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Recent approaches in scaffold engineering for bone defects feature hybrid hydrogels made of a polymeric network (retains water and provides light and porous structures) and inorganic ceramics (add mechanical strength and improve cell-adhesion). Innovative scaffold materials should also induce bone tissue formation and incorporation of stem cells (osteogenic differentiation) and/or growth factors (inducing/supporting differentiation). Recently, purinergic P2X and P2Y receptors have been found to significantly influence the osteogenic differentiation process of human mesenchymal stem cells (hMSC). (1) Aim of this work is to develop polysaccharide (PS) composites to be used as scaffolds containing complementary receptor ligands to enable guided stem cell differentiation towards bone formation.
Im Rahmen dieser Arbeit wurden zunächst neuartige ionische Agarosederivate synthetisiert und anschließend umfassend charakterisiert. Anionische Agarosesulfate mit einer regioselektiven Derivatisierung in Position G6 wurden durch homogene Umsetzung in ionischer Flüssigkeit erhalten. Kationische Agarosecarbamate mit einstellbarem Funktionalisierungsgrad waren durch einen zweistufigen Syntheseansatz zugänglich. Hierzu wurden zunächst Agarosephenylcarbonate in einer homogenen Synthese hergestellt, im Anschluss folgte eine Aminolyse zu den gewünschten funktionalen Agarosederivaten. Die ionischen Agarosederivate waren bereits bei geringen Funktionalisierungsgraden vollständig löslich in Wasser. Damit war es möglich, Alginatmikrokapseln polyelektrolytisch zu beschichten und diese als Träger für eine kontrollierte Wirkstofffreisetzung zu verwenden. Ebenfalls konnten Kompositgele aus Agarose, Hydroxyapatit und Agarosederivaten hergestellt und charakterisiert werden. Im zweiten Teil wurden sowohl die Kompositträgermaterialien als auch die Alginatmikrokapseln mit vier verschiedenen Modellwirkstoffen (ATP, Suramin, Methylenblau und A740003) beladen und die Wirkstofffreisetzung über einen Zeitraum von zwei Wochen untersucht. Für die ionischen Modellwirkstoffe erwiesen sich Kompositträgermaterialien mit ionischem Agarosederivat, die beschichteten Mikrokapseln sowie die Kombination aus Komposit und Kapseln als effektiv, um die Freisetzung auf bis zu 40% zu verlangsamen. Für die schlecht wasserlösliche Substanz A740003, ein Rezeptorligand für die osteogene Differenzierung von Stammzellen, wurde eine stark verzögerte Freisetzung aus Polyelektrolytemikrokapseln festgestellt. Mithilfe von literaturbekannten und neu entwickelten Anpassungsmodellen gelang es, die Diffusion als Hauptmechanismus der Wirkstofffreisetzung zu identifizieren und die Freisetzungskurven mathematisch akkurat zu beschreiben und daraus Rückschlüsse über die einzelnen Phasen der Freisetzung zu ziehen.
Small Molecules Enhance Scaffold-Based Bone Grafts via Purinergic Receptor Signaling in Stem Cells
(2018)
The need for bone grafts is high, due to age-related diseases, such as tumor resections, but also accidents, risky sports, and military conflicts. The gold standard for bone grafting is the use of autografts from the iliac crest, but the limited amount of accessible material demands new sources of bone replacement. The use of mesenchymal stem cells or their descendant cells, namely osteoblast, the bone-building cells and endothelial cells for angiogenesis, combined with artificial scaffolds, is a new approach. Mesenchymal stem cells (MSCs) can be obtained from the patient themselves, or from donors, as they barely cause an immune response in the recipient. However, MSCs never fully differentiate in vitro which might lead to unwanted effects in vivo. Interestingly, purinergic receptors can positively influence the differentiation of both osteoblasts and endothelial cells, using specific artificial ligands. An overview is given on purinergic receptor signaling in the most-needed cell types involved in bone metabolism-namely osteoblasts, osteoclasts, and endothelial cells. Furthermore, different types of scaffolds and their production methods will be elucidated. Finally, recent patents on scaffold materials, as wells as purinergic receptor-influencing molecules which might impact bone grafting, are discussed.
Renewable resources gain increasing interest as source for environmentally benign biomaterials, such as drug encapsulation/release compounds, and scaffolds for tissue engineering in regenerative medicine. Being the second largest naturally abundant polymer, the interest in lignin valorization for biomedical utilization is rapidly growing. Depending on resource and isolation procedure, lignin shows specific antioxidant and antimicrobial activity. Today, efforts in research and industry are directed toward lignin utilization as renewable macromolecular building block for the preparation of polymeric drug encapsulation and scaffold materials. Within the last five years, remarkable progress has been made in isolation, functionalization and modification of lignin and lignin-derived compounds. However, literature so far mainly focuses lignin-derived fuels, lubricants and resins. The purpose of this review is to summarize the current state of the art and to highlight the most important results in the field of lignin-based materials for potential use in biomedicine (reported in 2014–2018). Special focus is drawn on lignin-derived nanomaterials for drug encapsulation and release as well as lignin hybrid materials used as scaffolds for guided bone regeneration in stem cell-based therapies.
Renewable resources are gaining increasing interest as a source for environmentally benign biomaterials, such as drug encapsulation/release compounds, and scaffolds for tissue engineering in regenerative medicine. Being the second largest naturally abundant polymer, the interest in lignin valorization for biomedical utilization is rapidly growing. Depending on its resource and isolation procedure, lignin shows specific antioxidant and antimicrobial activity. Today, efforts in research and industry are directed toward lignin utilization as a renewable macromolecular building block for the preparation of polymeric drug encapsulation and scaffold materials. Within the last five years, remarkable progress has been made in isolation, functionalization and modification of lignin and lignin-derived compounds. However, the literature so far mainly focuses lignin-derived fuels, lubricants and resins. The purpose of this review is to summarize the current state of the art and to highlight the most important results in the field of lignin-based materials for potential use in biomedicine (reported in 2014⁻2018). Special focus is placed on lignin-derived nanomaterials for drug encapsulation and release as well as lignin hybrid materials used as scaffolds for guided bone regeneration in stem cell-based therapies.
Healing of large bone defects requires implants or scaffolds that provide structural guidance for cell growth, differentiation, and vascularization. In the present work, an agarose-hydroxyapatite composite scaffold was developed that acts not only as a 3D matrix, but also as a release system. Hydroxyapatite (HA) was incorporated into the agarose gels in situ in various ratios by a simple procedure consisting of precipitation, cooling, washing, and drying. The resulting gels were characterized regarding composition, porosity, mechanical properties, and biocompatibility. A pure phase of carbonated HA was identified in the scaffolds, which had pore sizes of up to several hundred micrometers. Mechanical testing revealed elastic moduli of up to 2.8 MPa for lyophilized composites. MTT testing on Lw35human mesenchymal stem cells (hMSCs) and osteosarcoma MG-63 cells proved the biocompatibility of the scaffolds. Furthermore, scaffolds were loaded with model drug compounds for guided hMSC differentiation. Different release kinetic models were evaluated for adenosine 5′-triphosphate (ATP) and suramin, and data showed a sustained release behavior over four days.
Mesenchymal Stem Cells
(2020)
Das Projekt adressiert ein Problem aus dem Bereich Medizintechnologie (ein NRW-Förderschwerpunkt): die Entwicklung eines für Patienten maßgeschneiderten Gewebeersatzmaterials, ein Knochensurrogat. Kritische (“critical size“) Knochendefekte stellen ein signifikantes Gesundheitsproblem dar, das durch die zurzeit gängigen Knochenersatzmaterialien nicht bzw. nicht effizient therapiert werden kann. Kritische Knochendefekte werden mit artifiziellen Biomaterialien behandelt, die bislang eine unzureichende Regenerationskapazität aufweisen.
Bone tissue engineering is an ever-changing, rapidly evolving, and highly interdisciplinary field of study, where scientists try to mimic natural bone structure as closely as possible in order to facilitate bone healing. New insights from cell biology, specifically from mesenchymal stem cell differentiation and signaling, lead to new approaches in bone regeneration. Novel scaffold and drug release materials based on polysaccharides gain increasing attention due to their wide availability and good biocompatibility to be used as hydrogels and/or hybrid components for drug release and tissue engineering. This article reviews the current state of the art, recent developments, and future perspectives in polysaccharide-based systems used for bone regeneration.
The goal of this study was to explore a route for introducing functionalities into agarose-based hydrogels to tune the physical, chemical, and biological properties. Several agarose derivatives were prepared by homogeneous synthesis, including anionic agarose sulfates (ASs), reactive azido agaroses (AZAs), and cationic agarose carbamates (ACs), as well as agarose tosylates (ATOSs) and agarose phenyl carbonates (APhCs). The products were characterized in terms of their molecular structure and solubility behavior. The results suggest that the native gel-forming ability of agarose is retained if the introduced functionalities are hydrophilic, and the overall degree of substitution is low (DS < 0.5). Thus, functional hydrogels from several agarose derivatives could be obtained. The mechanical stability of the functional hydrogels was decreased compared to native agarose gels but was still in a range that enables safe handling. An increase in mechanical strength could be achieved by blending functional agarose derivatives and agarose into composite hydrogels. Finally, it was demonstrated that the novel functional agarose hydrogels are biocompatible and can potentially stimulate interactions with cells and tissue.