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1.
J Biomech Eng ; 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34802060

RESUMO

Delayed long bone fracture healing and nonunion continue to be a significant socioeconomic burden. While mechanical stimulation is known to be an important determinant of the bone repair process, understanding how the magnitude, mode, and commencement of interfragmentary strain (IFS) affect fracture healing can guide new therapeutic strategies to prevent delayed healing or non-union. Mouse models provide a means to investigate the molecular and cellular aspects of fracture repair, yet there is only one commercially available, clinically-relevant, locking intramedullary nail (IMN) currently available for studying long bone fractures in rodents. Having access to alternative IMNs would allow a variety of mechanical environments at the fracture site to be evaluated, and the purpose of this proof-of-concept finite element analysis study is to identify which IMN design parameters have the largest impact on IFS in a murine transverse femoral osteotomy model. Using the dimensions of the clinically relevant IMN as a guide, the nail material, distance between interlocking screws, and clearance between the nail and endosteal surface were varied between simulations. Of these parameters, changing the nail material from stainless steel (SS) to polyetheretherketone (PEEK) had the largest impact on IFS. Reducing the distance between the proximal and distal interlocking screws substantially affected IFS only when nail modulus was low. Therefore, IMNs with low modulus (e.g., PEEK) can be used alongside commercially available SS nails to investigate the effect of initial IFS or stability on fracture healing with respect to different biological conditions of repair in rodents.

2.
JBMR Plus ; 5(9): e10530, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34532615

RESUMO

Osteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF-ß signaling plays an important role in dominant and recessive OI disease progression. Inhibition of TGF-ß signaling with a murine pan-specific TGF-ß neutralizing antibody (1D11) was shown to significantly increase trabecular bone volume and long bone strength in mouse models of OI. To investigate the frequency of dosing and dose options of TGF-ß neutralizing antibody therapy, we assessed the effect of 1D11 on disease progression in a dominant OI mouse model (col1a2 gene mutation at G610C). In comparison with OI mice treated with a control antibody, we attempted to define mechanistic effects of 1D11 measured via µCT, biomechanical, dynamic histomorphometry, and serum biomarkers of bone turnover. In addition, osteoblast and osteoclast numbers in histological bone sections were assessed to better understand the mechanism of action of the 1D11 antibody in OI. Here we show that 1D11 treatment resulted in both dose and frequency dependency, increases in trabecular bone volume fraction and ultimate force in lumbar bone, and ultimate force, bending strength, yield force, and yield strength in the femur (p ≤ 0.05). Suppression of serum biomarkers of osteoblast differentiation, osteocalcin, resorption, CTx-1, and bone formation were observed after 1D11 treatment of OI mice. Immunohistochemical analysis showed dose and frequency dependent decreases in runt-related transcription factor, and increase in alkaline phosphatase in lumbar bone sections. In addition, a significant decrease in TRACP and the number of osteoclasts to bone surface area was observed with 1D11 treatment. Our results show that inhibition of the TGF-ß pathway corrects the high-turnover aspects of bone disease and improves biomechanical properties of OI mice. These results highlight the potential for a novel treatment for osteogenesis imperfecta. © 2021 Sanofi-Genzyme. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

3.
J Hand Surg Am ; 46(11): 1030.e1-1030.e5, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34001410

RESUMO

PURPOSE: Finger avulsion injuries account for 5% of upper extremity injuries requiring evaluation in an emergency room. They are devastating injuries that require microvascular reconstruction or amputation. As public awareness rises, there is a growing market for silicone rings, with limited data on their ability to prevent ring avulsion injuries. METHODS: Five cadaver forearms were attached to a custom fixture, allowing for ring avulsion simulations. Specifically designed silicone or metal rings of varying sizes (#4-#11) were assigned to one of five fingers on each forearm, based on fit. The contralateral corresponding finger was tested using a ring of the same size in the other material. A preload of 2 N was applied to each ring, and ultimate failure force was determined by applying an upward force at a loading rate of 500 mm/sec until failure. Additionally, a fifth cadaver forearm was used to determine the ultimate failure force of silicone rings in a clenched fist position. RESULTS: The average ultimate failure force for silicone rings of all sizes was 53.0 N, compared to 495.2 N for metal rings of all sizes. The average ultimate failure force of silicone rings in the clenched fist position was increased across rings of all sizes, with an average of 99.9 N. There were no degloving injuries in the silicone ring avulsion group. CONCLUSIONS: Biomechanically, silicone rings have a significantly lower failure force than metal rings and may help prevent ring avulsion injuries. CLINICAL RELEVANCE: The use of silicone rings should be encouraged in professions where ring avulsion injuries are more likely, such as heavy labor.

4.
JBMR Plus ; 5(3): e10443, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33778319

RESUMO

Glucocorticoids increase bone fragility in patients in a manner that is underestimated by bone mass measurement. This study aimed to determine if the adult mouse could model this bone strength/bone mass discrepancy. Forty-two 13-week-old BALB/cJ mice were randomized into vehicle and glucocorticoid groups, implanted with vehicle or 6-methylprednisolone pellets, and necropsied after 60 and 120 days. Bone strength and bone mass/microarchitecture were assessed at the right central femur (CF; cortical-bone-rich) and sixth lumbar vertebral body (LVB6; trabecular-bone-rich). Bound water (BW) of the whole right femur was analyzed by proton-nuclear magnetic resonance (1H-NMR) relaxometry. Data were analyzed by two-factor ANOVA with time (day 60 and day 120) and treatment (vehicle and glucocorticoid) as main effects for all data. Significant interactions were further analyzed with a Tukey's post hoc test. Most bone strength measures in the CF were lower in the glucocorticoid group, regardless of the duration of treatment, with no time × treatment interaction. However, bone mass measures in the CF showed a significant time × treatment interaction (p = 0.0001). Bone strength measures in LVB6 showed a time × treatment interaction (p < 0.02) such that LVB6 strength was lower after 120 days of glucocorticoids compared with 120 days of vehicle treatment. Whole-femur-BW was lower with both glucocorticoid treatment (p = 0.0001) and time (p < 0.02), with a significant time × treatment interaction (p = 0.005). Glucocorticoid treatment of male BALB/cJ mice resulted in the lowering of bone strength in both cortical and trabecular bone that either appeared earlier or was greater than the treatment-related changes in bone mass/microarchitecture. The adult mouse may be a good model for investigating the bone strength/mass discrepancy observed in glucocorticoid-treated patients. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

5.
Bone Rep ; 14: 100743, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33490313

RESUMO

Severely injured patients are beleaguered by complications during convalescence, such as dysregulated biomineralization. Paradoxically, severely injured patients experience the loss of bone (osteoporosis), resulting in diminished skeletal integrity and increased risk of fragility fractures; yet they also accrue mineralization in soft tissues, resulting in complications such as heterotopic ossification (HO). The pathophysiology leading to dysregulated biomineralization in severely injured patients is not well defined. It has been postulated that these pathologies are linked, such that mineralization is "transferred" from the bone to soft tissue compartments. The goal of this study was to determine if severe injury-induced osteoporosis and soft tissue calcification are temporally coincident following injury. Using a murine model of combined burn and skeletal muscle injury to model severe injury, it was determined that mice developed significant progressive bone loss, detectable as early as 3 days post injury, and marked soft tissue mineralization by 7 days after injury. The observed temporal concordance between the development of severe injury-induced osteoporosis and soft tissue mineralization indicates the plausibility that these complications share a common pathophysiology, though further experiments are required.

6.
Bone ; 141: 115625, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32890778

RESUMO

Higher fracture risk in type 2 diabetes (T2D) is attributed to disease-specific deficits in micro-structural and material properties of bone, although the primary cause is not yet established. The TallyHO (TH) mouse is a polygenic model of early-onset T2D and obesity analogous to adolescent-onset T2D in humans. Due to incomplete penetrance of the phenotype, ~25% of male TH mice never develop hyperglycemia, providing a strain-matched, non-diabetic control. Utilizing this model of T2D, we examined the impact of glucose-lowering therapy with canagliflozin (CANA) on diabetic bone. Male TH mice with or without hyperglycemia (High BG, Low BG) were monitored from ~8 to 20 weeks of age, and compared to age-matched, male, TH mice treated with CANA from ~8 to 20 weeks of age. At 20 weeks, untreated TH mice with high BG [High BG: 687 ± 106 mg/dL] exhibited lower body mass, decrements in cortical bone of the femur (decreased cross-sectional area and thickness; increased porosity) and in trabecular bone of the femur metaphysis and L6 vertebra (decreased bone volume fraction, thickness, and tissue mineral density), as well as decrements in cortical and vertebral bone strength (decreased yield force and ultimate force) when compared to untreated TH mice with low BG [Low BG: 290 ± 98 mg/dL; p < 0.0001]. CANA treatment was metabolically advantageous, normalizing body mass, BG and HbA1c to values comparable to the Low BG group. With drug-induced glycemic improvement, cortical area and thickness were significantly higher in the CANA than in the High BG group, but deficits in strength persisted with lower yield force and yield stress (partially independent of bone geometry) in the CANA group. Additionally, CANA only partially prevented the T2D-related loss in trabecular bone volume fraction. Taken together, these findings suggest that the ability of CANA to lower glucose and normalized glycemic control ameliorates diabetic bone disease but not fully.


Assuntos
Diabetes Mellitus Tipo 2 , Preparações Farmacêuticas , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Glicemia , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Camundongos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
7.
Bone ; 137: 115438, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32480022

RESUMO

The likelihood of experiencing an osteoporotic fracture of one or more vertebral bodies increases with age, and this increase is not solely due to sex steroid deficiency. For the purpose of assessing the effectiveness of novel therapeutic strategies in the prevention of vertebral fractures among the elderly, we hypothesized that the BALB/c mouse model of aging phenocopies the age-related decrease in human VB strength. To test this hypothesis, we assessed the age-related changes in trabecular architecture of the L6 VB, with respect to those in the distal femur metaphysis, between 6-mo. (young adulthood, n = 20/sex) and 20-mo. of age (old age, n = 18/sex) and then determined how well the architectural characteristics, volumetric bone mineral density (vBMD), and predicted failure force from µCT-derived finite element analysis (µFEA) with linear elastic failure criteria explained the age-related variance in VB strength, which was the ultimate force during quasi-static loading of the VB in compression. While there was a pronounced age-related deterioration in trabecular architecture in the distal femur metaphysis of female and male BALB/c mice, the decrease in trabecular bone volume fraction and trabecular number between 6-mo. and 20-mo. of age occurred in male mice, but not in female mice. As such, the VB strength was lower with age in males only. Nonetheless, BV/TV and volumetric bone mineral density (vBMD) positively correlated with the ultimate compressive force of the L6 VB for both females and males. Whether using a fixed homogeneous distribution of tissue modulus (Et = 18 GPa) or a heterogeneous distribution of Et based on a positive relationship with TMD, the predicted failure force of the VB was not independent of age, thereby suggesting linear µFEA may not be a suitable replacement for mechanical-based measurements of strength with respect to age-related changes. Overall, the BALB/c mouse model of aging mimics the age-related in decline in human VB strength when comparing 6-mo. and 20-mo. old male mice. The decrease in VB strength in female mice may occur over a different age range.


Assuntos
Densidade Óssea , Vértebras Lombares , Animais , Feminino , Fêmur/diagnóstico por imagem , Análise de Elementos Finitos , Vértebras Lombares/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C
8.
J Wrist Surg ; 9(2): 116-123, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32257612

RESUMO

Background This article reviews the results of a surgical technique using three iterations of drilling , autologous cancellous bone grafting ( filling ), and use of an intraosseous compression screw for the treatment of nondisplaced or minimally displaced scaphoid delayed unions or nonunions. Methods Part 1-Cadaveric study: Three cadaveric scaphoids underwent stained cancellous bone graft packing and headless cannulated compression screw placement using a single iteration of drilling and graft packing. Three additional scaphoids were allocated to the triple "drill and fill" group, and underwent three iterations of drilling and graft packing before screw insertion. Graft particle distribution on mid-sagittal sections was assessed under fluorescence microscopy. Comparison of normalized areas between the single and triple "drill and fill" groups was performed using repeated measures ANOVA and Tukey's post hoc test. Part 2-Clinical study: Twelve patients with minimally displaced scaphoid delayed unions and nonunions treated between April 2007 and December 2013 with the triple "drill and fill" technique were included. The average follow-up was 60.4 weeks. Two fellowship-trained musculoskeletal radiologists independently reviewed images for fracture healing. Results By the histomorphometric analysis, there was improved autograft distribution along the screw tract, particularly within the proximal pole, with three iterations of drilling and filling. Clinically, 11 of 12 delayed unions and nonunions had healed. Conclusion Our results support the use of the "drill and fill" technique as an option for the treatment of select nondisplaced or minimally displaced scaphoid nonunions and delayed unions at the waist without avascular necrosis of the proximal pole. Level of Evidence This is a Level IV study.

9.
Bone ; 133: 115254, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31991250

RESUMO

Selective sodium-dependent glucose co-transporter 2 inhibitors (SGLT2Is) are oral hypoglycemic medications utilized increasingly in the medical management of hyperglycemia among persons with type 2 diabetes (T2D). Despite favorable effects on cardiovascular events, specific SGLT2Is have been associated with an increased risk for atypical fracture and amputation in subgroups of the T2D population, a population that already has a higher risk for typical fragility fractures than the general population. To better understand the effect of SGLT2 blockade on skeletal integrity, independent of diabetes and its co-morbidities, we utilized the "Jimbee" mouse model of slc5a2 gene mutation to investigate the impact of lifelong SGLT2 loss-of-function on metabolic and skeletal phenotype. Jimbee mice maintained normal glucose homeostasis, but exhibited chronic polyuria, glucosuria and hypercalciuria. The Jimbee mutation negatively impacted appendicular growth of the femur and resulted in lower tissue mineral density of both cortical and trabecular bone of the femur mid-shaft and distal femur metaphysis, respectively. Several components of the Jimbee phenotype were characteristic only of male mice compared with female mice, including reductions: in body weight; in cortical area of the mid-shaft; and in trabecular thickness within the metaphysis. Despite these decrements, the strength of femur diaphysis in bending (cortical bone), which increased with age, and the strength of L6 vertebra in compression (primarily trabecular bone), which decreased with age, were not affected by the mutation. Moreover, the age-related decline in bone toughness was less for Jimbee mice, compared with control mice, such that by 49-50 weeks of age, Jimbee mice had significantly tougher femurs in bending than C57BL/6J mice. These results suggest that chronic blockade of SGLT2 in this model reduces the mineralization of bone but does not reduce its fracture resistance.


Assuntos
Diabetes Mellitus Tipo 2 , Animais , Densidade Óssea , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Fêmur/diagnóstico por imagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Minerais , Transportador 2 de Glucose-Sódio/genética
10.
Bone ; 130: 115106, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689526

RESUMO

Recent clinical studies have revealed that a somatic mutation in MAP2K1, causing constitutive activation of MEK1 in osteogenic cells, occurs in melorheostotic bone disease in humans. We have generated a mouse model which expresses an activated form of MEK1 (MEK1DD) specifically in osteoprogenitors postnatally. The skeletal phenotype of these mice recapitulates many features of melorheostosis observed in humans, including extra-cortical bone formation, abundant osteoid formation, decreased mineral density, and increased porosity. Paradoxically, in both humans and mice, MEK1 activation in osteoprogenitors results in bone that is not structurally compromised, but is hardened and stronger, which would not be predicted based on tissue and matrix properties. Thus, a specific activating mutation in MEK1, expressed only by osteoprogenitors postnatally, can have a significant impact on bone strength through complex alterations in whole bone geometry, bone micro-structure, and bone matrix.


Assuntos
Osso e Ossos , Melorreostose , Animais , Camundongos , Mutação , Osteogênese , Fenótipo
11.
Bone ; 130: 115126, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678497

RESUMO

One possibility for the disproportionate increase in fracture risk with aging relative to the decrease in bone mass is an accumulation of changes to the bone matrix which deleteriously affect fracture resistance. In order to effectively develop new targets for osteoporosis, a preclinical model of the age-related loss in fracture resistance needs to be established beyond known age-related decreases in bone mineral density and bone volume fraction. To that end, we examined long bones of male and female BALB/c mice at 6-mo. and 20-mo. of age and assessed whether material and matrix properties of cortical bone significantly differed between the age groups. The second moment of area of the diaphysis (minimum and maximum principals for femur and radius, respectively) as measured by ex vivo micro-computed tomography (µCT) was higher at 20-mo. than at 6-mo. for both males and females, but ultimate moment as measured by three-point bending tests did not decrease with age. Cortical thickness was lower with age for males, but higher for old females. Partially accounting for differences in structure, material estimates of yield, ultimate stress, and toughness (left femur) were 12.6%, 11.1%, and 40.9% lower, respectively, with age for both sexes. The ability of the cortical bone to resist crack growth (right femur) was also 18.1% less for the old than for the young adult mice. These decreases in material properties were not due to changes in intracortical porosity as pore number decreased with age. Rather, age-related alterations in the matrix were observed for both sexes: enzymatic and non-enzymatic crosslinks by high performance liquid chromatography increased (femur), volume fraction of bound water by 1H-nuclear magnetic resonance relaxometry decreased (femur), cortical tissue mineral density by µCT increased (femur and radius), and an Amide I sub-peak ratio I1670/I1640 by Raman spectroscopy increased (tibia). Overall, there are multiple matrix changes to potentially target that could prevent the age-related decrease in fracture resistance observed in BALB/c mouse.


Assuntos
Densidade Óssea , Osso e Ossos , Animais , Osso e Ossos/diagnóstico por imagem , Matriz Extracelular , Feminino , Fêmur/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microtomografia por Raio-X
12.
JBMR Plus ; 3(6): e10135, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31346566

RESUMO

Being predictors of the mechanical properties of human cortical bone, bound and pore water measurements by magnetic resonance (MR) imaging are being developed for the clinical assessment of fracture risk. While pore water is a surrogate of cortical bone porosity, the determinants of bound water are unknown. Manipulation of organic matrix properties by oxidative deproteinization, thermal denaturation, or nonenzymatic glycation lowers bone toughness. Because bound water contributes to bone toughness, we hypothesized that each of these matrix manipulations affect bound water fraction (Vbw/Vbone). Immersing cadaveric bone samples in sodium hypochlorite (NaClO) for 96 hours did not affect tissue mineral density or cortical porosity, but rather decreased Vbw/Vbone and increased short-T2 pore water signals as determined by 1H nuclear MR relaxometry (1H NMR). Moreover, the post treatment Vbw/Vbone linearly correlated with the remaining weight fraction of the organic matrix. Heating bone samples at 110°C, 120°C, 130°C, and then 140°C (∼24 hours per temperature and rehydration for ∼24 hours before 1H NMR analysis) did not affect Vbw/Vbone. After subsequently heating them at 200°C, Vbw/Vbone increased. Boiling bone samples followed by heating at 110°C, 120°C, and then 130°C in water under pressure (8 hours per temperature) had a similar effect on Vbw/Vbone. Raman spectroscopy analysis confirmed that the increase in Vbw/Vbone coincided with an increase in an Amide I subpeak ratio that is sensitive to changes in the helical structure of collagen I. Glycation of bone by ribose for 4 weeks, but not in glucose for 16 weeks, decreased Vbw/Vbone, although the effect was less pronounced than that of oxidative deproteinization or thermal denaturation. We propose that MR measurements of bound water reflect the amount of bone organic matrix and can be modulated by collagen I helicity and by sugar-derived post translational modifications of the matrix. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

13.
J Orthop Trauma ; 33(10): e385-e393, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31259800

RESUMO

OBJECTIVES: To explore the effect of intramedullary pin size on the biology of a healing fracture, specifically endochondral angiogenesis. We hypothesized that fracture fixation with a smaller pin would permit greater interfragmentary strain resulting in increased total amount of vascular endothelial growth factor within the callus and greater angiogenesis compared to fixation with a larger pin. METHODS: Transverse mid-shaft femur fractures in 8-week-old mice were fixed with either a 23-gauge (G) or 30-G pin. Differences in interfragmentary strain at the fracture site were estimated between cohorts. A combination of histology, gene expression, serial radiography, and microcomputed tomography with and without vascular contrast agent were used to assess fracture healing and vascularity for each cohort. RESULTS: Larger soft-tissue callus formation increased vascular endothelial growth factor-A expression, and a corresponding increase in vascular volume was observed in the higher strain, 30-G cohort. Radiographic analysis demonstrated earlier hard callus formation with greater initial interfragmentary strain, similar rates of union between pin size cohorts, yet delayed callus remodeling in mice with the larger pin size. CONCLUSIONS: These findings suggest that the stability conferred by an intramedullary nail influences endochondral angiogenesis at the fracture.


Assuntos
Pinos Ortopédicos , Cartilagem/irrigação sanguínea , Fixação Intramedular de Fraturas/instrumentação , Consolidação da Fratura , Neovascularização Fisiológica , Animais , Calo Ósseo/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desenho de Prótese , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/fisiologia
14.
Sci Rep ; 9(1): 7195, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31076574

RESUMO

Developing clinical tools that assess bone matrix quality could improve the assessment of a person's fracture risk. To determine whether Raman spectroscopy (RS) has such potential, we acquired Raman spectra from human cortical bone using microscope- and fiber optic probe-based Raman systems and tested whether correlations between RS and fracture toughness properties were statistically significant. Calculated directly from intensities at wavenumbers identified by second derivative analysis, Amide I sub-peak ratio I1670/I1640, not I1670/I1690, was negatively correlated with Kinit (N = 58; R2 = 32.4%) and J-integral (R2 = 47.4%) when assessed by Raman micro-spectroscopy. Area ratios (A1670/A1690) determined from sub-band fitting did not correlate with fracture toughness. There were fewer correlations between RS and fracture toughness when spectra were acquired by probe RS. Nonetheless, the I1670/I1640 sub-peak ratio again negatively correlated with Kinit (N = 56; R2 = 25.6%) and J-integral (R2 = 39.0%). In best-fit general linear models, I1670/I1640, age, and volumetric bone mineral density explained 50.2% (microscope) and 49.4% (probe) of the variance in Kinit. I1670/I1640 and v1PO4/Amide I (microscope) or just I1670/I1640 (probe) were negative predictors of J-integral (adjusted-R2 = 54.9% or 37.9%, respectively). While Raman-derived matrix properties appear useful to the assessment of fracture resistance of bone, the acquisition strategy to resolve the Amide I band needs to be identified.


Assuntos
Osso Cortical/diagnóstico por imagem , Fraturas Ósseas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Espectral Raman , Adulto Jovem
15.
Bone ; 120: 187-193, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30394355

RESUMO

Greater understanding of the determinants of skeletal fragility is highly sought due to the great burden that bone affecting diseases and fractures have on economies, societies and health care systems. Being a complex, hierarchical composite of collagen type-I and non-stoichiometric substituted hydroxyapatite, bone derives toughness from its organic phase. In this study, we tested whether early observations that a strong correlation between bone collagen integrity measured by thermomechanical methods and work to fracture exist in a more general and heterogeneous sampling of the population. Neighboring uniform specimens from an established, highly characterized and previously published collection of human cortical bone samples (femur mid-shaft) were decalcified in EDTA. Fifty-four of the original 62 donors were included (26 male and 28 females; ages 21-101 years; aging, osteoporosis, diabetes and cancer). Following decalcification, bone collagen was tested using hydrothermal isometric tension (HIT) testing in order to measure the collagen's thermal stability (denaturation temperature, Td) and network connectivity (maximum rate of isometric tension generation; Max.Slope). We used linear regression and general linear models (GLMs) with several explanatory variables to determine whether relationships between HIT parameters and generally accepted bone quality factors (e.g., cortical porosity, pentosidine content [pen], pyridinoline content [pyd]), age, and measures of fracture toughness (crack initiation fracture toughness, Kinit, and total energy release/dissipation rate evaluated at the point of unstable fast fracture, J-int) were significant. Bone collagen connectivity (Max.Slope) correlated well with the measures of fracture toughness (R2 = 24-35%), and to a lesser degree with bound water fraction (BW; R2 = 7.9%) and pore water fraction (PW; R2 = 9.1%). Significant correlations with age, apparent volumetric bone mineral density (vBMD), and mature enzymatic [pyd] and non-enzymatic collagen crosslinks [pen] were not detected. GLMs found that Max.Slope and vBMD (or BW), with or without age as additional covariate, all significantly explained the variance in Kinit (adjusted-R2 = 36.7-49.0%). Also, the best-fit model for J-int (adjusted-R2 = 35.7%) included only age and Max.Slope as explanatory variables with Max.Slope contributing twice as much as age. Max.Slope and BW without age were also significant predictors of J-int (adjusted-R2 = 35.5%). In conclusion, bone collagen integrity as measured by thermomechanical methods is a key factor in cortical bone fracture toughness. This study further demonstrates that greater attention should be paid to degradation of the overall organic phase, rather than a specific biomarker (e.g. [pen]), when seeking to understand elevated fracture rates in aging and disease.


Assuntos
Osso e Ossos/metabolismo , Colágeno/metabolismo , Osso Cortical/patologia , Fraturas Ósseas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
J Biophotonics ; 11(8): e201700352, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29575566

RESUMO

Establishing a non-destructive method for spatially assessing advanced glycation end-products (AGEs) is a potentially useful step toward investigating the mechanistic role of AGEs in bone quality. To test the hypothesis that the shape of the amide I in the Raman spectroscopy (RS) analysis of bone matrix changes upon AGE accumulation, we incubated paired cadaveric cortical bone in ribose or glucose solutions and in control solutions for 4 and 16 weeks, respectively, at 37°C. Acquiring 10 spectra per bone with a 20X objective and a 830 nm laser, RS was sensitive to AGE accumulation (confirmed by biochemical measurements of pentosidine and fluorescent AGEs). Hyp/Pro ratio increased upon glycation using either 0.1 M ribose, 0.5 M ribose or 0.5 M glucose. Glycation also decreased the amide I sub-peak ratios (cm-1 ) 1668/1638 and 1668/1610 when directly calculated using either second derivative spectrum or local maxima of difference spectrum, though the processing method (eg, averaged spectrum vs individual spectra) to minimize noise influenced detection of differences for the ribose-incubated bones. Glycation however did not affect these sub-peak ratios including the matrix maturity ratio (1668/1690) when calculated using indirect sub-band fitting. The amide I sub-peak ratios likely reflected changes in the collagen I structure.


Assuntos
Osso Cortical/metabolismo , Análise Espectral Raman , Amidas/química , Arginina/análogos & derivados , Arginina/química , Arginina/metabolismo , Feminino , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação , Humanos , Cinética , Lisina/análogos & derivados , Lisina/química , Lisina/metabolismo , Masculino , Pessoa de Meia-Idade
17.
Bone ; 110: 204-214, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29438824

RESUMO

Fracture risk increases as type 2 diabetes (T2D) progresses. With the rising incidence of T2D, in particular early-onset T2D, a representative pre-clinical model is needed to study mechanisms for treating or preventing diabetic bone disease. Towards that goal, we hypothesized that fracture resistance of bone from diabetic TallyHO mice decreases as the duration of diabetes increases. Femurs and lumbar vertebrae were harvested from male, TallyHO mice and male, non-diabetic SWR/J mice at 16weeks (n≥12 per strain) and 34weeks (n≥13 per strain) of age. As is characteristic of this model of juvenile T2D, the TallyHO mice were obese and hyperglycemic at an early age (5weeks and 10weeks of age, respectively). The femur mid-shaft of TallyHO mice had higher tissue mineral density and larger cortical area, as determined by micro-computed tomography, compared to the femur mid-shaft of SWR/J mice, irrespective of age. As such, the diabetic rodent bone was structurally stronger than the non-diabetic rodent bone, but the higher peak force endured by the diaphysis during three-point (3pt) bending was not independent of the difference in body weight. Upon accounting for the structure of the femur diaphysis, the estimated toughness at 16weeks and 34weeks was lower for the diabetic mice than for non-diabetic controls, but neither toughness nor estimated material strength and resistance to crack growth (3pt bending of contralateral notched femur) decreased as the duration of hyperglycemia increased. With respect to trabecular bone, there were no differences in the compressive strength of the L6 vertebral strength between diabetic and non-diabetic mice at both ages despite a lower trabecular bone volume for the TallyHO than for the SWR/J mice at 34weeks. Amide I sub-peak ratios as determined by Raman Spectroscopy analysis of the femur diaphysis suggested a difference in collagen structure between diabetic and non-diabetic mice, although there was not a significant difference in matrix pentosidine between the groups. Overall, the fracture resistance of bone in the TallyHO model of T2D did not progressively decrease with increasing duration of hyperglycemia. However, given the variability in hyperglycemia in this model, there were correlations between blood glucose levels and certain structural properties including peak force.


Assuntos
Envelhecimento/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Fêmur/fisiopatologia , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Densidade Óssea/fisiologia , Cromatografia Líquida de Alta Pressão , Fêmur/metabolismo , Fraturas Ósseas/metabolismo , Fraturas Ósseas/fisiopatologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Camundongos , Análise Espectral Raman , Microtomografia por Raio-X
18.
JOR Spine ; 1(1): e1001, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31463433

RESUMO

Background context: Pseudarthrosis following spinal fusion remains problematic despite modern surgical and grafting techniques. In surgical spinal fusion, new bone forms via intramembranous and endochondral ossification, with endochondral ossification occurring in the hypoxic zones of the fusion bed. During bone development and fracture healing, the key cellular mediator of endochondral ossification is the hypertrophic chondrocyte given its ability to function in hypoxia and induce neovascularization and ossification. We therefore hypothesize that hypertrophic chondrocytes may be an effective bone graft alternative. Purpose: Spinal fusion procedures have increased substantially; yet 5% to 35% of all spinal fusions may result in pseudoarthrosis. Pseudoarthrosis may occur because of implant failure, infection, or biological failure, among other reasons. Advances in surgical techniques and bone grafting have improved fusion; however pseudarthrosis rates remain unacceptably high. Thus, the goal of this study is to investigate hypertrophic chondrocytes as a potential biological graft alternative. Methods: Using a validated murine fracture model, hypertrophic chondrocytes were harvested from fracture calluses and transplanted into the posterolateral spines of identical mice. New bone formation was assessed by X-ray, microcomputed tomography (µCT), and in vivo fluorescent imaging. Results were compared against a standard iliac crest bone graft and a sham surgery control group. Funding for this work was provided by the Department of Orthopaedics and Rehabilitation, the OREF (Grant #16-150), and The Caitlin Lovejoy Fund. Results: Radiography, µCT, and in vivo fluorescent imaging demonstrated that hypertrophic chondrocytes promoted bone formation at rates equivalent to iliac crest autograft. Additionally, µCT analysis demonstrated similar fusion rates in a subset of mice from the iliac crest and hypertrophic chondrocyte groups. Conclusions: This proof-of-concept study indicates that hypertrophic chondrocytes can promote bone formation comparable to iliac crest bone graft. These findings provide the foundation for future studies to investigate the potential therapeutic use of hypertrophic chondrocytes in spinal fusion.

19.
Appl Spectrosc ; 71(10): 2385-2394, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28708001

RESUMO

A decline in the inherent quality of bone tissue is a † Equal contributors contributor to the age-related increase in fracture risk. Although this is well-known, the important biochemical factors of bone quality have yet to be identified using Raman spectroscopy (RS), a nondestructive, inelastic light-scattering technique. To identify potential RS predictors of fracture risk, we applied principal component analysis (PCA) to 558 Raman spectra (370-1720 cm-1) of human cortical bone acquired from 62 female and male donors (nine spectra each) spanning adulthood (age range = 21-101 years). Spectra were analyzed prior to R-curve, nonlinear fracture mechanics that delineate crack initiation (Kinit) from crack growth toughness (Kgrow). The traditional ν1phosphate peak per amide I peak (mineral-to-matrix ratio) weakly correlated with Kinit (r = 0.341, p = 0.0067) and overall crack growth toughness (J-int: r = 0.331, p = 0.0086). Sub-peak ratios of the amide I band that are related to the secondary structure of type 1 collagen did not correlate with the fracture toughness properties. In the full spectrum analysis, one principal component (PC5) correlated with all of the mechanical properties (Kinit: r = - 0.467, Kgrow: r = - 0.375, and J-int: r = - 0.428; p < 0.0067). More importantly, when known predictors of fracture toughness, namely age and/or volumetric bone mineral density (vBMD), were included in general linear models as covariates, several PCs helped explain 45.0% (PC5) to 48.5% (PC7), 31.4% (PC6), and 25.8% (PC7) of the variance in Kinit, Kgrow, and J-int, respectively. Deriving spectral features from full spectrum analysis may improve the ability of RS, a clinically viable technology, to assess fracture risk.


Assuntos
Osso Cortical/química , Osso Cortical/fisiologia , Fraturas Ósseas/fisiopatologia , Análise Espectral Raman/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Colágeno/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Bone Rep ; 7: 1-8, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28736738

RESUMO

Those with type 1 diabetes (T1D) are more likely to suffer a fracture than age- and sex-matched individuals without diabetes, despite daily insulin therapy. In rodent studies examining the effect of bone- or glucose-targeting therapies on preventing the T1D-related decrease in bone strength, insulin co-therapy is often not included, despite the known importance of insulin signaling to bone mass accrual. Therefore, working toward a relevant pre-clinical model of diabetic bone disease, we assessed the effect of continuous subcutaneous insulin infusion (CSII) therapy at escalating doses on preserving bone and the effect of delayed CSII on rescuing the T1D-related bone deterioration in an established murine model of T1D. Osmotic minipumps were implanted in male DBA/2 J mice 2 weeks (prevention study) and 6 weeks (rescue study) after the first injection of streptozotocin (STZ) to deliver insulin at 0, 0.0625, 0.125, or 0.25 IU/day (prevention study; n = 4-5 per dose) and 0 or 0.25 IU/day (rescue study; n = 10 per group). CSII lasted 4 weeks in both studies, which also included age-matched, non-diabetic DBA/2 J mice (n = 8-12 per study). As the insulin dose increased, blood glucose decreased, body weight increased, a serum maker of bone resorption decreased, and a serum marker of bone formation increased such that each end-point characteristic was linearly correlated with dose. There were insulin dose-dependent relationships (femur diaphysis) with cross-sectional area of cortical bone and cortical thickness (micro-computed tomography) as well as structural strength (peak force endured by the mid-shaft during three-point bending). Likewise, trabecular bone volume fraction (BV/TV), thickness, and number (distal femur metaphysis) increased as the insulin dose increased. Delayed CSII improved glycated hemoglobin (HbA1c), but blood glucose levels remained relatively high (well above non-diabetic levels). Interestingly, it returned the resorption and formation markers to similar levels as those seen in non-T1D control mice. This apparent return after 4 weeks of CSII translated to a partial rescue of the structural strength of the femur mid-shaft. Delayed CSII also increased Tb.Th to levels seen in non-T1D controls but did not fully restore BV/TV. The use of exogenous insulin should be considered in pre-clinical studies investigating the effect of T1D on bone as insulin therapy maintains bone structure without necessarily lowering glucose below diabetic levels.

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