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The focus of the Cardiovascular Regenerative Medicine Research Group (CAVAREM) is in Regenerative Medicine.

We aim define new modalities for the intervention and prevention of cardiovascular diseases through the organ-specific application of stem/progenitor cells and “smart biomaterials”. The design of these biomaterials is guided by the results of our investigations on the organ-specific microenvironment and the molecular and cellular pathways involved in (patho)physiological tissue repair.

General introduction – Cardiovascular Regenerative Medicine

Organ and tissue damage, as the result of ischemic insult, fibrosis, or other, requires adequate repair i.e. regeneration. Regeneration of tissue damage is a complex process that involves inflammation, wound healing and remodeling. This process comprises of a microenvironment in which an intricate interplay of cells, mediators and Kamagra extracellular matrix accomplish regeneration. The post-damage microenvironment of tissues requires a stringent regulation, without which adverse reactions (e.g. fibrosis) may develop. In several cardiovascular diseases, tissue damage may extend beyond the intrinsic repair capacity of the human body. Therefore, Regenerative Medicine aims at the regeneration of damaged tissues or organs by employing and augmenting physiological regeneration mechanism by application of stem/progenitor cells, mediators and “smart biomaterials”.

The application of stem/progenitor cells requires appropriate guiding factors that provide instruction to these cells upon their administration in vivo, or their use to construct replacement tissue in vitro. A good understanding of the in vitro and in vivo plasticity of stem cells, in presence or absence of the post-damage microenvironment, will help the development of better regeneration therapies. In vitro, the construction of replacement tissue requires instructive 3-dimensional scaffolds that help to recreate the original tissue architecture, i.e. genuine tissue Ajanta Pharma Kamagra engineering. By themselves the biomaterials that are used to make scaffolds (e.g. solid or gel-like materials) elicit an inflammatory reponse upon implantation: the Foreign Body Reaction (FBR). The FBR can also be employed to augment regenerative therapies.

Title: Endothelial Plasticity: Shaping Health & Disease

Moonen, JAJ (2013).

ISBN: 978-90-367-5957-1

Abstract: It is well established that endothelial cells (EC) play a critical role in vascular physiology. Originally regarded as a passive barrier, the endothelium has become appreciated to be a complex tissue with multiple functions. EC regulate coagulation and vasomotor tone, modulate immune and inflammatory responses, and direct vascular development. As such they are crucial for shaping health which requires a high degree of adaptation and plasticity. Adverse stimuli such  Kamagra Oral jelly as pro-fibrotic and pro-inflammatory cytokines or reactive oxygen species, induce endothelial injury and dysfunction. When persistent, this dysfunction can result in endothelial-to-mesenchymal transition (EndMT) which contributes to fibro-proliferative disease. Hence, EC plasticity can also shape disease.
In this thesis we have investigated how local environmental cues dictate endothelial plasticity. We have shown that chronic inflammatory disease impacts endothelial progenitor cell (EPC) biology, through reducing their circulating numbers and by impairing their function. Both mature EC and EPC were shown to be highly plastic in vitro, as evidenced by their capacities to undergo TGF-beta-driven EndMT. Also we have shown how biochemical stimuli, i.e. pro-fibrotic and pro-inflammatory cytokines, can act in synergy in induction of EndMT. And finally, how hemodynamic forces modulate EndMT both through inhibition, and stimulation of this process. Thereby providing insights in the regulation of EndMT in vivo, and its potential involvement in disease. Most importantly, our studies have shown that EC retain a remarkable plasticity during adult life. These insights open new horizons for vascular regenerative medicine and challenge current dogmas on the pathophysiology of fibro-proliferative vascular disease.

Title: Tissue Engineering of Skeletal Muscle for Patients with Facial Paralysis

Koning, M (2012).

ISBN: 978-90-367-5561-0

Abstract: Significant loss of functional muscle tissue has a profound impact on a patient’s life due to the limited capacity of self-repair of the muscle. In a world

where millions are Kamagra 100mg Oral Jelly spent on appearance, an asymmetric, paralyzed face causes severe physical, social and psychological distress. The generation of skeletal muscle tissue using tissue engineering methods holds promise for future treatment of patients with facial paralysis. The main objective of this thesis was to improve tissue engineering of human skeletal muscle by providing new fundamental insights and tools. We show that human satellite cells are most suitable as a source for tissue engineering of autologous human skeletal muscle. In vitro cloned human satellite cells differentiate into either myotubes, which are immature muscle fibers, or new quiescent satellite cells. By manipulating the regulatory mechanism at post-transcriptional level through microRNAs, we can improve muscle fiber formation. Especially in elderly patient this therapeutic application is important since the regenerative capacity of our satellite cells declines during aging. Another important issue is that satellite cells, upon implantation, encounter an oxygen-deficient environment. We show that human satellite cells are resistant to an oxygen-deficient environment and in vivo differentiate into muscle fibers and quiescent satellite cells. Moreover, these muscle fibers are also well vascularized. In conclusion, our new insights and tools provide a solid basis for tissue engineering of human skeletal muscle from human satellite cells for patients with facial paralysis

Title: Tuned Polyurethanes for Soft Tissue Engineering

Jovanovic, D (2011).

ISBN: 978-90-367-4708-0

Abstract: The applications of tissue engineering are increasing rapidly in biomedicine. Researcher Daniela Jovanovic developed new synthetic biomaterials for scaffolds that can be used for soft tissue Kamagra Pillen regeneration, and possibly new tissue and organ formation, for example blood vessels or heart tissue. The focus of this research was on the development of biodegradable scaffolds. This is a crucial aspect for application, since recovery only occurs when physiological turnover and new tissue formation are balanced. Several commercially available biomaterials were modified with the aim to alter the biodegrading properties. The results are promising, because the new materials were incorporated well.

Title: Effects of structure, morphology and heparin(-like) coatings on the tissue reaction to poly(ethylene terephthalate).

Van Bilsen, PHJ (2009).

ISBN: 978-90-367-3672-5

Abstract: Het menselijke lichaam bestaat uit een groot aantal organen met verschillende functies. Bij veroudering en (chronische) ziekte kan er functieverlies van een weefsel of een orgaan optreden. Soms is het mogelijk om met behulp van een medisch implanteerbaar materiaal of apparaat een dergelijk functieverlies te ondervangen. Dit is bijvoorbeeld het geval bij een kunsthartklep (Figuur 1), een kunstbloedvat en een pacemaker. Implantaten Kamagra 100mg zoals deze bestaan meestal uit verschillende, lichaamsvreemde materialen. Wanneer een materiaal geïmplanteerd wordt, zal het lichaam op de aanwezigheid ervan reageren door middel van een vreemdlichaamsreactie (VLR). Het primaire doel hiervan is om het lichaamsvreemde materiaal te verwijderen, door het bijvoorbeeld af te breken. Indien dit niet lukt, vormt er zich een littekenachtig weefsel rondom het implantaat, met als doel om het af te schermen van het omliggende weefsel. Een dergelijk littekenachtig weefsel wordt ook wel kapsel genoemd.
Hoewel de meeste medisch implanteerbare materialen specifiek voor een toepassing zijn ontwikkeld, kan een voortdurende VLR de levensduur van een implantaat beperken. Het kan bijvoorbeeld de oorzaak zijn dat een kunsthartklep na verloop van jaren niet meer goed werkt. Hoewel de klep dan mechanisch nog in orde is, kan er een kapsel rondom de hartklep gevormd zijn dat de mechanische functie ervan beperkt. Dit kan leiden tot complicaties van de hartfunctie op langere termijn. De mate waarin een materiaal verenigbaar is met de biologische functie van een orgaan of een weefsel, wordt biocompatibiliteit genoemd.

Dit proefschrift beschrijft de VLR die ontstaat na implantatie van een veel gebruikt, niet afbreekbaar medisch materiaal poly(ethylene terephthalate), afgekort als PET. Dit materiaal wordt bijvoorbeeld gebruikt in producten voor de reparatie of vervanging van hartkleppen en bloedvaten. Er werd aangetoond dat een voortdurende VLR optreedt tegen geweven PET. De VLR tegen PETkan mogelijk verminderd worden door het oppervlak ervan te behandelen of te coaten met een ander, meer biocompatibel materiaal. In dit poefschrift zijn twee type coatings onderzocht waarmee werd getracht om de voortdurende VLR tegen geweven PET te verminderen en daarmee biocompatibiliteit van PET te vergroten.

Title: Endothelial Progenitor Cells in Vascular Regenerative Medicine – Towards ‘Designer Blood Vessels’ & ‘Therapeutic Neovascularzation’.

Krenning, G (2009).

ISBN: 978-90-367-3772-2

Abstract: The ability to restore vascular perfusion at sites of ischemic damage is essential for tissue regeneration. However, current therapies aimed to restore vascular perfusion are only successful when the large-diameter blood vessels (internal diameter (ID) > 6 mm) are affected. Hence, novel therapies such as tissue engineering of ‘designer’ blood Super Kamagra vessels and (stem) cell therapy for therapeutic neovascularization are warranted. In this thesis we have investigated the cellular plasticity of endothelial progenitor cells (EPC) and explored its applicability for vascular regenerative medicine. In part I, we have found that human EPC contain the intrinsic capacity to differentiate into both mature and functional endothelial cells (EC) and smooth muscle cells (SMC) on degradable biomaterials. These EC and SMC can be employed to tissue engineer bioartificial autologous small-diameter blood vessels. Furthermore, in part II, we have identified a paracrine function of EPC during (therapeutic) neovascularization by the secretion of pro-angiogenic growth factors and cytokines.

Thus, the EPC offers enormous potential for tissue engineering of ‘designer’ blood vessels as well as in (stem) cell therapy. Hence, in future perspective, EPC-based therapies will enable true tissue regeneration therapies and pose great possibilities for autologous therapies. In this chapter we will discuss the cellular plasticity of EPC and how that can be used to alleviate the pitfalls of current (cardio)vascular therapies. Also, we discuss future challenges for vascular regenerative medicine that originate from this thesis.