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Composite Regenerative Scaffolds
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. (Hilborn)ORCID iD: 0000-0001-8465-1764
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regenerative medicine and tissue engineering solutions of heavily innervated tissues are at this point lacklustre. This thesis expands our knowledge of appropriate acellular scaffolds for tissue repair in general and nerve regeneration in particular. The optimal surgical procedure for the implantation of artificial extracellular matrix (ECM) was evaluated for recombinant human collagen (RHCIII) implants. Suturing techniques, as well as the usage of human amniotic membrane “bandages” were evaluated. While complete regeneration of corneal tissues occurred, only slight differences in effects of surgical technique could be found.

The safety and efficacy of clinical trials using mesenchymal stromal cells (MSCs) was evaluated by conducting a systematic review and meta-analysis. MSC therapy was shown to be safe, with no increases mortality, rehospitalization or adverse events. There was also an indication of efficacy, as the overall mortality in the studies included was significantly smaller in the MSC treated group.

Multicomponent hydrogel capsules encapsulating single cells were developed. Capsules manufactured from gelatin, agarose and fibrinogen were compared to pure gelatin capsules. The composite capsules successfully delayed cell release and prolonged cell survival.

Surface patterning of collagen based biomimetic corneas was performed by microcontact printing. The ability of different sizes of fibronectin stripes to stimulate cell adhesion and proliferation was compared. The patterned surfaces improved cell adhesion, as well as proliferation markers.

Conductive polymer composites were manufactured for use as nerve guides. The guides were created from electrospun polycaprolactone fibers coated with a series of different poly(3,4-ethylenedioxythiophene) films. A comparison of nerve progenitor growth and differentiation on the composite fibers was performed. Both the effects of fiber composition and MSC co-culture was investigated, with or without electrostimulation. MSC treatments and polymer coating was both important for nerve cell differentiation and growth.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 37
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1741
Keywords [en]
nerve, neurite, regeneration, PEDOT, PEDOT:Tosylate, electrostimulation
National Category
Biomaterials Science Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-364454ISBN: 978-91-513-0496-0 (print)OAI: oai:DiVA.org:uu-364454DiVA, id: diva2:1259206
Public defence
2018-12-17, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-11-27 Created: 2018-10-29 Last updated: 2018-12-27
List of papers
1. Effect of Surgical Technique on Corneal Implant Performance.
Open this publication in new window or tab >>Effect of Surgical Technique on Corneal Implant Performance.
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2014 (English)In: Translational vision science & technology, ISSN 2164-2591, Vol. 3, no 2, article id 6Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Our aim was to determine the effect of a surgical technique on biomaterial implant performance, specifically graft retention.

METHODS: Twelve mini pigs were implanted with cell-free, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) cross-linked recombinant human collagen type III (RHCIII) hydrogels as substitutes for donor corneal allografts using overlying sutures with or without human amniotic membrane (HAM) versus interrupted sutures with HAM. The effects of the retention method were compared as well as the effects of collagen concentration (13.7% to 15% RHCIII).

RESULTS: All implanted corneas showed initial haze that cleared with time, resulting in corneas with optical clarity matching those of untreated controls. Biochemical analysis showed that by 12 months post operation, the initial RHCIII implants had been completely remodeled, as type I collagen, was the major collagenous protein detected, whereas no RHCIII could be detected. Histological analysis showed all implanted corneas exhibited regeneration of epithelial and stromal layers as well as nerves, along with touch sensitivity and tear production. Most neovascularization was seen in corneas stabilized by interrupted sutures.

CONCLUSIONS: This showed that the surgical technique used does have a significant effect on the overall performance of corneal implants, overlying sutures caused less vascularization than interrupted sutures.

TRANSLATIONAL RELEVANCE: Understanding the significance of the suturing technique can aid the selection of the most appropriate procedure when implanting artificial corneal substitutes. The same degree of regeneration, despite a higher collagen content indicates that future material development can progress toward stronger, more resistant implants.

Keywords
biomaterials, biosynthetic cornea, corneal regeneration, corneal transplantation, recombinant human collagen
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-364450 (URN)10.1167/tvst.3.2.6 (DOI)24749003 (PubMedID)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
2. Conductive PEDOT based coatings on microfibrous scaffolds: a nerve guide component
Open this publication in new window or tab >>Conductive PEDOT based coatings on microfibrous scaffolds: a nerve guide component
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2018 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-364452 (URN)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
3. Mesenchymal Stromal Cells for the Treatment of Ischemic Injury and Vascular Trauma: A Systematic Review and Meta-Analysis
Open this publication in new window or tab >>Mesenchymal Stromal Cells for the Treatment of Ischemic Injury and Vascular Trauma: A Systematic Review and Meta-Analysis
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2018 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-364451 (URN)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
4. Functional fabrication of recombinant human collagen-phosphorylcholine hydrogels for regenerative medicine applications.
Open this publication in new window or tab >>Functional fabrication of recombinant human collagen-phosphorylcholine hydrogels for regenerative medicine applications.
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2015 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 12, p. 70-80, article id S1742-7061(14)00486-3Article in journal (Refereed) Published
Abstract [en]

The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes for the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500μm thick RHCIII-MPC constructs comprising over 85% water are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, unlike the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30μm wide fibronectin stripes enhanced cell attachment and showed the highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.

Keywords
Collagen, Cornea, Hydrogel, Laser profiling, Surface modification
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-364449 (URN)10.1016/j.actbio.2014.10.035 (DOI)25448347 (PubMedID)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
5. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules.
Open this publication in new window or tab >>Controlled Delivery of Human Cells by Temperature Responsive Microcapsules.
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2015 (English)In: Journal of Functional Biomaterials, ISSN 2079-4983, E-ISSN 2079-4983, Vol. 6, no 2, p. 439-53Article in journal (Refereed) Published
Abstract [en]

Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line-human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation.

Keywords
cell delivery, cell encapsulation, human fibroblast, human umbilical vein endothelial cells, hydrogel, microcapsules, temperature responsive
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-364448 (URN)10.3390/jfb6020439 (DOI)26096147 (PubMedID)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29

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