The goal of this research is to determine the mechanisms that regulate cell and tissue responses to biomaterials that interface with bone. This proposal addresses the clinical need for dental and orthopedic implants that promote rapid osteointegration and earlier loading times, particularly when placed in bone compromised by disease or physiology of the patient. By understanding how surface morphology and chemistry modulate cell response, materials may be developed that control cell behavior through structural signaling, without the need for pharmacologic modification. We use structured surfaces as models to define which micron-, submicron-, and nanoscale features and chemistry regulate specific cell responses and to study the underlying mechanisms involved, with the long-term goal of creating rational biomimetic materials that facilitate normal tissue regeneration and repair. Our experimental hypothesis is that physical and chemical properties of a surface determine integrin expression, influencing cellular signaling and response to systemic factors that regulate osteogenesis and to autocrine and paracrine mediators of osteoblast differentiation. Moreover, changes in mesenchymal stem cells (MSCs) and osteoprogenitor cells on the substrate influence peri-implant bone formation through production of factors that modulate angiogenesis and osteogenesis. To test this hypothesis, we propose to examine osteoblast behavior in vitro and in vivo using novel materials with nanoscale features and well controlled chemistries. We will interrogate the substrate morphology and chemistry under individual cells using new imaging technology developed in our group, which permits us to identify living cells expressing specific mRNAs. We will use stably silenced cell lines that have reduced expression of specific proteins that mediate the response of osteoblasts to material surface microstructure and we will use an in vitro co-culture model as well as in vivo mouse and rat models that permit us to screen the clinical utility of the structural features identified in vitro, focusing on vasculogenesis/angiogenesis during bone healing in aged and osteopenic animals. We will (1) develop and characterize at the nanoscale, surface features and chemical functionalities that may modulate MSC differentiation and osteoblast phenotypic expression;(2) determine the mechanisms that mediate the differential effects of surface design features, including the role of integrins and Want signaling;and (3) assess how changes in surface design mediate peri- implant bone formation in vivo in aging and ovariectomized mice and rats.

Public Health Relevance

This proposal addresses the clinical need for dental and orthopedic implants that promote rapid osseointegration and earlier loading times, particularly when placed in bone compromised by disease or physiology of the patient. By understanding how surface morphology and chemistry modulate cell response, materials may be developed that control cell behavior through structural and chemical signaling, without the need for pharmacologic modification. We propose to perform studies that determine if cell and tissue responses can be improved if the surfaces have novel nanoscale properties including structural features as well as chemistries. We will test effectiveness both in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052102-08
Application #
8460922
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Panagis, James S
Project Start
2004-12-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$386,496
Indirect Cost
$100,207
Name
Virginia Commonwealth University
Department
None
Type
Schools of Engineering
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Cohen, D J; Cheng, A; Kahn, A et al. (2016) Novel Osteogenic Ti-6Al-4V Device For Restoration Of Dental Function In Patients With Large Bone Deficiencies: Design, Development And Implementation. Sci Rep 6:20493
Lin, Zhao; Rodriguez, Nicholas E; Zhao, Junjun et al. (2016) Selective enrichment of microRNAs in extracellular matrix vesicles produced by growth plate chondrocytes. Bone 88:47-55
Hotchkiss, Kelly M; Reddy, Gireesh B; Hyzy, Sharon L et al. (2016) Titanium surface characteristics, including topography and wettability, alter macrophage activation. Acta Biomater 31:425-34
Sedlaczek, Janina; Lohmann, Christoph H; Lotz, Ethan M et al. (2016) Effects of low-frequency ultrasound treatment of titanium surface roughness on osteoblast phenotype and maturation. Clin Oral Implants Res :
Boyan, B D; Cheng, A; Olivares-Navarrete, R et al. (2016) Implant Surface Design Regulates Mesenchymal Stem Cell Differentiation and Maturation. Adv Dent Res 28:10-7
Olivares-Navarrete, Rene; Hyzy, Sharon L; Boyan, Barbara D et al. (2015) Regulation of Osteoblast Differentiation by Acid-Etched and/or Grit-Blasted Titanium Substrate Topography Is Enhanced by 1,25(OH)2D3 in a Sex-Dependent Manner. Biomed Res Int 2015:365014
Olivares-Navarrete, Rene; Hyzy, Sharon L; Haithcock, David A et al. (2015) Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins. Bone 73:208-16
Olivares-Navarrete, Rene; Hyzy, Sharon L; Pan, Qingfen et al. (2015) Osteoblast maturation on microtextured titanium involves paracrine regulation of bone morphogenetic protein signaling. J Biomed Mater Res A 103:1721-31
Olivares-Navarrete, Rene; Hyzy, Sharon L; Slosar, Paul J et al. (2015) Implant materials generate different peri-implant inflammatory factors: poly-ether-ether-ketone promotes fibrosis and microtextured titanium promotes osteogenic factors. Spine (Phila Pa 1976) 40:399-404
Olivares-Navarrete, Rene; Rodil, Sandra E; Hyzy, Sharon L et al. (2015) Role of integrin subunits in mesenchymal stem cell differentiation and osteoblast maturation on graphitic carbon-coated microstructured surfaces. Biomaterials 51:69-79

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