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
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
Wang, Xiaokun; Schwartz, Zvi; Gittens, Rolando A et al. (2015) Role of integrin ?2 ?1 in mediating osteoblastic differentiation on three-dimensional titanium scaffolds with submicron-scale texture. J Biomed Mater Res A 103:1907-18
Lai, Min; Hermann, Christopher D; Cheng, Alice et al. (2015) Role of ?2?1 integrins in mediating cell shape on microtextured titanium surfaces. J Biomed Mater Res A 103:564-73
Olivares-Navarrete, Rene; Hyzy, Sharon L; Berg, Mark E et al. (2014) Osteoblast lineage cells can discriminate microscale topographic features on titanium-aluminum-vanadium surfaces. Ann Biomed Eng 42:2551-61
Gittens, Rolando A; Scheideler, Lutz; Rupp, Frank et al. (2014) A review on the wettability of dental implant surfaces II: Biological and clinical aspects. Acta Biomater 10:2907-18
Rupp, Frank; Gittens, Rolando A; Scheideler, Lutz et al. (2014) A review on the wettability of dental implant surfaces I: theoretical and experimental aspects. Acta Biomater 10:2894-906
Gittens, Rolando A; Olivares-Navarrete, Rene; Hyzy, Sharon L et al. (2014) Superposition of nanostructures on microrough titanium-aluminum-vanadium alloy surfaces results in an altered integrin expression profile in osteoblasts. Connect Tissue Res 55 Suppl 1:164-8
Bongiorno, Tom; Kazlow, Jacob; Mezencev, Roman et al. (2014) Mechanical stiffness as an improved single-cell indicator of osteoblastic human mesenchymal stem cell differentiation. J Biomech 47:2197-204
Gittens, Rolando A; Olivares-Navarrete, Rene; Schwartz, Zvi et al. (2014) Implant osseointegration and the role of microroughness and nanostructures: lessons for spine implants. Acta Biomater 10:3363-71
Cheng, Alice; Humayun, Aiza; Cohen, David J et al. (2014) Additively manufactured 3D porous Ti-6Al-4V constructs mimic trabecular bone structure and regulate osteoblast proliferation, differentiation and local factor production in a porosity and surface roughness dependent manner. Biofabrication 6:045007

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