupled with the enhanced bone formation in vivo, highlight the therapeutic potential of this combination. Future studies will aim to elucidate the underlying molecular mechanisms and assess the long-term outcomes for bone repair strategies. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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13 pages, 3678 KiB  
Article
De-Epithelization of the Human Amniotic Membrane Using a System Involving Ozonated Water and Ultrasound
by Francisco Dimitre Rodrigo Pereira Santos, Bianca Akemi Kawata, Tatiana Regina de Oliveira Heinzelmann, Marcia Guelma Santos Belfort, Maycon Crispim de Oliveira Carvalho, Sílvia Móbille Awoyama, João Gomes de Oliveira Neto, Carlos José de Lima and Adriana Barrinha Fernandes
Bioengineering 2024, 11(10), 987; https://doi.org/10.3390/bioengineering11100987 - 29 Sep 2024
Viewed by 734
Abstract
The aim of this study was to evaluate whether a system involving ozonated water and ultrasound causes de-epithelization of the human amniotic membrane (HAM). The experiment protocol was carried out in four stages. Stage I was carried out to determine the duration of [...] Read more.
The aim of this study was to evaluate whether a system involving ozonated water and ultrasound causes de-epithelization of the human amniotic membrane (HAM). The experiment protocol was carried out in four stages. Stage I was carried out to determine the duration of the experiment. Stage II comprised the first experiment, involving four groups of samples studied in triplicate: control/natural (IN), processed with ultrasound in a liquid medium (US), processed with ozonated water (O3), and processed with ozonated water combined with ultrasound (US_O3). Stage III was performed to confirm the results, following the same steps present in Stage II. Stage IV involved the use of oxygen to confirm the hypothesis. Histological analysis was carried out to verify whether the effects of O2 were similar to those of O3. The system was activated, and ozonation was carried out for 10 min, as in the previous experiment, reaching a concentration level of 3.0 mg/L. The samples were submerged and positioned in the reservoir and processed separately for 55 min. The biochemical properties were assessed using Fourier transform infrared spectroscopy, and the morphology was examined using histology and scanning electron microscopy. The spectra of the samples exhibited similarities; however, subtle changes were highlighted, such as smooth band shifts and intensity changes. The morphology indicated that ultrasound achieved more efficient HAM de-epithelialization compared to ultrasound combined with ozonated water and ozonated water alone. One plausible hypothesis for this observation is that cavitation represents the primary mechanism responsible for de-epithelialization. When ultrasound is combined with ozone, the bubbles generated by ozone gas reduce the cavitation effect. This study is pioneering as it demonstrates an ultrasound system capable of the efficient de-epithelialization of the HAM. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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16 pages, 6125 KiB  
Article
Evaluation of Human Bone Marrow Mesenchymal Stromal Cell (MSC) Functions on a Biomorphic Rattan-Wood-Derived Scaffold: A Comparison between Cultured and Uncultured MSCs
by Payal Ganguly, Jehan J. El-Jawhari, James Vun, Peter V. Giannoudis and Elena A. Jones
Bioengineering 2022, 9(1), 1; https://doi.org/10.3390/bioengineering9010001 - 21 Dec 2021
Cited by 5 | Viewed by 3411
Abstract
The reconstruction of large bone defects requires the use of biocompatible osteoconductive scaffolds. These scaffolds are often loaded with the patient’s own bone marrow (BM) cells to facilitate osteoinductivity and biological potency. Scaffolds that are naturally sourced and fabricated through biomorphic transitions of [...] Read more.
The reconstruction of large bone defects requires the use of biocompatible osteoconductive scaffolds. These scaffolds are often loaded with the patient’s own bone marrow (BM) cells to facilitate osteoinductivity and biological potency. Scaffolds that are naturally sourced and fabricated through biomorphic transitions of rattan wood (B-HA scaffolds) offer a unique advantage of higher mechanical strength and bioactivity. In this study, we investigated the ability of a biomorphic B-HA scaffold (B-HA) to support the attachment, survival and gene expression profile of human uncultured BM-derived mesenchymal stromal cells (BMSCs, n = 6) and culture expanded MSCs (cMSCs, n = 7) in comparison to a sintered, porous HA scaffold (S-HA). B-HA scaffolds supported BMSC attachment (average 98%) and their survival up to 4 weeks in culture. Flow cytometry confirmed the phenotype of cMSCs on the scaffolds. Gene expression indicated clear segregation between cMSCs and BMSCs with MSC osteogenesis- and adipogenesis-related genes including RUNX2, PPARγ, ALP and FABP4 being higher expressed in BMSCs. These data indicated a unique transcriptional signature of BMSCs that was distinct from that of cMSCs regardless of the type of scaffold or time in culture. There was no statistical difference in the expression of osteogenic genes in BMSCs or cMSCs in B-HA compared to S-HA. VEGF release from cMSCs co-cultured with human endothelial cells (n = 4) on B-HA scaffolds suggested significantly higher supernatant concentration with endothelial cells on day 14. This indicated a potential mechanism for providing vasculature to the repair area when such scaffolds are used for treating large bone defects. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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19 pages, 3120 KiB  
Article
Single-Cell RNA-Sequencing Identifies Infrapatellar Fat Pad Macrophage Polarization in Acute Synovitis/Fat Pad Fibrosis and Cell Therapy
by Dimitrios Kouroupis, Thomas M. Best, Lee D. Kaplan, Diego Correa and Anthony J. Griswold
Bioengineering 2021, 8(11), 166; https://doi.org/10.3390/bioengineering8110166 - 29 Oct 2021
Cited by 8 | Viewed by 3256
Abstract
The pathogenesis and progression of knee inflammatory pathologies is modulated partly by residing macrophages in the infrapatellar fat pad (IFP), thus, macrophage polarization towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes is important in joint disease pathologies. Alteration of M1/M2 balance contributes to the [...] Read more.
The pathogenesis and progression of knee inflammatory pathologies is modulated partly by residing macrophages in the infrapatellar fat pad (IFP), thus, macrophage polarization towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes is important in joint disease pathologies. Alteration of M1/M2 balance contributes to the initiation and progression of joint inflammation and can be potentially altered with mesenchymal stem cell (MSC) therapy. In an acute synovial/IFP inflammation rat model a single intra-articular injection of IFP-MSC was performed, having as controls (1) diseased rats not receiving IFP-MSC and (2) non-diseased rats. After 4 days, cell specific transcriptional profiling via single-cell RNA-sequencing was performed on isolated IFP tissue from each group. Eight transcriptomically distinct cell populations were identified within the IFP across all three treatment groups with a noted difference in the proportion of myeloid cells across the groups. Largely myeloid cells consisted of macrophages (>90%); one M1 sub-cluster highly expressing pro-inflammatory markers and two M2 sub-clusters with one of them expressing higher levels of canonical M2 markers. Notably, the diseased samples (11.9%) had the lowest proportion of cells expressing M2 markers relative to healthy (14.8%) and MSC treated (19.4%) samples. These results suggest a phenotypic polarization of IFP macrophages towards the pro-inflammatory M1 phenotype in an acute model of inflammation, which are alleviated by IFP-MSC therapy inducing a switch towards an alternate M2 status. Understanding the IFP cellular heterogeneity and associated transcriptional programs may offer insights into novel therapeutic strategies for disabling joint disease pathologies. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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Review

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29 pages, 754 KiB  
Review
The Effect of Diabetes Mellitus on IGF Axis and Stem Cell Mediated Regeneration of the Periodontium
by Nancy M. S. Hussein, Josie L. Meade, Hemant Pandit, Elena Jones and Reem El-Gendy
Bioengineering 2021, 8(12), 202; https://doi.org/10.3390/bioengineering8120202 - 3 Dec 2021
Cited by 2 | Viewed by 4032
Abstract
Periodontitis and diabetes mellitus (DM) are two of the most common and challenging health problems worldwide and they affect each other mutually and adversely. Current periodontal therapies have unpredictable outcome in diabetic patients. Periodontal tissue engineering is a challenging but promising approach that [...] Read more.
Periodontitis and diabetes mellitus (DM) are two of the most common and challenging health problems worldwide and they affect each other mutually and adversely. Current periodontal therapies have unpredictable outcome in diabetic patients. Periodontal tissue engineering is a challenging but promising approach that aims at restoring periodontal tissues using one or all of the following: stem cells, signalling molecules and scaffolds. Mesenchymal stem cells (MSCs) and insulin-like growth factor (IGF) represent ideal examples of stem cells and signalling molecules. This review outlines the most recent updates in characterizing MSCs isolated from diabetics to fully understand why diabetics are more prone to periodontitis that theoretically reflect the impaired regenerative capabilities of their native stem cells. This characterisation is of utmost importance to enhance autologous stem cells based tissue regeneration in diabetic patients using both MSCs and members of IGF axis. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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25 pages, 1004 KiB  
Review
Bone Marrow Multipotent Mesenchymal Stromal Cells as Autologous Therapy for Osteonecrosis: Effects of Age and Underlying Causes
by Jehan J El-Jawhari, Payal Ganguly, Elena Jones and Peter V Giannoudis
Bioengineering 2021, 8(5), 69; https://doi.org/10.3390/bioengineering8050069 - 17 May 2021
Cited by 9 | Viewed by 5079
Abstract
Bone marrow (BM) is a reliable source of multipotent mesenchymal stromal cells (MSCs), which have been successfully used for treating osteonecrosis. Considering the functional advantages of BM-MSCs as bone and cartilage reparatory cells and supporting angiogenesis, several donor-related factors are also essential to [...] Read more.
Bone marrow (BM) is a reliable source of multipotent mesenchymal stromal cells (MSCs), which have been successfully used for treating osteonecrosis. Considering the functional advantages of BM-MSCs as bone and cartilage reparatory cells and supporting angiogenesis, several donor-related factors are also essential to consider when autologous BM-MSCs are used for such regenerative therapies. Aging is one of several factors contributing to the donor-related variability and found to be associated with a reduction of BM-MSC numbers. However, even within the same age group, other factors affecting MSC quantity and function remain incompletely understood. For patients with osteonecrosis, several underlying factors have been linked to the decrease of the proliferation of BM-MSCs as well as the impairment of their differentiation, migration, angiogenesis-support and immunoregulatory functions. This review discusses the quality and quantity of BM-MSCs in relation to the etiological conditions of osteonecrosis such as sickle cell disease, Gaucher disease, alcohol, corticosteroids, Systemic Lupus Erythematosus, diabetes, chronic renal disease and chemotherapy. A clear understanding of the regenerative potential of BM-MSCs is essential to optimize the cellular therapy of osteonecrosis and other bone damage conditions. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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15 pages, 3693 KiB  
Review
Rejuvenated Stem/Progenitor Cells for Cartilage Repair Using the Pluripotent Stem Cell Technology
by Naoki Nakayama, Sudheer Ravuri and Johnny Huard
Bioengineering 2021, 8(4), 46; https://doi.org/10.3390/bioengineering8040046 - 10 Apr 2021
Cited by 3 | Viewed by 5019
Abstract
It is widely accepted that chondral defects in articular cartilage of adult joints are never repaired spontaneously, which is considered to be one of the major causes of age-related degenerative joint disorders, such as osteoarthritis. Since mobilization of subchondral bone (marrow) cells and [...] Read more.
It is widely accepted that chondral defects in articular cartilage of adult joints are never repaired spontaneously, which is considered to be one of the major causes of age-related degenerative joint disorders, such as osteoarthritis. Since mobilization of subchondral bone (marrow) cells and addition of chondrocytes or mesenchymal stromal cells into full-thickness defects show some degrees of repair, the lack of self-repair activity in adult articular cartilage can be attributed to lack of reparative cells in adult joints. In contrast, during a fetal or embryonic stage, joint articular cartilage has a scar-less repair activity, suggesting that embryonic joints may contain cells responsible for such activity, which can be chondrocytes, chondroprogenitors, or other cell types such as skeletal stem cells. In this respect, the tendency of pluripotent stem cells (PSCs) to give rise to cells of embryonic characteristics will provide opportunity, especially for humans, to obtain cells carrying similar cartilage self-repair activity. Making use of PSC-derived cells for cartilage repair is still in a basic or preclinical research phase. This review will provide brief overviews on how human PSCs have been used for cartilage repair studies. Full article
(This article belongs to the Special Issue Advances in Bone Regeneration with Multipotential Stromal Cells and Bioactive Materials)
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