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Why I’m Sure Testing Induced Stem Cells in Humans Will Be Safe

Why I’m Sure Testing Induced Stem Cells in Humans Will Be Safe | Stem Cell Regenerative Medicine | Scoop.it

Masayo Takahashi is at the Riken Center for Developmental Biology in Kobe, Japan, where she heads the Laboratory for Retinal Regeneration and is planning a pilot safety study using a type of stem cell to treat age-related blindness. Natasha Little: Later this year, you will make history when you begin...


Via Jacob Blumenthal
Christopher Duntsch's insight:

I think it is worthwhile to be more specific with blogs and statements. Stem cells are are not all the same. I would prefer as discussed below "Why I'm sure Testing induced IPSCs will be safe" Most with some background recognize that induced means IPSCs. But likely in blog context very few.

 

Embryonic stem cells have great potential, but tag along issues and concerns. Further, they are not proven as therapeutics in any venue to a such a degree that safety, efficacy, cell pharmacobiolgy are a given and human studies inevitably, even if the issue was not in part FDA restrictions. Generally speaking their role for tissue engineering for a given disease, is not define. What is defined is complete competency for growth and differentiation potential that is unlimited. That is certainly exciting, but that is just a start. Were we discussing a novel cancer drug this early in development it would not even be on the radar. For ESCs it is the potential that lies ahead that generates the excitement.,


Adult stem cells are further along in all aspects including clinical studies and applications. They are indeed safe and there has never been evidence otherwise. These days it seems every nextgen biotech or group is using a every stem cell for every purpose without rationale or basis. Indeed, it sometimes looks like like a mix and match with more approaches then successes. Nonetheless, despite two decades of great researcher that goes by to Weisman et al. in the early 90s, these cells only get the attention they deserve because in the appropriate venue they constantly produce. Stem cells work well when used in tissues from which they were derived. Adult stem cells are a prevent entity. 

 

I have no interest at this time in STAPs and will let others provide the proof of concept with actual R&D and developmental research to put these stem cells on my radar.

 

Regarding IPSCs, biology behind the induction of a human pluriopotent stem cell is indeed remarkable and has led to a much better understanding of underlying biology. On the one hand I think that sometimes we forget that half of why so much excitement revolves around them is the fact that ESCs can be avoided.  This an issue for some because the NIH will not fund ESC research  in general, and thus this bypassed a big problem.  For others because of the ethical issues that exist here given one's respective perspective. But I don't know we can say much about these cell just yet beyond the what we know from early studies and modeling. To think that we can approximate the infinitely complex biology of ESCs is ridiculous. To think that the artificial biology induced in an aged somatic cell with telomere biology associated with aging, with more exposure to toxins and DNA damaging agents simply because it its has been here longer and exposed more frequently (such as sunburns, much less real oncogenic toxins), and to think that he biology itself is definitive, retains the same developmental biology programs and patterns as ESCs of blastocyst development in uteror,  is not possible to say just yet as a historical fact.  

 

In the long term, IPSCs may not be the best choice for regenerative medicine. These stem cells, need years of research, long term outcomes studies, understanding of genomic stabity and phenotypic stability, and simply put much more developmental R&D. I am not putting any negativity into IPSC approaches. I just have always been more comfortable with naturally occurring stem cell sources whose biology is well understood. If one day that meant ESCs research may need to supported in this respect so be it. Time and understanding will get us there eventually. 

 

Nonetheless, I will be glad to see the data begin to stack up from more  and more animal and human studies with IPSCs and the truth of what lies in the future for IPSCs is in theses studies, not in opinons.

 

more...
Jacob Blumenthal's curator insight, February 6, 2014 3:02 AM

This is an interview with Masayo Takahashi about the first ever human clinical trial of induced pluripotent stem cells (iPSC). In this clinical trial skin cells will be taken from age-related macular degeneration patients, and will be reprogrammed into iPSC. These iPSC will be then differentiated into retinal pigment epithelium (RPE) cells in-vitro. The differentiated cells will be introduced back to the eyes of the patients.

Learn more about RPE cells:

http://discovery.lifemapsc.com/in-vivo-development/eye/retinal-pigmented-epithelium/mature-retinal-pigmented-epithelium-cells


Learn more about stem cells differentiation:

http://discovery.lifemapsc.com/stem-cell-differentiation


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Rescooped by Christopher Duntsch from Stem Cell Regenerative Medicine
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regenerative medicine How Stem Cells Fight Aging Adult Stem Cells

http://www.youtube.com/watch?v=g1satxvwazu stem cells,how stem cells fight aging,regenerative medicine,what are stem cells,cell differentiation,what is a ste...
Christopher Duntsch's insight:

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

more...
Christopher Duntsch's curator insight, February 1, 2:30 PM

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

Scooped by Christopher Duntsch
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regenerative medicine How Stem Cells Fight Aging Adult Stem Cells

http://www.youtube.com/watch?v=g1satxvwazu stem cells,how stem cells fight aging,regenerative medicine,what are stem cells,cell differentiation,what is a ste...
Christopher Duntsch's insight:

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

more...
Christopher Duntsch's curator insight, February 1, 2:45 PM

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

Scooped by Christopher Duntsch
Scoop.it!

Engineering Microenvironments for Stem Cells - Shaochen Chen, UC San Diego

Speaker: Shaochen Chen, Ph.D., Professor, NanoEngineering & Bioengineering; Co-Director, Biomaterials & Tissue Engineering Center, UC San Diego.
Christopher Duntsch's insight:

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

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Rescooped by Christopher Duntsch from Stem Cells & Tissue Engineering
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Could Growing Patient Stem Cells on a Synthetic Scaffold Slash Organ Transplant Waiting Lists? | MIT Technology Review

Could Growing Patient Stem Cells on a Synthetic Scaffold Slash Organ Transplant Waiting Lists?  | MIT Technology Review | Stem Cell Regenerative Medicine | Scoop.it

Via Jacob Blumenthal
Christopher Duntsch's insight:

This is not a new concept that should be aggressively developed and pursued.  Their are two tracks upon which this concept is traveling. One track is to artificially create in vitro a 3D scaffold for this purpose using current scaffold and matrix technology.  The second is to harvest organs or tissues and modify them in vitro for tissue engineering applications. A tissue is harvested, and biochemical and biophysical methodology are used to completely remove all of the donor tissue's biomaterial, with one exception. The final product is a shell of the former, and consists of the natural scaffold the tissue or organ originally possessed.  It is then used in vitro to build a new organ or tissue,  by seeding it with stem cells and other byproducts  over time, until a new organ or tissue is created for use in humans as part of tissue engineering and regenerative medicine approaches. Immunobiology and immunoreactivity are less of a challenge to overcome here because: the natural scaffold is not immunoreactive, and chemical modifications during preparation of the scaffold are even more protective; most stem cells that might be strategic for this approach demonstrate immunoprivilige or biology that suppresses immunoreactions; and finally, because this approach is one in which a patient's own stem cells would be a good donor source.

more...
Jacob Blumenthal's curator insight, January 28, 2014 4:53 PM

This review describes the work of a bioscience spin-off company called Harvard Apparatus Regenerative Technology, or HART in designing and production of polymeric scaffolds for organ replacement.

Come and learn about sem cells:

http://discovery.lifemapsc.com/stem-cell-differentiation

 

Rescooped by Christopher Duntsch from Stem Cells & Tissue Engineering
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Why I’m Sure Testing Induced Stem Cells in Humans Will Be Safe

Why I’m Sure Testing Induced Stem Cells in Humans Will Be Safe | Stem Cell Regenerative Medicine | Scoop.it

Masayo Takahashi is at the Riken Center for Developmental Biology in Kobe, Japan, where she heads the Laboratory for Retinal Regeneration and is planning a pilot safety study using a type of stem cell to treat age-related blindness. Natasha Little: Later this year, you will make history when you begin...


Via Jacob Blumenthal
Christopher Duntsch's insight:

I think it is worthwhile to be more specific with blogs and statements. Stem cells are are not all the same. I would prefer as discussed below "Why I'm sure Testing induced IPSCs will be safe" Most with some background recognize that induced means IPSCs. But likely in blog context very few.

 

Embryonic stem cells have great potential, but tag along issues and concerns. Further, they are not proven as therapeutics in any venue to a such a degree that safety, efficacy, cell pharmacobiolgy are a given and human studies inevitably, even if the issue was not in part FDA restrictions. Generally speaking their role for tissue engineering for a given disease, is not define. What is defined is complete competency for growth and differentiation potential that is unlimited. That is certainly exciting, but that is just a start. Were we discussing a novel cancer drug this early in development it would not even be on the radar. For ESCs it is the potential that lies ahead that generates the excitement.,


Adult stem cells are further along in all aspects including clinical studies and applications. They are indeed safe and there has never been evidence otherwise. These days it seems every nextgen biotech or group is using a every stem cell for every purpose without rationale or basis. Indeed, it sometimes looks like like a mix and match with more approaches then successes. Nonetheless, despite two decades of great researcher that goes by to Weisman et al. in the early 90s, these cells only get the attention they deserve because in the appropriate venue they constantly produce. Stem cells work well when used in tissues from which they were derived. Adult stem cells are a prevent entity. 

 

I have no interest at this time in STAPs and will let others provide the proof of concept with actual R&D and developmental research to put these stem cells on my radar.

 

Regarding IPSCs, biology behind the induction of a human pluriopotent stem cell is indeed remarkable and has led to a much better understanding of underlying biology. On the one hand I think that sometimes we forget that half of why so much excitement revolves around them is the fact that ESCs can be avoided.  This an issue for some because the NIH will not fund ESC research  in general, and thus this bypassed a big problem.  For others because of the ethical issues that exist here given one's respective perspective. But I don't know we can say much about these cell just yet beyond the what we know from early studies and modeling. To think that we can approximate the infinitely complex biology of ESCs is ridiculous. To think that the artificial biology induced in an aged somatic cell with telomere biology associated with aging, with more exposure to toxins and DNA damaging agents simply because it its has been here longer and exposed more frequently (such as sunburns, much less real oncogenic toxins), and to think that he biology itself is definitive, retains the same developmental biology programs and patterns as ESCs of blastocyst development in uteror,  is not possible to say just yet as a historical fact.  

 

In the long term, IPSCs may not be the best choice for regenerative medicine. These stem cells, need years of research, long term outcomes studies, understanding of genomic stabity and phenotypic stability, and simply put much more developmental R&D. I am not putting any negativity into IPSC approaches. I just have always been more comfortable with naturally occurring stem cell sources whose biology is well understood. If one day that meant ESCs research may need to supported in this respect so be it. Time and understanding will get us there eventually. 

 

Nonetheless, I will be glad to see the data begin to stack up from more  and more animal and human studies with IPSCs and the truth of what lies in the future for IPSCs is in theses studies, not in opinons.

 

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Jacob Blumenthal's curator insight, February 6, 2014 3:02 AM

This is an interview with Masayo Takahashi about the first ever human clinical trial of induced pluripotent stem cells (iPSC). In this clinical trial skin cells will be taken from age-related macular degeneration patients, and will be reprogrammed into iPSC. These iPSC will be then differentiated into retinal pigment epithelium (RPE) cells in-vitro. The differentiated cells will be introduced back to the eyes of the patients.

Learn more about RPE cells:

http://discovery.lifemapsc.com/in-vivo-development/eye/retinal-pigmented-epithelium/mature-retinal-pigmented-epithelium-cells


Learn more about stem cells differentiation:

http://discovery.lifemapsc.com/stem-cell-differentiation


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Standartization issues to be taken care for the development of cell therapy products

Standartization issues to be taken care for the development of cell therapy products | Stem Cell Regenerative Medicine | Scoop.it
To manufacture stem cells for cell therapy, standards for other materials critical for the cells' growth and survival must also be considered. (Do you know what ancillary materials are needed in order to manufacture a cell therapy?

Via Ella Buzhor
Christopher Duntsch's insight:

As a real world example, without naming the companies, at this time, there are two adult stem cell biotechnology companies that are very similar and of interest, pursuing the treatment of the same disease process and tissue anatomy. Company A is US based, and has the benefit of 8+ years of research, volumes of R&D and results / data, and all its data, IP, and outcomes, are documented, patented, and published. Company A has a more relevant / appropriate stem cell therapeutic, approach, and dose. Company A doses the tissue and disease process with 5 - 10*4 stem cells, and reports efficacy that ranges from 95% - 100%, and averages around 97% in all studies, and safety profiles that collectively considered to be near 100%. Conversely, company B is based in a very different geographic locale, and has fast tracked its R&D from literally announcing its intent, to entering clinical studies in less than 2 years. Company B has very little data to support its stem cell therapeutic, dosing, and approach. Company B doses the tissue and disease process with 5 x 10*7 cells (roughly 1000X higher than company A), and reports efficacy in some studies that is ~1-5%, and without detail admits in other studies no efficacy at all, and finally, reports a safety profile that is roughly 80 -90%. Company B is regulated in a very different area in the world and in a manner that is not rigorous, efficient, or consistent. Despite the dramatic differences between the two, company B continues to release financial reports, and press, that are positive and suggest present growth and real potential for growth going forward. Even more confusing, their valuation within the stock market they are publicly traded in, and public opinion of the company in general, by the public, current investors, and market analysts, remains stable, and at times even positive, and give the company a high valuation. These groups seem to be easily manipulated by efforts by the company to downplay negatives, explain away these results, and maintain a strong marketing front. I make the comparison here, to point out the relevance of my comments above for Pluristem Tx which similar in many respects to Company B, and to compare both to company A, US Biotec

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Carlos Garcia Pando's curator insight, January 23, 2014 4:18 AM

Wherever Standartization appears it means there is going to be a widespread industrialization process, and that there are already strong stake holders wanting to have an advantaged position to start the race.

 

But this is good for the industry in general.

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Pluristem stem cell trial to treat muscle injury meets main goal

Pluristem stem cell trial to treat muscle injury meets main goal | Stem Cell Regenerative Medicine | Scoop.it

Pluristem Therapeutics Ltd. (Nasdaq:PSTI; TASE: PLTR) today published the results of the efficacy and safety study, after six months of monitoring, in the Phase I/II clinical trial testing the safety and efficacy of PLacental eXpanded (PLX-PAD) cells in the treatment of muscle injury.


Via Ella Buzhor
Christopher Duntsch's insight:

Always glad to see clincal trials of any kind for adult stem cells, human pluripotent stem cells, and atypical stem cells types such as MSC, adipose stem cells, amniotic stem cells, and even placental stem cells. No matter what type of stem cell therapeutic, and what clinical being studied there is always something to learn.  That being said and I not terribly impressed with this report. My reasons are simply that results given are vague, without background,  statistics, protocols, and a closer look makes appear likely that these results may be simply taking what data they could document, and using that and the always newsworthy "Phase1/11 terminology" that implies much more.  First, a review of what I can find for this company, and its weblinks and communications, from a distance look more like a financially driven investor targeted valuation driver. Second, unless one looks deeper, the relevance of an isreal based stem cell company that is doing its studies in europe and elsewhere, with details about developemental studies to that paved the way into humans, regulatory guideline and standards met to go into humans, the rationale for a placenta stem cell therapeutic, the general pattern of finiding disase models first and then attempting to treat them with placental stem cells over and over, the lack of detail, literature, published patents, or at least the appearance that the company does not see value in providing links to these if they exist, the very vague and nondescript detail given for the model, the stem cell therapeutic and how it is delivered, a definition of their positive data and safety data that has meaning to the reader, and many more issues that make this report more  hype than anything. I can learn nothing from this report, or links that I can find to the company and other reports. I am not intentionally being negative, but without some rationale for all aspect of the company and its stem cell biologics and therapeutics, and without a real effort to be very transparent about all data, IP, patents, literature, etc, that the company would use a correlative for value and potential, again ... this becomes another "stem cell communication hype' that easily gets patients and those not well versed in this area excited and hopeful in a manner that is not the best approach for any group, whether academic, startup biotech, or funded and on the commerical end of the spectrum.

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Ella Buzhor's curator insight, January 22, 2014 3:20 PM

PLX-PAD cells fount to be safe and the primary efficacy endpoint of the study was reached. Patients treated with PLX-PAD had a greater improved change of maximal voluntary muscle contraction force than the placebo group. PLX cells may be beneficial for muscle and tendon injuries therapy.

Christopher Duntsch's curator insight, January 25, 2014 10:23 AM

In response to a question in another comment regarding outcome and its relation to the dose of the stem cell therapeutic.  First, I would not read to much into this issue as reported here, because dosing cannot be defined without the report providing more information. Further, although it may very with the disease model, stem cell therapeutics dosed in amounts that are in the range of 10M - 1000M, should be looked at with suspect. The reason, stem cells of all types, by definition, have unlimited growth potential, and indeed when crowded lose their stem cell phenotype. In my experience, when companies or RD groups use such high numbers, it more often than not indicates that early studies gave poor efficacy with lower doses and thus they increased the dose more and more to get some response of interest. Indeed putting viable cell type into any animal tissue or model in large numbers as in this case, could very easily result in cell biology at the target site for therapy, which artificially creates a scenario in which the so called safe data, or even efficacy reported, is a result of the known effect on a cell population when crowded, especially the context of damaged tissue which will significant inflammation and a myriad of cytokines that more likely than not will signal the cells in some manner and effect the results. Again, appearing to have biologic effect on the treated model, but false positives and false negatives instead. Most of the RD groups and the results reported in stem cell therapeutics for tissue engineering of a given disease process, in which the stem cell product is very officious, are dosing in numbers that range from 0.1% - 15% of the lowest dose the group reports using. Finally, at risk of sounding negative, their reporting of a better outcome with lower doses, actually is intuitive based on the above other stem cell paradigms.  Namely, the lower the dose, generally speaking, and the closer the dose comes to reaching an ideal value, the better the results. An example for clarification, would a therapeutic agent (X), that has properties that are directly related to the biology it influences, and that has an ideal dose to achieve the maximal efficacy and safety, but conversely is safe but less efficacy as the doses are decreased, and less effective as the dose exceed the ideal because the high dose override the natural biology that the agent influences, and begin to cause other biologic events that harm the cell. For example, no effect at the nanomolar and micromolar doses but safe nonetheless, ideal efficacy and good safety at millimolar dosing, then reverse in the amount efficacy as the dose is exponentially increased, while at the same increases amounts of toxicity.  This is a well understood part of the pharmacology of any small or macromolecule therapeutic, or the pharmacobiology of any stem cell therapeutic.  

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UCLA stem cell researchers track early development of human articular cartilage

Stem cell researchers from UCLA's Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have published the first study to identify the origin cells and track the early development of human articular cartilage, providing what...

Via Jacob Blumenthal
Christopher Duntsch's insight:

Foundation building, a valid, solid, and smart approach to building a genomic, epigenetic / TF factor and gene target cohesive model, stem cell and progenitor and cell biology paradigm, cell proliferation, migration, maturation, differentiation biologic, and all the intracellular and extracellular machinery that take a chaotic mass of cells and polymers and matrix and the like, and pull it together into ever increasing layers of organization best known as tissue fabrication.


This occurs as a first step to a complex end. Biomechanical forces, ECM and Cell Cell contact, polymer matrix biology, morphogens, and neighboring cells and tissues, all are a player in this. From pre-tissue a tissue forms, but not fully mature, certainly not functional, until much more occurs  Tissue remodeling, and structure function development of the first product of the effort described above are both needed and strategically part of the biology. 


Recreating said modeling as above, for cartilage development, whether static, structural, dynamic, or functional, will be an equally difficult and equally important first step for stem cell biology and cell biology of cartilage development into first tissue then structure and function. A first step nonetheless, but a milestone that cannot be bypassed.  That being a developmental biology model, integration of stem cell biology, and extrapolating from cells and molecular machines, to a full understanding at all levels what transpired to create the tissue or organ in question with its architecture, function, and purpose.


This may sound a like a lot to do about nothing, but while this is a foundation for next gen therapeutics, the translation from in vivo foundational studies and knowledge derived therein, to a stem cell based tissue engineered regenerative product of real substance, safety, efficacy  practicality, etc, once done well, is the single biggest challenge the stem cell biologist and tissue engineering scientist face in every aspect of animal biology at every level, in healthy and disease, in young and in old.


And why might that be. The answer why does not need to be sought long to be given. It is a simple matter to observe that a true in vitro 3D complex functional stem cell based biologic device with matrix biology and tissue engineering integrated into the system, and at the same time the overlay of cell biology paradigms that serve to lead the way for all yet do not exist until understood,  architected, and implemented by the scientist.


Only for these UCLA researchers and others now and that follow, they do not have the advantage of God's infinite science, nor that of the uncountable mistakes that occurred as building blocks of randomness came together every 600th time they interacted, and over 4 billion years, eventually created unimaginable intelligent design.  Indeed, the challenge is taking what has been learned, and what is known as well, and combining that with technologies and biomaterials from the tissue of interest, from surrogate molecules and matrix biology (both living, synthetic  and inert), and combining all into a 3D structure static and dynamical properties, architecture that gives function by design, and as above, the overlay of a near invisible yet all powerful cell biology protocol set that is the driver of the machine.

 

Compared to the foundational and translational studies that are so complex, slow to develop, and slow to translate, I think we will see a rapid acceleration in scientific and medical breakthroughs as the milestones of the first two phases slowly are reached.  However, this is more likely if there efforts parallel the scientific methods and a team effort for all those academic and commercial, scientific and clinical.  If the intent and drive is there, and the research is done well, then the final key biologic is that of the in vitro transition phase. Meaning integrating the biology of the biotechnology created into the human condition for disease or other clinical purpose should be similar to the inherent self driven and all knowing developmental biology of the foundation.


The nobel prize medicine here is in two areas, the early discovery science of the foundation, and all aspects of in vitro translation to human application.  That is something most don't quite grasp in the current day.

 

Christopher Duntsch, MD, PhD

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Jacob Blumenthal's curator insight, December 13, 2013 10:47 AM

Researchers from UCLA found that  recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) is a more efficient way to generate articular cartilage thenusin adult stem/progenitor cells. They published their findins in "Stem Cell Reports": http://www.cell.com/stem-cell-reports/abstract/S2213-6711(13)00124-0


To learn about the embryonic development of articular cartilage:

http://discovery.lifemapsc.com/in-vivo-development/cartilage


Rescooped by Christopher Duntsch from Tools and tips for scientific tinkers and tailors
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Gene-Set Analysis is Severely Biased When Applied to Genome-wide Methylation Data

Gene-Set Analysis is Severely Biased When Applied to Genome-wide Methylation Data | Stem Cell Regenerative Medicine | Scoop.it
@AliciaOshlack unrelated I just noticed you were senior author on GOseq. Did you ever see this http://t.co/AKj2QshKU0? Any thoughts?

Via Mel Melendrez-Vallard
Christopher Duntsch's insight:

Modeling DNA methylation and gene reguation that is tightly assoicated by largely unknown biomechanisms, a component of epigenetic biology, to identify and quantify detection and presumed interpretation bias of current genomicd assay and analysis of gene expression, is complicated challenge from start to finish. Identifying and quantifying the existence and nature of the bias respectfully, and relating that to biologic models in vitro, Implementation of internal or defined controls for methylation and demethylation states, for normal cells and pathologic or diseased cells, etc., and with all tightly related to changes in gene expression regulation know to occur, will collectiively allow scientists to bridge the gap by making biomathatic modeling of these well characterized models and controls at the molecular, cellular, and system genotype - phenotype level. This approach starts with defining the biology in detail, and working forward to use that for creating biomathmatic models, then working backwards form the biologics into the biomath, demonstrating precision and accuracy. With this accomplished, existing computational algorithims and assay / analysis technolgy for genomic expression studies and bioinformatics can be used to create modified computer algorithims, and modified assay / analysis technologies. Eventually all can be combined into one platform streamling genomics that is more comprehensive and relevant biologcally and genomic, gene expression, and phenotype levels..

 

 

 

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Science Documentary: Stem Cells,Regenerative Medicine,Artificial Heart,a future medicine documentary

Science Documentary: Stem Cells,Regenerative Medicine,Artificial Heart,a future medicine documentary In each and every one of our organs and tissue, we have ...
Christopher Duntsch's insight:

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

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Instructive Supramolecar Scaffolds for In Situ Cardiovascular Tissue Engineering

In-situ cardiovascular tissue engineering offers tremendous benefits to the field of regenerative medicine. The technology aims at the implantation of a synt...
Christopher Duntsch's insight:

(See below for a link to supplementary data, and an excellent review that is comprehensive for this topic)

 

A part from blood cells, most, if not all other, normal cells in human tissues are anchorage-dependent residing in a solid matrix called extracellular matrix (ECM). There are numerous  types of ECM in human tissues, which usually have multiple components and tissue-specific composition. Readers are directed to detailed reviews for types of ECM and their tissue-specific composition. As for the functions of ECM in tissues, they can be generally classified into five categories. ECM provides structural support and physical environment for cells residing in that tissue to attach, grow, migrate and respond to signals. ECM gives the tissue its structural and therefore mechanical properties, such as rigidity and elasticity that is associated with the tissue functions. For example, well-organized thick bundles of collagen type I in tendons are highly resistant to stretching and are responsible for the high tensile strength of tendons.

 

On the other hand, randomly distributed collagen fibrils and elastin fibers of skin are responsible for its toughness and elasticity. ECM may actively provide bioactive cues to the residing cells for regulation of their activities. For examples, the RGD sequence on fibronectin triggers binding events while the regular topological pattern stimulates preferred alignment of cells. ECM may act as reservoir of growth factors and potentiate their bioactivities. For example, heparin sulfate proteoglycans facilitate bFGF dimerization and thus activities. ECM provides a degradable physical environment so as to allow neovascularization and remodeling in response to developmental, physiological and pathological challenges during tissue dynamic processes namely morphogenesis, homeostasis and wound healing, respectively.

 

Intuitively, the best scaffold for an engineered tissue should be the ECM of the target tissue in its native state. Nevertheless, the multiple functions, the complex composition and the dynamic nature of ECM in native tissues make it difficult to mimic exactly. Therefore, contemporary concept of scaffolding in tissue engineering is to mimic the functions of native ECM, at least partially. As a result, the important roles played by scaffolds in engineered tissues, as reviewed elsewhere, are analogous to the functions of ECM in native tissues and are associated with their architectural, biological, and mechanical features.. Let us consider these functions and features as follows:

 

Architecture: Scaffolds should provide void volume for vascularization, new tissue formation and remodeling so as to facilitate host tissue integration upon implantation. The biomaterials should be processed to give a porous enough structure for efficient nutrient and metabolite transport without significantly compromising the mechanical stability of the scaffold. Moreover, the biomaterials should also be degradable upon implantation at a rate matching that of the new matrix production by the developing tissue. Cyto- and tissue compatibility: Scaffolds should provide support for either extraneously applied or endogenous cells to attach, grow and differentiate during both in vitro culture and in vivo implantation. The biomaterials used to fabricate the scaffolds need to be compatible with the cellular components of the engineered tissues and endogenous cells in host tissue. Bioactivity: Scaffolds may interact with the cellular components of the engineered tissues actively to facilitate and regulate their activities. The biomaterials may include biological cues such as cell-adhesive ligands to enhance attachment or physical cues such as topography to influence cell morphology and alignment. The scaffold may also serve as a delivery vehicle or reservoir for exogenous growth-stimulating signals such as growth factors to speed up regeneration. In this regard, the biomaterials need to be compatible with the biomolecules and amenable to an encapsulation technique for controlled release of the biomolecules with retained bioactivity. For example, hydrogels synthesized by covalent or ionic crosslinking can entrap proteins and release them by a mechanism controlled by swelling of the hydrogels. Mechanical property: Scaffolds provide mechanical and shape stability to the tissue defect. The intrinsic mechanical properties of the biomaterials used for scaffolding or their post-processing properties should match that of the host tissue. Recent studies on mechanobiology have highlighted the importance of mechanical properties of a scaffold on the seeded cells. Exerting traction forces on a substrate, many mature cell types, such as epithelial cells, fibroblasts, muscle cells, and neurons, sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. This mechanosensitivity has also been demonstrated in the differentiation of MSC,  when stiffness of the agarose gel would determine the differentiation tendency. The hMSC would differentiate along the neuronal, muscle, or bone lineages according to stiffness that approximate those of the brain, muscle, and bone tissues, respectively. 

 

--------------------

 

 For relevant figures and tables … 

 

http://www.slideshare.net/christopherduntsch/supplmentary-to-the-niche-matrix-tissue-engineering-discussion 

 

------------------

 

IN TISSUE ENGINEERING, GENERAL APPROACHES, MICROENVIRONMENT, TISSUE - SPECIFIC CONSIDERATIONS.  

 

-----------------

          

BP Chan and KW.Leong

 

-------------           

 

Eur Spine J. 2008 Dec; 17(Suppl 4): 467–479.           

 

-------------------

 

doi:10.1007/s00586-008-0745-3

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Orthopedic Regeneration With a Combination of Stem Cells, Gene ...

Orthopedic Regeneration With a Combination of Stem Cells, Gene ... | Stem Cell Regenerative Medicine | Scoop.it
The Duke team led by Farshid Guilak, director of orthopedic research at Duke University Medical Center, used gene therapy to make stem cells that synthesize their own growth factors. In brief, Guilak and his collaborators used genetically ...
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Decellularized thymus scaffolds for thymus tissue engineering - John Jackson


Via Jacob Blumenthal
Christopher Duntsch's insight:

This is not a new concept that should be aggressively developed and pursued.  Their are two tracks upon which this concept is traveling. One track is to artificially create in vitro a 3D scaffold for this purpose using current scaffold and matrix technology.  The second is to harvest organs or tissues and modify them in vitro for tissue engineering applications. A tissue is harvested, and biochemical and biophysical methodology are used to completely remove all of the donor tissue's biomaterial, with one exception. The final product is a shell of the former, and consists of the natural scaffold the tissue or organ originally possessed.  It is then used in vitro to build a new organ or tissue,  by seeding it with stem cells and other byproducts  over time, until a new organ or tissue is created for use in humans as part of tissue engineering and regenerative medicine approaches. Immunobiology and immunoreactivity are less of a challenge to overcome here because: the natural scaffold is not immunoreactive, and chemical modifications during preparation of the scaffold are even more protective; most stem cells that might be strategic for this approach demonstrate immunoprivilige or biology that suppresses immunoreactions; and finally, because this approach is one in which a patient's own stem cells would be a good donor source.

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Jacob Blumenthal's curator insight, February 10, 2014 12:31 PM

A very interesting talk by John Jackson from Wake Forest Institute for Regenerative Medicine on tissue engineering of the thymus using decellularized thymus scaffolds.

 

Stem Cells and Tissue Engineering scoops also in Facebook:

https://www.facebook.com/groups/STEMCELLSNET/

 

 

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Stimulus-triggered fate conversion of somatic cells into pluripotency - Nature

Stimulus-triggered fate conversion of somatic cells into pluripotency - Nature | Stem Cell Regenerative Medicine | Scoop.it

Via Jacob Blumenthal
Christopher Duntsch's insight:

This is fascinating and also just bizarre. Human Pluripotent Stem Cells by defintition iare getting more complex, more random. That does not mean the biology is not there, the approach does not work, but I am most happy when stem cell approaches are well studied, well defined, and rigorous. I do not think much of ESCs or IPSCs (or MSCs) for many reasons both obvious and subtle, but the stem cell biology is amazing. I remember when the first nature article was reported where skin cells were injected with OCT4, NANOG, STAT3, KLM5, and CMyc? That event led to the hypothesis that ESC biology was held in the master transcriptional regulators, especially NOS and NOS genes.  Then other approaches accomplished the same, such as simple epigenetic engineering. Small molecuale induction, culture conditions with modificatoins, etc. But this is just wild.I have not seen the article, and I am sure they do a good job explaining their results, but off the cuff I cannot imagine how this works. Acidic pH is not a strong stressor in my opinion, and I cannot extropolate biology from in vivo modeling to help me think about this (except intradiscal), but it is quite striking if true. Indeed, it is almost as if all those times while culturing cells and forgetting to change the media (with a drop in pH), I was making IPSCs. (bad humor) My only comment is to not get to excited just yet because they do not do much other than some basic assays to show ESC biology occuring.  A good start though. But still an unexpected and exciting response. I wish I had thought of that!

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Jacob Blumenthal's curator insight, January 30, 2014 1:14 AM

Researchers from Harvard medical school, report on a new method for generation of induced pluripotent stem cells (iPSC). This method is termed stimulus-triggered acquisition of pluripotency or STAP. The researchers suggest that a strong external stimuli such as a transient low-pH stressor can induce reprogramming of mammalian somatic cells, into  pluripotent cells. This could be a very big breakthrough in generation of iPSCS, that until now required nuclear transfer or introduction of transcription factors.

Reference: http://www.nature.com/nature/journal/v505/n7485/full/nature12968.html

 

Leran more about stem cells:

http://discovery.lifemapsc.com/stem-cell-differentiation

 

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Rescooped by Christopher Duntsch from Cell Therapy & Regenerative Medicine
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Pluristem stem cell trial to treat muscle injury meets main goal

Pluristem stem cell trial to treat muscle injury meets main goal | Stem Cell Regenerative Medicine | Scoop.it

Pluristem Therapeutics Ltd. (Nasdaq:PSTI; TASE: PLTR) today published the results of the efficacy and safety study, after six months of monitoring, in the Phase I/II clinical trial testing the safety and efficacy of PLacental eXpanded (PLX-PAD) cells in the treatment of muscle injury.


Via Ella Buzhor
Christopher Duntsch's insight:

In response to a question in another comment regarding outcome and its relation to the dose of the stem cell therapeutic.  First, I would not read to much into this issue as reported here, because dosing cannot be defined without the report providing more information. Further, although it may very with the disease model, stem cell therapeutics dosed in amounts that are in the range of 10M - 1000M, should be looked at with suspect. The reason, stem cells of all types, by definition, have unlimited growth potential, and indeed when crowded lose their stem cell phenotype. In my experience, when companies or RD groups use such high numbers, it more often than not indicates that early studies gave poor efficacy with lower doses and thus they increased the dose more and more to get some response of interest. Indeed putting viable cell type into any animal tissue or model in large numbers as in this case, could very easily result in cell biology at the target site for therapy, which artificially creates a scenario in which the so called safe data, or even efficacy reported, is a result of the known effect on a cell population when crowded, especially the context of damaged tissue which will significant inflammation and a myriad of cytokines that more likely than not will signal the cells in some manner and effect the results. Again, appearing to have biologic effect on the treated model, but false positives and false negatives instead. Most of the RD groups and the results reported in stem cell therapeutics for tissue engineering of a given disease process, in which the stem cell product is very officious, are dosing in numbers that range from 0.1% - 15% of the lowest dose the group reports using. Finally, at risk of sounding negative, their reporting of a better outcome with lower doses, actually is intuitive based on the above other stem cell paradigms.  Namely, the lower the dose, generally speaking, and the closer the dose comes to reaching an ideal value, the better the results. An example for clarification, would a therapeutic agent (X), that has properties that are directly related to the biology it influences, and that has an ideal dose to achieve the maximal efficacy and safety, but conversely is safe but less efficacy as the doses are decreased, and less effective as the dose exceed the ideal because the high dose override the natural biology that the agent influences, and begin to cause other biologic events that harm the cell. For example, no effect at the nanomolar and micromolar doses but safe nonetheless, ideal efficacy and good safety at millimolar dosing, then reverse in the amount efficacy as the dose is exponentially increased, while at the same increases amounts of toxicity.  This is a well understood part of the pharmacology of any small or macromolecule therapeutic, or the pharmacobiology of any stem cell therapeutic.  

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Ella Buzhor's curator insight, January 22, 2014 3:20 PM

PLX-PAD cells fount to be safe and the primary efficacy endpoint of the study was reached. Patients treated with PLX-PAD had a greater improved change of maximal voluntary muscle contraction force than the placebo group. PLX cells may be beneficial for muscle and tendon injuries therapy.

Christopher Duntsch's curator insight, January 25, 2014 8:40 AM

Always glad to see clincal trials of any kind for adult stem cells, human pluripotent stem cells, and atypical stem cells types such as MSC, adipose stem cells, amniotic stem cells, and even placental stem cells. No matter what type of stem cell therapeutic, and what clinical being studied there is always something to learn.  That being said and I not terribly impressed with this report. My reasons are simply that results given are vague, without background,  statistics, protocols, and a closer look makes appear likely that these results may be simply taking what data they could document, and using that and the always newsworthy "Phase1/11 terminology" that implies much more.  First, a review of what I can find for this company, and its weblinks and communications, from a distance look more like a financially driven investor targeted valuation driver. Second, unless one looks deeper, the relevance of an isreal based stem cell company that is doing its studies in europe and elsewhere, with details about developemental studies to that paved the way into humans, regulatory guideline and standards met to go into humans, the rationale for a placenta stem cell therapeutic, the general pattern of finiding disase models first and then attempting to treat them with placental stem cells over and over, the lack of detail, literature, published patents, or at least the appearance that the company does not see value in providing links to these if they exist, the very vague and nondescript detail given for the model, the stem cell therapeutic and how it is delivered, a definition of their positive data and safety data that has meaning to the reader, and many more issues that make this report more  hype than anything. I can learn nothing from this report, or links that I can find to the company and other reports. I am not intentionally being negative, but without some rationale for all aspect of the company and its stem cell biologics and therapeutics, and without a real effort to be very transparent about all data, IP, patents, literature, etc, that the company would use a correlative for value and potential, again ... this becomes another "stem cell communication hype' that easily gets patients and those not well versed in this area excited and hopeful in a manner that is not the best approach for any group, whether academic, startup biotech, or funded and on the commerical end of the spectrum.

Rescooped by Christopher Duntsch from Stem Cells & Tissue Engineering
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Bioactive Scaffolds for the Controlled Formation of Complex Skeletal Tissues | InTechOpen

Bioactive Scaffolds for the Controlled Formation of Complex Skeletal Tissues | InTechOpen, Published on: 2011-08-29. Authors: Sandra Hofmann and Marcos Garcia-Fuentes

Via Jacob Blumenthal
Christopher Duntsch's insight:

This is a good review and report of what is trending now in tissue engineering. The push early was therapies with cells derived from mature tissue, or tissue sections from mature tissues, that were transferred into a degenerated, damaged, or diseased tissue with the hope of some sort of therapeutic or regenerative healing or reversal of the disease process. There are a few exceptions, but this approach never worked well in vitro, in vivo in animals, much less in the clinical studies that followed. The shift to stem cell technologies was a paradigm shift and in the right direction, but still there has not been a great deal of success using stem cell therapies in isolation. There are rare exceptions as always (HSCs and BM transplants).

 

Years ago and even more so recently, the definition of tissue engineering, has changed significantly. There are now so called core components, and is agreed by most that the ‘sum of the parts are greater than the "whole". In the most basic sense, I would think it could be simplified to 1) a stem cell product or therapeutic 2) support factors of many types … growth factors, nutrients, supplements, etc., 3) a 3D scaffold of some type.

 

This article keys in on successes that have begun to be seen in the scientific literature as of late. Namely, that in addition to the above, one must consider the impact of stem cells as before, but also of progenitor cells, changes in phenotype that are smart and strategic and also in line with fundamental biology, and for lack of a better word for it, developmental biology.  In any normal solid organ, there is a rare but immortal adult stem cell population, and that stem cell is quiescent most often, at least in a healthy state. However, inflammation and other molecular events that occur with disease and damage and degeneration can push quiescent stem cells to asymmetrically give off early progenitors. These are the machines of tissue development, as they are of effective regenerative medicine.

 

As early progenitors mature, they change in phenotype, lose stem cell phenotypy, and gain terminal lineage phenotypy. Eventually, as cells proliferate and migrate and fill a tissue niche, they crowd and mature and secrete ECM and enzymes.  EC enzymes such as MMPs, and Cell surface adhesion molecules and receptors, interact with ECM such as proteoglycans and glycosaminoglycans, and eventually cells fix in space in time, communicate locally, and organize. The result is prefabricated tissue that is the infrastructure and architectural pathway to the end goal.. As this remodels continuously, the cell and tissue and the structure / architecture remodels and continues to mature and evolve.  Ideally, a relatively regenerated tissue with structure, order, and function, is left where once there was damaged or nonfunctional tissue.

 

The point of the above is that the rough approximation of developmental biology in vitro in not just important but required  for successful tissue engineering. And this requires more than the three core components mentioned. Without more detail, it is enough to simply make these descriptive comments. Despite the lack of detail for what follows, it is fairly logical to assume that an in vitro developmental biology influence is indeed a key fourth core for tissue engineering.

 

Principles of Tissue Engineering with the following four core components.

1 A stem cell that is a proven therapeutic for the treated condition.

2 A supportive mix of growth factors, small molecules, media, glucose, ECM, as indicated.

3 A synthetic or organic but biocompatible 3D scaffold, and;

4 A series of key steps, protocols, manipulations that provide a  developmental nature or influence to the biological device prior to transplant into the animal.

 

In summary, a definition of an ideal tissue engineering product: A stem cell therapeutic, seeded into a tissue engineering complex in vitro, supplemented with ECM, GFs, supplements, etc, which, after methods and protocols are carried forward correctly, results in a comprehensive biological device or structure that has the following components:

1 a retained stem cell fraction with a phenotypically correct phenotype,

2 an early progenitor fraction rapidly dividing and migrating throughout the structure, and,

3  a small late progenitor fraction that is beginning to some degree to mature to the lineage of the cells needed for the tissue treated.

 

The importance is that the biological device used for tissue engineering is: primed genetically, epigenetically, and with respect to its cell and molecular phenotype; phenotypically more effective at integrating / assimilating into the target tissue, and immediately starts to grow, mature, change, and regenerate the tissue defect or replace / treat / supplement a diseased or degenerated tissue. Makes sense.

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Jacob Blumenthal's curator insight, January 17, 2014 4:43 AM

This is an open-access book chapter entitled "Bioactive Scaffolds for the Controlled Formation of Complex Skeletal Tissues".

Also check the regenerative medicine and tissue engineering book collection:

http://www.intechopen.com/subjects/tissue-engineering-and-regenerative-medicine

 

 

Scooped by Christopher Duntsch
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Multipotent Stem Cell Proteins Support Soft Tissue Regeneration - PR Web (press release)

Multipotent Stem Cell Proteins Support Soft Tissue Regeneration - PR Web (press release) | Stem Cell Regenerative Medicine | Scoop.it
Multipotent Stem Cell Proteins Support Soft Tissue Regeneration
PR Web (press release)
In addition to "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration,” Dr.
Christopher Duntsch's insight:

2 D tissue engineering provides an effective and relevant model from which several types of cell and molecular assays can be derived. 2 D cell culture studies and tissue engineering approaches are a gateway approach to studying cell and molecular biology in biomaterials relevant to a given model of interest. 2 D tissue engineering approaches and models are relatively simple, inexpensive, high-yield, and high through put. Examples of information that can be gained includes migration and motility, differentiation, proliferation, response of a given cell type to a supplemented biologic of interest, morphologic biology, providing a source of biomaterial for molecular assays, and many others. However, it should be always kept in mind that monolayer culture is considered artificial and less biologically accurate as a microenvironment of cells in culture. Thus, 2 D studies are good for learning through research in a rapid and inexpensive manner, but all results should be validated in 3 D in vitro assays, and if not in animal models, then in complex in vitro bioreactor systems with laminar fluid dynamics, and antigravity, mechancial agitation technology.  These systems, when combined with stem cell biology, tissue engineering, matrix science, and 3D tissue regenerative med, can indeed efficientlly create tissue structures ex vivo.

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