scholarly journals 3D bioprinting spatiotemporally defined patterns of growth factors to tightly control tissue regeneration

2020 ◽  
Vol 6 (33) ◽  
pp. eabb5093 ◽  
Author(s):  
Fiona E. Freeman ◽  
Pierluca Pitacco ◽  
Lieke H. A. van Dommelen ◽  
Jessica Nulty ◽  
David C. Browe ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Tissue Regeneration ◽  
Point Of Care ◽  
Release Kinetics ◽  
Spatial Gradient ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Bone Defect Healing

Therapeutic growth factor delivery typically requires supraphysiological dosages, which can cause undesirable off-target effects. The aim of this study was to 3D bioprint implants containing spatiotemporally defined patterns of growth factors optimized for coupled angiogenesis and osteogenesis. Using nanoparticle functionalized bioinks, it was possible to print implants with distinct growth factor patterns and release profiles spanning from days to weeks. The extent of angiogenesis in vivo depended on the spatial presentation of vascular endothelial growth factor (VEGF). Higher levels of vessel invasion were observed in implants containing a spatial gradient of VEGF compared to those homogenously loaded with the same total amount of protein. Printed implants containing a gradient of VEGF, coupled with spatially defined BMP-2 localization and release kinetics, accelerated large bone defect healing with little heterotopic bone formation. This demonstrates the potential of growth factor printing, a putative point of care therapy, for tightly controlled tissue regeneration.

scholarly journals Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jarrin ◽  
Abrar Hakami ◽  
Ben Newland ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Growth Factors ◽  
Growth Factor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Delivery Systems ◽  
Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

Development of growth factor-incorporating liposomes for integration into scaffolds as a method to improve tissue regeneration

2021 ◽  
Author(s):  
E. Natsaridis ◽  
P. Mouzoura ◽  
F. Gkartziou ◽  
A. Marazioti ◽  
S.G. Antimisiaris
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Tissue Regeneration ◽  
Structural Characteristics ◽  
Drug Carriers ◽  
Growth Factor Delivery ◽  
Liposomal Form ◽  
Liposomal Drug ◽  
Hydrophilic Nature ◽  
Rapid Clearance

This review is an update about the efforts to develop liposomal carriers for growth factor delivery. It is well known that growth factors have the potential to enhance/accelerate tissue regeneration, however their poor stability which results in rapid loss of their activity, together with their rapid clearance from defected tissues (when applied as free molecules) is a serious drawback for their use; their highly hydrophilic nature and low capability to permeate through biological barriers (cell membranes) are additional factors that limit their applicability. In the last years, the advantages of liposomal drug delivery systems have motivated efforts to deliver growth factors (GFs) in liposomal form. Herein, after briefly introducing the basic structural characteristics of liposome types and their advantages when used as drug carriers, as well as the basic problems encountered when GFs are applied for tissue regeneration, we focus on recent reports about development and potential regenerative effects of liposomal GFs, towards defects of various tissues. The methodologies used for incorporation, attachment or immobilization of liposomal GFs in order to sustain their retention at the defected tissues, are highlighted as well.

scholarly journals PEG grafted chitosan scaffold for dual growth factor delivery for enhanced wound healing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amritha Vijayan ◽  
Sabareeswaran A. ◽  
G. S. Vinod Kumar
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Treated Group ◽  
Growth Factor Delivery ◽  
Chitosan Scaffold ◽  
Collagen Formation ◽  
Dual Growth Factor Delivery

AbstractApplication of growth factors at wound site has improved the efficiency and quality of healing. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) induce proliferation of various cells in wound healing. Delivery of growth factor from controlled release systems protect it from degradation and also result in sustained delivery of it at the site of injury. The goal of the study was to develop a Polyethylene glycol (PEG) cross-linked cotton-like chitosan scaffold (CS-PEG-H) by freeze-drying method and chemically conjugate heparin to the scaffold to which the growth factors can be electrostatically bound and evaluate its wound healing properties in vitro and in vivo. The growth factor containing scaffolds induced increased proliferation of HaCaT cells, increased neovascularization and collagen formation seen by H and E and Masson’s trichrome staining. Immunohistochemistry was performed using the Ki67 marker which increased proliferation of cells in growth factor containing scaffold treated group. Frequent dressing changes are a major deterrent to proper wound healing. Our system was found to release both VEGF and bFGF in a continuous manner and attained stability after 7 days. Thus our system can maintain therapeutic levels of growth factor at the wound bed thereby avoiding the need for daily applications and frequent dressing changes. Thus, it can be a promising candidate for wound healing.

scholarly journals PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

2016 ◽  
Vol 113 (16) ◽  
pp. E2306-E2315 ◽  
Author(s):  
Vashe Chandrakanthan ◽  
Avani Yeola ◽  
Jair C. Kwan ◽  
Rema A. Oliver ◽  
Qiao Qiao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Tissue Regeneration ◽  
Somatic Cells ◽  
Dependent Manner ◽  
Cell Plasticity ◽  
Differentiation Potential ◽  
Multipotent Stem Cells ◽  
Differentiated Cells

Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor–AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

scholarly journals Growth factors are released by mechanically wounded endothelial cells.

1989 ◽  
Vol 109 (2) ◽  
pp. 811-822 ◽  
Author(s):  
P L McNeil ◽  
L Muthukrishnan ◽  
E Warder ◽  
P A D'Amore
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Growth Factors ◽  
Growth Factor ◽  
Mechanical Forces ◽  
Fibroblast Growth ◽  
Growth Promoting ◽  
Transient Plasma

Growth factors may be required at sites of mechanical injury and normal wear and tear in vivo, suggesting that the direct action of mechanical forces on cells could lead to growth factor release. Scraping of cells from the tissue culture substratum at 37 degrees C was used to test this possibility. We show that scraping closely mimics in vitro both the transient plasma membrane wounds observed in cells subject to mechanical forces in vivo (McNeil, P. L., and S. Ito. 1989. Gastroenterology. 96:1238-1248) and the transient plasma membrane wounds shown here to occur in endothelial cells under normal culturing conditions. Scraping of endothelial cells from the culturing substratum released into the culture medium a potent growth-promoting activity for Swiss 3T3 fibroblasts. Growth-promoting activity was released rapidly (within 5 min) after scraping but was not subsequently degraded by the endothelial cells for at least 24 h thereafter. A greater quantity of growth-promoting activity was released by cells scraped 4 h after plating than by those scraped 4 or 7 d afterwards. Thus release is not due to scraping-induced disruption of extracellular matrix. Release was only partially cold inhibitable, was poorly correlated with the level of cell death induced by scraping, and did not occur when cells were killed with metabolic poisons. These results suggest that mechanical disruption of plasma membrane, either transient or permanent, is the essential event leading to release. A basic fibroblast growth factor-like molecule and not platelet-derived growth factor appears to be partially responsible for the growth-promoting activity. We conclude that one biologically relevant route of release of basic fibroblast growth factor, a molecule which lacks the signal peptide sequence for transport into the endoplasmic reticulum, could be directly through mechanically induced membrane disruptions of endothelial cells growing in vivo and in vitro.

Fibrin-based biomaterials to deliver human growth factors

2003 ◽  
Vol 89 (03) ◽  
pp. 573-582 ◽  
Author(s):  
Catalina Wong ◽  
Elisabeth Inman ◽  
Reiner Spaethe ◽  
Sam Helgerson
Keyword(s):  
Growth Factors ◽  
Fibrin Sealant ◽  
Release Kinetics ◽  
Chorioallantoic Membrane ◽  
Human Growth ◽  
Growth Stimulation ◽  
Research Society ◽  
Individual Growth ◽  
Angiogenic Growth Factors

SummaryFibrin-based biomaterial preparations can be used as provisional growth matrices for cells important in tissue repair during wound healing in vivo. Their efficacy can be enhanced by including bioactive agents that promote specific cellular responses. This study examined the controlled delivery of the angiogenic growth factors bFGF, VEGF165, and VEGF121 using biomatrix preparations prepared from Fibrin Sealant product components. The growth factors were added prior to formation of the Fibrin Sealant clots, and the release kinetics of the proteins from the clots measured. The results indicated that the proteins were released from the clots more slowly in the order bFGF << VEGF165 < VEGF121. The biologic activity of the growth factors delivered from Fibrin Sealant clots was established by assaying growth stimulation of human microvascular endothelial cells (HMVEC) and angiogenesis in the chicken embryo chorioallantoic membrane (CAM) model of neovascularization. In the latter assay, clots containing bFGF, VEGF165, or V EGF121 all displayed angiogenic activity. However, delivery of either bFGF, VEGF165, or VEGF121 alone resulted in a significant percentage of clots becoming filled with blood, indicating that the newly developing vessels invading the clots were leaky and immature. In contrast, this hemorrhaging behavior did not occur with delivery of combinations, e.g., (VEGF165 + VEGF121) or (VEGF165 + bFGF), indicating that the vessels were more mature than those produced in response to single growth factors. Thus, delivering a combination of growth factors constituted an improvement over the delivery of individual growth factors for enhancing neovascularization.Part of this research was presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society held in Munich, Germany.

118. CHARACTERISATION OF HEPARAN SULPHATE PROTEOGLYCANS IN THE MATURING CUMULUS OOCYTE COMPLEX

2009 ◽  
Vol 21 (9) ◽  
pp. 37
Author(s):  
L. N. Watson ◽  
M. Sasseville ◽  
R. B. Gilchrist ◽  
D. L. Russell
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor ◽  
Heparan Sulphate ◽  
Cumulus Cells ◽  
Receptor Interaction ◽  
Heparan Sulphate Proteoglycans ◽  
Tgfβ Superfamily

Many growth factors including members of the transforming growth factor beta (TGFβ) superfamily and epidermal growth factor (Egf)-like ligands signal via interactions with heparan sulphate proteoglycans (HSPGs). Cell surface HSPGs can act by sequestering ligands at their site of action, by presenting a ligand to its signalling receptor, or by preventing ligand-receptor interaction. The oocyte secreted factors (OSF) growth differentiation factor 9 and bone morphogenetic protein 15 are members of the TGFβ superfamily that act selectively on cumulus cells. Conversely Egf-like ligands are secreted by mural granulosa cells and transmit LH-induced signals to cumulus cells. We investigated the possibility that HSPGs contribute to the spatially restricted responses these signals exert on cumulus cells. Syndecan-1 and Glypican-1 are cell surface HSPGs that are involved in numerous biological processes, including growth factor regulation, cell proliferation and differentiation. Microarray analysis showed Syndecan-1 and Glypican-1 mRNA expression induced 6-fold (P=10-9) and 3-fold (P=10-7) respectively in Egf+FSH stimulated cumulus oocyte complexes (COCs). Furthermore, Syndecan-1 and Glypican-1 mRNA were induced 27- and 16-fold respectively in COCs after hCG treatment of mice. Syndecan-1 and Glypican-1 protein was localised specifically to the COC through immunohistochemical analysis. In Vitro Maturation (IVM) of oocytes is a valuable alternative to gonadotropin mediated superovulation, but IVM COCs are less competent than those matured in vivo. Several components of the COC have been shown to be altered in IVM, including the chondroitin sulphate proteoglycan Versican. COCs from mice that underwent IVM in the presence of Egf+FSH and cilostamide for 16 hours had >16 fold reduced mRNA for Syndecan-1 when compared with In Vivo matured COCs. The lack of Syndecan-1 in IVM COCs could reduce signalling capacity of growth factors including OSFs. This may contribute to the reduced capacity of IVM oocytes to fertilise and produce a healthy embryo, and ultimately, a healthy offspring.

Expression of Soluble Syndecan-1 or Heparanase by Myeloma Cells Enhances Levels of Angiogenic Growth Factors Present in Endothelial Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3448-3448
Author(s):  
Yang Yang ◽  
Ashley Elizabeth Frith ◽  
Allison Theus ◽  
Veronica Macleod ◽  
Ralph D. Sanderson
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Fold Increase ◽  
Conditioned Media ◽  
High Rate ◽  
In Vivo Studies ◽  
Angiogenic Growth Factors ◽  
Myeloma Cells

Abstract Multiple myeloma is a devastating cancer with a high rate of morbidity and mortality. Our previous in vivo studies demonstrate that both shed syndecan-1 and heparanase can promote myeloma tumor growth, metastasis and angiogenesis. To examine the mechanism underlying this enhanced angiogenesis, human umbilical vein endothelial cells (HUVEC) were cocultured with cells of the CAG myeloma cell line (vector-only controls, CAGcontrol) or CAG cells engineered to express high levels of either soluble syndecan-1 ectodomain (CAGssyn1 ) or heparanase ( CAGHPSE ). After coculture for 48 hours, levels of angiogenic growth factors present in the endothelial cells were examined. The goal was to determine if expression of either soluble syndecan-1 or heparanase by CAG myeloma cells altered growth factor levels relative to those present when control CAG cells were used. Co-culture with CAGssyn1 or CAGHPSE cells did not enhance endothelial levels of FGF-2, while levels of hepatoma-derived growth factor (HDGF) and hepatocyte growth factor (HGF) were elevated in endothelia growing in the presence of CAGssyn1 cells but not CAGHPSE cells or CAGcontrol cells. However, VEGF levels present in endothelial cells were substantially enhanced by the presence of CAGssyn1 (1.9-fold increase) or CAGHPSE cells (1.6-fold increase). Surprisingly, levels of VEGF in conditioned media of cocultures containing either CAGssyn1 or CAGHPSE cells was low. In contrast, when cultured in the absence of HUVECs, VEGF levels were elevated in conditioned media of both CAGssyn1and CAGHPSE cells. Addition of this conditioned media containing high levels of VEGF to HUVECs growing in the absence of CAG cells did not result in an elevation of VEGF levels in the endothelial cells. Together, these experiments suggest that VEGF expression is upregulated in CAG cells expressing high levels of shed syndecan-1 or heparanase and that VEGF becomes associated with the endothelial cells only when they are cultured in the presence of the myeloma cells. This cross-talk between myeloma and endothelial cells may lead to the enhanced angiogenesis that occurs in vivo in tumors formed by myeloma cells producing high levels of shed syndecan-1 and/or heparanase.

scholarly journals AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

2000 ◽  
Vol 20 (14) ◽  
pp. 5041-5047 ◽  
Author(s):  
Jaime Font de Mora ◽  
Myles Brown
Keyword(s):  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Mapk Activation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

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