investigated the osteogenic potential of human MSCs on surfaces and hydrogels functionalized with full-length fibronectin (FN), fibronectin fragments (FNIII910 and FNIII10) and a more 51-specific mutated fibronectin fragment (FNIII9*-10) and demonstrated that FNIII9*-10 and FNIII9-10 supported higher MSC differentiation than FN64. limited biological performance of current orthopaedic implants, such as joint replacement prostheses, bone screws and bone grafts, presents a large and growing socioeconomic burden in the United States. For example, in 2004, the failure of replacement joints prompted 86,000 revision surgeries for hip and knee arthroplasties at a cost of $3.2 billion, and those surgery numbers are projected to exceed 3.6 million by 20301. Similarly, the loosening of screws for spinal implants and fracture fixation in osteoporotic patients are major clinical concerns, with high failure rates estimated to be 1827%24and 523%57respectively. Furthermore, over 600,000 bone grafting procedures are performed annually in the U.S. to treat non-healing skeletal defects caused by traumatic injury and cancer89. However, autografts, SW044248 the gold standard of treatment, are limited by donor site supply and morbidity10, and allografts are limited by increased resorption, poor mechanical properties and the risk of infection910. Therefore, there is a significant need for improved orthopaedic materials which promote implant integration into host bone and enhance bone formation. Bone contains multiple cells types such as osteoblasts, osteoclasts and osteocytes; osteoblasts are the major cell type responsible for bone formation. Osteoblasts differentiate from SW044248 mesenchymal stem cells and osteoprogenitor cells found primarily in the bone marrow in a multi-step process in which the Cbfa1/Runx-2 transcription factor plays a crucial role11. Stem cells differentiate into osteoprogenitors with limited self-renewal capacity, then to pre-osteoblasts with limited proliferation, and finally to mature osteoblasts, which secrete osteoid, the unmineralized organic component of bone matrix. As the deposited osteoid is mineralized, osteoblasts become trapped within lacunae as osteocytes, become bone lining cells, or die by apoptosis12. Biomaterials which can modulate the response of host osteoblast and osteoprogenitor cells to the implant may be crucial to improving the mechanical fixation of implants and osteogenic capacity of bone grafts. For example, implant osseointegration, defined by the enhancement of new bone formation in direct contact with the implant as well as implant fixation within the first 2 years, has been shown to be predictive of the long-term success of implants1314. Therefore, materials that engage osteoblast receptors and induce peri-implant bone formation may effectively address the problems of arthroplasties and screw loosening. Similarly, although bone has an innate capacity to regenerate through intramembranous and endochondral ossification15, in non- or delayed- unions, biomaterial grafts that augment this healing capacity by upregulating osteoblast-mediated bone formation may present viable alternatives to autografts. As successful orthopaedic biomaterials must support the adhesion, organization, differentiation and matrix mineralization of osteoblasts and osteoprogenitor cells, many strategies have focused on recapitulating natural biological cues which regulate these processes. Cell fates such as proliferation and differentiation are determined by a complex interplay of signals from the extracellular environment. These signals include (1) insoluble molecules within the extracellular matrix, (2) soluble and/or matrix-associated biochemicals such as systemic hormones or growth factors and cytokines that act locally, and (3) cell-cell receptors (Fig. 1). The ECM itself contains multiple types of insoluble molecules, Rabbit polyclonal to ACOT1 forming a meshwork of structural proteins to which adhesive proteins, proteoglycans and glycosaminoglycans are associated16. This complex biological supramolecular scaffold provides a compelling model for biomimetic strategies which mimic ECM protein, growth factor or hydroxyapatite mineral chemistry or architecture to create a synthetic matrix to control tissue-specific cell responses. Architectural ECM-mimetic approaches include nanofiber scaffolds that recapitulate the structure of proteins within ECM17, substrates with features which mimic native ECM nanotopography18, and composites which recreate the mineral content and mechanical properties of bone matrix1920. This review will focus on 1) bone ECM composition and key integrins implicated in osteogenic differentiation, 2) orthopedic biomaterials functionalized with ECM motifs, and 3) growth factor derived peptides. == Fig 1. == Bioactive signals found SW044248 within the extracellular environment in bone. == 2. Bone ECM composition and key integrins implicated in osteogenesis == The composition and spatial orientation of ECM varies for each SW044248 tissue type. These differences in ECM composition/orientation may be useful in tailoring biomaterials to direct tissue-specific cellular responses as each type of ECM molecule may regulate cell differentiation differentially by SW044248 interacting with specific cell receptors21. In bone, the ECM consists of mainly of an organic phase known as osteoid, which constitutes approximately 20% of bone mass, and a mineral phase (Table 1). The organic fraction of bone consists of over 90% type I collagen22, other minor collagens such as types III and V, and 5% non-collagenous proteins. The non-collagenous proteins in bone include osteocalcin, osteonectin, osteopontin, adhesion proteins such as fibronectin and vitronectin and proteoglycans such as versican, decorin and hyaluronan23. The mineral phase of bone is composed.