Enhanced Retention of rhBMP-2In Vivo by Thermoreversible Polymers

Abstract

Temperature‐sensitive polymers were prepared for in vivo delivery of recombinant human Bone Morphogenetic Protein‐2 (rhBMP‐2). The polymers were designed to overcome a critical limitation of current rhBMP‐2 delivery systems, namely to provide a mechanism for in situ retention of the protein. The polymers were based on N‐isopropylacrylamide (NiPAM). Ethyl methacrylate (EMA) and N‐acryloxysuccinimide (NASI) were incorporated into the NiPAM polymer to reduce the lower critical solution temperature and to conjugate to proteins, respectively. To test capacity of polymers to retain rhBMP‐2, rhBMP‐2 were labeled with 125I, formulated with the polymers and were either implanted with a collagen sponge or injected directly into an intramuscular site in rats. The results indicated that implantation with a relatively low polymer concentration (3.9 mg/mL) did not result in significant rhBMP‐2 retention, but increasing the polymer concentration (28.7 mg/mL) gave a better retention with NiPAM/NASI polymers. In the injectable mode, NiPAM/NASI and NiPAM/EMA gave ∼ 200‐fold better retention after 9 days in vivo. We conclude that synthetic, temperature‐sensitive polymers can be engineered to sequester and retain osteoinductive proteins at a site of administration. Devices with an enhanced osteopotency should result by delivering rhBMP‐2 with the prepared biomaterials.

Peri-implant reactivity and osteoinductive potential of immobilized rhBMP-2 on titanium carriers

“…Release rates of rhBMP-2, locally administered in rats, have been reported with half-lives between 2 and 4 days [29]. This is in agreement with release rates from collagen in vitro with halflives of 2-3 days [30]. Although the number of side effects is low, the application of rhBMP-2 in large amounts (e.g.…”

Synthetic Thermoreversible Polymers Are Compatible with Osteoinductive Activity of Recombinant Human Bone Morphogenetic Protein 2

“…5 The thermoreversible polymers were previously shown to be suitable for delivery of therapeutic proteins, 6 antithrombogenic agents, 7 and mammalian cells. 8 The thermoreversible feature of the polymers allows one to carry out desired manipulations in a solution phase but eventually a solid phase can be induced on exposure to a temperature above the transition temperature of the polymers (also known as the lower critical solution temperature, LCST).…”

“…10,11 When a select group of thermoreversible polymers was used to deliver rhBMP-2, in vivo rhBMP-2 retention was found to depend on the physicochemical properties of the polymers as well as the polymer concentration. 5 The choice of the delivery mode, injectable as a solution versus implantable with a collagen carrier, was also influential, the former giving improved retention. 5 Irrespective of the rhBMP-2 retention, however, it is critical that the polymers be compatible with the rhBMP-2-induced osteoinductive activity.…”

“…5 The choice of the delivery mode, injectable as a solution versus implantable with a collagen carrier, was also influential, the former giving improved retention. 5 Irrespective of the rhBMP-2 retention, however, it is critical that the polymers be compatible with the rhBMP-2-induced osteoinductive activity.…”

“…The implant system was chosen so that the retention of the proteins was not affected. 5 It was our aim to test the bioactivity of rhBMP-2 in the absence of retention effects so that the only variable influencing osteoinductive activity was the presence of polymers.…”