Biomedical subjects

Angela S P Lin

Publications and source records attributed to Angela S P Lin.

6 recordsLinked to original sources

PubMed2006

Age-related changes in trabecular bone microdamage initiation.

With age, alterations occurring in bone quality, quantity, and microarchitecture affect the resistance of trabecular bone to local failure. The clinical implications of these changes are evident by the observed exponential increase in fracture incidence with age. Although age-related development of skeletal fragility is well established, it is unclear how the local failure properties of bone change with age. We previously reported a specimen-specific technique to assess microstructural stresses and strains associated with microdamage initiation but did not assess age-related changes. In this study, we compared younger (average age 2 years) and older (average age 10 years) bovine trabecular bone to evaluate how alterations in bovine bone quantity and quality with age affect the local mechanical environment associated with microdamage formation. The results show strong positive correlations between microdamage and local stresses and strains for both younger and older bovine trabecular bone. Correlation strength was slightly improved (<8%) for some parameters by incorporating heterogeneous local material properties based on mineral density into the finite element models. Within individual trabeculae, average stresses and strains were significantly higher in microdamaged trabeculae compared to randomly selected undamaged trabeculae, regardless of age. However, damaged trabeculae in older bone were found to have higher stresses and lower strains than those from younger bone. Corresponding differences in mineral density, microarchitecture, and FEM-determined local material properties were also observed between the two groups. Taken together, these data suggest marked age-related changes in the mechanics of microdamage initiation at the trabecular level. The combined experimental, computational, and histochemical approaches used in this study provide an improved understanding of microdamage initiation and bone quality.

Aging↗

PubMed2005

Periosteal progenitor cell fate in segmental cortical bone graft transplantations: implications for functional tissue engineering.

UNLABELLED: A murine segmental femoral bone graft model was used to show the essential role of donor periosteal progenitor cells in bone graft healing. Transplantation of live bone graft harvested from Rosa 26A mice showed that approximately 70% of osteogenesis on the graft was attributed to the expansion and differentiation of donor periosteal progenitor cells. Furthermore, engraftment of BMP-2-producing bone marrow stromal cells on nonvital allografts showed marked increases in cortical graft incorporation and neovascularization, suggesting that gene-enhanced, tissue engineered functional periosteum may improve allograft incorporation and repair. INTRODUCTION: The loss of cellular activity in a structural bone allograft markedly reduces its healing potential compared with a live autograft. To further understand the cellular mechanisms for structural bone graft healing and repair and to devise a therapeutic strategy aimed at enhancing the performance of allograft, we established a segmental femoral structural bone graft model in mice that permits qualitative and quantitative analyses of graft healing and neovascularization. MATERIALS AND METHODS: Using this segmental femoral bone graft model, we transplanted live isografts harvested from Rosa 26A mice that constitutively express beta-galactosidase into their wildtype control mice. In an attempt to emulate the osteogenic and angiogenic properties of periosteum, we applied a cell-based, adenovirus-mediated gene therapy approach to engraft BMP-2-producing bone marrow stromal cells onto devitalized allografts. RESULTS: X-gal staining for donor cells allowed monitoring the progression of periosteal progenitor cell fate and showed that 70% of osteogenesis was attributed to cellular proliferation and differentiation of donor progenitor cells on the surface of the live bone graft. Quantitative muCT analyses showed a 3-fold increase in new bone callus formation and a 6.8-fold increase in neovascularization for BMP-2/stromal cell-treated allograft compared with control acellular allografts. Histologic analyses showed the key features of autograft healing in the BMP-2/stromal cell-treated allografts, including the formation of a mineralized bone callus completely bridging the segmental defects, abundant neovascularization, and extensive resorption of bone graft. CONCLUSIONS: The marked improvement of healing in these cellularized allografts suggests a clinical strategy for engineering a functional periosteum to improve the osteogenic and angiogenic properties of processed allografts.

Acid Phosphatase↗

PubMed2005

Biological effects of rAAV-caAlk2 coating on structural allograft healing.

Structural bone allografts often fracture due to their lack of osteogenic and remodeling potential. To overcome these limitations, we utilized allografts coated with recombinant adeno-associated virus (rAAV) that mediate in vivo gene transfer. Using beta-galactosidase as a reporter gene, we show that 4-mm murine femoral allografts coated with rAAV-LacZ are capable of transducing adjacent inflammatory cells and osteoblasts in the fracture callus following transplantation. While this LacZ vector had no effect on allograft healing, bone morphogenetic protein signals delivered via rAAV-caAlk2 coating induced endochondral bone formation directly on the cortical surface of the allograft by day 14. By day 28 there was evidence of remodeling of the new woven bone and massive osteoclastic resorption of the cortical surface of the rAAV-caAlk2-coated allografts only. Micro-CT analysis of rAAV-LacZ- vs rAAV-caAlk2-coated allografts after 42 days of healing demonstrated a significant increase in new bone formation (0.67 +/- 0.21 vs 2.49 +/- 0.40 mm(3); P < 0.005). Furthermore, the 3D micro-CT images of femurs grafted with rAAV-Alk2-coated allografts provided the first evidence that complete bridging of bone around a cortical allograft is possible. These results indicate that cell-free, rAAV-coated allografts have the potential to revitalize in vivo following transplantation.

Activin Receptors, Type II↗

PubMed2004

Estrogen prevents bone loss through transforming growth factor beta signaling in T cells.

Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-gamma-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-gamma production is instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism is unknown. We now show that mice with T cell-specific blockade of type beta transforming growth factor (TGFbeta) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-gamma production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGFbeta levels in the bone marrow, and overexpression of TGFbeta in vivo prevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGFbeta-dependent mechanism, and that TGFbeta signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGFbeta production in the bone marrow is a critical "upstream" mechanism by which E prevents bone loss, and enhancement of TGFbeta levels in vivo may constitute a previously undescribed therapeutic approach for preventing bone loss.

Animals↗

PubMed2004

Microcomputed tomography imaging of skeletal development and growth.

Skeletogenesis is an exquisitely orchestrated and dynamic process, culminating in the formation of highly variable and complex mineralized structures that are optimized for their function. While cellular and molecular biology studies have provided tremendous recent progress toward understanding how patterns of bone formation are regulated, high resolution imaging techniques such as microcomputed tomography (micro-CT) can provide complementary quantitative information about the progressive changes in three-dimensional (3-D) skeletal morphology and density that occur during early skeletal development and postnatal growth. Furthermore, recently developed in vivo micro-CT systems promise to be a powerful and efficient tool for noninvasively monitoring normal skeletogenesis, as well as for evaluating the effects of genetic or environmental manipulation. This review focuses on the use of micro-CT imaging and analysis to better understand normal and abnormal skeletal development and growth.

Animals↗

PubMed2003

Microarchitectural and mechanical characterization of oriented porous polymer scaffolds.

Biodegradable porous polymer scaffolds are widely used in tissue engineering to provide a structural template for cell seeding and extracellular matrix formation. Scaffolds must often possess sufficient structural integrity to temporarily withstand functional loading in vivo or cell traction forces in vitro. Both the mechanical and biological properties of porous scaffolds are determined in part by the local microarchitecture. Quantification of scaffold structure-function relationships is therefore critical for optimizing mechanical and biological performance. In this study, porous poly(L-lactide-co-DL-lactide) scaffolds with axially oriented macroporosity and random microporosity were produced using a solution coating and porogen decomposition method. Microarchitectural parameters were quantified as a function of porogen concentration using microcomputed tomography (micro-CT) analysis and related to compressive mechanical properties. With increasing porogen concentration, volume fraction decreased consistently due to microarchitectural changes in average strut thickness, spacing, and density. The three-dimensional interconnectivity of the scaffold porosity was greater than 99% for all porogen concentration levels tested. Over a porosity range of 58-80%, the average compressive modulus and ultimate strength of the scaffolds ranged from 43.5-168.3 MPa and 2.7-11.0 MPa, respectively. Thus, biodegradable porous polymer scaffolds have been produced with oriented microarchitectural features designed to facilitate vascular invasion and cellular attachment and with initial mechanical properties comparable to those of trabecular bone.

3T3 Cells↗