Technology

Biomaterial-based local sustained delivery allows long term effective local drug levels without side effects elsewhere in the body. Drug-loaded biomaterials slowly release their cargo locally by diffusion and biomaterial degradation.

Effective, safe and long-term pain relief in osteoarthritis and chronic low back pain can be achieved by local biomaterial-based controlled release of drugs such as anti-inflammatory agents. A solid body of preclinical evidence was generated on intra-articular and intradiscal release of the anti-inflammatory drug celecoxib. Celecoxib is an efficient anti-inflammatory drug that has serious side effects upon oral intake, and has difficulties reaching the joint fluid and intervertebral disc at therapeutic levels via the blood. However, celecoxib delivered intra-articularly and intradiscally by biomaterial microspheres was observed to be safe and result in long-term reduction of inflammation and pain in small animals and canine patients, at doses of less than the equivalent of one single pill for daily intake. The Epione proprietory biomaterial platform is already in human patients for other drug delivery applications. Moreover, the platform also allows for loading and delivery of other payloads including protein drugs, thereby also paving the way towards, for example, the delivery of regenerative factors.

Tellegen AR, Rudnik-Jansen I, Utomo L, Versteeg S, Beukers M, Maarschalkerweerd R, van Zuilen D, van Klaveren NJ, Houben K, Teske E, van Weeren PR, Karssemakers-Degen N, Mihov G, Thies J, Eijkelkamp N, Creemers LB, Meij BP, Tryfonidou MA. Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients. Osteoarthritis Cartilage. 2022 Dec 5:S1063-4584(22)00934-7. doi: 10.1016/j.joca.2022.11.008.

Tellegen A, Beukers M, Jansen I, van Klaveren N, How KL, Woike N, Mihov G, Thies J, Teske E, Creemers L, Tryfonidou M, Meij B. Intra-articular slow-release triamcinolone acetonide from polyesteramide microspheres as a treatment for osteoarthritis. Pharmaceutics. 2021 Mar 11;13(3):372 https://doi.org/10.3390/pharmaceutics13030372

Rudnik-Jansen I, Schrijver K, Woike N, Tellegen A, Versteeg S, Emans P, Mihov G, Thies J, Eijkelkamp N, Tryfonidou M, Creemers L. Intra-articular injection of triamcinolone acetonide releasing biomaterial microspheres inhibits pain and inflammation in an acute arthritis model. Drug Deliv. 2019 Dec;26(1):226-236. https://doi.org/10.1080/10717544.2019.1568625

Rudnik-Jansen I, Tellegen AR, Pouran B, Schrijver K, Meij BP, Emans PJ, de Gendt E, Thomas RE, Kik MJL, de Visser HM, Weinans H, Egas A, van Maarseveen E, Woike N, Mihov G, Thies J, Tryfonidou MA, Creemers LB. Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing. Br J Pharmacol. 2019 Oct;176(20):4050-4064. https://doi.org/10.1111/bph.14817

Rudnik-Jansen I, Tellegen A, Beukers M, Öner F, Woike N, Mihov G, Thies J, Meij B, Tryfonidou M, Creemers L. Safety of intradiscal delivery of triamcinolone acetonide by a poly(esteramide) microsphere platform in a large animal model of intervertebral disc degeneration. Spine J. 2019 May;19(5):905-919.

Rudnik-Jansen I, Woike N, de Jong S, Versteeg S, Kik M, Emans P, Mihov G, Thies J, Eijkelkamp N, Tryfonidou M, Creemers L. Applicability of a Modified Rat Model of Acute Arthritis for Long-Term Testing of Drug Delivery Systems. Pharmaceutics. 2019 Feb 7;11(2). https://doi.org/10.3390/pharmaceutics11020070

Tellegen AR, Rudnik-Jansen I, Pouran B, de Visser HM, Weinans HH, Thomas RE, Kik MJL, Grinwis GCM, Thies JC, Woike N, Mihov G, Emans PJ, Meij BP, Creemers LB, Tryfonidou MA. Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis. Drug Deliv. 2018 Nov;25(1):1438-1447 https://doi.org/10.1080/10717544.2018.1482971

Tellegen AR, Rudnik-Jansen I, Beukers M, Miranda-Bedate A, Bach FC, de Jong W, Woike N, Mihov G, Thies JC, Meij BP, Creemers LB, Tryfonidou MA. Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model. J Control Release. 2018 Sep 28;286:439-450. https://doi.org/10.1016/j.jconrel.2018.08.019

Tellegen AR, Willems N, Beukers M, Grinwis GCM, Plomp SGM, Bos C, van Dijk M, de Leeuw M, Creemers LB, Tryfonidou MA, Meij BP. Intradiscal application of a PCLA-PEG-PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What’s in it for humans? J Tissue Eng Regen Med. 2018 Mar;12(3):642-652).

Rudnik-Jansen I, Colen S, Berard J, Plomp S, Que I, van Rijen M, Woike N, Egas A, van Osch G, van Maarseveen E, Messier K, Chan A, Thies J, Creemers L. Prolonged inhibition of inflammation in osteoarthritis by triamcinolone acetonide released from a polyester amide microsphere platform. J Control Release. 2017 Mar 9;253:64-72. https://doi.org/10.1016/j.jconrel.2017.03.014

Willems N, Mihov G, Grinwis GC, van Dijk M, Schumann D, Bos C, Strijkers GJ, Dhert WJ, Meij BP, Creemers LB, Tryfonidou MA. Safety of intradiscal injection and biocompatibility of polyester amide microspheres in a canine model predisposed to intervertebral disc degeneration. J Biomed Mater Res B Appl Biomater. 2017 May;105(4):707-714. https://doi.org/10.1002/jbm.b.33579

Janssen M, Timur UT, Woike N, Welting TJ, Draaisma G, Gijbels M, van Rhijn LW, Mihov G, Thies J, Emans PJ. Celecoxib-loaded PEA microspheres as an auto regulatory drug-delivery system after intra-articular injection. 2016 J. Control. Release 244, 30–40. https://doi.org/10.1016/j.jconrel.2016.11.003

Willems N, Yang HY, Langelaan ML, Tellegen AR, Grinwis GC, Kranenburg HJ, Riemers FM, Plomp SG, Craenmehr EG, Dhert WJ, Papen-Botterhuis NE, Meij BP, Creemers LB, Tryfonidou MA. Biocompatibility and intradiscal application of a thermoreversible celecoxib-loaded poly-N-isopropylacrylamide MgFe-layered double hydroxide hydrogel in a canine model. 2015 Arthr Res Ther Aug 20;17(1):214. https://doi.org/10.1186/s13075-015-0727-x

Yang HY, van Dijk M, Licht R, Beekhuizen M, van Rijen M, Janstål MK, Öner FC, Dhert WJ, Schumann D, Creemers LB. Applicability of a newly developed bioassay for determining bioactivity of anti-inflammatory compounds in release studies–celecoxib and triamcinolone acetonide released from novel PLGA-based microspheres. Pharm Res. 2015 Feb;32(2):680-90.

Tellegen A, Beukers M, Jansen I, van Klaveren N, How KL, Woike N, Mihov G, Thies J, Teske E, Creemers L, Tryfonidou M, Meij B. Intra-articular slow-release triamcinolone acetonide from polyesteramide microspheres as a treatment for osteoarthritis. Pharmaceutics. 2021 Mar 11;13(3):372 https://doi.org/10.3390/pharmaceutics13030372

Rudnik-Jansen I, Schrijver K, Woike N, Tellegen A, Versteeg S, Emans P, Mihov G, Thies J, Eijkelkamp N, Tryfonidou M, Creemers L. Intra-articular injection of triamcinolone acetonide releasing biomaterial microspheres inhibits pain and inflammation in an acute arthritis model. Drug Deliv. 2019 Dec;26(1):226-236. https://doi.org/10.1080/10717544.2019.1568625

Rudnik-Jansen I, Tellegen AR, Pouran B, Schrijver K, Meij BP, Emans PJ, de Gendt E, Thomas RE, Kik MJL, de Visser HM, Weinans H, Egas A, van Maarseveen E, Woike N, Mihov G, Thies J, Tryfonidou MA, Creemers LB. Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing. Br J Pharmacol. 2019 Oct;176(20):4050-4064. https://doi.org/10.1111/bph.14817

Rudnik-Jansen I, Tellegen A, Beukers M, Öner F, Woike N, Mihov G, Thies J, Meij B, Tryfonidou M, Creemers L. Safety of intradiscal delivery of triamcinolone acetonide by a poly(esteramide) microsphere platform in a large animal model of intervertebral disc degeneration. Spine J. 2019 May;19(5):905-919.

Rudnik-Jansen I, Woike N, de Jong S, Versteeg S, Kik M, Emans P, Mihov G, Thies J, Eijkelkamp N, Tryfonidou M, Creemers L. Applicability of a Modified Rat Model of Acute Arthritis for Long-Term Testing of Drug Delivery Systems. Pharmaceutics. 2019 Feb 7;11(2). https://doi.org/10.3390/pharmaceutics11020070

Tellegen AR, Rudnik-Jansen I, Pouran B, de Visser HM, Weinans HH, Thomas RE, Kik MJL, Grinwis GCM, Thies JC, Woike N, Mihov G, Emans PJ, Meij BP, Creemers LB, Tryfonidou MA. Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis. Drug Deliv. 2018 Nov;25(1):1438-1447 https://doi.org/10.1080/10717544.2018.1482971

Tellegen AR, Rudnik-Jansen I, Beukers M, Miranda-Bedate A, Bach FC, de Jong W, Woike N, Mihov G, Thies JC, Meij BP, Creemers LB, Tryfonidou MA. Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model. J Control Release. 2018 Sep 28;286:439-450. https://doi.org/10.1016/j.jconrel.2018.08.019

Tellegen AR, Willems N, Beukers M, Grinwis GCM, Plomp SGM, Bos C, van Dijk M, de Leeuw M, Creemers LB, Tryfonidou MA, Meij BP. Intradiscal application of a PCLA-PEG-PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What’s in it for humans? J Tissue Eng Regen Med. 2018 Mar;12(3):642-652).

Rudnik-Jansen I, Colen S, Berard J, Plomp S, Que I, van Rijen M, Woike N, Egas A, van Osch G, van Maarseveen E, Messier K, Chan A, Thies J, Creemers L. Prolonged inhibition of inflammation in osteoarthritis by triamcinolone acetonide released from a polyester amide microsphere platform. J Control Release. 2017 Mar 9;253:64-72. https://doi.org/10.1016/j.jconrel.2017.03.014

Willems N, Mihov G, Grinwis GC, van Dijk M, Schumann D, Bos C, Strijkers GJ, Dhert WJ, Meij BP, Creemers LB, Tryfonidou MA. Safety of intradiscal injection and biocompatibility of polyester amide microspheres in a canine model predisposed to intervertebral disc degeneration. J Biomed Mater Res B Appl Biomater. 2017 May;105(4):707-714. https://doi.org/10.1002/jbm.b.33579

Janssen M, Timur UT, Woike N, Welting TJ, Draaisma G, Gijbels M, van Rhijn LW, Mihov G, Thies J, Emans PJ. Celecoxib-loaded PEA microspheres as an auto regulatory drug-delivery system after intra-articular injection. 2016 J. Control. Release 244, 30–40. https://doi.org/10.1016/j.jconrel.2016.11.003

Willems N, Yang HY, Langelaan ML, Tellegen AR, Grinwis GC, Kranenburg HJ, Riemers FM, Plomp SG, Craenmehr EG, Dhert WJ, Papen-Botterhuis NE, Meij BP, Creemers LB, Tryfonidou MA. Biocompatibility and intradiscal application of a thermoreversible celecoxib-loaded poly-N-isopropylacrylamide MgFe-layered double hydroxide hydrogel in a canine model. 2015 Arthr Res Ther Aug 20;17(1):214. https://doi.org/10.1186/s13075-015-0727-x

Yang HY, van Dijk M, Licht R, Beekhuizen M, van Rijen M, Janstål MK, Öner FC, Dhert WJ, Schumann D, Creemers LB. Applicability of a newly developed bioassay for determining bioactivity of anti-inflammatory compounds in release studies–celecoxib and triamcinolone acetonide released from novel PLGA-based microspheres. Pharm Res. 2015 Feb;32(2):680-90.

Degradable microspheres loaded with pain killing drugs are injected in the joint with osteoarthritis or in the intervertebral disc between the bony vertebral bodies in the spine. By slow diffusion and in the course of degradation of the microsphere polymer into natural components, the drugs are released over a long period of time into the joint and the intervertebral disc and exert their anti-inflammatory and pain killing effects.

Microsphere-based delivery of drugs in the osteoarthritic knee joint

Microsphere-based delivery of drugs in the degenerated intervertebral disc