Extended and sequential delivery of protein from injectable thermoresponsive hydrogels

Abstract

Thermoresponsive hydrogels are attractive for their injectability and retention in tissue sites where they may serve as a mechanical support and as a scaffold to guide tissue remodeling. Our objective in this report was to develop a thermoresponsive, biodegradable hydrogel system that would be capable of protein release from two distinct reservoirs – one where protein was attached to the hydrogel backbone, and one where protein was loaded into biodegradable microparticles mixed into the network. Thermoresponsive hydrogels consisting of N-isopropylacrylamide (NIPAAm), 2-hydroxyethyl methacrylate (HEMA), and biodegradable methacrylate polylactide (MAPLA) were synthesized along with modified copolymers incorporating 1 mol% protein-reactive methacryloxy N,hydroxysuccinimide (MANHS), hydrophilic acrylic acid (AAc), or both. In vitro, bovine serum albumin (BSA) release was studied from hydrogels, poly(lactide-co-glycolide) microparticles, or microparticles mixed into the hydrogels. The synthesized copolymers were able to gel below 37°C and release protein in excess of 3 months. The presence of MANHS and AAc in the copolymers was associated with higher loaded protein retention during thermal transition (45% vs 22%) and faster release (2 months), respectively. Microspheres entrapped in the hydrogel released protein in a delayed fashion relative to microspheres in saline. The combination of a protein-reactive hydrogel mixed with protein-loaded microspheres demonstrated a sequential release of specific BSA populations. Overall, the described drug delivery system combines the advantages of injectability, degradability, extended release, and sequential release which may be useful in tissue engineering applications.

Swelling, thermal and mechanical properties of NIPAM-based terpolymeric hydrogel

“…Thermoresponsive hydrogels are those which respond to stimuli such as temperature and discussed by virtue of their potential uses in various fields of biotechnology, biomedical and drug delivery [1][2][3][4]. The thermoresponsive hydrogels are also used in separation science due to their swelling behavior in aqueous medium [5][6][7].…”

Spatially and temporally controlled hydrogels for tissue engineering

“…The field of tissue engineering and drug delivery has evolved from using simple hydrogel systems capable of releasing single molecules to designing advanced systems capable of releasing multiple molecules in a simultaneous or sequential manner [213–217]. The advancement in hydrogel fabrication techniques has extended our capacities to investigate biochemical signaling at the nanoscale level by the development of micro- and nanoscale delivery systems.…”

The Pharmacology of Regenerative Medicine

“…In addition to or instead of hydrolytic or proteolytic "internal triggers," it may be advantageous to have internal or external triggers such as pH change, temperature change, enzyme, ultrasound or other energy input, or light-triggered degradation (Balmayor et al, 2008;Narayanan et al, 2012;Nelson et al, 2012) (Fig. 7Bi).…”

“…These sequences may also be grafted into synthetic materials or natural materials that do not contain the sequences inherently (Connelly et al, 2011;Rafat et al, 2012;Sapir et al, 2011). (Bi) Internal bonds that are susceptible to cleavage through internal or external stimuli such as heat, pH, ultrasound, or light (Balmayor et al, 2008;Narayanan et al, 2012;Nelson et al, 2012) allow control over rates of degradation; (Bii) Nano-or microparticles may be also be incorporated into the scaffold (Biondi et al, 2009) and may slowly release their contents (typical for microparticles) or may themselves be released from the material (e.g., nanoparticles). A last important consideration in the material's degradation is the fashion by which it degrades.…”