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Fagerholm, Per
Publications (10 of 93) Show all publications
Ong, J. A., Auvinet, E., Forget, K. J., Lagali, N., Fagerholm, P., Griffith, M., . . . Brunette, I. (2016). 3D Corneal Shape After Implantation of a Biosynthetic Corneal Stromal Substitute. Investigative Ophthalmology and Visual Science, 57(6), 2355-2365
Open this publication in new window or tab >>3D Corneal Shape After Implantation of a Biosynthetic Corneal Stromal Substitute
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2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 6, p. 2355-2365Article in journal (Refereed) Published
Abstract [en]

PURPOSE. The current and projected shortage of transplantable human donor corneas has prompted the development of long-term alternatives to human donor tissue for corneal replacement. The biosynthetic stromal substitutes (BSS) characterized herein represent a potentially safe alternative to donor organ transplantation for anterior corneal stromal diseases. The goal of this phase 1 safety study was to characterize the three-dimensional (3D) corneal shape of the first 10 human patients implanted with a BSS and assess its stability over time. METHODS. Ten patients underwent anterior lamellar keratoplasty using a biosynthetic corneal stromal implant for either advanced keratoconus or central corneal scarring. Surgeries were performed at Linkoping University Hospital, between October and November 2007. Serial corneal topographies were performed on all eyes up to a 4-year follow-up when possible. Three-dimensional shape average maps were constructed for the 10 BSS corneas and for 10 healthy controls. Average 3D shape corneal elevation maps, difference maps, and statistics maps were generated. RESULTS. The biosynthetic stromal substitutes implants remained stably integrated into the host corneas over the 4-year follow-up period, without signs of wound dehiscence or implant extrusion. The biosynthetic stromal substitutes corneas showed steeper surface curvatures and were more irregular than the healthy controls. CONCLUSIONS. Corneal astigmatism and surface steepness were observed 4 years after BSS implantation, while the implants remained stably integrated in the host corneas. Future studies will indicate if biomaterials technology will allow for the optimization of postoperative surface irregularity after anterior stromal replacement, a new window of opportunity that is not available with traditional corneal transplantation techniques.

Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2016
Keywords
corneal implants; artificial cornea; corneal topography; corneal transplantation; keratoconus
National Category
Ophthalmology
Identifiers
urn:nbn:se:liu:diva-130307 (URN)10.1167/iovs.15-18271 (DOI)000378041700001 ()27136462 (PubMedID)
Note

Funding Agencies|Canadian Institutes of Health Research, Canada [MOP 106517]; Stem Cell Network, Ottawa, ON, Canada; FRQS Research in Vision Network, Montreal, QC, Canada; County Council of Ostergotland, Sweden; Charles-Albert Poissant Research Chair in Corneal Transplantation, University of Montreal, Canada

Available from: 2016-07-31 Created: 2016-07-28 Last updated: 2018-01-22
Rafat, M., Xeroudaki, M., Koulikovska, M., Sherrell, P., Groth, F., Fagerholm, P. & Lagali, N. (2016). Composite core-and-skirt collagen hydrogels with differential degradation for corneal therapeutic applications. Biomaterials, 83, 142-155
Open this publication in new window or tab >>Composite core-and-skirt collagen hydrogels with differential degradation for corneal therapeutic applications
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2016 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 83, p. 142-155Article in journal (Refereed) Published
Abstract [en]

Scarcity of donor tissue to treat corneal blindness and the need to deliver stem cells or pharmacologic agents to ensure corneal graft survival are major challenges. Here, new composite collagen-based hydrogels are developed as implants to restore corneal transparency while serving as a possible reservoir for cells and drugs. The composite hydrogels have a centrally transparent core and embedded peripheral skirt of adjustable transparency and degradability, with the skirt exhibiting faster degradation in vitro. Both core and skirt supported human epithelial cell populations in vitro and the skirt merged homogeneously with the core material to smoothly distribute a mechanical load in vitro. After in vivo transplantation in rabbit corneas over three months, composites maintained overall corneal shape and integrity, while skirt degradation could be tracked in vivo and non-invasively due to partial opacity. Skirt degradation was associated with partial collagen breakdown, thinning, and migration of host stromal cells and macrophages, while the central core maintained integrity and transparency as host cells migrated and nerves regenerated.

IMPACT:

This study indicates the feasibility of a collagen-based composite hydrogel to maintain corneal stability and transparency while providing a degradable peripheral reservoir for cell or substance release.

Keywords
Composite; Cornea; Degradation; Femtosecond laser; Keratoplasty; Porcine collagen
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125229 (URN)10.1016/j.biomaterials.2016.01.004 (DOI)000371651700012 ()26773670 (PubMedID)
Note

Funding agencies:  Abbott Medical Optics Inc, Solna, Sweden

Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-01-22
Ihnatko, R., Edén, U., Fagerholm, P. & Lagali, N. (2016). Congenital Aniridia and the Ocular Surface. OCULAR SURFACE, 14(2), 196-206
Open this publication in new window or tab >>Congenital Aniridia and the Ocular Surface
2016 (English)In: OCULAR SURFACE, ISSN 1542-0124, Vol. 14, no 2, p. 196-206Article in journal (Refereed) Published
Abstract [en]

Aniridia is a congenital pan-ocular disorder caused by haplo-insufficiency of Pax6, a crucial gene for proper development of the eye. Aniridia affects a range of eye structures, including the cornea, iris, anterior chamber angle, lens, and fovea. The ocular surface, in particular, can be severely affected by a progressive pathology termed aniridia-associated keratopathy (AAK), markedly contributing to impaired vision. The purpose of this review is to provide an update of the current knowledge of the genetic, clinical, micro-morphological, and molecular aspects of AAK. We draw upon material presented in the literature and from our own observations in large aniridia cohorts. We summarize signs and symptoms of AAK, describe current options for management, and discuss the latest research findings that may lead to better diagnosis and new treatment or prevention strategies for this debilitating ocular surface condition.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2016
Keywords
aniridia; aniridia-associated keratopathy; congenital aniridia; gene mutations; haplo-insufficiency; iris; Pax6 gene
National Category
Psychiatry
Identifiers
urn:nbn:se:liu:diva-128758 (URN)10.1016/j.jtos.2015.10.003 (DOI)000375222400012 ()
Note

Funding Agencies|Ogonfonden; Swedish Research Council [2012-2472]; Country of Ostergotland; Kronprinsessan Margaretas Arbetsnamnd

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2018-01-22
Islam, M. M., Ravichandran, R., Olsen, D., Kozak Ljunggren, M., Fagerholm, P., Lee, C.-J., . . . Phopase, J. (2016). Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation. RSC Advances, 6(61), 55745-55749
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, p. 55745-55749Article 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
Buznyk, O., Pasyechnikova, N., Islam, M. M., Iakymenko, S., Fagerholm, P. & Griffith, M. (2015). Bioengineered Corneas Grafted as Alternatives to Human Donor Corneas in Three High-Risk Patients. Clinical and Translational Science, 8(5), 558-562
Open this publication in new window or tab >>Bioengineered Corneas Grafted as Alternatives to Human Donor Corneas in Three High-Risk Patients
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2015 (English)In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 8, no 5, p. 558-562Article in journal (Refereed) Published
Abstract [en]

Corneas with severe pathologies have a high risk of rejection when conventionally grafted with human donor tissues. In this early observational study, we grafted bioengineered corneal implants made from recombinant human collagen and synthetic phosphorylcholine polymer into three patients for whom donor cornea transplantation carried a high risk of transplant failure. These patients suffered from corneal ulcers and recurrent erosions preoperatively. The implants provided relief from pain and discomfort, restored corneal integrity by promoting endogenous regeneration of corneal tissues, and improved vision in two of three patients. Such implants could in the future be alternatives to donor corneas for high-risk patients, and therefore, merits further testing in a clinical trial.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keywords
collagen; epithelium; grafting; patients; remodeling; transplantation
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:liu:diva-122789 (URN)10.1111/cts.12293 (DOI)000363652100024 ()25996570 (PubMedID)
Note

Funding Agencies|Swedish Research Council (EU Nanomedicine project "I-CARE") [521-2012-5706]; Integrative Regenerative Medicine Centre, Linkoping, Sweden; Swedish Institute fellowship

Available from: 2015-11-23 Created: 2015-11-23 Last updated: 2018-01-10
Koulikovska, M., Rafat, M., Petrovski, G., Veréb, Z., Akhtar, S., Fagerholm, P. & Lagali, N. (2015). Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique. Tissue Engineering. Part A, 21(5-6), 1116-1130
Open this publication in new window or tab >>Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique
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2015 (English)In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, no 5-6, p. 1116-1130Article in journal (Refereed) Published
Abstract [en]

Severe shortage of donor corneas for transplantation, particularly in developing countries, has prompted the advancement of bioengineered tissue alternatives. Bioengineered corneas that can withstand transplantation while maintaining transparency and compatibility with host cells, and that are additionally amenable to standardized low-cost mass production are sought. In this study, a bioengineered porcine construct (BPC) was developed to function as a biodegradable scaffold to promote corneal stromal regeneration by host cells. Using high-purity medical-grade type I collagen, high 18% collagen content and optimized EDC-NHS cross-linker ratio, BPCs were fabricated into hydrogel corneal implants with over 90% transparency and four-fold increase in strength and stiffness compared with previous versions. Remarkably, optical transparency was achieved despite the absence of collagen fibril organization at the nanoscale. In vitro testing indicated that BPC supported confluent human epithelial and stromal-derived mesenchymal stem cell populations. With a novel femtosecond laser-assisted corneal surgical model in rabbits, cell-free BPCs were implanted in vivo in the corneal stroma of 10 rabbits over an 8-week period. In vivo, transparency of implanted corneas was maintained throughout the postoperative period, while healing occurred rapidly without inflammation and without the use of postoperative steroids. BPC implants had a 100% retention rate at 8 weeks, when host stromal cells began to migrate into implants. Direct histochemical evidence of stromal tissue regeneration was observed by means of migrated host cells producing new collagen from within the implants. This study indicates that a cost-effective BPC extracellular matrix equivalent can incorporate cells passively to initiate regenerative healing of the corneal stroma, and is compatible with human stem or organ-specific cells for future therapeutic applications as a stromal replacement for treating blinding disorders of the cornea.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2015
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114699 (URN)10.1089/ten.tea.2014.0562 (DOI)000350549500025 ()25412075 (PubMedID)
Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2018-01-22Bibliographically approved
Koulikovska, M., Szymanowski, O., Lagali, N. & Fagerholm, P. (2015). Platelet Rich Plasma Prolongs Myofibroblast Accumulation in Corneal Stroma with Incisional Wound. Current Eye Research, 40(11), 1102-1110
Open this publication in new window or tab >>Platelet Rich Plasma Prolongs Myofibroblast Accumulation in Corneal Stroma with Incisional Wound
2015 (English)In: Current Eye Research, ISSN 0271-3683, E-ISSN 1460-2202, Vol. 40, no 11, p. 1102-1110Article in journal (Refereed) Published
Abstract [en]

Purpose: The purpose of this study was to determine whether platelet rich plasma (PRP) has an effect on corneal stromal cells in a rat model of wound healing following corneal incision. Materials and Methods: The effect of PRP on corneal wound healing in vivo was investigated in a corneal incision wound model in rats. 40 rats were wounded by deep corneal incision, and treated with either topically administered PRP (20 rats) or sodium chloride (20 rats). At 4 hours and 1, 3, and 5 days after incision, α-smooth muscle actin (α SMA), SMAD2 and SMAD3 expression and apoptosis in stromal cells were evaluated by immunohistochemistry, and IL-1β mRNA expression was evaluated by real time PCR.

Results: PRP treated corneas exhibited reduced stromal cell apoptosis at day 3 and day 5 (p = 0.038, and <0.001, respectively) relative to controls. Interleukin-1β mRNA expression, however, was unchanged in PRP treated corneas relative to controls. Topical PRP treatment resulted in a higher proportion of αSMA-positive myofibroblasts recruited to the wound site relative to control corneas. PRP did not affect activation of SMAD2 but activation of SMAD3 was significantly reduced at day 1 (p=0.001) and dramatically increased at day 5 (p=0.032).

Conclusions: PRP treatment resulted in suppressed stromal cell apoptosis followed by SMAD3 activation and a greater proportion of myofibroblasts present at the wound site. Suppression of stromal cell apoptosis after corneal wounding by use of a growth factor rich formulation may lead to myofibroblast accumulation by modulation of the TGF-β pathway.

Place, publisher, year, edition, pages
Taylor & Francis, 2015
Keywords
Platelet rich plasma, corneal wound healing, α-smooth muscle actin, apoptosis, keratocytes
National Category
Cell and Molecular Biology Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-114698 (URN)10.3109/02713683.2014.978478 (DOI)000369891500004 ()
Note

Funding agencies:Swedish Research Council, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, County Council of Ostergotland 

Vid tiden för disputation förelåg publikationen endast som manuskript

Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2018-01-22Bibliographically approved
Koulikovska, M., Szymanowski, O., Lagali, N. & Fagerholm, P. (2015). Topical Biglycan Modulates Stromal Cell Apoptosis in Corneal Incisional Wound Model.
Open this publication in new window or tab >>Topical Biglycan Modulates Stromal Cell Apoptosis in Corneal Incisional Wound Model
2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose: The purpose of this study was to determine whether exogenous topicallyapplied biglycan has an effect on corneal stromal cells during wound healing.

Methods: Enzyme-linked immunosorbent assay (ELISA) was used to determine the effect of biglycan on cell survival in vitro following IL-1β induced cell death. In a corneal incisional wound model, 40 rats were wounded and treated with either topically administered biglycan or sodium chloride (sham control). At 4 hours and 1, 2, and 5 days after incision, α-smooth muscle actin (SMA) expression and apoptosis in stromal cells were evaluated by immunohistochemistry.

Results: In vitro, biglycan significantly enhanced IL-1β-induced apoptosis of myofibroblasts (p = 0.038), but not corneal fibroblasts. Biglycan treated corneas exhibited reduced stromal cell apoptosis at 4 hours, day 1 and day 5 (p = 0.012, 0.040, and 0.048, respectively) and increased apoptosis at day 3 (p = 0.003) relative to controls. In wounded corneas, biglycan appeared to promote early accumulation of myofibroblasts and initiate an earlier subsequent apoptosis of these cells, relative to controls.

Conclusion: Biglycan appears to accelerate corneal wound healing in vivo by modulating myofibroblast apoptosis, resulting in removal of myofibroblasts that may otherwise compromise corneal transparency.

Keywords
Corneal wound healing; biglycan; keratocytes; IL-1β; α-SMA
National Category
Cell and Molecular Biology Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-114697 (URN)
Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2018-01-22
Fagerholm, P., Lagali, N., Carlsson, D. J., Merrett, K. & Griffith, M. (2014). Corrigendum to “Corneal Regeneration Following Implantation of a Biomimetic Tissue-Engineered Substitute”  [vol 2, Issue 2, pg 162-164, 2009]. Clinical and Translational Science, 7(4), 347-347
Open this publication in new window or tab >>Corrigendum to “Corneal Regeneration Following Implantation of a Biomimetic Tissue-Engineered Substitute”  [vol 2, Issue 2, pg 162-164, 2009]
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2014 (English)In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 7, no 4, p. 347-347Article in journal (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110485 (URN)10.1111/cts.12183 (DOI)000340548300018 ()
Available from: 2014-09-15 Created: 2014-09-12 Last updated: 2018-01-22Bibliographically approved
Kozak Ljunggren, M., Elizondo, R. A., Edin, J., Olsen, D., Merrett, K., Lee, C.-J., . . . Griffith, M. (2014). Effect of Surgical Technique on Corneal Implant Performance. Translational Vision Science & Technology, 3(2), 1-13
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, p. 1-13Article 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.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology, 2014
Keywords
biosynthetic cornea; corneal regeneration; biomaterials; recombinant human collagen; corneal transplantation
National Category
Medical and Health Sciences Biomaterials Science Ophthalmology
Identifiers
urn:nbn:se:liu:diva-108585 (URN)10.1167/tvst.3.2.6 (DOI)24749003 (PubMedID)
Available from: 2014-06-30 Created: 2014-06-30 Last updated: 2015-08-10Bibliographically approved
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