scholarly journals Bone Morphogenetic Proteins, Carriers, and Animal Models in the Development of Novel Bone Regenerative Therapies

Materials ◽  
2021 ◽  
Vol 14 (13) ◽  
pp. 3513
Author(s):  
Nikola Stokovic ◽  
Natalia Ivanjko ◽  
Drazen Maticic ◽  
Frank P. Luyten ◽  
Slobodan Vukicevic
Keyword(s):  
Animal Models ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Animal Experiments ◽  
Inorganic Materials ◽  
New Bone Formation ◽  
Segmental Bone ◽  
Posterolateral Spinal Fusion ◽  
Regenerative Therapies ◽  
Observation Period

Bone morphogenetic proteins (BMPs) possess a unique ability to induce new bone formation. Numerous preclinical studies have been conducted to develop novel, BMP-based osteoinductive devices for the management of segmental bone defects and posterolateral spinal fusion (PLF). In these studies, BMPs were combined with a broad range of carriers (natural and synthetic polymers, inorganic materials, and their combinations) and tested in various models in mice, rats, rabbits, dogs, sheep, and non-human primates. In this review, we summarized bone regeneration strategies and animal models used for the initial, intermediate, and advanced evaluation of promising therapeutical solutions for new bone formation and repair. Moreover, in this review, we discuss basic aspects to be considered when planning animal experiments, including anatomical characteristics of the species used, appropriate BMP dosing, duration of the observation period, and sample size.

INFLUENCE OF ETHYLENE OXIDE STERILIZATION ON NEW BONE FORMATION INDUCED BY BOVINE BONE MORPHOGENETIC PROTEIN

2000 ◽  
Vol 04 (04) ◽  
pp. 287-295
Author(s):  
Tarmo Pekkarinen ◽  
T. Sam Lindholm ◽  
Aulis Marttinen ◽  
Oili Hietala ◽  
Pekka Jalovaara
Keyword(s):  
Bone Formation ◽  
Ethylene Oxide ◽  
Bone Morphogenetic Proteins ◽  
Exposure Time ◽  
Clinical Settings ◽  
Bovine Bone ◽  
New Bone Formation ◽  
Morphogenetic Protein ◽  
Oxide Concentration ◽  
Different Temperatures

Bone morphogenetic proteins (BMPs) have the capacity to induce and accelerate bone regeneration. Before experimental and clinical settings, BMP must be sterilized. Ethylene oxide (EO) gas sterilizations at different temperatures are commonly used but the effects of that on the osteoinductive capacity of BMP have been the subject of controversy. Here, we investigated the effects of three different EO sterilization methods on the osteoinductivity of partially purified native bovine BMP (bBMP). Gelatin capsules containing 3 mg of bBMP were sterilized as follows: (i) manually inside a dessicator with 12% EO spray (20°C, exposure time 2 h); (ii) with an EO gas sterilizer (Steri-Vac 4XL, temperature 29°C, exposure time 4 h 10 min, ethylene oxide concentration 860 mg/l); (iii) with an EO gas sterilizer (Steri-Vac 5XL, temperature 42°C, exposure time 3 h, ethylene oxide concentration 700 mg/l). The sterilization processes were monitored with samples of Bacillus subtilis (3M, Attest 1264). Osteoinductivity of bBMP was verified by bioassay. After 21 days of implantation of bBMP into the muscle pouches of mice, the animals were killed and new bone formation was measured radiographically and histologically. The EO sterilization techniques used did not significantly decrease the osteoinductive activity of BMP. It is concluded that commercial EO gas equipment sterilization is effective for sterilized BMP and does not decrease the osteoinductive capacity of bovine BMP.

scholarly journals Can Some Physical Therapy and Manual Techniques Generate Potentially Osteogenic Levels of Strain Within Mammalian Bone?

1999 ◽  
Vol 79 (10) ◽  
pp. 931-938
Author(s):  
Andrew W Wilson ◽  
Helen MS Davies ◽  
Glenn A Edwards ◽  
Brian L Grills
Keyword(s):  
Physical Therapy ◽  
Bone Formation ◽  
Ex Vivo ◽  
Compressive Strain ◽  
Animal Experiments ◽  
New Bone Formation ◽  
Joint Injuries ◽  
Mechanical Devices ◽  
Almost All

Abstract Background and Purpose. Although physical therapy techniques are used to alleviate pain and stiffness in joint injuries, whether these methods are capable of affecting bone is unknown. For example, can these techniques potentially influence bone formation or resorption? To begin exploring this possibility, this study investigated the ability of 4 manual techniques to generate levels of compressive strains that presumably can stimulate bone metabolism. Subjects. Six 3,4 metacarpals from three 3-year-old Merino ewes were used. Methods. A rosette strain gauge was implanted onto the dorsomedial cortex of each ovine 3,4 metacarpal. Four different manual procedures were applied on 2 occasions on each metacarpal in vivo and ex vivo. Mean peak principal compressive strains were calculated for each technique. Results. Levered bending produced greater mean peak compressive strains than almost all other manual procedures tested in vivo or ex vivo. Conclusion and Discussion. Manual levered bending created levels of compressive strain similar in magnitude to those created by mechanical devices used in previous animal experiments to induce new bone formation (osteogenesis). This animal model appears to be suitable for investigating the effects of manually applied procedures on bone and may establish whether manual techniques can stimulate bone formation.

scholarly journals Lack of repair of rat skull critical size defect treated with bovine morphometric protein bound to microgranular bioabsorbable hydroxyapatite

2004 ◽  
Vol 15 (3) ◽  
pp. 175-180 ◽  
Author(s):  
Gabriel Ramalho Ferreira ◽  
Tania Mary Cestari ◽  
José Mauro Granjeiro ◽  
Rumio Taga
Keyword(s):  
Foreign Body ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Repair ◽  
Critical Size ◽  
Bovine Bone ◽  
New Bone Formation ◽  
Body Type ◽  
Granulomatous Reaction ◽  
Post Surgery

The ability of a pool of bovine bone morphogenetic proteins bound to synthetic microgranular hydroxyapatite (BMPb-HA) to stimulate bone repair was determined in rat critical size defects. An 8-mm diameter defect was created in the calvaria of 25 rats. In 15 rats, the defects were filled with BMPb-HA homogenized with blood (experimental group), and in 10 rats the defects were filled only with blood clots (control). The calvariae of experimental rats were collected 1, 3 and 6 months after surgery and of the control rats at the end of surgery and 6 months thereafter. The morphometric results obtained in the radiographs showed an absence of new bone formation at 1 and 3 months post-surgery and, histologically, the defects were filled with fibrous connective tissue and numerous foci of a foreign body-type granulomatous reaction around hydroxyapatite agglomerates. At the end of 6 months, the number and size of the granulomatous foci decreased and the area of the defects was reduced by 22% compared to the 0-hour control due to the formation of new bone at their borders, although the mean area was similar to the 6-month control. We conclude that the use of BMPb-HA in the treatment of critical size bone defects of the rat skull leads to the formation of a foreign body-type granulomatous reaction that markedly inhibits new bone formation, suggesting that synthetic microgranular hydroxyapatite does not represent a good carrier for BMP-induced bone formation.

scholarly journals Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis

2021 ◽  
pp. annrheumdis-2021-220002
Author(s):  
Zihao Li ◽  
Siwen Chen ◽  
Haowen Cui ◽  
Xiang Li ◽  
Dongying Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Ankylosing Spondylitis ◽  
Animal Models ◽  
Bone Formation ◽  
Rna Sequencing ◽  
Adhesion Force ◽  
Immunofluorescence Staining ◽  
New Bone Formation ◽  
Tenascin C ◽  
Hippo Signalling

ObjectivesThe aim of this study was to identify the role of tenascin-C (TNC) in entheseal new bone formation and to explore the underlying molecular mechanism.MethodsLigament tissue samples were obtained from patients with ankylosing spondylitis (AS) during surgery. Collagen antibody-induced arthritis and DBA/1 models were established to observe entheseal new bone formation. TNC expression was determined by immunohistochemistry staining. Systemic inhibition or genetic ablation of TNC was performed in animal models. Mechanical properties of extracellular matrix (ECM) were measured by atomic force microscopy. Downstream pathway of TNC was analysed by RNA sequencing and confirmed with pharmacological modulation both in vitro and in vivo. Cellular source of TNC was analysed by single-cell RNA sequencing (scRNA-seq) and confirmed by immunofluorescence staining.ResultsTNC was aberrantly upregulated in ligament and entheseal tissues from patients with AS and animal models. TNC inhibition significantly suppressed entheseal new bone formation. Functional assays revealed that TNC promoted new bone formation by enhancing chondrogenic differentiation during endochondral ossification. Mechanistically, TNC suppressed the adhesion force of ECM, resulting in the activation of downstream Hippo/yes-associated protein signalling, which in turn increased the expression of chondrogenic genes. scRNA-seq and immunofluorescence staining further revealed that TNC was majorly secreted by fibroblast-specific protein-1 (FSP1)+fibroblasts in the entheseal inflammatory microenvironment.ConclusionInflammation-induced aberrant expression of TNC by FSP1+fibroblasts promotes entheseal new bone formation by suppressing ECM adhesion forces and activating Hippo signalling.

scholarly journals Alveolar wound healing after implantation with a pool of commercially available bovine bone morphogenetic proteins (BMPs): a histometric study in rats

2007 ◽  
Vol 18 (1) ◽  
pp. 29-33 ◽  
Author(s):  
Romeu Felipe Elias Calixto ◽  
Juliana Mazzonetto Teófilo ◽  
Luiz Guilherme Brentegani ◽  
Teresa Lúcia Lamano-Carvalho
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Volume Fraction ◽  
Male Rats ◽  
Bovine Bone ◽  
New Bone Formation ◽  
Bovine Collagen ◽  
Histologic Pattern ◽  
Hematoxylin And Eosin ◽  
And Control

The capacity of a commercially available pool of bovine bone morphogenetic proteins (BMPs) to stimulate osteogenesis in the rat alveolar healing was investigated by histometric analysis. Male rats were anesthetized and had their upper incisor extracted. A pool of purified bovine BMPs adsorbed to microgranular resorbable hydroxyapatite was agglutinated with bovine collagen and saline before implantation into the alveolar socket. The implanted and control rats (n=30 per group) were sacrificed 1 to 9 weeks postoperatively, the hemi-maxillae were decalcified, processed for paraffin embedding and semi-serial longitudinal sections were obtained and stained with hematoxylin and eosin. The volume fraction of alveolar healing components was estimated by a differential point-counting method in histologic images. The results showed that in both, control and implanted rats, the alveolar healing followed the histologic pattern usually described in the literature. Quantitative data confirmed that the BMPs mixture did not stimulate new bone formation in the alveolar socket of implanted rats. These results suggest that the pool of BMPs adsorbed to hydroxyapatite and agglutinated with bovine collagen did not warrant incorporation of the osteoinductive proteins to a slow-absorption system that would allow a BMPs release rate compatible to that of new bone formation, and thus more adequate to osteoinduction.

scholarly journals Bone Regeneration in Load-Bearing Segmental Defects, Guided by Biomorphic, Hierarchically Structured Apatitic Scaffold

2021 ◽  
Vol 9 ◽  
Author(s):  
Elizaveta Kon ◽  
Francesca Salamanna ◽  
Giuseppe Filardo ◽  
Berardo Di Matteo ◽  
Nogah Shabshin ◽  
...  
Keyword(s):  
Calcium Phosphate ◽  
Bone Formation ◽  
Porous Structure ◽  
Bone Defects ◽  
Minor Amount ◽  
Composition Analysis ◽  
New Bone Formation ◽  
Load Bearing ◽  
Segmental Bone ◽  
Segmental Bone Defects

The regeneration of load-bearing segmental bone defects remains a significant clinical problem in orthopedics, mainly due to the lack of scaffolds with composition and 3D porous structure effective in guiding and sustaining new bone formation and vascularization in large bone defects. In the present study, biomorphic calcium phosphate bone scaffolds (GreenBone™) featuring osteon-mimicking, hierarchically organized, 3D porous structure and lamellar nano-architecture were implanted in a critical cortical defect in sheep and compared with allograft. Two different types of scaffolds were tested: one made of ion-doped hydroxyapatite/β-tricalcium-phosphate (GB-1) and other made of undoped hydroxyapatite only (GB-2). X-ray diffraction patterns of GB-1 and GB-2 confirmed that both scaffolds were made of hydroxyapatite, with a minor amount of β-TCP in GB-1. The chemical composition analysis, obtained by ICP-OES spectrometer, highlighted the carbonation extent and the presence of small amounts of Mg and Sr as doping ions in GB-1. SEM micrographs showed the channel-like wide open porosity of the biomorphic scaffolds and the typical architecture of internal channel walls, characterized by a cell structure mimicking the natural parenchyma of the rattan wood used as a template for the scaffold fabrication. Both GB-1 and GB-2 scaffolds show very similar porosity extent and 3D organization, as also revealed by mercury intrusion porosimetry. Comparing the two scaffolds, GB-1 showed slightly higher fracture strength, as well as improved stability at the stress plateau. In comparison to allograft, at the follow-up time of 6 months, both GB-1 and GB-2 scaffolds showed higher new bone formation and quality of regenerated bone (trabecular thickness, number, and separation). In addition, higher osteoid surface (OS/BS), osteoid thickness (OS.Th), osteoblast surface (Ob.S/BS), vessels/microvessels numbers, as well as substantial osteoclast-mediated implant resorption were observed. The highest values in OS.Th and Ob. S/BS parameters were found in GB-1 scaffold. Finally, Bone Mineralization Index of new bone within scaffolds, as determined by micro-indentation, showed a significantly higher microhardness for GB-1 scaffold in comparison to GB-2. These findings suggested that the biomorphic calcium phosphate scaffolds were able to promote regeneration of load-bearing segmental bone defects in a clinically relevant scenario, which still represents one of the greatest challenges in orthopedics nowadays.

scholarly journals Growth and Morphogenetic Factors in Bone Induction: Role of Osteogenin and Related Bone Morphogenetic Proteins in Craniofacial and Periodontal Bone Repair

1992 ◽  
Vol 3 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Ugo Ripamonti ◽  
A. Hari Reddi
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Repair ◽  
Bone Development ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Prototype Model ◽  
Bone Induction ◽  
New Bone Formation

Bone has considerable potential for repair as illustrated by the phenomenon of fracture healing. Repair and regeneration of bone recapitulate the sequential stages of development. It is well known that demineralized bone matrix has the potential to induce new bone formation locally at a heterotopic site of implantation. The sequential development of bone is reminiscent of endochondral bone differentiation during bone development. The collagenous matrix-induced bone formation is a prototype model for matrix-cell interactions in vivo. The developmental cascade includes migration of progenitor cells by chemotaxis, attachment of cells through fibronectin, proliferation of mesenchymal cells, and differentiation of bone. The bone inductive protein, osteogenin, was isolated by heparin affinity chromatography. Osteogenin initiates new bone formation and is promoted by other growth factors. Recently, the genes for osteogenin and related bone morphogenetic proteins were cloned and expressed. Recombinant osteogenin is osteogenic in vivo. The future prospects for bone induction are bright, and this is an exciting frontier with applications in oral and orthopaedic surgery.

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