While the vast majority of modern oral implants are successful, every implant journal and international conference has papers and presentations about implant failures. One common symptom of implant failure is fibrous encapsulation, which typically arises from a lack of primary stability of the implant. Clinical standards dictate that a unstable implant must be removed and, if sufficient bone stock remains, replaced. However, there is little guarantee that the next implant attempt will be successful because the underlying etiology of the initial failure is often not understood in the first place. Certainly biomechanical factors influence implant stability in bone. To examine this problem area, we have developed a novel, reproducible, in vivo model in the mouse maxilla to rigorously test our hypothesis that excessive strain drives peri-implant cells to differentiate along a fibroblastic rather than an osteoblastic lineage. In the same model we also propose to test two clinically relevant strategies to prevent -- and potentially reverse - the perplexing problem of fibrous encapsulation of a failed implant.
In AIM 1 we will test how peri-implant strain affects interfacial cell proliferation, angiogenesis, and osteogenic differentiation. We have adapted a miniature in vivo loading device from our previous work in mice tibiae to create a new mouse model with several unique features: 1) Complete implant instability is caused by placing a maxillary implant into an oversized hole, creating fibrous encapsulation;2) The model allows us to stabilize this implant (using a miniature rigid I-beam bonded to adjacent teeth) to test if stabilization promotes osteogenic healing in the peri-implant space;and 3) Using I-beams designed to be stiff in the vertical direction but less stiff in the horizontal direction, we can apply known horizontal loads o deflect the beam and its attached implant by known amounts, thereby creating controlled implant micromotion and interfacial strains. Collectively, these experiments will allow us to unravel critical relationships among implant instability, interfacial strain, and osseointegration.
AIM 2 asks whether a fibrous-tissue-encapsulated (loose) implant can be rescued. The answer lies in whether peri-implant cells are irreversibly specified as fibroblasts, or whether their fate can be altered. One series of tests will examine whether nano-textured implants can prevent the proliferation and differentiation of fibroblasts that can culminate in fibrous encapsulation. A second series of tests will introduce a pro-osteogenic biological signal, Wnt3, into the implant bed at the time of placement, followed by assays for Wnt responsiveness in the peri-implant space using Wnt "reporter" along with cell proliferation and induction of the osteogenic program. Collectively, results will provide a scientific rationale for improving osseointegration in patient in which there is inadequate bone support or sub-optimal osteogenic healing.

Public Health Relevance

Loosening and failure of load-bearing bone implants remain a major health problem. In order to ameliorate this problem, this project is trying to understand why certain biomechanical conditions at the oral bone-implant interface are dangerous to bone healing, while others are safe and beneficial to healing. Our work focuses on two key problems: 1) the role of deformation (strain) of healing tissues;and 2) how to rescue an interface that has already developed a fibrous tissue encapsulation due to lack of primary stability. Our aim is to generate basic science enabling improved design of oral implants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
9R01DE024000-10A1
Application #
8762070
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wan, Jason
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$693,103
Indirect Cost
$221,040
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305