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The Interaction of BMP2-Induced Defect Healing in Rat and Fixator Stiffness Modulates Matrix Alignment and Contraction.

ABSTRACT: Successful fracture healing requires a tight interplay between mechanical and biological cues. In vitro studies illustrated that mechanical loading modulates bone morphogenetic protein (BMP) signaling. However, in the early phases of large bone defect regeneration in vivo, the underlying mechanisms leading to this mechanosensation remained unknown. We investigated the interaction of BMP2 stimulation and mechanical boundary conditions in a rat critical-sized femoral defect model (5?mm) stabilized with three distinctly different external fixator stiffness. Defects were treated with 5??g rhBMP2 loaded on an absorbable collagen sponge. Early matrix alignment was monitored by second-harmonic generation imaging. Bony bridging of defects and successive healing was monitored by histology at day 7 and day 14 as well as in vivo microCT at days 10, 21, and 42 post-operation. Femora harvested at day 42 were characterized mechanically assessing torsional load to failure ex vivo. At tissue level, differences between groups were visible at day 14 with manifest bone formation in the microCT. Histologically, we observed prolonged chondrogenesis upon flexible fixation, whereas osteogenesis started earlier after rigid and semirigid fixation. At later time points, there was a boost of bone tissue formation upon flexible fixation, whereas other groups already displayed signs of tissue maturation. Based on gene expression profiling, we analyzed the mechanobiological interplay. Already at day 3, these analyses revealed differences in expression pattern, specifically of genes involved in extracellular matrix formation. Gene regulation correlating with fixator stiffness was pronounced at day 7 comprising genes related to immunological processes and cellular contraction. The influence of loading on matrix contraction was further investigated and confirmed in a 3D bioreactor. Taken together, we demonstrate an early onset of mechanical conditions influencing BMP2-induced defect healing and shed light on gene regulatory networks associated with extracellular matrix organization and contraction that seemed to directly impact healing outcomes. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

SUBMITTER: Schwarz C

PROVIDER: S-EPMC6124159 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The Interaction of BMP2-Induced Defect Healing in Rat and Fixator Stiffness Modulates Matrix Alignment and Contraction.

Schwarz Carolin C Ott Claus-Eric CE Wulsten Dag D Brauer Erik E Schreivogel Sophie S Petersen Ansgar A Hassanein Kerstin K Roewer Linda L Schmidt Tanja T Willie Bettina M BM Duda Georg N GN

JBMR plus 20180417 3

Successful fracture healing requires a tight interplay between mechanical and biological cues. In vitro studies illustrated that mechanical loading modulates bone morphogenetic protein (BMP) signaling. However, in the early phases of large bone defect regeneration in vivo, the underlying mechanisms leading to this mechanosensation remained unknown. We investigated the interaction of BMP2 stimulation and mechanical boundary conditions in a rat critical-sized femoral defect model (5 mm) stabilized ...[more]

PMID: 30283901

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Project description:Critical-sized cranial bone defect remains a great clinical challenge. With advantages in regenerative medicine, injectable hydrogels incorporated with bioactive molecules show great potential in promoting cranial bone repair. Recently, we developed a dual delivery system by sequential release of bone morphogenetic protein 2 (BMP2) followed by insulin-like growth factor 1 (IGF1) in microparticles (MPs), and an injectable alginate/collagen (alg/col)-based hydrogel. In this study, we aim to evaluate the effect of dual delivery of BMP2 and IGF1 in MPs through the injectable hydrogel in critical-sized cranial bone defect healing. The gelatin MPs loaded with BMP2 and poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carboxyl (PLGA-PEG-COOH) MPs loaded with IGF1 were prepared, respectively. The encapsulation efficiency and release profile of growth factors in MPs were measured. A cranial defect model was applied to evaluate the efficacy of the dual delivery system in bone regeneration. Adult Sprague Dawley rats were subjected to osteotomy to make an ⌀8-mm cranial defect. The injectable hydrogel containing MPs loaded with BMP2 (2 μg), IGF1 (2 μg), or a combination of BMP2 (1 μg) and IGF1 (1 μg) were injected to the defect site. New bone formation was evaluated by microcomputed tomography, histological analysis, and immunohistochemistry after 4 or 8 weeks. Data showed that dual delivery of the low-dose BMP2 and IGF1 in MPs through alg/col-based hydrogel successfully restored cranial bone as early as 4 weeks after implantation, whose effect was comparable to the single delivery of high-dose BMP2 in MPs. In conclusion, this study suggests that dual delivery of BMP2 and IGF1 in MPs in alg/col-based hydrogel achieves early bone regeneration in critical-sized bone defect, with advantage in reducing the dose of BMP2. Impact Statement Sequential release of bone morphogenetic protein 2 (BMP2) followed by insulin-like growth factor 1 (IGF1) in two different microparticles promotes critical-sized bone defect healing. This dual delivery system reduces the dose of BMP2 by supplementing IGF1, which may diminish the potential side effects of BMP2.

Project description:Background: Bone grafts are in high demand due to the increase in the cases of bone defects mainly caused by trauma, old age, and disease-related bone damages. Tissue-engineered calcium phosphate (CaP) biomaterials match the major inorganic contents of bone, thereby could be the potential bone graft substitute. However, CaP-bone grafts lack the osteoinductivity that is vital for effective bone regeneration. In this study, we aimed to test the bone defect healing potential of biomimetically fabricated low dose BMP2-doped CaP (BMP2.BioCaP) grafts in a large animal model. Methods: Low dose BMP2 was doped internally (BMP2-int.BioCaP) or on the surface of CaP (BMP2-sur.BioCaP) grafts during the fabrication process. Our previous study showed the robust bone regenerative potential of BMP2-int.BioCaP and BMP2-sur.BioCaP grafts in the rat ectopic model. In this study, we investigated the bone defect healing potential of BMP2.BioCaP grafts in sheep humerus/femoral defects, as well as compared with that of autologous bone graft and clinically used deproteinized bovine bone (DBB) xenograft. Results: Different ways of BMP2 doping did not affect the surface morphology and degradation properties of the graft materials. Micro-CT and histology results showed robustly higher bone defect-healing potential of the BMP2.BioCaP grafts compared to clinically used DBB grafts. The bone defect healing potential of BMP2.BioCaP grafts was as effective as that of the autologous bone graft. Although, BMP2-int.BioCaP doped half the amount of BMP2 compared to BMP2-sur.BioCaP, its' bone defect healing potential was even robust. The BMP2.BioCaP grafts showed less immunogenicity compared to BioCaP or DBB grafts. The volume density of blood vessel-like and bone marrow-like structures in both BMP2.BioCaP graft groups were in a similar extent to the autologous group. Meticulous observation of higher magnification histological images showed active bone regeneration and remodeling during bone defect healing in BMP2.BioCaP graft groups. Conclusion: The robust bone regenerative potential of BMP2.BioCaP grafts in the ectopic model and in-situ bone defects in small and large animals warrant the pre-clinical studies on large animal critical-sized segmental bone defects.

Project description:Background: Grafting of biomaterial in alveolar defect facilitates bone healing and orthodontic treatment. BMP2-functionalized biomimetic calcium phosphate (BioCaP) graft had shown excellent bone defect healing potential in many preclinical studies. In this study, we aimed to investigate the influence of BioCaP graft on surgical alveolar bone defect healing during orthodontic tooth movement (OTM) in beagle dogs. Methods: Nine Beagle dogs were randomly assigned to three groups: control, deproteinized bovine bone (DBB), and BioCaP. The maxillary second premolars were protracted into the defects of the extracted maxillary first premolar for 8 weeks. The rate of OTM, alveolar remodeling and bone defect healing were evaluated by histology, histomorphometry, and cone beam computed tomography (CBCT) imaging. Periodontal probing depth was analyzed. Gingival cervicular fluid was collected at week 4 and 8, and the IL-1? level was measured by ELISA. Results: The histological sections of the bone defect showed more newly formed bone in the BioCaP group. The percentage of new bone formation in the BioCaP group was 1.61-, and 1.25-fold higher compared to the control and DBB group, respectively. After 8 weeks of OTM, the resorption rate of BioCaP was 1.42-fold higher compared to DBB. The root resorption index in the DBB group was 1.87-, and 1.39-fold higher compared to the control and BioCaP group, respectively. CBCT images showed 1.92-, and 1.36-fold higher bone mineral density in the BioCaP group compared to the control and DBB group, respectively. There was no significant difference in OTM among the three groups. The distance between the enamel cementum and the crest of the alveolar ridge in the control group was 1.45-, and 1.69-fold higher compared to DBB and BioCaP group, respectively. Periodontal probing depth at week 8 was reduced in the BioCaP group compared to the control. IL-1? concentration in the gingival cervicular fluid was significantly lower in the BioCaP group compared to the control group at week 4 and 8. Conclusion: BioCaP graft robustly promoted bone regeneration and alveolar bone defect healing without affecting OTM. BioCaP graft caused less alveolar bone recession and root resorption of traction tooth with favorable periodontal attachment level indicating that BioCaP as a bioactive and functional bone filling material for alveolar bone defects during orthodontic treatment.

Project description:UnlabelledThere is increasing evidence that the physical environment is a critical mediator of tumor behavior. Hepatocellular carcinoma (HCC) develops within an altered biomechanical environment, and increasing matrix stiffness is a strong predictor of HCC development. The aim of this study was to establish whether changes in matrix stiffness, which are characteristic of inflammation and fibrosis, regulate HCC cell proliferation and chemotherapeutic response. Using an in vitro system of "mechanically tunable" matrix-coated polyacrylamide gels, matrix stiffness was modeled across a pathophysiologically relevant range, corresponding to values encountered in normal and fibrotic livers. Increasing matrix stiffness was found to promote HCC cell proliferation. The proliferative index (assessed by Ki67 staining) of Huh7 and HepG2 cells was 2.7-fold and 12.2-fold higher, respectively, when the cells were cultured on stiff (12 kPa) versus soft (1 kPa) supports. This was associated with stiffness-dependent regulation of basal and hepatocyte growth factor-stimulated mitogenic signaling through extracellular signal-regulated kinase, protein kinase B (PKB/Akt), and signal transducer and activator of transcription 3. β1-Integrin and focal adhesion kinase were found to modulate stiffness-dependent HCC cell proliferation. Following treatment with cisplatin, we observed reduced apoptosis in HCC cells cultured on stiff versus soft (physiological) supports. Interestingly, however, surviving cells from soft supports had significantly higher clonogenic capacity than surviving cells from a stiff microenvironment. This was associated with enhanced expression of cancer stem cell markers, including clusters of differentiation 44 (CD44), CD133, c-kit, cysteine-X-cysteine receptor 4, octamer-4 (CXCR4), and NANOG.ConclusionIncreasing matrix stiffness promotes proliferation and chemotherapeutic resistance, whereas a soft environment induces reversible cellular dormancy and stem cell characteristics in HCC. This has implications for both the treatment of primary HCC and the prevention of tumor outgrowth from disseminated tumor cells. (HEPATOLOGY 2011;).

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The Interaction of BMP2-Induced Defect Healing in Rat and Fixator Stiffness Modulates Matrix Alignment and Contraction.

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The Interaction of BMP2-Induced Defect Healing in Rat and Fixator Stiffness Modulates Matrix Alignment and Contraction.

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