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Restoring organ function by means of regenerative medicine (REGENERATE)

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This research line has been redefined: the focus is now on tissue repair reactions as seen after tissue damage and after implantation of biomaterials. The main goal is to understand the nature of the fibrotic reaction, and how we can interfere with it in order to combat fibrosis and to modulate the foreign body reaction. Our primary cells of interest are the fibroblasts and macrophages.

Programme Leaders   Mission  

Mission: To realize the re-establishment of tissue and organ function by means of biological or engineering intervention strategies based on an understanding of the determinants of cell plasticity, in particular the role of micro-environment and extracellular matrix, thus enabling to manipulate the structure-function-environment relationship in an integrative fashion.
Aim: The central aim of regenerative medicine is the functional repair of damaged or diseased tissues and organs by application of modulating molecules and/or (stem) cells with the guidance of polymeric scaffolds.
Rationale: Regenerative Medicine is a promising and rapidly developing multidisciplinary research area. Most regenerative medicine approaches currently deal with the repair of tissues rich in extracellular matrix. A main problem in these approaches is the establishment of a functional collagen network. We here investigate the homeostasis of collagen in normal and fibrotic tissues, tissue repair processes (with a focus on inflammation), and the use of materials to restore organ functions (with a focus on the foreign body reaction). 

Description of the Programme  

Regenerative medicine aims at the generation of functional biological tissues for the replacement of diseased or impaired tissues. To do so, often (stem) cells are used in combination with a degradable biomaterial that serves as a temporary scaffold and which is replaced by the tissue in question. Tissue damage and biomaterials implanted into the body invariably evoke an inflammatory response, which sets the stage for tissue repair. The progression from inflammation to repair should be regulated in such a way that tissue repair is adequate, but often aberrant inflammation will lead to fibrosis.

The research program focuses various aspects of tissue (re)generation, repair and remodeling, including inflammation. Our main research questions are:

  1. What is the role of key cellular and molecular players in determining the balance between inflammation, physiologic repair and aberrant repair (fibrosis)? 
  2. How can we orchestrate the tissue microenvironment in order to promote repair and/or prevent fibrosis?
  3. How can we translate basic insight into above aspects into new therapeutic approaches (e.g. by means of smart biomaterials / drug delivery)?


Organ and tissue repair

Organ and tissue damage invariably leads to inflammation, which makes way for tissue repair. The interplay between inflammatory cell subsets dictates the outcome of inflammation, but is poorly understood mechanistically. Therefore, more fundamental research is necessary into research questions concerning the cellular composition of inflammatory processes in settings of organ damage and the in vivo foreign body reactions, the cellular plasticity of macrophages, the modulation of the transition from inflammation to repair, the possibilities to use local drug delivery in order to achieve reparative outcomes, and even the difference between fetal and adult wound healing.

The foreign body response

With the implantation of materials the non-specific immune system will start the foreign body response (FBR). Macrophages are key players in the FBR, as well as the giant cells that are formed by means of fusion of macrophages. Controlling the activation of macrophages and the formation of giant cells are powerful tools to modulate the FBR, thereby improving regenerative strategies to repair tissues. Therefore, also here macrophages are the focus of our attention, including the role of macrophage subsets, the molecular basis of macrophage fusion, the molecular basis of collagen degradation by macrophages and giant cells, their communication with fibroblasts, the role of fibroblasts in collagen deposition (capsule formation; stromal formation), and the role of physical and chemical parameters of biomaterials on the onset and evolution of the foreign body reaction.

Fibrosis

Within the two research areas described above fibrosis is a unifying factor. Fibrosis also is the pathological outcome of wound healing processes in a variety of organs (e.g. heart, liver, lung, kidney, skin) through the deposition of an excessive amount of collagen, being the hallmark of fibrosis. The pathogenesis of fibrosis remains poorly understood, mainly because it is unknown what subsets of fibroblasts are involved in collagen deposition. Also the role of collagen-modifying enzymes in fibrosis is poorly understood. Therefore, understanding the pathways leading to an excessive accumulation of collagen can help to define intervention points for novel therapeutics to benefit regenerative medicine approaches as well as to prevent organ-related fibrosis. In fact, therapy will be targeting the amount of collagen deposited

Relevance to Healthy Ageing  

Trauma, disease, and ageing can leave critical defects that the body cannot heal by itself.  Using a combination of cells, bioactive molecules, biomaterials, and mechanical conditioning, regenerative medicine seeks to achieve functional restoration of tissues and organs.  Regenerative medicine will help to produce extended healthy longevity, as we will be able to repair damage. Ageing can be viewed as a set of precursors of the diseases and disabilities of elderly age: a set of side-effects of normal metabolism that accumulate throughout life and eventually impair and overwhelm our biology. In improving patient care, especially in relation with tissue loss or dysfunction, the use of proper biomaterials plays a key role. The shift from tissue removal to tissue replacement and at present, tissue regeneration is driven by the evolution of biomaterials from bioinert to bioactive and bioresorbable associated with advances in molecular biology, and by the increasingly complex biomedical problems of an ageing and more active population. Especially fibrosis is prominent in ageing processes as well as in many chronic diseases, and represents an enormous health burden; it is estimated that > 25% of deaths can be attributed to disorders concerning fibrosis of organs such as kidney, liver and lung. Therefore controlling fibrosis can contribute to both organ repair and improved integration of biomaterials.

Principal Investigators