Growth factor delivery

Transcription

1 Growth factor delivery S. Swaminathan Director Centre for Nanotechnology & Advanced Biomaterials School of Chemical & Biotechnology SASTRA University Thanjavur Tamil Nadu Joint Initiative of IITs and IISc Funded by MHRD Page 1 of 8

2 Table of Contents 1. WHAT ARE GROWTH FACTORS AND WHAT ARE ITS FUNCTIONS? CAN GROWTH FACTOR ENHANCE THE TISSUE REGENERATION PROCESS? WHAT ARE THE REQUIREMENTS OR CRITERIA THAT HAVE TO BE FULFILLED FOR GROWTH FACTOR DELIVERY? DELIVERY SYSTEMS Can delivery system be controlled for release of growth factors? Has any growth factor delivery system been commercialized?...8 Joint Initiative of IITs and IISc Funded by MHRD Page 2 of 8

3 1. What are growth factors and what are its functions? Growth factor (GF) is a broad terminology, which comprises all soluble proteins that are secreted essentially by a wide variety of cells to transmit signals specific for the activation of cellular fate process that includes cell differentiation, migration and proliferation. Based on the response that GF elicits, they are broadly categorized as chemokines and cytokines. Chemokines mediate cell migration while the latter activates cell proliferation and differentiation. Growth factors secreted by signalling cells act as ligands and binds to receptors on the receiving cell surface. Apart from playing crucial role in signal transduction between cells, it also exhibits communication between cell and its ECM or microenvironment. Growth factors are quite versatile in the way they are destined to activate cellular processes; some of them stimulate function in different cell types, while some are specific towards a particular cell-type and certain GFs activates secondary messengers. GFs activate various signalling pathways, which cross-links with each other. The unveiling of such complex pathways has revealed the pivotal role of GFs in important physiologic processes such as stimulation of stem cells, morphogenesis, wound healing, angiogenesis and so on. Growth factors are given names after the type of cells that they are targeted for as in platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), nerve growth factors (NGF), and so on. Delivering these growth factors is also critical and importantly they can induce differentiation of stem cells, prevents dedifferentiation and transdifferentiation of mature cells. For instance, hepatocytes and chondrocytes have the property of transdifferentiation to fibroblasts and dedifferentiation to mesenchymal stem cells respectively. Specific growth factors can be employed to prevent this and maintain the cells in their differentiated phenotype. Joint Initiative of IITs and IISc Funded by MHRD Page 3 of 8

4 Some of the GFs with their targeted organs and functions have been tabulated below: Growth factor Targets Primary activity Vascular Endothelial Blood vessel Significant role in angiogenesis as it Growth Factor (VEGF) promotes migration, proliferation and survival of endothelial cells Transforming Growth Brain, skin Proliferation of basal cells or neural Factor (TGF-β) cells, plays role in wound healing process TGF-β Bone, cartilage Bone-forming cells proliferation and differentiation, inhibits proliferation of epithelial cells, promotes wound healing, performs anti-inflammatory function, inhibits macrophage and lymphocyte proliferation Platelet-Derived Growth Factor (PDGF) Neural Growth Factor (NGF) Insulin-Like Growth Factor (IGF) Hepatocyte Factor (HGF) Growth Fibroblast growth factor (FGF) Epidermal Factor (EGF) Growth Skin, blood vessel, muscle, bone, cartilage Brain, spine, nerve Muscle, bone, cartilage, liver, lung, kidney, nerve, skin Liver, muscle, bone Blood vessel, bone, skin, nerve, spine, muscle Vital role in morphogenesis, promotes proliferation, migration, and growth of endothelial cells, connective tissue and smooth muscle cells. Proliferation and survival of neurons, promotes neurite outgrowth Inhibits apoptosis and enhances proliferation of many types of cells, IGF-1 is also called somatomedin C and is related to proinsulin Differentiation, proliferation and migration of mesenchymal stem cells, prevents trans or dedifferentiation of hepatocytes Inhibits embryonic stem cells differentiation, regulates migration, proliferation and survival of endothelial cells, induces mesoderm formation in early embryos Skin, nerve Growth, proliferation and differentiation of epithelial cells Joint Initiative of IITs and IISc Funded by MHRD Page 4 of 8

5 Bone Morphogenetic Protein (BMP-2) Bone, cartilage Osteoblasts migration and differentiation BMP-7 Kidney, bone Renal development, differentiation and migration of osteoblasts Angiopoietin (Ang) Erythropoietin (Epo) Blood vessel, heart, muscle Bone marrow derived cells Maturation and stabilization of blood vessel Induces differentiation and proliferation of erythrocytes 2. Can growth factor enhance the tissue regeneration process? Undoubtedly, growth factors would definitely promote successful regeneration by tissue engineering. They can be included as best candidates for biomolecular signals along with cells and scaffold for the accomplishment of the tissue engineering triad. GFs are capable of dictating the fate of cells in scaffold largely depends on the optimal concentration, chemical identity and duration of their action. Thus exogenous delivery of these molecules is majorly considered and has become attractive component of tissue engineering. A better understanding of the properties of growth factor is very important to achieve precisely controlled signalling of these factors at the site of action for potential control over regenerative process. Growth factors have shorter half-life, unstable and hence an appropriate carrier system is a must for growth factor delivery. 3. What are the requirements or criteria that have to be fulfilled for growth factor delivery? Important considerations to be kept in mind while designing a delivery system for growth factor includes Joint Initiative of IITs and IISc Funded by MHRD Page 5 of 8

6 i. Identifying the growth factors based on the tissue type that is aimed for regeneration. This depends on the complete understanding of the complex developmental process of the tissue that is targeted and the identification of the growth factor which would potentially carry out the function ii. Mode of the delivery system is very important and this again should be chosen based on the tissue that is targeted. The system can be both targeted and non-targeted, although targeted systems are preferred as most tissues have heterogeneous population of cells and growth factors act in the paracrine fashion with slow diffusion iii. Stability of the delivery system: Based on the half-life of the growth factors, the carrier system should complement to the stability of the protein and should achieve delivery of GF within the optimal range that is required iv. The release profile of the GF should preferably be sustained as most growth factor signalling are intended for long term activity at the administered site until the injured tissue gets replaced by the formation of new tissues. The necessity of administration of GF in frequent doses can be overcome by sustained release. Thus, biomaterials for growth factor delivery are chosen such that they satisfy the criteria mentioned above. 4. Delivery Systems The current strategies adopted for growth factor delivery can be categorized into two broad types chemical immobilization and physical encapsulation. The scheme is based on the carriers that are grouped and is been represented in the chart below. Joint Initiative of IITs and IISc Funded by MHRD Page 6 of 8

7 Fig 1: Various growth factor delivery strategies Chemical immobilization refers to the chemical conjugation, direct charge-charge binding, indirect binding via intermediate proteins or other biomolecules, physical adsorption due to hydrogen bonding or hydrophobic interaction, or affinity interaction of growth factor with the polymeric (synthetic or natural) substrate. Some of the GFs will be active in the bound state and they activate cells, which come in contact with matrix. Some requires cleavage from their bound form to become active and exhibit their function. Covalent and non-covalent incorporation are included in this category. Using this modality NGF fusion protein has been immobilized to polymeric fibrin, which gets activated as the molecule gets released by proteolytic cleavage. This system has shown enhancement in nerve regeneration. Chemical conjugation also includes coupling of the functional moiety of a large molecule i.e. small oligopeptides that mimics the functional part of a molecule with the matrix for enhanced delivery and activity of the growth factor. Covalent chemical conjugation is advantageous as it can provide prolonged release than the non-covalent method. Although the Joint Initiative of IITs and IISc Funded by MHRD Page 7 of 8

8 disadvantage is that the processing parameters favours only few growth factors to be conjugated to the matrix by this method. Physical encapsulation refers to the dispersion of growth factors during the fabrication of scaffold and is a simple alternative for chemical signals. Fabrication of scaffold by various methods as particulate leaching, phase separation, phase emulsion, etc., can be used for loading the growth factors. The complete characterization of the scaffold for the ideal properties along with the release profile of the growth factors is essential. Polymeric nanospheres, nanoparticles or liposomal carriers can also be used for the physical encapsulation. Liposomes are more advantageous when biocompatibility is of concern, as it does not involve any harsh organic solvents for processing. 4.1 Can delivery system be controlled for release of growth factors? Yes, it can be tailored with responsive molecules that make them release its contents in response to the environmental conditions. The common triggering agents such as ph, temperature or proteolytic enzymes are used to release the contents. Other agents such as light, electric, magnetic fields and ultra-sound can also regulate or control the release of the therapeutic molecules. 4.2 Has any growth factor delivery system been commercialized? Regranex is the first Food and Drug Administration (FDA) approved growth factor system for tissue regeneration. Regranex is a topically applied gel for the treatment of diabetic foot ulcers. This product is based on PDGF (0.01% recombinant PDGF-BB), delivered in a carboxymethylcellulose-based gel. Joint Initiative of IITs and IISc Funded by MHRD Page 8 of 8