Application of AMOR in Craniofacial Rabbit Bone Bioengineering

Endogenous molecular and cellular mediators modulate tissue repair and regeneration. We have recently described antibody mediated osseous regeneration (AMOR) as a novel strategy for bioengineering bone in rat calvarial defect. This entails application of anti-BMP-2 antibodies capable ofin vivocapturing of endogenous osteogenic BMPs (BMP-2, BMP-4, and BMP-7). The present study sought to investigate the feasibility of AMOR in other animal models. To that end, we examined the efficacy of a panel of anti-BMP-2 monoclonal antibodies (mAbs) and a polyclonal Ab immobilized on absorbable collagen sponge (ACS) to mediate bone regeneration within rabbit calvarial critical size defects. After 6 weeks,de novobone formation was demonstrated by micro-CT imaging, histology, and histomorphometric analysis. Only certain anti-BMP-2 mAb clones mediated significantin vivobone regeneration, suggesting that the epitopes with which anti-BMP-2 mAbs react are critical to AMOR. Increased localization of BMP-2 protein and expression of osteocalcin were observed within defects, suggesting accumulation of endogenous BMP-2 and/or increased de novo expression of BMP-2 protein within sites undergoing bone repair by AMOR. Considering the ultimate objective of translation of this therapeutic strategy in humans, preclinical studies will be necessary to demonstrate the feasibility of AMOR in progressively larger animal models.

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Bone defect reconstruction via endochondral ossification: A developmental engineering strategy

Journal of Tissue Engineering ◽

10.1177/20417314211004211 ◽

2021 ◽

Vol 12 ◽

pp. 204173142110042

Author(s):

Rao Fu ◽

Chuanqi Liu ◽

Yuxin Yan ◽

Qingfeng Li ◽

Ru-Lin Huang

Keyword(s):

Bone Regeneration ◽

Bone Defect ◽

Bone Repair ◽

Endochondral Ossification ◽

Current Knowledge ◽

Endochondral Bone ◽

Defect Reconstruction ◽

Hypoxic Conditions ◽

Bone Defect Reconstruction

Traditional bone tissue engineering (BTE) strategies induce direct bone-like matrix formation by mimicking the embryological process of intramembranous ossification. However, the clinical translation of these clinical strategies for bone repair is hampered by limited vascularization and poor bone regeneration after implantation in vivo. An alternative strategy for overcoming these drawbacks is engineering cartilaginous constructs by recapitulating the embryonic processes of endochondral ossification (ECO); these constructs have shown a unique ability to survive under hypoxic conditions as well as induce neovascularization and ossification. Such developmentally engineered constructs can act as transient biomimetic templates to facilitate bone regeneration in critical-sized defects. This review introduces the concept and mechanism of developmental BTE, explores the routes of endochondral bone graft engineering, highlights the current state of the art in large bone defect reconstruction via ECO-based strategies, and offers perspectives on the challenges and future directions of translating current knowledge from the bench to the bedside.

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Zn-Containing Membranes for Guided Bone Regeneration in Dentistry

Polymers ◽

10.3390/polym13111797 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1797

Author(s):

Manuel Toledano ◽

Marta Vallecillo-Rivas ◽

María T. Osorio ◽

Esther Muñoz-Soto ◽

Manuel Toledano-Osorio ◽

...

Keyword(s):

Mechanical Properties ◽

Bone Regeneration ◽

Bone Healing ◽

Bone Repair ◽

Complex Modulus ◽

Bacterial Colonization ◽

Guided Bone Regeneration ◽

M2 Macrophage

Barrier membranes are employed in guided bone regeneration (GBR) to facilitate bone in-growth. A bioactive and biomimetic Zn-doped membrane with the ability to participate in bone healing and regeneration is necessary. The aim of the present study is to state the effect of doping the membranes for GBR with zinc compounds in the improvement of bone regeneration. A literature search was conducted using electronic databases, such as PubMed, MEDLINE, DIMDI, Embase, Scopus and Web of Science. A narrative exploratory review was undertaken, focusing on the antibacterial effects, physicochemical and biological properties of Zn-loaded membranes. Bioactivity, bone formation and cytotoxicity were analyzed. Microstructure and mechanical properties of these membranes were also determined. Zn-doped membranes have inhibited in vivo and in vitro bacterial colonization. Zn-alloy and Zn-doped membranes attained good biocompatibility and were found to be non-toxic to cells. The Zn-doped matrices showed feasible mechanical properties, such as flexibility, strength, complex modulus and tan delta. Zn incorporation in polymeric membranes provided the highest regenerative efficiency for bone healing in experimental animals, potentiating osteogenesis, angiogenesis, biological activity and a balanced remodeling. Zn-loaded membranes doped with SiO2 nanoparticles have performed as bioactive modulators provoking an M2 macrophage increase and are a potential biomaterial for promoting bone repair. Zn-doped membranes have promoted pro-healing phenotypes.

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Melatonin decorated 3D-printed beta-tricalcium phosphate scaffolds promoting bone regeneration in a rat calvarial defect model

Journal of Materials Chemistry B ◽

10.1039/c8tb03361g ◽

2019 ◽

Vol 7 (20) ◽

pp. 3250-3259 ◽

Cited By ~ 2

Author(s):

Yali Miao ◽

Yunhua Chen ◽

Xiao Liu ◽

Jingjing Diao ◽

Naru Zhao ◽

...

Keyword(s):

Bone Regeneration ◽

Tricalcium Phosphate ◽

Calvarial Defect ◽

Defect Model ◽

Beta Tricalcium Phosphate ◽

3D Printed ◽

Rat Calvarial Defect

3D-printed β-TCP scaffolds decorated with melatonin via dopamine mussel-inspired chemistry enhance the osteogenesis and in vivo bone regeneration.

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Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair

Bone and Joint Research ◽

10.1302/2046-3758.710.bjr-2018-0015.r2 ◽

2018 ◽

Vol 7 (10) ◽

pp. 548-560 ◽

Cited By ~ 8

Author(s):

I. Qayoom ◽

D. B. Raina ◽

A. Širka ◽

Š. Tarasevičius ◽

M. Tägil ◽

...

Keyword(s):

Bone Resorption ◽

Bone Regeneration ◽

Bone Morphogenetic Proteins ◽

Bone Repair ◽

Biological Effects ◽

Research Groups ◽

Preclinical Models ◽

Implant Fixation ◽

Local Use

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions. Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.

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Genetically Engineered-MSC Therapies for Non-unions, Delayed Unions and Critical-size Bone Defects

International Journal of Molecular Sciences ◽

10.3390/ijms20143430 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3430 ◽

Cited By ~ 6

Author(s):

Jaime Freitas ◽

Susana Gomes Santos ◽

Raquel Madeira Gonçalves ◽

José Henrique Teixeira ◽

Mário Adolfo Barbosa ◽

...

Keyword(s):

Bone Regeneration ◽

Animal Studies ◽

Bone Repair ◽

Critical Size ◽

Clinical Problem ◽

Cell Types ◽

Bone Defects ◽

Genetically Engineered ◽

Beneficial Effects

The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to aid the current therapeutic approaches. Mesenchymal stem/stromal cells (MSCs) are able to promote bone regeneration. Their beneficial effects can be improved by modulating the expression levels of specific genes with the purpose of stimulating MSC proliferation, osteogenic differentiation or their immunomodulatory capacity. In this context, the genetic engineering of MSCs is expected to further enhance their pro-regenerative properties and accelerate bone healing. Herein, we review the most promising molecular candidates (protein-coding and non-coding transcripts) and discuss the different methodologies to engineer and deliver MSCs, mainly focusing on in vivo animal studies. Considering the potential of the MSC secretome for bone repair, this topic has also been addressed. Furthermore, the promising results of clinical studies using MSC for bone regeneration are discussed. Finally, we debate the advantages and limitations of using MSCs, or genetically-engineered MSCs, and their potential as promoters of bone fracture regeneration/repair.

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Cellularizing hydrogel-based scaffolds to repair bone tissue: How to create a physiologically relevant micro-environment?

Journal of Tissue Engineering ◽

10.1177/2041731417712073 ◽

2017 ◽

Vol 8 ◽

pp. 204173141771207 ◽

Cited By ~ 28

Author(s):

Mathieu Maisani ◽

Daniele Pezzoli ◽

Olivier Chassande ◽

Diego Mantovani

Keyword(s):

Bone Regeneration ◽

Bone Tissue ◽

Bone Repair ◽

Critical Issue ◽

Bone Defects ◽

Bone Tissue Regeneration ◽

Differentiation Potential ◽

Promising Alternative

Tissue engineering is a promising alternative to autografts or allografts for the regeneration of large bone defects. Cell-free biomaterials with different degrees of sophistication can be used for several therapeutic indications, to stimulate bone repair by the host tissue. However, when osteoprogenitors are not available in the damaged tissue, exogenous cells with an osteoblast differentiation potential must be provided. These cells should have the capacity to colonize the defect and to participate in the building of new bone tissue. To achieve this goal, cells must survive, remain in the defect site, eventually proliferate, and differentiate into mature osteoblasts. A critical issue for these engrafted cells is to be fed by oxygen and nutrients: the transient absence of a vascular network upon implantation is a major challenge for cells to survive in the site of implantation, and different strategies can be followed to promote cell survival under poor oxygen and nutrient supply and to promote rapid vascularization of the defect area. These strategies involve the use of scaffolds designed to create the appropriate micro-environment for cells to survive, proliferate, and differentiate in vitro and in vivo. Hydrogels are an eclectic class of materials that can be easily cellularized and provide effective, minimally invasive approaches to fill bone defects and favor bone tissue regeneration. Furthermore, by playing on their composition and processing, it is possible to obtain biocompatible systems with adequate chemical, biological, and mechanical properties. However, only a good combination of scaffold and cells, possibly with the aid of incorporated growth factors, can lead to successful results in bone regeneration. This review presents the strategies used to design cellularized hydrogel-based systems for bone regeneration, identifying the key parameters of the many different micro-environments created within hydrogels.

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In Vivo Behavior of Bioactive Glass-Based Hybrids in Animal Models For Bone Regeneration

10.20944/preprints202012.0788.v1 ◽

2020 ◽

Author(s):

Shal N

Keyword(s):

Bioactive Glass ◽

Bone Regeneration ◽

Bone Repair ◽

Weight Bearing ◽

Chemical Properties ◽

Experimental Conditions ◽

Wide Range ◽

The Matrix ◽

Hybrid Biomaterials

This review presents the recent advances and the current state-of-the-art of bioactive glass-based hybrid biomaterials for bone regeneration. Hybrid materials comprise two (or more) constituents at the nanometre scale, in which typically, one constituent is organic and functions as the matrix phase and the other constituent is inorganic and behaves as the filler phase. Such materials, thereby, more closely resemble natural bio-nanocomposites such as bone. Various glass compositions in combination with a wide range of natural and synthetic polymers have been evaluated in vivo under experimental conditions ranging from unloaded critical-sized defects to mechanically-loaded, weight-bearing sites with highly favourable outcomes. Additional possibilities include controlled release of anti-osteoporotic drugs, ions, antibiotics, pro-angiogenic substances and pro-osteogenic substances. Histological and morphological evaluations suggest the formation of new, highly vascularised bone that displays signs of remodelling over time. With the possibility to tailor the mechanical and chemical properties through careful selection of individual components, as well as the overall geometry (from mesoporous particles and micro-/nanospheres to 3D scaffolds and coatings) through innovative manufacturing processes, such biomaterials present exciting new avenues for bone repair and regeneration.

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In vivo approach on femur bone regeneration of white rat (Rattus norvegicus) with the use of hydroxyapatite from cuttlefish bone (Sepia spp.) as bone filler

Veterinary World ◽

10.14202/vetworld.2019.809-816 ◽

2019 ◽

Vol 12 (6) ◽

pp. 809-816

Author(s):

Aminatun Aminatun ◽

D.E. Fadhilah Handayani ◽

Prihartini Widiyanti ◽

Dwi Winarni ◽

Siswanto Siswanto

Keyword(s):

Bone Regeneration ◽

Bone Repair ◽

Control Group ◽

Bovine Bone ◽

Lamellar Bone ◽

In Vivo Test ◽

Femur Bone ◽

Woven Bone ◽

Bone Filler

Background: Hydroxyapatite (HA) from bovine bone has been widely used as bone filler in many fractures cases. HA can also be made from cuttlefish bone (Sepia spp.) that has abundant availability in Indonesia and contains 84% CaCO3, which is a basic ingredient of HA. However, research on the effects of HA from cuttlefish bone on bone regeneration parameters has not been done yet. Aim: This study aimed to determine femur bone regeneration of white rats (Rattus norvegicus) through the use of HA from cuttlefish bone (Sepia spp.) as bone filler. Materials and Methods: HA was made using the hydrothermal method by mixing 1M aragonite (CaCO3) from cuttlefish bone and 0.6 M NH4H2PO4 at 200°C for 12 h followed by sintering at 900°C for 1 h. In vivo test was carried out in three groups, including control group, bovine bone-derived HA group, and cuttlefish bone-derived HA group. The generation of femur bone was observed through the number of osteoblasts, osteoclasts, woven bone, lamellar bone, havers system, and repair bone through anatomical pathology test for 28 days and 56 days. Results: Anatomical pathology test results are showed that administration of bovine bone-derived HA and cuttlefish bone-derived HA increased the number of osteoblasts, osteoclasts, woven bone, lamellar bone, havers system, and bone repair at recuperation of 56 days. Statistical test using Statistical Package for the Social Sciences with Kruskal–Wallis and Mann–Whitney U-test was resulted in significant differences between the bovine bone-derived HA control group and the cuttlefish-derived HA control group. There was no significant difference toward the indication of bone formation through the growth of osteoblasts, osteoclasts, woven bone, lamellar bone, havers system, and bone repair in the bovine bone-derived HA and cuttlefish bone-derived HA groups. Conclusion: It can be concluded that cuttlefish bone-derived HA has the potential as bone filler based on the characteristics of bone regeneration through in vivo test.

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Biased Pol II fidelity contributes to conservation of functional domains in the Potato spindle tuber viroid genome

PLoS Pathogens ◽

10.1371/journal.ppat.1009144 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1009144

Author(s):

Jian Wu ◽

David M. Bisaro

Keyword(s):

Rna Polymerase Ii ◽

De Novo ◽

Potato Spindle Tuber Viroid ◽

Mutation Rates ◽

Wild Type ◽

Pol Ii ◽

Synonymous Mutations ◽

Novel Strategy ◽

Critical Regions

Accurate calculation of mutation rates for viruses and viroids is necessary for evolutionary studies and to evaluate adaptation potential. However, estimation of in vivo mutation rates is complicated by selection, which leads to loss or proliferation of certain mutations. To minimize this concern, lethal mutations, including nonsense and non-synonymous mutations, have been used to determine mutation rates for several viruses and viroids, including Potato spindle tuber viroid (PSTVd). However, this approach has limitations, including focus on a relatively small number of genome sites and the possibility that mutations may not actually be lethal or may be maintained by wild type individuals. To avoid selection bias altogether, we sequenced minus-strand PSTVd dimers from concatemeric replication intermediates. The underlying rationale is that mutations found in only one of the monomers were likely generated de novo during RNA polymerase II (Pol II) transcription of the circular plus-strand RNA genome. This approach yielded an apparent Pol II error rate of ~1/1837 nucleotides per transcription cycle, and an estimated mutation rate of ~1/919 nucleotides for a single replication cycle. Remarkably, de novo mutations were nearly absent from the most conserved, replication-critical regions of the PSTVd genome, suggesting that sequence conservation is a consequence of both essential function and template optimization for greater Pol II fidelity. Such biased fidelity may constitute a novel strategy to ensure population success while allowing abundant sampling of sequence space in other genome regions. Comparison with variants in progeny populations derived from a cloned, wild type PSTVd master sequence revealed that most de novo mutations were lost through selection.

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Amorphous Calcium Magnesium Phosphate Nanocomposites with Superior Osteogenic Activity for Bone Regeneration

Regenerative Biomaterials ◽

10.1093/rb/rbab068 ◽

2021 ◽

Author(s):

Yingying Jiang ◽

Shuo Tan ◽

Jianping Hu ◽

Xin Chen ◽

Feng Chen ◽

...

Keyword(s):

Bone Regeneration ◽

Bone Repair ◽

Magnesium Phosphate ◽

In Vivo Studies ◽

Potential Candidate ◽

Collagen Scaffolds ◽

Edge Structure ◽

X Ray ◽

Calcium Magnesium

Abstract The seek of bioactive materials for promoting bone regeneration is a challenging and long-term task. Functionalization with inorganic metal ions or drug molecules are considered effective strategies to improve the bioactivity of various existing biomaterials. Herein, amorphous calcium magnesium phosphate (ACMP) nanoparticles and simvastatin (SIM)-loaded ACMP (ACMP/SIM) nanocomposites were developed via a simple coprecipitation strategy. The physiochemical property of ACMP/SIM were explored using transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and high performance liquid chromatograph (HPLC), and the role of Mg2+ in the formation of ACMP/SIM was revealed using X-ray absorption near-edge structure (XANES). After that, the transformation process of ACMP/SIM in simulated body fluid (SBF) was also tracked to simulate and explore the in vivo mineralization performance of materials. We find that ACMP/SIM releases ions of Ca2+, Mg2+ and PO43-, when it is immersed in SBF at 37 °C, and a phase transformation occured during which the initially amorphous ACMP turns into self-assembled hydroxyapatite (HAP). Furthermore, ACMP/SIM displays high cytocompatibility and promotes the proliferation and osteogenic differentiation of MC3T3-E1 cells. For the in vivo studies, lamellar ACMP/SIM/Collagen scaffolds with aligned pore structures were prepared and used to repair a rat defect model in calvaria. ACMP/SIM/Collagen scaffolds show a positive effect in promoting the regeneration of calvaria defect after 12 weeks. The bioactive ACMP/SIM nanocomposites are promising as bone repair materials. Considering the facile preparation process and superior in vitro/vivo bioactivity, the as-prepared ACMP/SIM would be a potential candidate for bone related biomedical applications.

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