Translating tissue engineering technology platforms into cancer research

Abstract

Technology platforms originally developed for tissue engineering applications produce valuable models that mimic three-dimensional (3D) tissue organization and function to enhance the understanding of cell/tissue function under normal and pathological situations. These models show that when replicating physiological and pathological conditions as closely as possible investigators are allowed to probe the basic mechanisms of morphogenesis, differentiation and cancer. Significant efforts investigating angiogenetic processes and factors in tumorigenesis are currently undertaken to establish ways of targeting angiogenesis in tumours. Anti-angiogenic agents have been accepted for clinical application as attractive targeted therapeutics for the treatment of cancer. Combining the areas of tumour angiogenesis, combination therapies and drug delivery systems is therefore closely related to the understanding of the basic principles that are applied in tissue engineering models. Studies with 3D model systems have repeatedly identified complex interacting roles of matrix stiffness and composition, integrins, growth factor receptors and signalling in development and cancer. These insights suggest that plasticity, regulation and suppression of these processes can provide strategies and therapeutic targets for future cancer therapies. The historical perspective of the fields of tissue engineering and controlled release of therapeutics, including inhibitors of angiogenesis in tumours is becoming clearly evident as a major future advance in merging these fields. New delivery systems are expected to greatly enhance the ability to deliver drugs locally and in therapeutic concentrations to relevant sites in living organisms. Investigating the phenomena of angiogenesis and anti-angiogenesis in 3D in vivo models such as the Arterio-Venous (AV) loop mode in a separated and isolated chamber within a living organism adds another significant horizon to this perspective and opens new modalities for translational research in this field.

Fig. 1

The so-called ‘first-generation scaffolds’ have been studied over the last 5 years in different clinical applications. FDA approved mPCL scaffolds (Osteopore International, Singapore) have been implanted to regenerate the iliac crest after autograft was taken for spinal fusion surgery. Burr hole plugs are used for cranioplasties and deformable but at the same time strong enough sheets for orbital floor reconstructions. Reprinted with permission from Wiley Interscience.

Fig. 3

Left panel: OB scaffold + PC3-N (>40 days of culture). Right panel: OB scaffold + LNCap (>40 days of culture).

Fig. 2

Images of the human osteoblast construct (hOB) 2 days post seeding with prostate cancer cell lines. (A) SEM images at different maginification (40×, 300× and 1000×, from top to bottom) showing morphology and distribution of the cancer cells on hOB constructs. (B) CLSM images of the co-cultures stained with anti-pan Cytokeratin (cancer cells, green labelling) and Phalloidin (osteoblasts, red labelling).

Fig. 4

(A) Isosurface rendering of micro-CT scan from a rat AV-loop following Microfil®– perfusion and explanation, demonstrating dense vascular sprouting originating from the AV-loop. (B) First application of the AV-loop sheep model using fibrin as a matrix: intra-operative aspect of micro-anastomosed AV-loop in the sheep's groin placed into a custom made isolation chamber, which is then filled with biocompatible fibrin matrix. (C) Intra-vital imaging of AV-loop in the sheep model: by super-imposing serial MRI – scans and segmented angio-CT – scans the increase of vascular sprouting from the sheep AV-loop in concordance with increased perfusion within the chamber can be visualized intravitally. (D) Murine embryonal EPCs were suspended in a 3D fibrin matrix and constructs were subjected to histological analysis after 8 days. Cell proliferation in numerous multicellular clusters, some of them forming lumen-like structures, can be appreciated. Magnification 25-fold. (E) A detailed view confirms presence of multicellular clusters of EPCs. Magnification 200-fold. (F) Morphologic observations are confirmed by the presence of Ki-67⁺ EPCs, identified by their pink staining, indicating cell proliferation within the fibrin matrix. Magnification 200-fold.