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Engineering and Functionalization of Degradable Scaffolds for Medical Implant Applications
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The treatment of bone defects is facing the situation of lacking donations for autotransplantation. As a valid approach, scaffold-based tissue engineering combines the construction of well-defined porous scaffolds with advanced cell culturing technology to guide tissue regeneration. The role for the scaffold is to provide a suitable environment with a sufficient mechanical stiffness, supports for cell attachment, migration, nutrients and metabolite transport and space for cell remodeling and tissue regeneration. The random copolymers poly(L-lactide-co-ɛ-caprolactone) (poly(LLA-co-CL)) and poly(L-lactide-co-1,5-dioxepan-2-one) (poly(LLA-co-DXO)) have been successfully incorporated into 3D porous scaffolds to induce specific interactions with cells and direct osteogenic cell differentiation. In this thesis, these scaffolds have been modified in chemical and physical ways to map and understand requirements for bone regeneration. Scaffold functionalities and properties, such as hydrophilicity, stiffness, size/shape, and reproducibility, were studied. The hydrophilicity was varied by adding 3–20 % (w/w) Tween 80 to poly(LLA-co-CL) and poly(LLA-co-DXO) respectively, which resulted in contact angles from 35° to 15°. With 3 % Tween 80, the resultant mechanical and thermal properties were similar to pristine polymer materials. Tween 80 did not significantly influence cell attachment or proliferation but did stimulate the mRNA expression of osteogenetic markers. The surface functionality and mechanical properties were altered by introducing nanodiamond particles (n-DP) into poly(LLA-co-CL) scaffolds by means of surface physisorption or hybrid blending. Scaffold with n-DP physisorbed showed improved cell attachment, differentiation, and bone reformation. Hybrid n-DP/poly(LLA-co-CL) composites were obtained by direct blending of polylactide modified n-DP (n-DP-PLA) with poly(LLA-coCL). The n-DP-PLA was prepared by sodium hydride-mediated anionic polymerization using n-DP as the initiator. Prepared n-DP-PLA could be dispersed homogenously in organic solvents and blended with poly(LLA-coCL) solution. The n-DP-PLA particles were homogenously distributed in the composite material, which significantly improved mechanical properties. For comparison, the addition of benzoquinone-modified n-DP (n-DP-BQ) did not reinforce poly(LLA-co-CL). This indicated the importance of specific surface grafting, which determined different particle-polymer interactions. For the treatment of critical size defects, a large porous poly(LLA-co-CL) scaffold (12.5 mm diameter × 25 mm thickness) was developed and produced by molding and salt-leaching methods. The large porous scaffolds were evaluated in a scaffold-customized perfusion-based bioreactor system. It was obvious that the scaffold could support improved cell distribution and support the stimulation of human mesenchymal stem cell (hMSC) especially with dynamic flow in a bioreactor. To improve the scaffolding technique, a three-dimensional fiber deposition (3DF) technique was employed to build layer-based scaffolds. Poly(LLA-coCL) scaffolds produced by the 3DF method showed enhanced mechanical properties and a homogeneous distribution of human osteoblasts (hOBs) in the scaffolds. Although poly(LLA-co-CL) was thermally degraded, the degradation did not influence the scaffold mechanical properties. Based on the computerized design, a 3DF scaffold of amorphous copolymer poly(LLAco-CL) provides high-precision control and reproducibility. In summary, the design of porous scaffolds is one of the essential factors in tissue engineering as to mimicking the intrinsic extracellular environment. For bone tissue engineering, an optimized scaffold can maintain a contact angle greater than 35 degrees. Pristine or modified n-DP, introduced as an additive by surface physisorption or direct blending, can improve scaffold mechanical properties and cell response. Various sizes of scaffolds can be easily produced by a mold-mediated salt-leaching method. However, when 100 % reproducibility is required, the 3DF method can be used to create customizable scaffolds.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2014. , 73 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2014:36
Keyword [en]
Tissue engineering, nanodiamond, scaffold, bioreactor
National Category
Polymer Technologies
Research subject
Fibre and Polymer Science
Identifiers
URN: urn:nbn:se:kth:diva-152605ISBN: 978-91-7595-256-7 (print)OAI: oai:DiVA.org:kth-152605DiVA: diva2:750602
Public defence
2014-10-17, Kollegiesalen, Brinellvägen 8, KTH, Stockholm, 13:44 (English)
Opponent
Supervisors
Funder
EU, FP7, Seventh Framework Programme, Vascubone
Note

QC 20140929

Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2014-09-29Bibliographically approved
List of papers
1. Surfactant as a Critical Factor When Tuning the Hydrophilicity in Three-Dimensional Polyester-Based Scaffolds: Impact of Hydrophilicity on Their Mechanical Properties and the Cellular Response of Human Osteoblast-Like Cells
Open this publication in new window or tab >>Surfactant as a Critical Factor When Tuning the Hydrophilicity in Three-Dimensional Polyester-Based Scaffolds: Impact of Hydrophilicity on Their Mechanical Properties and the Cellular Response of Human Osteoblast-Like Cells
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2014 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 4, 1259-1268 p.Article in journal (Refereed) Published
Abstract [en]

In tissue engineering, the hydrophilicity of porous scaffolds is essential and influences protein and cell adhesion as well as nutrient diffusion into the scaffold. The relative low hydrophilicity of degradable polyesters, which limits diffusion of nutrients, is a major drawback in large porous scaffolds of these materials when used for bone tissue engineering and repair of critical size defects. Designing porous biodegradable polymer scaffolds with improved hydrophilicity, while maintaining their mechanical, thermal, and degradation properties is therefore of clinical interest. Here, surfactants were used to tune the hydrophilicity and material properties. A total of 3-20% (w/w) of surfactant, polysorbate 80 (Tween 80), was used as an additive in poly(L-lactide-co-1,5-diozepan-2-one) [poly(LLA-co-DXO)] and poly(L-lactide)-co-(epsilon-caprolactone) [poly(LLA-co-CL)] scaffolds. A significantly decreased water contact angle was recorded for all the blends and the crystallinity, glass transition temperature and crystallization temperature were reduced with increased amounts of surfactant. Copolymers with the addition of 3% Tween 80 had comparable mechanical properties as the pristine copolymers. However, the E-modulus and tensile stress of copolymers decreased significantly with the addition of 10 and 20% Tween 80. Initial cell response of the material was evaluated by seeding human osteoblast-like cells (HOB) on the scaffolds. The addition of 3% Tween 80 did not significantly influence cell attachment or proliferation, while 20% Tween 80 significantly inhibited osteoblast proliferation. RT-PCR results showed that 3% Tween 80 stimulated mRNA expression of alkaline phosphatase (ALP), osteoprotegerin (OPG), and bone morphogenetic protein-2 (BMP-2).

Keyword
Marrow Stromal Cells, Human-Endothelial Cells, Critical-Size Defects, In-Vitro, Bone, Differentiation, Wettability, Proteins, Adhesion, Proliferation
National Category
Biochemistry and Molecular Biology Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-145591 (URN)10.1021/bm401818e (DOI)000334571600018 ()2-s2.0-84898669991 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 242175
Note

QC 20140611

Available from: 2014-06-11 Created: 2014-05-23 Last updated: 2017-12-05Bibliographically approved
2. Biological Effects of Functionalizing Copolymer Scaffolds with Nanodiamond Particles
Open this publication in new window or tab >>Biological Effects of Functionalizing Copolymer Scaffolds with Nanodiamond Particles
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2013 (English)In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 19, no 15-16, 1783-1791 p.Article in journal (Refereed) Published
Abstract [en]

Significant evidence has indicated that poly(L-lactide)-co-(epsilon-caprolactone) [(poly(LLA-co-CL)] scaffolds could be one of the suitable candidates for bone tissue engineering. Oxygen-terminated nanodiamond particles (n-DP) were combined with poly(LLA-co-CL) and revealed to be positive for cell growth. In this study, we evaluated the influence of poly(LLA-co-CL) scaffolds modified by n-DP on attachment, proliferation, differentiation of bone marrow stromal cells (BMSCs) in vitro, and on bone formation using a sheep calvarial defect model. BMSCs were seeded on either poly(LLA-co-CL)-or n-DP-coated scaffolds and incubated for 1 h. Scanning electron microscopy (SEM) and fluorescence microscopy were used in addition to protein and DNA measurements to evaluate cellular attachment on the scaffolds. To determine the effect of n-DP on proliferation of BMSCs, cell/scaffold constructs were harvested after 3 days and evaluated by Bicinchoninic Acid (BCA) protein assay and SEM. In addition, the osteogenic differentiation of cells grown for 2 weeks on the various scaffolds and in a dynamic culture condition was evaluated by real-time RT-PCR. Unmodified and modified scaffolds were implanted into the calvaria of six-year-old sheep. The expression of collagen type I (COL I) and bone morphogenetic protein-2 (BMP-2) after 4 weeks as well as the formation of new bone after 12 and 24 weeks were analyzed by immunohistochemistry and histology. Scaffolds modified with n-DP supported increased cell attachment and the mRNA expression of osteopontin (OPN), bone sialoprotein (BSP), and BMP-2 were significantly increased after 2 weeks of culture. The BMSCs had spread well on the various scaffolds investigated after 3 days in the study with no significant difference in cell proliferation. Furthermore, the in vivo data revealed more positive staining of COLI and BMP-2 in relation to the n-DP-coated scaffolds after 4 weeks and presented more bone formation after 12 and 24 weeks. n-DP modification significantly increased cell attachment and differentiation of BMSCs on poly(LLA-co-CL) scaffolds in vitro and enhanced bone formation in vivo.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2013
Keyword
Bone marrow stromal cells (BMSCs), Bone morphogenetic protein-2, Bone tissue engineering, Cellular attachments, Immunohistochemistry, Nano-diamond particles, Osteogenic differentiation, Significant differences
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-125552 (URN)10.1089/ten.tea.2012.0336 (DOI)000321039800013 ()2-s2.0-84879622713 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 242175
Note

QC 20130812

Available from: 2013-08-12 Created: 2013-08-09 Last updated: 2017-12-06Bibliographically approved
3. Disaggregation and Anionic Activation of Nanodiamonds Mediated by Sodium Hydride: A New Route to Functional Aliphatic Polyester-Based Nanodiamond Materials
Open this publication in new window or tab >>Disaggregation and Anionic Activation of Nanodiamonds Mediated by Sodium Hydride: A New Route to Functional Aliphatic Polyester-Based Nanodiamond Materials
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2014 (English)In: Particle & particle systems characterization, ISSN 0934-0866, E-ISSN 1521-4117, Vol. 32, no 1, 35-42 p.Article in journal (Refereed) Published
Abstract [en]

Polylactide-modified nanodiamond particles (n-DP-g-PLA) are prepared by sodium-hydride-activated nanodiamond-initated anionic ring-opening polymerization. Activated nanodiamond particles repel each other, preventing agglomeration during the polymerization. This universal modification provides a platform for the functionalization of all types of nanoparticles containing hydroxyl groups.

Keyword
Amphiphilic graft, Core-shell composite, Grafting from, Lactide, Nanoparticle
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:kth:diva-152607 (URN)10.1002/ppsc.201400098 (DOI)000347727600004 ()2-s2.0-84920918909 (Scopus ID)
Note

QC 20150227

Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2017-12-05Bibliographically approved
4. Reinforced Degradable Biocomposite by Homogenously Distributed Functionalized Nanodiamond Particles
Open this publication in new window or tab >>Reinforced Degradable Biocomposite by Homogenously Distributed Functionalized Nanodiamond Particles
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2015 (English)In: Macromolecular materials and engineering (Print), ISSN 1438-7492, E-ISSN 1439-2054, Vol. 300, no 4, 436-447 p.Article in journal (Refereed) Published
Abstract [en]

Severe phase separation was observed in blending nanodiamond particle (n-DP) in poly (L-lactide-co-e-caprolactone) (poly(LLA-co-CL)) scaffold. In this study we optimized the scaffold by the addition of 1-50% (w/w) polylactide modified n-DP (n-DP-PLA) or benzoquinone-modified n-DP (n-DP-BQ). Composed by 10% n-DP-PLA, composite had 6 times higher E-modulus in tensile test, whereas the maximum reinforcement can be higher than 15 times. However, n-DP-BQ composites conserved the mechanical properties, and thermal properties of the polymer substrate. The attachment, spreading and growth of UE7T13 cells on modified n-DP composites were similar to poly(LLA-co-CL), and independent to n-DP concentrations. In summary, a proper modified n-DP is the key to reinforce poly(LLA-co-CL) for tissue engineering.

Keyword
composites, reinforcement, grafting from, nanodiamond, polylactide
National Category
Materials Engineering
Identifiers
urn:nbn:se:kth:diva-152609 (URN)10.1002/mame.201400387 (DOI)000352646000006 ()2-s2.0-84926514032 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 242175
Note

QC 20150508. Updated from manuscript to article in journal.

Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2017-12-05Bibliographically approved
5. Evaluation of a perfusion bioreactor for efficient seeding and advanced culture conditions of large bone substitute materials addressing critical size defects
Open this publication in new window or tab >>Evaluation of a perfusion bioreactor for efficient seeding and advanced culture conditions of large bone substitute materials addressing critical size defects
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:kth:diva-152611 (URN)
Note

QS 2014

Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2014-09-29Bibliographically approved
6. Degradable amorphous scaffolds with enhanced mechanical properties and homogeneous cell distribution produced by a three-dimensional fiber deposition method
Open this publication in new window or tab >>Degradable amorphous scaffolds with enhanced mechanical properties and homogeneous cell distribution produced by a three-dimensional fiber deposition method
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2012 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 100A, no 10, 2739-2749 p.Article in journal (Refereed) Published
Abstract [en]

The mechanical properties of amorphous, degradable, and highly porous poly(lactide-co-caprolactone) structures have been improved by using a 3D fiber deposition (3DF) method. Two designs of 3DF scaffolds, with 45 degrees and 90 degrees layer rotation, were printed and compared with scaffolds produced by a salt-leaching method. The scaffolds had a porosity range from 64% to 82% and a high interconnectivity, measured by micro-computer tomography. The 3DF scaffolds had 89 times higher compressive stiffness and 35 times higher tensile stiffness than the salt-leached scaffolds. There was a distinct decrease in the molecular weight during printing as a consequence of the high temperature. The chain microstructure was, however, not affected; the glass transition temperature and the decomposition temperature were constant. Human OsteoBlast-like cells were cultured in vitro and the cell morphology and distribution were observed by scanning electron microscopy and fluorescence microscopy. The cell distribution on the 3DF scaffolds was more homogeneous than the salt-leached scaffolds, suggesting that 3DF scaffolds are more suitable as porous biomaterials for tissue engineering. These results show that it is possible to design and optimize the properties of amorphous polymer scaffolds. The 3DF method produce amorphous degradable poly(lactide-co-caprolactone) that are strong and particularly suitable for cell proliferation.

Keyword
3D fiber deposition method, amorphous degradable copolymer, aliphatic polyester, scaffold, cell distribution
National Category
Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-96625 (URN)10.1002/jbm.a.34210 (DOI)000307888200023 ()2-s2.0-84865630684 (Scopus ID)
Note

QC 20121004

Available from: 2012-06-07 Created: 2012-06-07 Last updated: 2017-12-07Bibliographically approved

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