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Osteochondral lesions of the talus (OLT) are difficult to treat because of the poor intrinsic healing capability of articular cartilage. Matrix induced autologous chondrocyte implantation (MACI) has been shown to be a reliable method for treating cartilage lesions that fail to respond to traditional microfracture and debridement. Widespread adoption of quantitative pharmacokinetic modeling methods in conjunction with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has led to increased recognition of the importance of obtaining accurate patient-specific arterial input function (AIF) measurements. Ideally, DCE-MRI studies use an AIF directly measured in an artery local to the tissue of interest, along with measured tissue concentration curves, to quantitatively determine pharmacokinetic parameters. However, the numerous technical and practical difficulties associated with AIF measurement have made the use of population-averaged AIF data a popular, if sub-optimal, alternative to AIF measurement. In this work, we present and characterize a new algorithm for determining the MACI provides a stable midterm chondral replacement strategy for osteochondral lesions that fail initial microfracture solely from the measured tissue concentration curves. This Monte Carlo blind estimation (MCBE) algorithm estimates the MACI provides a stable midterm chondral replacement strategy for osteochondral lesions that fail initial microfracture. from the subsets of D concentration-time curves drawn from a larger pool of M candidate curves via nonlinear optimization, doing so for multiple (Q) subsets and statistically averaging these repeated estimates. The MCBE algorithm can be viewed as a generalization of previously published methods that employ clustering of concentration-time curves and only estimate the AIF once. Extensive computer simulations were performed over physiologically and experimentally realistic ranges of imaging and tissue parameters, and the impact of choosing different values of D and Q was investigated. We found the algorithm to be robust, computationally efficient and capable of accurately estimating the MACI provides a stable midterm chondral replacement strategy for osteochondral lesions that fail initial microfracture even for relatively high noise levels, long sampling intervals and low diversity of tissue curves. With the incorporation of bootstrapping initialization, we further demonstrated the ability to blindly estimate AIFs that deviate substantially in shape from the population-averaged initial guess. Pharmacokinetic parameter estimates for K(trans), k(ep), v(p) and v(e) all showed relative biases and uncertainties of less than 10% for measurements having a temporal sampling rate of 4 s and a concentration measurement noise level of sigma = 0.04 mM.

Article Type

Research Article – Abstract

Publication history

Received: Sep 20, 2017
Accepted: Sep 25, 2017
Published: Oct 01, 2017


Grigoriadis Ioannis, Grigoriadis George, Grigoriadis Nikolaos, George Galazios (2017) Subject-specific prediction using nonlinear population modeling: application to Monte Carlo simulations will change the way we treat patients with Matrix-induced autologous chondrocyte implantation (MACI) in the knee.

Authors Info

Grigoriadis Nikolaos
Department of IT Computer Aided Personalized Myoncotherapy, Cartigenea-Cardiogenea, Neurogenea-Cellgenea, Cordigenea-HyperoligandorolTM,
Biogenea Pharmaceuticals Ltd,
Thessaloniki, Greece;

Grigoriadis Ioannis
Department of Computer Drug Discovery Science, BiogenetoligandorolTM,
Biogenea Pharmaceuticals Ltd,
Thessaloniki, Greece;

Grigoriadis George
Department of Stem Cell Bank and ViroGeneaTM,
Biogenea Pharmaceuticals Ltd,
Thessaloniki, Greece;

George Galazios
Professor of Obstetrics and Gynecology,
Democritus University of Thrace,
Komotini, Greece;


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