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Thiol-Ene/Yne Adhesives for Tissue Fixation
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Coating Technology.ORCID iD: 0000-0001-8595-0037
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The utilization of adhesives in surgery has not reached its full potential and research in the field is encouraged by the surgeons’ desire for improved alternatives to today’s tissue fixation strategies. Here, adhesive resins based on thiol-ene coupling (TEC) chemistry or thiol-yne coupling (TYC) chemistry are exploited to develop tissue adhesives that cure fast and on-demand via photoinitiation. In order to make safer adhesives, macromolecular components and systems with high conversion of functional groups were developed to minimize leakage of unreacted monomers.To develop macromolecular resin components, allyl-functional dendritic-linear-dendritic (DLD) co-polymers were synthesized with a poly(ethylene glycol) (PEG) core chain and hyperbranched structures of 2,2-bis(hydroxymethyl) propionic acid (bis-MPA) to capitalize on the rheological properties of dendritic structures. The dendritic structures interfered with the crystallization of the PEG segment and the DLD’s liquid appearance enabled their use as macromolecular components without solvent. The DLDs were cured with a thiol crosslinker and the strategy disclosed degradable soft tissue adhesives with good adhesion to wet porcine skin.Mussel inspired dopamine derivatives was evaluated as adhesion-enhancing primers for bone adhesives. The addition of NaOH to the primer solutions increased the shear bond strengths of the adhesive to bone. The highest bond strengths with the tested dopamine derivatives were obtained when a combination of thiol and ene-functional derivatives were used.With inspiration from dental resin adhesives, a fully TEC based adhesive system was developed with excellent shear bond strength to wet bone substrates. The adhesive system enabled superior fixation of phalangeal fracture models compared to the daily used Kirschner wires and could even compete with a screw fixated metal plate. The adhesive materials proved biocompatible in initial in vitro and in vivo studies.Strong and rigid materials for fracture fixation were developed via a strategy of using highly crosslinked triazine-trione monomers and TEC or TYC chemistry. The development resulted in TYC resin based materials with mechanical properties that very well can compete with poly(ether ether ketone) (PEEK) that is used in biomedical load bearing applications due to its high strength, toughness and inertness.

Abstract [sv]

Användningen av lim inom kirurgin har ännu inte nått sin fulla potential och kirurgernas önskan om förbättrade alternativ till dagens metoder för vävnadsfixering uppmuntrar till forskning inom området. I det här arbetet har reaktioner mellan tiolgrupper och kol-kol dubbel- (TEC) eller trippelbindningar (TYC) använts för att utveckla vävnadslim som härdar snabbt via fotoinitiering. För att göra säkra lim har makromolekylära limkomponenter och system med hög omsättning av funktionella grupper utvecklats för att minimera läckage av oreagerade monomerer.För att utveckla makromolekylära limkomponenter som utnyttjar de reologiska egenskaperna från dendritiska strukturer, syntetiserades allylfunktionella dendritisk-linjär-dendritiska (DLD) sampolymerer med ett mittsegment av poly (etylenglykol) (PEG) och hyperförgrenade strukturer av 2,2-bis (hydroximetyl) propionsyra syra (bis-MPA). De dendritiska strukturerna hindrade kristallisationen av PEG-segmentet och flytande polymerer erhölls som kunde användas som limkomponenter utan lösningsmedel. DLD komponenterna härdade snabbt med hjälp av en tioltvärbindare, vilket resulterade i nedbrytbara lim för mjuk vävnad med god vidhäftning mot fuktig grishud.Musselinspirerade dopaminderivat utvärderades som adhesionsförhöjande primers för benlim. Genom att tillsätta NaOH i pirmerlösningarna ökade bindningsstyrkan för benlimmet. De högsta bindningsstyrkorna med hjälp av dopaminederivaten erhölls när tiolderivat och derivat med dubbelbindningar användes tillsammans.Med inspiration från dentallim utvecklades ett helt TEC baserat limsystem med utmärkt adhesion till våta bensubstrat. Limsystemet möjliggjorde fixering av falangfraktursmodeller som presterade bättre än fixeringar med Kirschnerstift som används dagligen för frakturfixering. Dessutom kunde limmet även konkurrera med en skruvfixerad metallplatta. Limmaterialet visade sig vara biokompatibelt vid initiala in vitro och in vivo studier.För att göra starka och styva material för frakturfixeringar utvecklades tätt tvärbundna material baserade på triazin-trion (TATO) monomerer via TEC eller TYC-kemi. Utvecklingen resulterade i material med mekaniska egenskaper som mycket väl kan konkurrera med poly(etereterketon) (PEEK) som används i lastbärande biomedicinska applikationer på grund av sin goda hållfasthet och stabilitet i fysiologisk miljö.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2018. , p. 64
Series
TRITA-CBH-FOU ; 2018:17
National Category
Polymer Chemistry
Research subject
Fibre and Polymer Science
Identifiers
URN: urn:nbn:se:kth:diva-227154ISBN: 978-91-7729-784-0 (print)OAI: oai:DiVA.org:kth-227154DiVA, id: diva2:1206401
Public defence
2018-06-08, K1, Teknikringen 46, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg Foundation, 2012-0196VINNOVA, 2014-03777
Note

QC 20180517

Available from: 2018-05-17 Created: 2018-05-16 Last updated: 2018-05-17Bibliographically approved
List of papers
1. Linear Dendritic Block Copolymers as Promising Biomaterials for the Manufacturing of Soft Tissue Adhesive Patches Using Visible Light Initiated Thiol-Ene Coupling Chemistry
Open this publication in new window or tab >>Linear Dendritic Block Copolymers as Promising Biomaterials for the Manufacturing of Soft Tissue Adhesive Patches Using Visible Light Initiated Thiol-Ene Coupling Chemistry
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2015 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 25, no 42, p. 6596-6605Article in journal (Refereed) Published
Abstract [en]

A library of dendritic-linear-dendritic (DLD) materials comprising linear poly(ethylene glycol) and hyperbranched dendritic blocks based on 2,2-bis(hydroxymethyl) propionic acid is successfully synthesized and post-functionalized with peripheral allyl groups. Reactive DLDs with pseudo-generations of 3 to 6 (G3-G6) are isolated in large scale allowing their thorough evaluation as important components for the development of biomedical adhesives. Due to their branched nature and inherent degradable ester-bonds, promising biomaterial resins are accomplished with suitable viscosity, eliminating the excessive use of co-solvents. By utilizing benign high-energy visible light initiated thiol-ene coupling chemistry, DLDs together with tris[2-(3-mercaptopropionyloxy) ethyl] isocyanurate and surgical mesh enable the fabrication of soft tissue adhesive patches (STAPs) within a total irradiation time of 30 s. The STAPs display the ability to create good adhesion to wet soft tissue and encouraging results in cytotoxicity tests. All crosslinked materials are also found to degrade after being stored in human blood plasma and phosphate buffered saline. The proposed benign methodology coupled with the promising features of the crosslinked materials is herein envisioned as a soft tissue adhesive with properties that do not exist in currently available tissue adhesives.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2015
National Category
Condensed Matter Physics Chemical Sciences Materials Engineering
Identifiers
urn:nbn:se:kth:diva-180135 (URN)10.1002/adfm.201503235 (DOI)000365532100004 ()2-s2.0-84948422356 (Scopus ID)
Note

QC 20160114

Available from: 2016-01-14 Created: 2016-01-07 Last updated: 2018-05-17Bibliographically approved
2. Activated dopamine derivatives as primers for adhesive-patch fixation of bone fractures
Open this publication in new window or tab >>Activated dopamine derivatives as primers for adhesive-patch fixation of bone fractures
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2016 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 31, p. 26398-26405Article in journal (Refereed) Published
Abstract [en]

For the stabilization of complex bone fractures, tissue adhesives are an attractive alternative to conventional implants, often consisting of metal plates and screws whose fixation may impose additional trauma on the already fractured bone. This study reports on the synthesis and evaluation of activated dopamine derivatives as primers for fiber-reinforced-adhesive patches in bone-fracture stabilization strategies. The performance of synthesized dopamine derivatives are evaluated with regard to the adhesive shear strength of formed bone patches, as well as cell viability and surface properties. Dopamine-derived primers with methacrylamide, allyl, and thiol functional groups were found to significantly increase the adhesive shear strength of adhesive patches. Furthermore, deprotonation of the primer solution was determined to be essential in order to achieve good adhesion. In conclusion, the primer solutions that were found to give the best adhesion were the once where dopa-thiol was used in combination with either dopamethacrylamide or dopa-allyl, resulting in shear bond strengths of 0.29 MPa.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2016
National Category
Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-185678 (URN)10.1039/c5ra23142f (DOI)000372812300090 ()2-s2.0-84961191443 (Scopus ID)
Note

QC 20160425

Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2018-05-16Bibliographically approved
3. High-Performance Thiol–Ene Composites Unveil a New Era of Adhesives Suited for Bone Repair
Open this publication in new window or tab >>High-Performance Thiol–Ene Composites Unveil a New Era of Adhesives Suited for Bone Repair
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2018 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028Article in journal (Refereed) Published
Abstract [en]

The use of adhesives for fracture fixation can revolutionize the surgical procedures toward more personalized bone repairs. However, there are still no commercially available adhesive solutions mainly due to the lack of biocompatibility, poor adhesive strength, or inadequate fixation protocols. Here, a surgically realizable adhesive system capitalizing on visible light thiol–ene coupling chemistry is presented. The adhesives are carefully designed and formulated from a novel class of chemical constituents influenced by dental resin composites and self-etch primers. Validation of the adhesive strengthis conducted on wet bone substrates and accomplished via fiber-reinforced adhesive patch (FRAP) methodology. The results unravel, for the first time, on the promise of a thiol–ene adhesive with an unprecedented shear bondstrength of 9.0 MPa and that surpasses, by 55%, the commercially available acrylate dental adhesive system Clearfil SE Bond of 5.8 MPa. Preclinical validation of FRAPs on rat femur fracture models details good adhesion to the bone throughout the healing process, and are found biocompatible not giving rise to any inflammatory response. Remarkably, the FRAPs are found to withstand loads up to 70 N for 1000 cycles on porcine metacarpal fractures outperforming clinically used K-wires and match metal plates and screw implants.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Polymer Chemistry Biomaterials Science
Identifiers
urn:nbn:se:kth:diva-227151 (URN)10.1002/adfm.201800372 (DOI)
Funder
VINNOVA, 2014-03777Knut and Alice Wallenberg Foundation, 2012-0196Swedish Research Council, 2010-435EU, Horizon 2020, MSCA-IF-2014-655649
Note

QC 20180509

Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-16Bibliographically approved
4. Highly crosslinked triazine-trione materials for fracture fixation based on TEC and TYC chemistry
Open this publication in new window or tab >>Highly crosslinked triazine-trione materials for fracture fixation based on TEC and TYC chemistry
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(English)Manuscript (preprint) (Other academic)
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-227152 (URN)
Funder
Knut and Alice Wallenberg Foundation, 2012-0196
Note

QC 20180517

Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-17Bibliographically approved

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