Reconstructive and regenerative medicine About theme
Our aim is to strengthen the already existing synergy between the participating laboratories by stimulating interaction between clinicians, basic scientists and private partners in the Nijmegen area. We seek to develop therapies that will improve the quality of healthcare.read more
Reconstructive and regenerative medicine About themeThis theme focuses on the development and clinical translation of innovative diagnosis and therapies, including regenerative medicine and nano-medicine, for personalized care and cure of patients needing reconstructions of lost or damaged tissues. This will be achieved by transdisciplinary research by leading research groups in the fields of medicine, dentistry, biochemistry, chemistry, biology and materials science.
Reconstructive and Regenerative Medicine (RRM) is a center of excellence combining unique expertise present at the Radboudumc in the fields of cell biology, biochemistry, immunology, tissue engineering, molecular biology, biomaterials, chemistry, transplantation biology and clinical research. It is the leading research center in regenerative medicine in the Netherlands. The RRM bridges the bench-to-bedside gap by unifying a large number of renowned research groups focusing both on basic science and on clinical translation (such as tissue engineering, biomaterials and stem cell therapy). To this end, RRM participates in numerous leading national and international research programs funded by Dutch, European or American funding agencies.
- We will investigate clinical applications for musculoskeletal diseases.
- We will investigate applications for kidney diseases.
- We are investigating applications for the urogenital tract.
- We are looking for applications for skin diseases.
- We are investigating reconstructive surgical procedures and TERM applications.
Lines of research
Reconstructive and regenerative medicine
An additional line of research on renal regeneration focuses on development of living membranes for an intradialytic biological kidney support device. End-stage renal disease patients have uremic complications that result in high cardiovascular morbidity and a poor quality of life, despite hemodialysis. Uremia is caused by the retention of a large group of molecules with different physical and chemical properties that are not sufficiently cleared by hemodialysis. Within RRM, a cell device (BioKid) will be developed capable of effective clearance of these toxins ex vivo. The BioKid will comprise of multiple so-called living membranes, i.e. tight monolayers of human renal epithelial cells that are grown on newly designed semi-permeable bioactive polymer membranes. A unique supramolecular approach will be used to develop a 2D bioactive polymer membrane that regulates long-lived monolayer integrity and cell viability under uremic conditions. The expertise and knowledge gained on the supramolecular 2D bioactive polymer membrane will be translated into a 3D configuration that will be applied in a simple in vitro set-up as a cell-aided intradialytic uremic toxin removal device. This will serve as a proof of principle for a more sophisticated device that can be used in the future to treat uremic symptoms in end-stage renal disease patients on dialysis.
Renal diseases may develop to end-stage renal disease, when the renal function is not sufficient anymore for a proper physiology. When no transplant kidney is available, patients with end-stage renal diseases go into dialysis, which is a renal replacement therapy that highly impacts the quality of life in a negative manner. Approaches to develop a portable, miniaturized dialysis device, could lead to a wearable artificial kidney (WAK) that could be operated constantly. However, to reach this goal, several requirements with respect to the sorbents, water handling and filtration membranes has to be met. Currently, research is focused on improving biomaterials as building blocks of an wearable artificial kidney. This research is focused on reconstituting the carbohydrate layers normally existing in the capillary filter, on sophisticated filtration membranes that contain sorbents in addition (mixed matrix membranes). Parameters that are addressed are biocompatibility and fouling of the filter. At the long term the ultimate goal is to develop an artificial capillary filter ex vivo consisting of the glomerular cell types constituting the capillary filter, i.e. podocytes and glomerular endothelium. Also at the long term, it is a challenge how to direct stem cells to repair a damaged capillary filter in vivo.
Within RRM, research focuses on:
- improvement of biomaterials to develop a miniaturized wearable kidney device as replacement for current dialysis treatment
- development of an artificial capillary filter ex vivo, existing of podocytes and glomerular endothelium
- directing stem cells to repair a damaged capillary in vivo
Musculoskeletal and regeneration
Reconstructive and regenerative medicine
Bone and joint diseases cause more functional limitations in the adult population than any other group of disorders, and represent the most common medical cause for long-term sickness absence in developed countries. As life expectancy increases and degenerative bone diseases become more urgent, a rapidly expanding number of patients will need effective bone regeneration therapies. Regeneration of large bone defects is currently a significant challenge for dental, maxillofacial, trauma and orthopedic surgeons. This problem is further enhanced because the majority of these patients suffer from additional medical problems, (such as osteoporosis, diabetes or cancer) which strongly reduce the regenerative capacity of native bone tissue. Therefore, a next generation of off-the-shelf available bone substitute materials with an equal performance to autologous bone needs to be developed.
Various projects within RRM are dedicated to development of such novel materials for bone regeneration which can be processed into various application forms ranging from two-dimensional coatings, surface modifications and membranes to three-dimensional (nano)fibers, micro/nanoparticles, scaffolds, gels and cements. In addition, we investigate their biological performance both in vitro and in vivo.
Calcium phosphate bioceramics are currently recognized as the most effective class of bone-substituting materials due to their chemical similarity to bone mineral. Although extensive knowledge is available on the relationship between physicochemical characteristics of CaP ceramics and their biological behavior, the favorable properties of calcium phosphate ceramics on bone healing are still not explained unambiguously. To unravel this mechanism, we carry out fundamental research on the mechanism of action of calcium phosphate bioceramics.
In addition, a strong need exists for novel drug release technologies to facilitate local and controlled (co-) delivery of (multiple) biomolecules such as growth factors (to stimulate stem cell homing as well as osteo- and angiogenesis), chemotherapeutics as well as anabolic or anti-catabolic drugs (e.g. small molecules). Finally, novel coatings and nano/microtextures on top of endosseous implants are being developed within RRM to improve the healing response to bone implants (both oral and orthopedic) in order to comply with the trend towards implant installation under increasingly challenging conditions characterized by e.g. lower bone mineral densities and corresponding reduced anchoring capacity of bone tissues.
RRM develops new effective therapies to prevent joint diseases and to regenerate damaged joint tissues, mainly focused on articular cartilage. Osteoarthritis is a major topic since this disease is the most prevalent affliction that leads to cartilage damage and loss of joint function in humans. Osteoarthritis is the most common form of human arthritis which affects over than 70 million European citizens. Nowadays no efficient therapy is available on the market. Most of treatments proposed to the patients do not prevent the anatomic progression of the disease, they are focused on pain reducing and overall patient functioning and safety improvement. Although osteoarthritis is a disease of the cartilage also other tissues like subchondral bone and synovium have recently been shown to be involved in tissue remodeling within the osteoarthritic joint. The synovial lining layer which covers the inside of diarthodial joints comprises macrophages and these macrophages become activated during osteoarthritis to produce high amounts of cytokines and growth factors which drive cartilage destruction but also new formation of cartilage/bone. Within RRM, we are focusing on a new treatment concept validation based on cell therapy by injecting adipose stromal cells in the diseased articulation to activate the regeneration of the cartilage. Adipose derived stem cells (ASC) have recently been shown to exhibit immunosuppressive properties.
To regenerate functional articular cartilage, tight control of the differentiation of stem cells to chondrocytes is essential. In this process, growth factors (TGF beta, BMPs and wnts) and inflammatory cytokines (e.g. IL-1, TNF alpha) and their respective receptors play a dominant role. A big problem in the differentiation of stem cells to chondrocytes relates to the fact that this differentiation does not result in stable articular cartilage, but that chondrocytes undergo terminal differentiation and finally die. Moreover, in real life regeneration of cartilage does not take place in a healthy joint, but always in a joint with disturbed homeostasis and elevated levels of inflammatory cytokines. Both the control of terminal differentiation of chondrocytes and modulation of cartilage regeneration by inflammatory cytokines are investigated with the final goal to control chondrocytes differentiation and achieve stable cartilage formation. Within RRM, we also collaborate with the Department of Orthopedics on the development of a meniscal transplant that restores joint homeostasis, thereby preventing the development of secondary osteoarthritis.
Research within RRM focuses on wound healing and scarring in mucosa, muscle, and skin after cleft palate repair. Scar formation in the mucosa and muscles of the palate after surgery causes growth disturbances of the upper jaw, and impairs speech. In the skin, scarring can reduce the mobility of the joints and cause esthetic problems. RRM aims to develop strategies to reduce scarring in mucosa, skin, and muscle tissue in order to restore normal function. The scarring of internal organs such as muscle, lung, liver and kidney is generally termed fibrosis. Scarring and fibrosis have a large impact on the quality of life, and present major health care costs for society. Crucial processes in both scarring and fibrosis are the appearance of myofibroblasts and the accumulation of ECM components, which prevent complete tissue regeneration. The fibrotic process is promoted by mechanical loading and the failure of cytoprotective mechanisms in the tissue. The research involves two- and three-dimensional in vitro culture models for fibroblasts and muscle cells, and in vivo wound healing models in rats and mice. Strategies are developed to limit the fibrotic process by the application of cells, growth factors, ECM peptides and cytoprotective molecules.
This research within RRM is focused on the restoration of meniscus tissue and prevent osteoarthritis of the articular cartilage due to meniscus pathology. After damaging a meniscus by a traumatic event, the changed mechanical loading onto cartilage and the changes in joint homeostasis will induce a cascade of events in the joint which eventually leads to osteoarthritis. This research line is focused on the prevention of osteoarthritis after a meniscus trauma. Several therapeutic interventions are being developed in the following sub-projects:
- Development of a meniscus glue. If a tear in the meniscus could be glued together by a biological glue that allows the meniscus to heal itself, a normal joint biomechanics could be maintained and development of osteoarthritis will be prevented.
- Development resorbable implants for young patients. After a partial meniscectomy joint biomechanics could be restored by resorbable or permanent porous scaffolds that enable tissue ingrowth and differentiation into new meniscus tissue. Mechanical loading is likely one of the key factors influencing the regenerative process, influencing cellular differentiation, matrix production and matrix degradation, not only of the meniscus tissue that is engineered but also of the other tissues in the joint. In this research line within RRM, new bio-inspired scaffolds for meniscus regeneration in young patients are being developed. Since meniscus tissue has a highly anisotropic organization and architecture, scaffolds will be developed which will allow the direct differentiation of tissue into the needed anisotropy.
- Development of a permanent meniscus implant.For a severely damaged meniscus no therapeutic solutions are available yet. A permanent meniscus implant will be developed for the elderly patient with a severely damaged meniscus.
- Joint homeostasis after implantation in the joint of chondroprotective meniscus implants. The implantation of an artificial meniscus will induce a reaction in the joint. Besides functionality of a new implant it is also of crucial importance that the implant will prevent osteoarthritis and not disturb the normal joint homeostasis. Within RRM we investigate the reaction of the joint on the implant and optimize the implant in such a way that joint homeostasis is maintained or restored after implantation of a construct in close collaboration with the Department of Experimental Rheumatology.
Skin tissue and regenerationBiomaterials for skin replacement are currently being applied on patients with burn wounds, surgical wounds and ulcers. These skin substitutes include both acellular and cellular devices. More research in this area is necessary, however, in order to overcome major problems like contraction and scarring.
Within RRM, tissue-engineered 3D models are being developed to study the biology of normal and diseased skin. Diseases of interest include psoriasis, atopic dermatitis, wound healing and skin cancer. These models can be used to evaluate anti-inflammatory drugs and wound dressings in vitro, and to study tumor invasion. Our established models involve epidermis that is completely regenerated on de-epidermized dermis, collagen gels or filters. Currently we are extending our systems to include inflammatory cells (T-lymphocytes, dendritic cells) and cancer cells (melanoma).
Surgery and regenerative medicineWithin the clinical field of surgery, RRMis active in tissue engineering and reconstructive medicine regarding abdominal, vascular, and pediatric surgery. In abdominal surgery focus is on common disturbances of surgical healing and repair mechanisms such as intra-abdominal adhesion formation, anastomotic leak, incisional hernia and chronic inflammation. Core activities is development and testing of biomaterials to prevent intra-abdominal complications (e.g. adhesion formation, anastomotic healing, incisional hernia). Cooperations exist with several departments within RRM (Dept. of Bio-organic Chemistry) and universities abroad.
In vascular and pediatric surgery the loss or congenital absence of vital tissues is a major clinical problem. The research focuses on the engineering of tissues that are lacking or became lost in patients. Vascular constructs for replacement and bypass surgery and tissue replacement such as bowel, diaphragm and abdominal wall or bladder defects are being designed, developed and tested in several research projects.
Urogenital tissue and regenerationWithin RRM, the research on urogenital tissue regeneration is focused on congenital anomalies of the urogenital tract. The research specializes in urogenital tissue engineering and regenerative medicine, genetic and environmental factors in the etiology of urological defects in children, and pediatric urology outcome research. Within RRM, surgeons and scientists collaborate to provide a positive interaction between clinical and basic research. Ample expertise is present on in vitro cell cultures of urological cell types, bioreactors, surgical techniques, small and large animal models to study the potential of urological tissue engineering and regenerative medicine solutions, clinical trials, ethical aspects and an urological biobank. Within RRM, very close collaborations have been built with the Departments of Biochemistry, Pediatric Surgery, Gynaecology, Pre-clinical research (SYRCLE) and Ethics.
Research focus areas include
- i) acellular urogenital tissue engineering
- ii) biopolymer reinforced collagen constructs
- iii) biomolecules and growth factor effects
- iv) cell-seeded constructs for urological reconstructions
- v) urinary diversions using biological materials
- vi) bladder and urethra reconstructions, and vii) cell therapy for urinary incontinence
Information only available in Dutch.