Direct contribution of skeletal muscle mesenchymal progenitors to bone repair

AbstractTissue regeneration relies on the activation of tissue resident stem cells concomitant with a transient fibrous tissue deposition to allow functional tissue recovery. Bone regeneration involves skeletal stem/progenitors from periosteum and bone marrow, the formation of a fibrous callus followed by the deposition of cartilage and bone to consolidate the fracture. Here, we show that mesenchymal progenitors residing in skeletal muscle adjacent to the bone fracture play a crucial role in mediating the initial fibrotic response to bone injury and also participate in cartilage and bone formation in the fracture callus. Combined lineage and scRNAseq analyses reveal that skeletal muscle mesenchymal progenitors adopt a fibrogenic fate before they engage in a chondrogenic fate after fracture. In polytrauma, where bone and skeletal muscle are injured, skeletal muscle mesenchymal progenitors fail to undergo fibrogenesis and chondrogenesis. This leads to impaired healing and persistent callus fibrosis originating from skeletal muscle. Thus, essential bone-muscle interactions govern bone regeneration through the direct contribution of skeletal muscle as a source of mesenchymal progenitors driving the fibrotic response and fibrotic remodeling, and supporting cartilage and bone formation.

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Direct contribution of skeletal muscle mesenchymal progenitors to bone repair

Nature Communications ◽

10.1038/s41467-021-22842-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anais Julien ◽

Anuya Kanagalingam ◽

Ester Martínez-Sarrà ◽

Jérome Megret ◽

Marine Luka ◽

...

Keyword(s):

Skeletal Muscle ◽

Bone Healing ◽

Bone Repair ◽

Fibrotic Response ◽

Mesenchymal Progenitors ◽

Fibrotic Tissue ◽

Bone Injury ◽

Single Cell Rna Sequencing ◽

Musculoskeletal Trauma

AbstractBone regenerates by activation of tissue resident stem/progenitor cells, formation of a fibrous callus followed by deposition of cartilage and bone matrices. Here, we show that mesenchymal progenitors residing in skeletal muscle adjacent to bone mediate the initial fibrotic response to bone injury and also participate in cartilage and bone formation. Combined lineage and single-cell RNA sequencing analyses reveal that skeletal muscle mesenchymal progenitors adopt a fibrogenic fate before they engage in chondrogenesis after fracture. In polytrauma, where bone and skeletal muscle are injured, skeletal muscle mesenchymal progenitors exhibit altered fibrogenesis and chondrogenesis. This leads to impaired bone healing, which is due to accumulation of fibrotic tissue originating from skeletal muscle and can be corrected by the anti-fibrotic agent Imatinib. These results elucidate the central role of skeletal muscle in bone regeneration and provide evidence that skeletal muscle can be targeted to prevent persistent callus fibrosis and improve bone healing after musculoskeletal trauma.

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3D-printed Biomimetic Bioactive Glass Scaffolds for Bone Regeneration in Rat Calvarial Defects

International Journal of Bioprinting ◽

10.18063/ijb.v6i2.274 ◽

2020 ◽

Vol 6 (2) ◽

Author(s):

Krishna C. R. Kolan ◽

Yue-Wern Huang ◽

Julie A. Semon ◽

Ming C. Leu

Keyword(s):

Compressive Strength ◽

Bone Formation ◽

Bone Regeneration ◽

Borate Glass ◽

Bone Repair ◽

Selective Laser Sintering ◽

Fibrous Tissue ◽

Bone Morphogenetic Protein 2 ◽

Significant Difference ◽

Calvarial Defects

The pore geometry of scaffold intended for the use in the bone repair or replacement is one of the most important parameters in bone tissue engineering. It affects not only the mechanical properties of the scaffold but also the amount of bone regeneration after implantation. Scaffolds with five different architectures (cubic, spherical, x, gyroid, and diamond) at different porosities were fabricated with bioactive borate glass using the selective laser sintering (SLS) process. The compressive strength of scaffolds with porosities ranging from 60% to 30% varied from 1.7 to 15.5 MPa. The scaffold’s compressive strength decreased significantly (up to 90%) after 1-week immersion in simulated body fluids. Degradation of scaffolds is dependent on porosity, in which the scaffold with the largest surface area has the largest reduction in strength. Scaffolds with traditional cubic architecture and biomimetic diamond architecture were implanted in 4.6 mm diameter full-thickness rat calvarial defects for 6 weeks to evaluate the bone regeneration with or without bone morphogenetic protein 2 (BMP-2). Histological analysis indicated no significant difference in bone formation in the defects treated with the two different architectures. However, the defects treated with the diamond architecture scaffolds had more fibrous tissue formation and thus have the potential for faster bone formation. Overall, the results indicated that borate glass scaffolds fabricated using the SLS process have the potential for bone repair and the addition of BMP-2 significantly improves bone regeneration.

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Repair of critical-size porcine craniofacial bone defects using a collagen-polycaprolactone composite biomaterial

10.1101/2021.04.19.440506 ◽

2021 ◽

Author(s):

Marley J Dewey ◽

Derek J Milner ◽

Daniel Weisgerber ◽

Colleen Flanagan ◽

Marcello Rubessa ◽

...

Keyword(s):

Bone Formation ◽

Bone Regeneration ◽

Fibrous Tissue ◽

Bone Defects ◽

Large Animal ◽

Collagen Scaffolds ◽

Shape Fitting ◽

Large Animal Models ◽

3D Printed ◽

Mineralized Collagen

Regenerative medicine approaches for massive craniomaxillofacial bone defects face challenges associated with the scale of missing bone, the need for rapid graft-defect integration, and challenges related to inflammation and infection. Mineralized collagen scaffolds have been shown to promote mesenchymal stem cell osteogenesis due to their porous nature and material properties, but are mechanically weak, limiting surgical practicality. Previously, these scaffolds were combined with 3D-printed polycaprolactone mesh to form a scaffold-mesh composite to increase strength and promote bone formation in sub-critical sized porcine ramus defects. Here, we compare the performance of mineralized collagen-polycaprolactone composites to the polycaprolactone mesh in a critical-sized porcine ramus defect model. While there were no differences in overall healing response between groups, our data demonstrated broadly variable metrics of healing regarding new bone infiltration and fibrous tissue formation. Abscesses were present surrounding some implants and polycaprolactone polymer was still present after 9-10 months of implantation. Overall, while there was limited successful healing, with 2 of 22 implants showed substantial levels of bone regeneration, and others demonstrating some form of new bone formation, the results suggest targeted improvements to improve repair of large animal models to more accurately represent craniomaxillofacial bone healing. Notably, strategies to increase osteogenesis throughout the implant, modulate the immune system to support repair, and employ shape-fitting tactics to avoid implant micromotion and resultant fibrosis. Improvements to the mineralized collagen scaffolds involve changes in pore size and shape to increase cell migration and osteogenesis and inclusion or delivery of factors to aid vascular ingrowth and bone regeneration.

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Tissue Engineering Strategies to Promote Bone Repair

Materials Science Forum ◽

10.4028/www.scientific.net/msf.941.2495 ◽

2018 ◽

Vol 941 ◽

pp. 2495-2500 ◽

Cited By ~ 1

Author(s):

Anne Margaux Collignon ◽

Gaël Y. Rochefort

Keyword(s):

Tissue Engineering ◽

Bone Regeneration ◽

Bone Tissue ◽

Bone Healing ◽

Bone Repair ◽

Population Aging ◽

Local Bone ◽

Bone Injury ◽

Autologous Bone

Bone displays an amazing capacity for endogenous self-remodeling. However, compromised bone healing and recovering is on the ascent because of population aging, expanding rate of bone injury and the clinical requirement for the advancement of elective choices to autologous bone unions. Current strategies, including biomolecules, cell treatments, biomaterials and diverse combinations of these, are presently created to encourage the vascularization and the engraftment of the grafts, to reproduce at last a bone tissue with similar properties and attributes of the local bone. In this review, we look through the current techniques that are right now created, utilizing biomolecules, cells and biomaterials, to initiate, coordinate and potentiate bone regeneration and healing after damage and further talk about the natural procedures related with this repair.

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Evaluation of the Long-Term Results of Rat Cranial Bone Repair Using a Particular Xenograft

Journal of Oral Implantology ◽

10.1563/aaid-joi-d-09-00064 ◽

2010 ◽

Vol 36 (3) ◽

pp. 167-173 ◽

Cited By ~ 5

Author(s):

Hakan Develioglu ◽

SerpilÜnver Saraydın ◽

Ünal Kartal ◽

Levent Taner

Keyword(s):

Bone Formation ◽

Bone Repair ◽

Fibrous Tissue ◽

Bone Defects ◽

Parietal Bone ◽

Control Area ◽

Cranial Bone ◽

Long Term Results ◽

Tissue Samples ◽

Defect Sites

Abstract Bone defects that cannot be healed completely are termed critical-sized defects and can be used to test bone grafts for medicine, dentistry, and periodontology. The aim of the present study was to detect the effects of a xenograft (Unilab Surgibone) on bone building in experimentally created parietal bone defects in rats. Standardized parietal bone defects were created in 16 rats, and each defect had a circular morphology 6 mm in diameter. The right defect sites were filled with porous particle material, and the left site was used as control. After the 3rd, 6th, and 12th months, rats were killed and tissue samples obtained from the related site of the cranium. Subsequently, histological sections were taken and stained with different stains for evaluation under light microscope. The rate of bone formation was assessed using a semiquantitative method. These results showed that dense collagenous tissue was observed in the control area during the third month, whereas xenograft particles were surrounded by a fibrous tissue layer at the implantation site. Osteoclast-like cells were also observed. There was also no significant bone repair at other observation periods. It can be concluded that the material used had no evidence of resorption and does not enhance bone formation. However, it seems biocompatible, osteoconductive, and could be used in a limited manner as a material for filling osseous defects in clinical practice.

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Periosteal Augmentation of Allograft Bone and its Effect on Implant Fixation - An Experimental Study on 12 Dogs§

The Open Orthopaedics Journal ◽

10.2174/1874325001307010018 ◽

2013 ◽

Vol 7 (1) ◽

pp. 18-24 ◽

Cited By ~ 3

Author(s):

Jeppe Barckman ◽

Jorgen Baas ◽

Mette Sørensen ◽

Joan E Bechtold ◽

Kjeld Soballe

Keyword(s):

Bone Formation ◽

Bone Graft ◽

Bone Repair ◽

Fibrous Tissue ◽

Titanium Implants ◽

Allograft Bone ◽

New Bone Formation ◽

Implant Fixation ◽

Implant Surface ◽

Cambium Layer

Purpose: Periosteum provides essential cellular and biological components necessary for fracture healing and bone repair. We hypothesized that augmenting allograft bone by adding fragmented autologous periosteum would improve fixation of grafted implants. Methods: In each of twelve dogs, we implanted two unloaded cylindrical (10 mm x 6 mm) titanium implants into the distal femur. The implants were surrounded by a 2.5-mm gap into which morselized allograft bone with or without addition of fragmented autologous periosteum was impacted. After four weeks, the animals were euthanized and the implants were evaluated by histomorphometric analysis and mechanical push-out test. Results: Although less new bone was found on the implant surface and increased volume of fibrous tissue was present in the gap around the implant, no difference was found between treatment groups regarding the mechanical parameters. Increased new bone formation was observed in the immediate vicinity of the periosteum fragments within the bone graft. Conclusion: The method for periosteal augmentation used in this study did not alter the mechanical fixation although osseointegration was impaired. The observed activity of new bone formation at the boundary of the periosteum fragments may indicate maintained bone stimulating properties of the transplanted cambium layer. Augmenting the bone graft by smaller fragments of periosteum, isolated cambium layer tissue or cultured periosteal cells could be studied in the future.

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Effects of strontium ions with potential antibacterial activity on in vivo bone regeneration

10.21203/rs.3.rs-18054/v2 ◽

2020 ◽

Author(s):

Nafiseh Baheiraei ◽

Hossein Eyni ◽

Bita bakhshi ◽

Raziyeh Najafloo

Keyword(s):

Antibacterial Activity ◽

Bone Formation ◽

Bone Regeneration ◽

Bone Repair ◽

Early Stage ◽

Antibacterial Activities ◽

Calvarial Bone ◽

Alizarin Red

Abstract Background: Bioactive glasses (BGs) have attracted added attention in the structure of the scaffolds for bone repair applications. Different metal ions could be doped in BGs to induce specific biological responses. Among these ions, strontium (Sr) is considered as an effective and safe doping element with promising effects on bone formation and regeneration.Methods: In this experiment, we evaluated the antibacterial activities of the gelatin-BG (Gel-BG) and Gel-BG/Sr scaffolds in vitro. The osteogenic properties of the prepared scaffolds were also assessed in rabbit calvarial bone defects for 12 weeks. Alizarin Red, Hematoxylin & Eosin (H&E) and Masson’s Trichrome staining were performed to assess bone regeneration and the obtained results were compared with those without Sr. Also, histomorphometric data were obtained to evaluate the new bone, residual graft, and connective tissue.Results: Both scaffolds showed in vivo bone formation during 12 weeks with the newly formed bone area in Gel-BG/Sr scaffold was higher than that in Gel-BG scaffolds after the whole period. Based on the histological results, Gel-BG/Sr exhibited acceleration of early-stage bone formation in vivo. The results of antibacterial investigation showed that although both Gel-BG/Sr and Gel-BG effectively inhibited the growth of Escherichia coli (E. coli) but, only Gel-BG/Sr structure could lead to a 3 log reduction in Staphylococcus aureus (S. aureus). Conclusions: Our results confirmed that Sr doped BG is a favorable candidate for bone tissue engineering with superior antibacterial activity and bone regeneration capacity compared with similar counterparts having no Sr ion.

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Effects of strontium ions with potential antibacterial activity on in vivo bone regeneration

10.21203/rs.3.rs-18054/v1 ◽

2020 ◽

Author(s):

Nafiseh Baheiraei ◽

Hossein Eyni ◽

Bita bakhshi ◽

Raziyeh Najafloo

Keyword(s):

Antibacterial Activity ◽

Bone Formation ◽

Bone Regeneration ◽

Bone Repair ◽

Early Stage ◽

Antibacterial Activities ◽

Calvarial Bone ◽

Alizarin Red

Abstract Background Bioactive glasses (BGs) have attracted added attention in the structure of the scaffolds for bone repair applications. Different metal ions could be doped in BGs to induce specific biological responses. Among these ions, strontium (Sr) is considered as an effective and safe doping element with promising effects on bone formation and regeneration. Methods In this experiment, we evaluated the antibacterial activities of the gelatin-BG (Gel-BG) and Gel-BG/Sr scaffolds in vitro. The osteogenic properties of the prepared scaffolds were also assessed in rabbit calvarial bone defects for 12 weeks. Alizarin Red, Hematoxylin & Eosin (H&E) and Masson’s Trichrome staining were performed to assess bone regeneration and the obtained results were compared with those without Sr. Also, histomorphometric data were obtained to evaluate the new bone, residual graft, and connective tissue. Results Both scaffolds showed in vivo bone formation during 12 weeks with the newly formed bone area in Gel-BG/Sr scaffold was higher than that in Gel-BG scaffolds after the whole period. Based on the histological results, Gel-BG/Sr exhibited acceleration of early-stage bone formation in vivo. The results of antibacterial investigation showed that although both Gel-BG/Sr and Gel-BG effectively inhibited the growth of Escherichia coli (E. coli) but, only Gel-BG/Sr structure could lead to a 3 log reduction in Staphylococcus aureus (S. aureus). Conclusions: Our results confirmed that Sr doped BG is a favorable candidate for bone tissue engineering with superior antibacterial activity and bone regeneration capacity compared with similar counterparts having no Sr ion.

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Collagen Sponge Functionalized with Chimeric Anti-BMP-2 Monoclonal Antibody Mediates Repair of Critical-Size Mandibular Continuity Defects in a Nonhuman Primate Model

BioMed Research International ◽

10.1155/2017/8094152 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Yilin Xie ◽

Yingying Su ◽

Seiko Min ◽

Jianxia Tang ◽

Bee Tin Goh ◽

...

Keyword(s):

Bone Formation ◽

Bone Repair ◽

De Novo ◽

3D Analysis ◽

Collagen Scaffolds ◽

Primate Model ◽

Bone Injury ◽

Morphogenetic Protein ◽

Osseous Regeneration ◽

Continuity Defects

Antibody-mediated osseous regeneration (AMOR) has been introduced by our research group as a tissue engineering approach to capture of endogenous growth factors through the application of specific monoclonal antibodies (mAbs) immobilized on a scaffold. Specifically, anti-Bone Morphogenetic Protein- (BMP-) 2 mAbs have been demonstrated to be efficacious in mediating bone repair in a number of bone defects. The present study sought to investigate the application of AMOR for repair of mandibular continuity defect in nonhuman primates. Critical-sized mandibular continuity defects were created in Macaca fascicularis locally implanted with absorbable collagen sponges (ACS) functionalized with chimeric anti-BMP-2 mAb or isotype control mAb. 2D and 3D analysis of cone beam computed tomography (CBCT) imaging demonstrated increased bone density and volume observed within mandibular continuity defects implanted with collagen scaffolds functionalized with anti-BMP-2 mAb, compared with isotype-matched control mAb. Both CBCT imaging and histologic examination demonstrated de novo bone formation that was in direct apposition to the margins of the resected bone. It is hypothesized that bone injury may be necessary for AMOR. This is evidenced by de novo bone formation adjacent to resected bone margins, which may be the source of endogenous BMPs captured by anti-BMP-2 mAb, in turn mediating bone repair.

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Organic Bovine Graft Associated With PRP In Rabbit Calvaria

Arquivos Internacionais de Otorrinolaringologia ◽

10.1590/s1809-48722011000200014 ◽

2011 ◽

Vol 15 (02) ◽

pp. 208-213

Author(s):

Lara Maria Alencar Ramos ◽

Jonas Dantas Batista ◽

Darceny Zanetta-Barbosa ◽

Paula Dechichi ◽

Flaviana Soares Rocha

Keyword(s):

Bone Formation ◽

Bone Repair ◽

Fibrous Tissue ◽

Giant Cells ◽

Histological Evaluation ◽

Bovine Bone ◽

New Bone Formation ◽

Organic Group ◽

Group I ◽

Significant Difference

Summary Introduction: Repairing large bone defects is a huge challenge that reconstructive surgery currently faces. Objective: The objective of this study was to perform the histological evaluation of bone repair in rabbit calvaria when using bovine bone graft (Gen-ox-organic®) associated with platelet-rich plasma (PRP). Method: 12 rabbits were used and two bone fragments were bilaterally removed from calvaria. Then, 24 surgical sites were randomly divided into 3 groups: coagulum (group I), organic (group II) and PRP-included organic (group III). After four weeks, the animals were sacrificed and the grafted area removed, fixed in 10% formalin with PBS 0.1 M, and embedded in paraffin. Study method: The analyzed histological parameters were: defective area filled with the newly-formed bone, graft's giant cells and particles, as well as the new bone formation associated with the particles. Group I's defects were filled with fibrous tissue attaching the periosteum and revealed a little bone formation peripherally. In both groups II and III, a similar standard was noticed in addition to the absence of graft particles and giant cells. There was no significant difference in the number of giant cells, graft particles and new bone formation around the particles between the grafted material and the PRP-related group. Conclusion: The results achieved indicate that the organic biomaterial neither separately nor jointly with PRP improves bone regeneration.

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