Degradation, intra-articular retention and biocompatibility of monospheres composed of [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers.
In this study, we investigated the use of microspheres with a narrow particle size distribution ('monospheres') composed of biodegradable poly(DL-lactide)-PEG-poly(DL-lactide)-b-poly(L-lactide) multiblock copolymers that are potentially suitable for local sustained drug release in articular joints. Monospheres with sizes of 5, 15 and 30μm and a narrow particle size distribution were prepared by a micro-sieve membrane emulsification process. During in vitro degradation, less crystallinity, higher swelling and accelerated mass loss during was observed with increasing the PEG content of the polymer. The monospheres were tested in both a small (mice/rat) and large animal model (horse). In vivo imaging after injection with fluorescent dye loaded microspheres in mice knees showed that monospheres of all sizes retained within the joint for at least 90days, while the same dose of free dye redistributed to the whole body within the first day after intra-articular injection. Administration of monospheres in equine carpal joints caused a mild transient inflammatory response without any clinical signs and without degradation of the cartilage, as evidenced by the absence of degradation products of sulfated glycosaminoglycans or collagen type 2 in the synovial fluid. The excellent intra-articular biocompatibility was confirmed in rat knees, where μCT-imaging and histology showed neither changes in cartilage quality nor quantity. Given the good intra-articular retention and the excellent biocompatibility, these novel poly(DL-lactide)-PEG-poly(DL-lactide)-b-poly(L-lactide)-based monospheres can be considered a suitable platform for intra-articular drug delivery.



This paper demonstrates the great potential in intra-articular drug delivery of monodisperse biodegradable microspheres which were prepared using a new class of biodegradable multi-block copolymers and a unique membrane emulsification process allowing the preparation of microspheres with a narrow particle size distribution (monospheres) leading to multiple advantages like better injectability, enhanced reproducibility and predictability of the in vivo release kinetics. We report not only on the synthesis and preparation, but also in vitro characterization, followed by in vivo testing of intra-articular biocompatibility of the monospheres in both a small and a large animal model. The favourable intra-articular biocompatibility combined with the prolonged intra-articular retention (>90days) makes these monospheres an interesting drug delivery platform. What should also be highlighted is the use of horses; a very accurate translational model for the human situation, making the results not only relevant for equine healthcare, but also for the development of novel human OA therapies.
Department of Orthopaedics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: m.sandker@erasmusmc.nl.
Maria J
MJ
Sandker
InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands. Electronic address: luisa.duque@fu-berlin.de.
Luisa F
LF
Duque
Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80163, 3508 TD Utrecht, The Netherlands. Electronic address: e.redout@uu.nl.
Everaldo M
EM
Redout
Percuros B.V., P.O. Box 217, 7500 AE Enschede, The Netherlands. Electronic address: achan@percuros.com.
Alan
A
Chan
Department of Radiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: I.que@lumc.nl.
Ivo
I
Que
Department of Radiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: c.w.g.m.lowik@lumc.nl.
Clemens W G M
CWGM
Löwik
InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands. Electronic address: klijnstra@innocorepharma.com.
Evelien C
EC
Klijnstra
Department of Orthopaedics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: n.kops@erasmusmc.nl.
Nicole
N
Kops
InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX Groningen, The Netherlands. Electronic address: r.steendam@innocorepharma.com.
Rob
R
Steendam
Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80163, 3508 TD Utrecht, The Netherlands. Electronic address: r.vanweeren@uu.nl.
Rene
R
van Weeren
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Postbus 80082, 3508 TB Utrecht, The Netherlands. Electronic address: w.e.hennink@uu.nl.
Wim E
WE
Hennink
Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; Department of Biomechanical Engineering TUDelft, Mekelweg 2, 2628 CD Delft, The Netherlands. Electronic address: h.h.weinans@umcutrecht.nl.
Harrie
H
Weinans
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D002356:Cartilage / Q000187:drug effects; D005453:Fluorescence; D006736:Horses; D007270:Injections, Intra-Articular; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008422:Materials Testing / Q000379:methods*; D051379:Mice; D008863:Microspheres; D008970:Molecular Weight; D010316:Particle Size; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D017208:Rats, Wistar; D013582:Synovial Fluid / Q000187:drug effects; D013696:Temperature; D055114:X-Ray Microtomography
D001672:Biocompatible Materials; D011091:Polyesters; D011092:Polyethylene Glycols; C033616:poly(lactide)
Anti-inflammatory; Biocompatibility; Biodegradable polymers; Intra-articular; Monodisperse microspheres