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Biomedicines
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New Ground-Breaking Strategy in Bone Regeneration
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New Ground-Breaking Strategy in Bone Regeneration

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 22280

Special Issue Editors

Dr. Toni Ibrahim

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Guest Editor
Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Interests: osteo-oncology; rare tumors; head and neck tumors; immunotherapy; regenerative medicine
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Davide Maria Donati

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Guest Editor
3rd Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Interests: osteosarcoma; soft tissue sarcoma; 3D prosthesis; bone reconstrution; 3D in vitro models
Dr. Laura Mercatali

E-Mail Website
Guest Editor
Osteoncology Unit, Bioscience Laboratory, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Interests: osteo-oncology; rare tumors; regenerative medicine; 3D culture; zebrafish in vivo models
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro De Vita

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Guest Editor
Osteoncology and Rare Tumors Center (CDO-TR), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
Interests: osteo-oncology; rare tumors; head and neck tumors; regenerative medicine; nanotechnology; 3D culture
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The complexity of bone tissue is reflected in the difficulty of treating its pathological diseases. Bone fractures, bone resorption, and bone deposition represent the leading events of interest in a variety of pathological conditions. These complications are a prominent source of morbidity, being associated with clinical complications that affect patient quality of life, impair functional autonomy, and reduce survival. Dissecting the complex interactions that subsist between the different bone-associated cell types represents a challenge for the international scientific community. In this regard, a pivotal role is played by bone regeneration in which a number of molecular–signaling pathways are involved in an effort to remodel and restore skeletal function. This well-orchestrated physiological process is insufficient, compromised or impaired in several clinical settings, including: bone defects created by trauma, infection, tumor resection, skeletal related events and abnormalities, vascular necrosis, and osteoporosis.

To solve this drawback, a multitude of therapeutic strategies have been proposed in order to clinically manage bone disease and to achieve bone augmentation. Autologous or allogeneic bone grafts together with bone-graft substitutes, tissue engineering, mesenchymal stem cells, osteoprogenitors, gene therapy, and mechanical stability devices are currently under translational and clinical investigation to enhance bone regeneration in a variety of orthopedic and maxillofacial procedures. This Special Issue will provide an overview of the recent advances in translational and clinical research focusing on the landscape of bone treatment and regeneration. An outlook will be given on recent findings on bone primitive tumors, bone metastases, bone health, and development of bone regeneration devices and techniques.

Original research and reviews are welcome.

Dr. Toni Ibrahim
Prof. Dr. Davide Maria Donati
Dr. Laura Mercatali
Dr. Alessandro De Vita
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. Biomedicines 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 2600 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

  • bone regeneration
  • bone metastases
  • bone health
  • bone primitive tumors
  • 3D scaffold
  • bone-targeted therapy
  • osteoinduction
  • osteogenesis
  • osteoconduction

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 160 KiB  
Editorial
New Ground-Breaking Strategies in Bone Regeneration—In Memory of Nerio Ceroni
by Alessandro De Vita, Davide Maria Donati, Laura Mercatali and Toni Ibrahim
Biomedicines 2022, 10(4), 855; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040855 - 06 Apr 2022
Cited by 1 | Viewed by 1210
Abstract
This editorial article is dedicated to the memory of the Nerio Ceroni, the grandfather of the first author [...] Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)

Research

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17 pages, 4191 KiB  
Article
A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences
by Alessandro De Vita, Silvia Vanni, Giacomo Miserocchi, Valentina Fausti, Federica Pieri, Chiara Spadazzi, Claudia Cocchi, Chiara Liverani, Chiara Calabrese, Roberto Casadei, Federica Recine, Lorena Gurrieri, Alberto Bongiovanni, Toni Ibrahim and Laura Mercatali
Biomedicines 2022, 10(2), 372; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020372 - 03 Feb 2022
Cited by 28 | Viewed by 4437
Abstract
Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, [...] Read more.
Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management. Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)
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11 pages, 3849 KiB  
Article
Short-Term Bone Healing Response to Mechanical Stimulation—A Case Series Conducted on Sheep
by Jan Barcik, Manuela Ernst, Marc Balligand, Constantin Edmond Dlaska, Ludmil Drenchev, Stephan Zeiter, Devakara R. Epari and Markus Windolf
Biomedicines 2021, 9(8), 988; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080988 - 10 Aug 2021
Cited by 5 | Viewed by 1987
Abstract
It is well known that mechanical stimulation promotes indirect fracture healing by triggering callus formation. We investigated the short-term response of healing tissue to mechanical stimulation to compare the changes in tissue stiffness during stimulation and resting phases in a preclinical case-series. Four [...] Read more.
It is well known that mechanical stimulation promotes indirect fracture healing by triggering callus formation. We investigated the short-term response of healing tissue to mechanical stimulation to compare the changes in tissue stiffness during stimulation and resting phases in a preclinical case-series. Four sheep underwent a tibial osteotomy and were instrumented with a custom-made active fixator which applied a mechanical stimulation protocol of 1000 cycles/day, equally distributed over 12 h, followed by 12 h of rest. During each cycle, a surrogate metric for tissue stiffness was measured, enabling a continuous real-time monitoring of the healing progression. A daily stiffness increase during stimulation and an increase during resting were evaluated for each animal. One animal had to be excluded from the evaluation due to technical reasons. For all included animals, the stiffness began to increase within the second week post-op. A characteristic pattern was observed during daily measurements: the stiffness dropped considerably within the first stimulation cycles followed by a steady rise throughout the rest of the stimulation phase. However, for all included animals, the average daily stiffness increase within the first three weeks post operation was larger during resting than during stimulation (Sheep I: 16.9% vs. −5.7%; Sheep II: 14.7% vs. −1.8%; Sheep III: 8.9% vs. 1.6%). A continuous measurement of tissue stiffness together with a controlled fracture stimulation enabled the investigation of the short-term effects of specific stimulatory parameters, such as resting periods. Resting was identified as a potentially determining factor for bone healing progression. Optimizing the ratio between stimulation and resting may contribute to more robust fracture healing in the future. Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)
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19 pages, 6926 KiB  
Article
Development of Vancomycin Delivery Systems Based on Autologous 3D Platelet-Rich Fibrin Matrices for Bone Tissue Engineering
by Arita Dubnika, Karina Egle, Marite Skrinda-Melne, Ingus Skadins, Jayakumar Rajadas and Ilze Salma
Biomedicines 2021, 9(7), 814; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070814 - 13 Jul 2021
Cited by 9 | Viewed by 3400
Abstract
Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, [...] Read more.
Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, but patients still undergo additional treatment with antibiotic drugs before, during, and even after the implantation of biomaterials with PRF. These systematically used drugs spread throughout the blood and lead not only to positive effects but may also induce adverse side effects on healthy tissues. Vancomycin hydrochloride (VANKA) is used to treat severe Staphylococcal infections but its absorption in the target tissue after oral administration is low; therefore, in this study, we have developed and analyzed two kinds of VANKA carriers—liposomes and microparticles in 3D PRF matrices. The adjustment, characterization, and analysis of VANKA carriers in 3D PRF scaffolds is carried out in terms of encapsulation efficiency, drug release kinetics and antibacterial activity; furthermore, we have studied the micro- and macrostructure of the scaffolds with microtomography. Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)
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20 pages, 3808 KiB  
Article
Mandible Biomechanics and Continuously Erupting Teeth: A New Defect Model for Studying Load-Bearing Biomaterials
by Jonathan Z. Baskin, Brandon M. White, Amit Vasanji, Thomas E. Love and Steven J. Eppell
Biomedicines 2021, 9(7), 730; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070730 - 25 Jun 2021
Cited by 5 | Viewed by 3572
Abstract
Animals with elodont dentition and unfused mandible symphyses are hypothesized to have symmetric incisor morphology. Since these animals maintain their teeth by gnawing, they may provide physiologic feedback on mechanical function when unilateral mandible defects are created that manifest as ipsilateral changes in [...] Read more.
Animals with elodont dentition and unfused mandible symphyses are hypothesized to have symmetric incisor morphology. Since these animals maintain their teeth by gnawing, they may provide physiologic feedback on mechanical function when unilateral mandible defects are created that manifest as ipsilateral changes in tooth structure. This defect model would potentially generate important information on the functional/mechanical properties of implants. Rats’ and rabbits’ mandibles and teeth are analyzed with µCT at baseline and post-intervention (n = 8 for each). Baseline incisors were compared. In a unilateral mandible pilot study, defects—ranging from critical size defect to complete ramus osteotomies—were created to assess effect on dentition (rats, n = 7; rabbits, n = 6). Within 90% confidence intervals, animals showed no baseline left/right differences in their incisors. There are apparent dental changes associated with unilateral defect type and location. Thus, at baseline, animals exhibit statistically significant incisor symmetry and there is an apparent relationship between mandible defect and incisor growth. The baseline symmetry proven here sets the stage to study the degree to which hemi-mandible destabilizing procedures result in measurable & reproducible disruption of dental asymmetry. In a validated model, an implant designed to function under load that prevents incisor asymmetry would provide supporting evidence that the implant has clinically useful load-bearing function. Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)
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Review

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26 pages, 1884 KiB  
Review
Nature-Inspired Unconventional Approaches to Develop 3D Bioceramic Scaffolds with Enhanced Regenerative Ability
by Andrea Ruffini, Monica Sandri, Massimiliano Dapporto, Elisabetta Campodoni, Anna Tampieri and Simone Sprio
Biomedicines 2021, 9(8), 916; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080916 - 29 Jul 2021
Cited by 14 | Viewed by 3339
Abstract
Material science is a relevant discipline in support of regenerative medicine. Indeed, tissue regeneration requires the use of scaffolds able to guide and sustain the natural cell metabolism towards tissue regrowth. This need is particularly important in musculoskeletal regeneration, such as in the [...] Read more.
Material science is a relevant discipline in support of regenerative medicine. Indeed, tissue regeneration requires the use of scaffolds able to guide and sustain the natural cell metabolism towards tissue regrowth. This need is particularly important in musculoskeletal regeneration, such as in the case of diseased bone or osteocartilaginous regions for which calcium phosphate-based scaffolds are considered as the golden solution. However, various technological barriers related to conventional ceramic processing have thus far hampered the achievement of biomimetic and bioactive scaffolds as effective solutions for still unmet clinical needs in orthopaedics. Driven by such highly impacting socioeconomic needs, new nature-inspired approaches promise to make a technological leap forward in the development of advanced biomaterials. The present review illustrates ion-doped apatites as biomimetic materials whose bioactivity resides in their unstable chemical composition and nanocrystallinity, both of which are, however, destroyed by the classical sintering treatment. In the following, recent nature-inspired methods preventing the use of high-temperature treatments, based on (i) chemically hardening bioceramics, (ii) biomineralisation process, and (iii) biomorphic transformations, are illustrated. These methods can generate products with advanced biofunctional properties, particularly biomorphic transformations represent an emerging approach that could pave the way to a technological leap forward in medicine and also in various other application fields. Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)
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10 pages, 1229 KiB  
Review
Can Optimizing the Mechanical Environment Deliver a Clinically Significant Reduction in Fracture Healing Time?
by Jan Barcik and Devakara R. Epari
Biomedicines 2021, 9(6), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060691 - 18 Jun 2021
Cited by 9 | Viewed by 2880
Abstract
The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness [...] Read more.
The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness that potential are rare. In fact, the current clinical practice with an initially partial or non-weight-bearing approach appears to contradict the findings from animal experiments that early mechanical stimulation is critical. Therefore, we posed the question as to whether optimizing the mechanical environment over the course of healing can deliver a clinically significant reduction in fracture healing time. In reviewing the evidence from pre-clinical studies that investigate the influence of mechanics on bone healing, we formulate a hypothesis for the stimulation protocol which has the potential to shorten healing time. The protocol involves confining stimulation predominantly to the proliferative phase of healing and including adequate rest periods between applications of stimulation. Full article
(This article belongs to the Special Issue New Ground-Breaking Strategy in Bone Regeneration)
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