Biji Balakrishnan

Self-crosslinked oxidized alginate/gelatin hydrogel as injectable, adhesive biomimetic scaffolds for cartilage regeneration

Biopolymeric hydrogels that mimic the properties of extracellular matrix have great potential in promoting cellular migration and proliferation for tissue regeneration. The authors reported earlier that rapidly gelling, biodegradable, injectable hydrogels can be prepared by self-crosslinking of periodate oxidized alginate and gelatin in the presence of borax, without using any toxic crosslinking agents. The present paper investigates the suitability of this hydrogel as a minimally invasive injectable, cell-attractive and adhesive scaffold for cartilage tissue engineering for the treatment of osteoarthritis. Time and frequency sweep rheology analysis confirmed gel formation within 20s. The hydrogel integrated well with the cartilage tissue, with a burst pressure of 70±3mmHg, indicating its adhesive nature. Hydrogel induced negligible inflammatory and oxidative stress responses, a prerequisite for the management and treatment of osteoarthritis. Scanning electron microscopy images of primary murine chondrocytes encapsulated within the matrix revealed attachment of cells onto the hydrogel matrix. Chondrocytes demonstrated viability, proliferation and migration within the matrix, while maintaining their phenotype, as seen by expression of collagen type II and aggrecan, and functionality, as seen by enhanced glycosoaminoglycan (GAG) deposition with time. DNA content and GAG deposition of chondrocytes within the matrix can be tuned by incorporation of bioactive signaling molecules such as dexamethasone, chondroitin sulphate, platelet derived growth factor (PDGF-BB) and combination of these three agents. The results suggest that self-crosslinked oxidized alginate/gelatin hydrogel may be a promising injectable, cell-attracting adhesive matrix for neo-cartilage formation in the management and treatment of osteoarthritis.

Carboxymethyl-chitosan-tethered lipid vesicles: hybrid nanoblanket for oral delivery of paclitaxel.

We describe the development and evaluation of a hybrid lipopolymeric system comprising carboxymethyl chitosan (CMC), covalently tethered to phosphatidylethanolamine units on the surface of lipid nanovesicles, for oral delivery of paclitaxel. The bioploymer is intended to act as a blanket, thereby shielding the drug from harsh gastrointestinal conditions, whereas the lipid nanovesicle ensures high encapsulation efficiency of paclitaxel and its passive targeting to tumor. CMC-tethered nanovesicles (LN-C-PTX) in the size range of 200-300 nm improved the gastrointestinal resistance and mucoadhesion properties as compared with unmodified lipid nanovesicles (LN-PTX). Conjugation of CMC did not compromise the cytotoxic potential of paclitaxel yet facilitated the interaction and uptake of the nanovesicles by murine melanoma (B16F10) cells through an ATP-dependent process. CMC-conjugated nanovesicles, upon oral administration in rats, improved the plasma concentration profile of paclitaxel, with 1.5 fold increase in its bioavailability and 5.5 folds increase in elimination half life in comparison with Taxol. We also found that CMC in addition to providing a gastric resistant coating also imparted stealth character to the nanovesicles, thereby reducing their reticuloendothelial system (RES)-mediated uptake by liver and spleen and bypassing the need for PEGylation. In vivo efficacy in subcutaneous model of B16F10 showed significantly improved tumor growth inhibition and survival with CMC-tethered nanovesicles as compared with unmodified nanovesicles, both administered orally. LN-C-PTX exhibited therapeutic efficacy comparable to Taxol and Abraxane and also showed reduced toxicity and improved survival. Overall, these results suggest the therapeutic potential of CMC tethered nanovesicles as a platform for oral administration of paclitaxel and also unravel the ability of CMC to impart stealth character to the nanoparticles, thereby preventing their RES clearance.

Borate aided Schiff's base formation yields in situ gelling hydrogels for cartilage regeneration

Injectable in situ forming, biodegradable and extracellular matrix (ECM) mimicking hydrogels have great possibilities in tissue engineering. Simple and easily translated methods, while circumventing toxicity, stability and scale-up issues, are in great demand for the preparation of these hydrogels. This paper aims to investigate how the borate complexation of oxidized carboxymethyl cellulose (CMC), followed by Schiffs reaction with gelatin without using any extraneous cross-linking agents can lead to the development of injectable, cost-effective, biodegradable ECM mimics for cartilage tissue engineering. Tuning of gelation kinetics and cross-linking density of the system is easily achievable by just adjusting the concentration of components. Hydrogels reveal porous structure, biodegradability and biocompatibility with negligible inflammatory response and minimal reactive oxygen species (ROS) generation. The hydrogel integrates well with host cartilage tissue, thereby stabilizing it and preventing further degeneration, which is essential for osteoarthritis management. Migration of chondrocytes seeded on the surface of the gel to the interior is envisaged as a cell attracting property of the matrix to guide tissue repair in cartilage defects. Chondrocytes exhibit cluster formation within the matrix and support proliferation and functionality. These results support the potential of this hydrogel as an injectable cost-effective matrix for cartilage tissue engineering.