Monitoring angiogenesis in soft‐tissue engineered constructs for calvarium bone regeneration: an in vivo longitudinal DCE‐MRI study

Tissue engineering is a promising technique for bone repair and can overcome the major drawbacks of conventional autogenous bone grafting. In this in vivo longitudinal study, we proposed a new tissue‐engineering paradigm: inserting a biological soft‐tissue construct within the bone defect to enhance angiogenesis for improved bone regeneration. The construct acts as a resorbable scaffold to support desired angiogenesis and cellular activity and as a vector of vascular endothelial growth factor, known to promote both vessel and bone growth. Dynamic contrast‐ enhanced magnetic resonance imaging was performed to investigate and characterize angiogenesis necessary for bone formation following the proposed paradigm of inserting a VEGF‐impregnated tissue‐engineered construct within the critical‐sized calvarial defect in the membranous parietal bone of the rabbit. Results show that a model‐free quantitative approach, the normalized initial area under the curve metric, provides sensitive and reproducible measures of vascularity that is consistent with known temporal evolution of angiogenesis during bone regeneration. Copyright © 2009 John Wiley & Sons, Ltd.

[1]  A. Padhani,et al.  Reproducibility of dynamic contrast‐enhanced MRI in human muscle and tumours: comparison of quantitative and semi‐quantitative analysis , 2002, NMR in biomedicine.

[2]  H. Cheng Dynamic contrast-enhanced MRI in oncology drug development. , 2007, Current clinical pharmacology.

[3]  R. Magin,et al.  Magnetic resonance microscopy for monitoring osteogenesis in tissue-engineered construct in vitro , 2006, Physics in medicine and biology.

[4]  M A Horsfield,et al.  A simple, reproducible method for monitoring the treatment of tumours using dynamic contrast-enhanced MR imaging , 2006, British Journal of Cancer.

[5]  J L Evelhoch,et al.  Key factors in the acquisition of contrast kinetic data for oncology , 1999, Journal of magnetic resonance imaging : JMRI.

[6]  R. Marx,et al.  "Mandibular and facial reconstruction" rehabilitation of the head and neck cancer patient. , 1996, Bone.

[7]  D. Conover,et al.  Quantification of Massive Allograft Healing with Dynamic Contrast Enhanced-MRI and Cone Beam-CT: A Pilot Study , 2008, Clinical orthopaedics and related research.

[8]  Wilhelm Horger,et al.  Quantitative T2 Mapping of Matrix-Associated Autologous Chondrocyte Transplantation at 3 Tesla: An In Vivo Cross-Sectional Study , 2007, Investigative radiology.

[9]  J. Mintorovitch,et al.  Comparison of Magnetic Properties of MRI Contrast Media Solutions at Different Magnetic Field Strengths , 2005, Investigative radiology.

[10]  M. Knopp,et al.  Dynamic contrast‐enhanced MRI using Gd‐DTPA: Interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors , 2001, Magnetic resonance in medicine.

[11]  Donald S. Williams,et al.  Cerebral perfusion during anesthesia with fentanyl, isoflurane, or pentobarbital in normal rats studied by arterial spin‐labeled MRI , 2001, Magnetic resonance in medicine.

[12]  P. Babyn,et al.  Dynamic Gd‐DTPA enhanced MRI as a surrogate marker of angiogenesis in tissue‐engineered bladder constructs: A feasibility study in rabbits , 2005, Journal of magnetic resonance imaging : JMRI.

[13]  Martin A Lodge,et al.  Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  G. Sándor,et al.  Hyperbaric oxygen results in increased vascular endothelial growth factor (VEGF) protein expression in rabbit calvarial critical-sized defects. , 2008, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[15]  J. Kanczler,et al.  Osteogenesis and angiogenesis: the potential for engineering bone. , 2008, European cells & materials.

[16]  Eleftherios Tsiridis,et al.  Bone substitutes: an update. , 2005, Injury.

[17]  T. K. Hunt,et al.  Noninvasive assessment of wound-healing angiogenesis with contrast-enhanced MRI. , 2002, Academic radiology.

[18]  S. George,et al.  Matrix metalloproteinase control of capillary morphogenesis. , 2008, Critical reviews in eukaryotic gene expression.

[19]  A. Haase,et al.  Snapshot flash mri. applications to t1, t2, and chemical‐shift imaging , 1990, Magnetic resonance in medicine.

[20]  D J Collins,et al.  Evaluation of response to treatment using DCE-MRI: the relationship between initial area under the gadolinium curve (IAUGC) and quantitative pharmacokinetic analysis , 2006, Physics in medicine and biology.

[21]  V. Goldberg,et al.  Natural history of autografts and allografts. , 1987, Clinical orthopaedics and related research.

[22]  Jonathan B. Cohen,et al.  The Osteogenetic Phases of Regeneration of Bone , 1956 .

[23]  A. Jackson,et al.  Comparative study into the robustness of compartmental modeling and model‐free analysis in DCE‐MRI studies , 2006, Journal of magnetic resonance imaging : JMRI.

[24]  W. Axhausen The osteogenetic phases of regeneration of bone; a historial and experimental study. , 1956, Journal of Bone and Joint Surgery. American volume.

[25]  H. Cheng,et al.  Quantifying angiogenesis in VEGF‐enhanced tissue‐engineered bladder constructs by dynamic contrast‐enhanced MRI using contrast agents of different molecular weights , 2007, Journal of magnetic resonance imaging : JMRI.

[26]  Hai-Ling Margaret Cheng,et al.  Investigation and optimization of parameter accuracy in dynamic contrast‐enhanced MRI , 2008, Journal of magnetic resonance imaging : JMRI.

[27]  N. Ebraheim,et al.  Bone‐Graft Harvesting From Iliac and Fibular Donor Sites: Techniques and Complications , 2001, The Journal of the American Academy of Orthopaedic Surgeons.

[28]  S. Othman,et al.  Ultrasound Accelerated Bone Tissue Engineering Monitored with Magnetic Resonance Microscopy , 2006, 2006 International Conference of the IEEE Engineering in Medicine and Biology Society.

[29]  G. Sándor,et al.  Hyperbaric oxygen results in an increase in rabbit calvarial critical sized defects. , 2006, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[30]  C. Baudelet,et al.  Effect of anesthesia on the signal intensity in tumors using BOLD-MRI: comparison with flow measurements by Laser Doppler flowmetry and oxygen measurements by luminescence-based probes. , 2004, Magnetic resonance imaging.

[31]  E. Pitman Significance Tests Which May be Applied to Samples from Any Populations , 1937 .

[32]  M. Todd,et al.  The Dose‐related Effects of Nitric Oxide Synthase Inhibition on Cerebral Blood Flow during Isoflurane and Pentobarbital Anesthesia , 1994, Anesthesiology.

[33]  P. Tofts Modeling tracer kinetics in dynamic Gd‐DTPA MR imaging , 1997, Journal of magnetic resonance imaging : JMRI.

[34]  Joanna Leadbetter,et al.  Magnetic Resonance Imaging Measurements of the Response of Murine and Human Tumors to the Vascular-Targeting Agent ZD6126 , 2004, Clinical Cancer Research.

[35]  U Kneser,et al.  Tissue engineering of bone: the reconstructive surgeon's point of view , 2006, Journal of cellular and molecular medicine.

[36]  P. Hurn,et al.  Inhalational Anesthetics as Neuroprotectants or Chemical Preconditioning Agents in Ischemic Brain , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[37]  G. Wright,et al.  Rapid high‐resolution T1 mapping by variable flip angles: Accurate and precise measurements in the presence of radiofrequency field inhomogeneity , 2006, Magnetic resonance in medicine.

[38]  P. Babyn,et al.  Dynamic contrast-enhanced MRI to quantify VEGF-enhanced tissue-engineered bladder graft neovascularization: pilot study. , 2006, Journal of Biomedical Materials Research. Part A.