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Extracellular matrix mimetic multi-functional scaffolds for tissue engineering and biomedical applications
Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regeneration of functional tissues or complex organs via the combination of viable cells, biomimetic scaffolds, morphogenic factors, and external biophysical cues are the principle aims of Tissue Engineering (TE). TE relies on the use of artificial 3D scaffolds that can mimic the microenvironment of native tissue to harness the regenerative potential of cells. The 3D scaffold provides an appropriate structural and functional support to foster the dynamic interplay of cells and signalling molecules to facilitate the formation of functional tissue. Taking inspiration from the multi-component and multi-functional role of native extracellular matrices (ECM), scaffold engineering provides a platform to understand and integrate the critical features from micro to macro scale necessary for repair and regeneration of tissues. Scaffold engineering also enables the interconnection of TE with its sub-disciplines such as drug delivery, in vitro disease modelling, biosensors or surgical science etc., by designing appropriate multi-functional scaffolds suitable for target specific applications.

This thesis, addresses existing challenges to manipulate and customise ECM mimicking scaffolds and approaches to overcome these problems, by emphasising the importance of biomaterial design that can emulate the native ECM and potentially be tuned for tissue specific applications. Type I Collagen was functionalised with reactive methacrylate groups without altering its native triple helical structure. Methacrylated collagen (MAC) was further used as a functional building block to fabricate tuneable multifunctional scaffolds using bio-orthogonal thiol-Michael addition click chemistry by optimising several biophysical and biochemical parameters. This method provides the flexibility needed to fabricate injectable and implantable scaffolds based on the same functional components by tuning the modulus from Pa to kPa, thus rendering scaffolds suitable for use for either soft or hard tissues. The versatility of the scaffolds was evaluated by using it as pre-fabricated substrate for human corneal epithelial cells and as an injectable scaffold encapsulated with cardiac progenitor cells.

The potential of MAC serving as a building block for engineering tailored made ECM mimetic scaffolds was further demonstrated by fabricating smart multi-functional stimuliresponsive scaffolds and conductive scaffolds using a free-radical co-polymerisation technique by choosing appropriate counterparts (polymers). The co-polymerisation of MAC and N-isopropyl acrylamide (NIPAm) formed an in situ, fast gellable, dual responsive (temp and pH) hydrogel comprising covalently linked networks of collagen and thermoresponsive NIPAm polymer. The multi-functionality of these hydrogels was demonstrated as an in-situ depot-forming tunable delivery platform for proteins and small drugs and as a structural support for human skeletal muscle cells. Pyrrole as a monomer was co-polymerised with MAC resulting in MAC-polypyrrole conductive hydrogel scaffold. The utility of ECM mimetic injectable conductive hydrogel scaffold was explored as a long-term continuous glucose-monitoring sensor under physiological conditions.

Further, to overcome several challenges of Collagen such as inconsistent batch-tobatch reproducibility, risk of disease transmission, stability etc., a collagen-like-peptide (CLP) scaffold was designed as an alternative to collagen. This thesis demonstrates the use of Flexible Template Assisted Self-Assembly (TASS) of CLPs to mimic higher order collagen triple helical assembly by conjugating 38 amino acid length CLP with a multi-arm PEG maleimide template. 8-armPEG conjugated CLP (PEG-CLP) was used to fabricate robust hydrogel scaffolds using carbodiimide chemistry. The biocompatibility and potential of CLP scaffolds as an alternative to collagen was demonstrated by implanting it in mini pigs using corneal transplantation as a test bed. The bottom up-approach to assemble ECM mimetic functional peptides also allows us to design or manipulate CLPs with other bioactive motifs such as RGD or IKVAV to promote specific cell activities suitable for specific tissue regeneration.

Overall, this thesis provides a modular platform to engineer multi-functional tunable ECM scaffolds based on type I Collagen and collagen-like peptides that combines multiple structural and bio-functional features for wide range of tissue engineering applications.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. , 75 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1890
National Category
Medical Materials
Identifiers
URN: urn:nbn:se:liu:diva-142769ISBN: 9789176854051 (print)OAI: oai:DiVA.org:liu-142769DiVA: diva2:1154496
Public defence
2018-01-15, Planck, Fysikhuset, Campus Valla, Linköping, 10:00 (English)
Opponent
Supervisors
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2017-12-01Bibliographically approved
List of papers
1. Intelligent ECM mimetic injectable scaffolds based on functional collagen building blocks for tissue engineering and biomedical applications
Open this publication in new window or tab >>Intelligent ECM mimetic injectable scaffolds based on functional collagen building blocks for tissue engineering and biomedical applications
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2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 34, 21068-21078 p.Article in journal (Refereed) Published
Abstract [en]

Hydrogels comprising natural extracellular matrix (ECM) components are very attractive as scaffolds for regenerative medicine applications due to their inherent biointeractive properties. Responsive materials that adapt to their surrounding environments and regulate transport of ions and bioactive molecules manifest significant advantages for biomedical applications. Although there are many exciting challenges, the opportunity to design, fabricate and engineer stimuli-responsive polymeric systems based on ECM components is particularly attractive for regenerative medicine. Here we describe a one-pot approach to fabricate in situ fast gellable intelligent ECM mimetic scaffolds, based on methacrylated collagen building blocks with mechanical properties that can be modulated in the kPa-MPa range and that are suitable for both soft and hard tissues. Physiochemical characterizations demonstrate their temperature and pH responsiveness, together with the structural and enzymatic resistance that make them suitable scaffolds for long-term use in regenerative medicine and biomedical applications. The multifunctionality of these hydrogels has been demonstrated as an in situ depot-forming delivery platform for the adjustable controlled release of proteins and small drug molecules under physiological conditions and as a structural support for adhesion, proliferation and metabolic activities of human cells. The results presented herein should be useful to the design and fabrication of tailor-made scaffolds with tunable properties that retain and exhibit sustained release of growth factors for promoting tissue regeneration.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:liu:diva-137627 (URN)10.1039/c7ra02927f (DOI)000399722300040 ()2-s2.0-85018519019 (Scopus ID)
Note

Funding Agencies|Swedish Research Council Junior Researcher Project [621-2012-4286]; CeNano PhD student salary grant; FP7-Health-Innovation program, acronym HESUB [2-2013-601700]

Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2017-11-29Bibliographically approved
2. Functionalised type-1 collagen as a hydrogel building block for bio-orthogonal tissue engineering applications (vol 4, pg 318, 2016)
Open this publication in new window or tab >>Functionalised type-1 collagen as a hydrogel building block for bio-orthogonal tissue engineering applications (vol 4, pg 318, 2016)
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2017 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 5, no 26, 5284-5284 p.Article in journal (Refereed) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2017
National Category
Physical Sciences Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-139559 (URN)10.1039/c7tb90075a (DOI)000404868400026 ()
Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-11-02
3. Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications
Open this publication in new window or tab >>Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications
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2016 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 4, no 2, 318-326 p.Article in journal (Refereed) Published
Abstract [en]

In this study, we derivatized type I collagen without altering its triple helical conformation to allow for facile hydrogel formation via the Michael addition of thiols to methacrylates without the addition of other crosslinking agents. This method provides the flexibility needed for the fabrication of injectable hydrogels or pre-fabricated implantable scaffolds, using the same components by tuning the modulus from Pa to kPa. Enzymatic degradability of the hydrogels can also be easily fine-tuned by variation of the ratio and the type of the crosslinking component. The structural morphology reveals a lamellar structure mimicking native collagen fibrils. The versatility of this material is demonstrated by its use as a pre-fabricated substrate for culturing human corneal epithelial cells and as an injectable hydrogel for 3-D encapsulation of cardiac progenitor cells.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2016
National Category
Physical Sciences Chemical Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124491 (URN)10.1039/c5tb02035b (DOI)000367335200016 ()
Note

Funding Agencies|Swedish Research Council [621-2012-4286, 521-2012-5706]; NSERC; UOHI

Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30
4. Applications of self-assembling peptide scaffolds in regenerative medicine: the way to the clinic
Open this publication in new window or tab >>Applications of self-assembling peptide scaffolds in regenerative medicine: the way to the clinic
2014 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 2, no 48, 8466-8478 p.Article in journal (Refereed) Published
Abstract [en]

Peptides that self-assemble into well-defined nanofibrous networks provide a prominent alternative to traditional biomaterials for fabricating scaffolds for use in regenerative medicine and other biomedical applications. Such scaffolds can be generated by decorating a peptide backbone with other bioactives such as cell specific adhesion peptides, growth factors and enzyme cleavable sequences. They can be designed to mimic the three-dimensional (3D) structural features of native ECM and can therefore also provide insight into the ECM-cell interactions needed for development of scaffolds that can serve as regeneration templates for specific target tissues or organs. This review highlights the potential application of self-assembling peptides in regenerative medicine.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2014
National Category
Physical Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113073 (URN)10.1039/c4tb01095g (DOI)000345529400002 ()
Note

Funding Agencies|Swedish Research Council, Sweden [2012-42315-94008-81]

Available from: 2015-01-09 Created: 2015-01-08 Last updated: 2017-12-05
5. Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation
Open this publication in new window or tab >>Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation
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2016 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 61, 55745-55749 p.Article in journal (Refereed) Published
Abstract [en]

Extracellular matrix proteins like collagen promote regeneration as implants in clinical studies. However, collagens are large and unwieldy proteins, making small functional peptide analogs potentially ideal substitutes. Self-assembling collagen-like-peptides conjugated with PEG-maleimide were assembled into hydrogels. When tested pre-clinically as corneal implants in mini-pigs, they promoted cell and nerve regeneration, forming neo-corneas structurally and functionally similar to natural corneas.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2016
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-130324 (URN)10.1039/c6ra08895c (DOI)000378275400008 ()
Note

Funding Agencies|Vinnova Indo-Sweden grant [2013-04645]; Integrative Regenerative Medicine Centre, Linkoping University (LiU); Region Ostergotland; Swedish Research Council grant [621-2012-4286]

Available from: 2016-07-29 Created: 2016-07-28 Last updated: 2017-11-28

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Ravichandran, Ranjithkumar

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