Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.

Intervertebral disc degeneration is characterized by a cascade of cellular, biochemical and structural changes that may lead to functional impairment and low back pain. Interleukin-1 beta (IL-1β) is strongly implicated in the etiology of disc degeneration, however there is currently no direct evidence linking IL-1β upregulation to downstream biomechanical changes. The objective of this study was to evaluate long-term agarose culture of nucleus pulposus (NP) cells as a potential in vitro model system to investigate this. Bovine NP cells were cultured in agarose for 49 days in a defined medium containing transforming growth factor-beta 3, after which both mechanical properties and composition were evaluated and compared to native NP. The mRNA levels of NP cell markers were compared to those of freshly isolated NP cells. Glycosaminoglycan (GAG) content, aggregate modulus and hydraulic permeability of mature constructs were similar to native NP, and aggrecan and SOX9 mRNA levels were not signifi cantly different from freshly isolated cells. To investigate direct links between IL-1β and biomechanical changes, mature agarose constructs were treated with IL-1β, and effects on biomechanical properties, extracellular matrix composition and mRNA levels were quantifi ed. IL-1β treatment resulted in upregulation of a disintegrin and metalloproteinase with thrombospondin motifs 4, matrix metalloproteinase-13 and inducible nitric oxide sythase, decreased GAG and modulus, and increased permeability. To evaluate the model as a test platform for therapeutic intervention, cotreatment with IL-1β and IL-1 receptor antagonist (IL-1ra) was evaluated. IL-1ra signifi cantly attenuated degradative changes induced by IL-1β. These results suggest that this in vitro model represents a reliable and cost-effective platform for evaluating new therapies for disc degeneration.

Obstructed transport of biological molecules can result in improper release of pharmaceuticals or biologics from biomedical devices. Recent studies have shown that nonionic surfactants, such as Pluronic® F68 (F68), positively alter biomaterial properties, such as mesh size and microcapsule diameter. To further understand the effect of F68 (incorporated at concentrations well above the critical micelle concentration (CMC)) in traditional biomaterials, the transport properties of BSA and riboflavin were investigated in F68-alginate composite hydrogels. Results indicate that small molecule transport (represented by riboflavin) was not significantly hindered by F68 in homogeneously crosslinked hydrogels (up to an 11% decrease in loading capacity and 14% increase in effective diffusion coefficient, Deff), while protein transport in homogeneously crosslinked hydrogels (represented by BSA) was significantly affected (up to a 43% decrease in loading capacity and 40% increase in Deff). For inhomogeneously crosslinked hydrogels (CaCl2 or BaCl2 gelation), the Deff increased up to 50% and 83% for small molecule and proteins, respectively. Variation in the alginate gelation method was shown to affect transport through measurable changes in swelling ratio (30% decrease) and observable changes in crosslinking structure as well as up to a 3.6 and 11.8-fold difference in Deff for riboflavin and BSA, respectively. The change in protein transport properties is a product of mesh size restrictions (10–25 nm estimated by mechanical properties) and BSA-F68 interaction (DLS). Taken as a whole, these results show that incorporation of a nonionic surfactant at concentrations above the CMC can affect device functionality by impeding the transport of large biological molecules.

Terminal, or postprocessing, sterilization of composite biomaterials is crucial for their use in wound healing and tissue-engineered devices. Recent research has focused on optimizing traditional biomaterial formulations to create better products for commercial and academic use which incorporate hydrophobic compounds or secondary gel networks. To use a hydrogel in a clinical setting, terminal sterilization is necessary to ensure patient safety. Lyophilization, gamma-irradiation, and ethylene oxide treatment all have negative consequences when applied to alginate scaffolds for clinical use. Here, we aim to find alternative terminal sterilization methods for alginate and alginate-based composite hydrogels which maintain the structure of composite alginate networks for use in biomedical applications. A thorough investigation of the effect of common sterilization methods on swollen alginate-based hydrogels has not been reported and therefore, this work examines autoclaving, ethanol washing, and ultraviolet light as sterilization techniques for alginate and alginate/Pluronic® F68 composite hydrogels. Preservation of structural integrity is evaluated using shear rheology and analysis of water retention, and efficacy of sterilization is determined via bacterial persistence within the hydrogel. Results indicate that ethanol sterilization is the best method of those investigated because ethanol washing results in minimal effects on mechanical properties and water retention and eliminates bacterial persistence. Furthermore, this study suggests that ethanol treatment is an efficacious method for terminally sterilizing interpenetrating networks or other composite hydrogel systems.

The oral administration of hematological factor IX can offer a convenient prophylactic treatment for hemophilia B patients. pH-Responsive hydrogels based on poly(methacrylic acid)-grafted-poly(ethylene glycol) (P(MAA-g-EG)) have been engineered as delivery vehicles for factor IX. In oral delivery, such hydrogel carriers protected factor IX from the gastric environment and released it under intestinal conditions as demonstrated by evaluation of the loading and release of factor IX. Tailoring of the hydrogel networks improved the loading of factor IX within the microcarriers, which is critical for minimizing protein degradation. Optimizing the loading conditions by increasing the incubation time and using a reduced ionic strength buffer further improved the delivery potential of the microcarriers. The presence of the microcarriers significantly enhanced the oral absorption of factor IX in vitro. As shown in this work, P(MAA-g-EG) microcarriers are promising candidates for the oral delivery of factor IX.