Macro/Nano-Gel Composite as an Injectable and Bioactive Bulking Material for the Treatment of Urinary Incontinence

Abstract

Many women around the world are suffering from urinary incontinence, defined as the unintentional leakage of urine by external abnormal pressure. Although various kinds of materials have been utilized to treat this disease, therapies that are more effective are still needed for the treatment of urinary incontinence. Here, we present a macro/nanogel composed of in situ forming gelatin-based macrogels and self-assembled heparin-based nanogels, which can serve as an injectable and bioactive bulking material for the treatment of urinary incontinence. The hybrid hydrogels were prepared via enzymatic reaction in the presence of horseradish peroxidase and hydrogen peroxide. Incorporating a growth factor (GF)-loaded heparin nanogel into a gelatin gel matrix enabled the hybrid gel matrix to release GF continuously up to 28 days. Moreover, we demonstrated that the hydrogel composites stimulated the regeneration of the urethral muscle tissue surrounding the urethral wall and promoted the recovery of their biological function when injected in vivo. Thus, the macro/nanohydrogels may provide an advanced therapeutic technique for the treatment of urinary incontinence as well as an application for regenerative medicine.

Pharmacology of Heparin and Related Drugs

“…The heparin mimetic alginate-sulfate in an alginate hydrogel gives controlled release of HGF (Ruvinov et al, 2010) and improved tissue vascularization, intended for cardiovascular repair. Injectable gelatin/heparin gels loaded with growth factors have been devised to encourage urethral muscle development in urinary incontinence (Park et al, 2014).…”

Dual Enzyme-Triggered In Situ Crosslinkable Gelatin Hydrogels for Artificial Cellular Microenvironments

“…The authors synthesized and characterized GPT conjugates (tyramine contents, 146.6 μmol g −1 of polymer) as described in their previous work . The authors purchased horseradish peroxidase (HRP, type VI, salt‐free, 250−330 units mg −1 solid), GOx (type X‐S from Aspergullusniger, lyophilized powder, 100−250 units mg −1 solid), d ‐(+)‐glucose, and H 2 O 2 from Sigma Aldrich (St. Louis, MO, USA).…”

“…These reactions proceed under mild conditions and eventually lead to covalent bonds between specific functional group of polymer substrates . Among these, horseradish peroxide HRP)‐mediated crosslinking reaction has become an attractive method to create in situ forming hydrogels, due to its substrate specificity and efficiency, tunable reaction rate, controllable crosslinking density, mild reaction conditions, and biocompatibility . In this reaction, the interaction between HRP and hydrogen peroxide (H 2 O 2 ) initiates radical generation from phenol‐rich polymers, which in turn leads to rapid hydrogel formation through di‐phenol conjugation .…”

“…In this reaction, the interaction between HRP and hydrogen peroxide (H 2 O 2 ) initiates radical generation from phenol‐rich polymers, which in turn leads to rapid hydrogel formation through di‐phenol conjugation . As both HRP and H 2 O 2 contribute to controlling the degree of crosslinking, the roles of each of these reagents in designing in situ forming hydrogels have been well identified . In particular, H 2 O 2 plays a critical role as a crosslinking agent in controlling crosslinking density, being converted into water molecules in the HRP‐mediated oxidative reaction.…”

Thermoresponsive Nanogels Based on Different Polymeric Moieties for Biomedical Applications

“…The two main characteristics of nanogels are their small size (up to 1000 nm) and high swelling ratio or water content [ 46 ]. Due to these properties, nanogels have become an excellent platform in many medical applications, including photo-imaging [ 47 ], tissue regeneration [ 48 ], cancer therapy [ 49 ] and gene delivery [ 50 ]. This is based on their remarkable characteristics, such as their high capacity for drug entrapment and release [ 51 ], tailorable size [ 52 ], tuneable toxicity [ 53 ], high stability, controlled and sustained drug release [ 54 ], precise targeted delivery [ 55 ], and high biodegradability [ 56 ].…”