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Multifunctional Biomimetic Scaffolds Tailored for Cardiac Regeneration
Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nature has had millions of years to perfect the structural components of the human body, but has also produced the dysfunctions that result in the cancers and diseases, which ruin that perfection. Congenital heart defects, and myocardial infarction lead to scarring that remodels heart muscle, decreasing the contractility of the heart, with profound consequences for the host. Regenerative medicine is the study of strategies to return diseased body parts to their evolutionarily optimum structure.

Nature has had millions of years to perfect the structural components of the human body, but has also produced the dysfunctions that result in the cancers and diseases, which ruin that perfection. Congenital heart defects, and myocardial infarction lead to scarring that remodels heart muscle, decreasing the contractility of the heart, with profound consequences for the host. Regenerative medicine is the study of strategies to return diseased body parts to their evolutionarily optimum structure. Cells alone cannot develop into functional tissue, as they require mechanical support and chemical signals from the extracellular matrix in order to play the correct role in the body. In order to imitate the process of tissue formation optimized by nature, scaffolds are developed as the architectural support for tissue regeneration. To mimic the elasticity and strength seen in the heart muscle is one of the major scientific conundrums of our time. The development of new multifunctional materials for scaffolds is an accepted solution for repairing failing heart muscle. In this thesis I accept the notion that endogenous cardiac cells can play a major role in addressing this problem, if we can attract them to the site of defect or injury and make them proliferate. I then proceed to show how improving on a commonly used synthetic polymer was used to develop two new biomaterials.

Polycaprolactone (PCL) fibers and sheets were studied for their ability to adsorb proteins based on their surface energies. We found that although the wettability of the PCL might be similar to positive controls for cell attachment, the large differences in surface energies may account for the increased serum protein adsorption and limit cell adhesion. The effect of fiber morphology was then investigated with respect to proliferation of mesenchymal stem cells and cardiac progenitor cells. PCL was also mechanically enhanced with thiophene conjugated single walled carbon nanotubes (T-CNT); where small concentrations of the T-CNT allowed for a 2.5 fold increase in the percentage of elongation, while retaining the proliferation profile of the cardiac progenitor cells. Although PCL is a well-known implant material, the ability to attract and adhere cardiac cells was limited. Therefore we sought to develop new biomaterials with fiber morphologies similar to the muscle fiber of the heart, but with surface energies similar to positive controls for cell attachment. Poly[2,3-bis-(3-octyloxyphenyl)quinoxaline-5,8-diyl-alt-thiophene-2,5-diyl] (TQ1) was then explored as a ribbon fiber and compared to collagen with embryonic cardiac cells, in vitro, and then implanted into rats for in vivo long term evaluations. The cardiac cells had a preferential adhesion to the TQ1 fibers, and in vivo, the fibers attracted more blood vessels and regrew functional tissue compared to the collagen controls. TQ1 fibers had the added ability to emit light in the near infrared region, which would allow for consistent tracking of the material. Although this material offered the morphological preference for the cardiac cells, it does not degrade and nor did it offer electrical conductivity. The heart muscle is an electrically active muscle. The dead tissue that is formed in the ischemic area loses its ability to  transfer the electrical signals. Hence, I have then developed collagen fibrous materials with silver nanowires to help store and inject charges that would be generated during the contraction of the heart muscle. The silver nanowires served to help carry charges whilst providing resistance to bacterial growth on the material. The collagen/silver nanowires composites were mechanically apt for the culture of embryonic cardiac cells.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. , 80 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1686
National Category
Physical Sciences Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-120773DOI: 10.3384/diss.diva-120773ISBN: 978-91-7519-021-1 (print)OAI: oai:DiVA.org:liu-120773DiVA: diva2:848329
Public defence
2015-08-28, Planck, Fysikhuset, Campus Valla, Linköping, 09:15 (English)
Opponent
Supervisors
Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2017-01-11Bibliographically approved
List of papers
1. Polycaprolactone–thiophene-conjugated carbon nanotube meshes as scaffolds for cardiac progenitor cells
Open this publication in new window or tab >>Polycaprolactone–thiophene-conjugated carbon nanotube meshes as scaffolds for cardiac progenitor cells
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2014 (English)In: Journal of Biomedical Materials Research. Part B - Applied biomaterials, ISSN 1552-4973, E-ISSN 1552-4981, Vol. 102, no 7, 1553-1561 p.Article in journal (Refereed) Published
Abstract [en]

The myocardium is unable to regenerate itself after infarct, resulting in scarring and thinning of the heart wall. Our objective was to develop a patch to buttress and bypass the scarred area, while allowing regeneration by incorporated cardiac stem/progenitor cells (CPCs). Polycaprolactone (PCL) was fabricated as both sheets by solvent casting, and fibrous meshes by electrospinning, as potential patches, to determine the role of topology in proliferation and phenotypic changes to the CPCs. Thiophene-conjugated carbon nanotubes (T-CNTs) were incorporated to enhance the mechanical strength. We showed that freshly isolated CPCs from murine hearts neither attached nor spread on the PCL sheets, both with and without T-CNT. As electrospun meshes, however, both PCL and PCL/T-CNT supported CPC adhesion, proliferation, and differentiation. The incorporation of T-CNT into PCL resulted in a significant increase in mechanical strength but no morphological changes to the meshes. In turn, proliferation, but not differentiation, of CPCs into cardiomyocytes was enhanced in T-CNT containing meshes. We have shown that changing the topology of PCL, a known hydrophobic material, dramatically altered its properties, in this case, allowing CPCs to survive and differentiate. With further development, PCL/T-CNT meshes or similar patches may become a viable strategy to aid restoration of the postmyocardial infarction myocardium.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
Keyword
topology, carbon nanotubes, polycaprolactone, cardiac progenitor cells, electrospun meshes
National Category
Clinical Medicine Basic Medicine Physical Sciences
Identifiers
urn:nbn:se:liu:diva-111488 (URN)10.1002/jbm.b.33136 (DOI)000342963000020 ()24664884 (PubMedID)
Available from: 2014-10-19 Created: 2014-10-19 Last updated: 2017-12-05Bibliographically approved
2. Influence of Polycaprolactone Scaffold Topography on Progenitor and Mesenchymal Cell Proliferation
Open this publication in new window or tab >>Influence of Polycaprolactone Scaffold Topography on Progenitor and Mesenchymal Cell Proliferation
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Polycaprolactone (PCL) is a frequently used polymer for tissue engineering applications and has been suggested as a suitable scaffold for cardiac regeneration. PCL can be effectively procesed using electrospinning to form fibrous scaffolds with defined topographies. The topography, as well as the materials and suraface properties, signficanltly effect the performance and host response of the scaffold. We have investigated the effect of PCL scaffold topology on protein adsorption and how this translate to cell adhesion and proliferation. PCL sheets are relatively hydrophobic with a water contact angle of 72o. The surface energy of PCL (20 mJ m‐2) was obatined using the Good van OSS and Chaudhury (GvOC) method, and is in the range of many antifouling materials. Non-specific protein adsorption on PCL sheets was yet substantial (0.45 mg cm‐2) when exposed to serum. A lower protein surface concentration was seen on fibrous PCL scaffolds prepared by electrospinning, presumably as a consequence of the lower diffusion in the scaffold. Proliferation of mesenchymal stem cells and cardiac progenitor cells was significantly improved when cultured on PCL sheets pre-treated with serum, but significantly lower than for fibrous PCL scaffolds. For the latter, no significant effect of serum pretreatment was observed, indicating that for PCL, fibre dimensions and scaffold topography has a larger influence on cell adhesion and proliferation than a high surface concentration of adsorbed proteins.

National Category
Clinical Medicine Basic Medicine Physical Sciences
Identifiers
urn:nbn:se:liu:diva-120769 (URN)
Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2015-08-24Bibliographically approved
3. Near-Infrared Emitting and Pro-Angiogenic Electrospun Conjugated Polymer Scaffold for Optical Biomaterial Tracking
Open this publication in new window or tab >>Near-Infrared Emitting and Pro-Angiogenic Electrospun Conjugated Polymer Scaffold for Optical Biomaterial Tracking
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2015 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 25, no 27, 4274-4281 p.Article in journal (Refereed) Published
Abstract [en]

Noninvasive tracking of biomaterials is vital for determining the fate and degradation of an implant in vivo, and to show its role in tissue regeneration. Current biomaterials have no inherent capacity to enable tracing but require labeling with, for example, fluorescent dyes, or nanoparticles. Here a novel biocompatible fully conjugated electrospun scaffold is described, based on a semiconducting luminescent polymer that can be visualized in situ after implantation using fluorescence imaging. The polymer, poly [2,3-bis-(3-octyloxyphenyl)quinoxaline-5,8-diyl-alt -thiophene-2,5-diyl] (TQ1), is electrospun to form a fibrous mat. The fibers display fluorescence emission in the near-infrared region with lifetimes in the sub-nanosecond range, optimal for in situ imaging. The material shows no cytotoxic behaviors for embryonic chicken cardiomyocytes and mouse myoblasts, and cells migrate onto the TQ1 fibers even in the presence of a collagen substrate. Subcutaneous implantations of the material in rats show incorporation of the TQ1 fibers within the tissue, with limited inflammation and a preponderance of small capillaries around the fibers. The fluorescent properties of the TQ1 fibers are fully retained for up to 90 d following implantation and they can be clearly visualized in tissue using fluorescence and lifetime imaging, thus making it both a pro-angiogenic and traceable biomaterial.

Place, publisher, year, edition, pages
Wiley: 12 months, 2015
Keyword
biomaterials, conjugated polymers, near-infrared, angiogenesis, electrospinning
National Category
Biomaterials Science Polymer Chemistry
Identifiers
urn:nbn:se:liu:diva-120449 (URN)10.1002/adfm.201500351 (DOI)000357996600011 ()
Note

Funding Agencies|Linkoping University; Swedish Foundation for Strategic Research; Swedish Research Council

Available from: 2015-08-12 Created: 2015-08-11 Last updated: 2017-12-04
4. Electroactive biomimetic collagen-silver nanowire composite scaffolds
Open this publication in new window or tab >>Electroactive biomimetic collagen-silver nanowire composite scaffolds
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2016 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 8, no 29, 14146-14155 p.Article in journal (Refereed) Published
Abstract [en]

Electroactive biomaterials are widely explored as bioelectrodes and as scaffolds for neural and cardiac regeneration. Most electrodes and conductive scaffolds for tissue regeneration are based on synthetic materials that have limited biocompatibility and often display large discrepancies in mechanical properties with the surrounding tissue causing problems during tissue integration and regeneration. This work shows the development of a biomimetic nanocomposite material prepared from self-assembled collagen fibrils and silver nanowires (AgNW). Despite consisting of mostly type I collagen fibrils, the homogeneously embedded AgNWs provide these materials with a charge storage capacity of about 2.3 mC cm(-2) and a charge injection capacity of 0.3 mC cm(-2), which is on par with bioelectrodes used in the clinic. The mechanical properties of the materials are similar to soft tissues with a dynamic elastic modulus within the lower kPa range. The nanocomposites also support proliferation of embryonic cardiomyocytes while inhibiting the growth of both Gram-negative Escherichia coli and Gram-positive Staphylococcus epidermidis. The developed collagen/AgNW composites thus represent a highly attractive bioelectrode and scaffold material for a wide range of biomedical applications.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2016
National Category
Biomaterials Science
Identifiers
urn:nbn:se:liu:diva-131731 (URN)10.1039/c6nr02027e (DOI)000381815000038 ()27385421 (PubMedID)
Note

Funding Agencies|Linkoping University; Swedish Foundation for Strategic Research (SSF).

The previous status of this article was Manuscript and the working title was Collagen-Silver Nanowire Composites as Electrically Activeand Antibacterial Scaffolds for Embryonic Cardiac Cell Proliferation,

Available from: 2016-09-30 Created: 2016-09-30 Last updated: 2017-11-30Bibliographically approved

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