Hyperbaric oxygen-generating hydrogels
Graphical abstract
Introduction
Polymeric hydrogels have been widely utilized as therapeutic vehicles and implants in a broad range of biomedical applications, such as tissue regenerative medicine, wound management, and drug delivery [[1], [2], [3], [4]]. In particular, in situ cross-linkable hydrogels have attracted substantial attention as injectable matrices owing to their tunable properties, minimal invasiveness, and easy encapsulation of therapeutic agents [5]. Recently, many researchers have endeavored to develop dynamic hydrogel matrices that can stimulate the surrounding tissues through various physical, chemical and biological changes when injected into the body. Many studies have demonstrated that the stimuli have been implicated as crucial factors in facilitating wound healing process and tissue repair [[6], [7], [8]].
Oxygen plays a critical role as a metabolic substrate and as a signaling molecule regulating cellular activities, including cell survival, proliferation, migration, and differentiation [9,10]. Growing evidence has demonstrated that oxygen is a crucial factor in wound healing and tissue regeneration, including inflammation, proliferation, collagen synthesis and angiogenesis [[11], [12], [13]]. In particular, an excess supply of oxygen or higher than a normal partial pressure of oxygen (defined as hyperoxia) has been shown to facilitate wound healing process and tissue regeneration. The hyperoxic condition elevates cellular oxygen levels and to temporally increase intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, which could promote wound healing processes such as proliferation and wound remodeling [[14], [15], [16]]. To date, various therapeutic approaches (e.g., hyperbaric oxygen therapy (HBOT) [17], oxygen carriers [[18], [19], [20]], and peroxide materials [[21], [22], [23]]) have been utilized as oxygen delivery systems for the treatment of wound and vascular disorders as well as tissue regenerative medicine applications. HBOT is currently in clinical use; however, it has limitations such as limited oxygen diffusion and pulmonary damage. Although oxygen carriers and peroxides have been widely used, surmounting some of their limitations, such as toxicity and burst release of oxygen, remains a challenge [24,25]. Although various oxygen-generating biomaterials have been developed, it is still challenging to develop advanced oxygen-delivering carriers that overcome these limitations.
Herein, we report a new type of oxygen-generating biomaterials, hyperbaric oxygen-generating (HOG) hydrogels, that can serve as a bioactive acellular matrix generating hyperbaric oxygen. We demonstrate that the HOG hydrogels rapidly generate oxygen at hyperbaric levels within the matrices and that oxygen was released from the hydrogels in a sustained manner. The HOG hydrogel enhances the proliferative activities of human dermal fibroblasts (HDFs) and endothelial cells (ECs) in vitro and promotes wound healing and repair with enhanced tissue ingrowth and neovascularization from the host tissues in vivo. We suggest that our HOG hydrogel is a promising oxygen-delivering carrier for the treatment of wound and vascular disorders as well as tissue regenerative medicine applications.
Section snippets
Materials
For polymer synthesis and hydrogel fabrication, gelatin (Gtn, type A from porcine skin, less than 300 bloom), 2-iminothiolane hydrochloride (Traut's reagent, TR), calcium peroxide (CaO2), anhydrous dimethyl sulfoxide (DMSO), deuterium oxide (D2O) and catalase (from bovine liver powder, 2000–5000 units/mg) were purchased from Sigma-Aldrich (Saint Louis, MO) and used as obtained without purification. Dulbecco's phosphate-buffered saline (DPBS) was supplied by Gibco (Grand Island, NY). Tris-HCl
Synthesis and characterization of GtnSH polymers
We first synthesized thiolated gelatin (GtnSH) polymers by conjugating Traut's reagent (TR) to a gelatin (Gtn) backbone (Fig. S1a) as previously reported [26]. We selected Gtn as the polymer backbone because of its various desirable properties, including biocompatibility, low cost, and easy modification, as well as its bioactivity [6,32,33]. The chemical structure of the GtnSH conjugates was characterized using proton nuclear magnetic resonance spectrometry (1H NMR). We found that the peak
Conclusion
This study developed a new class of biomaterial that can generate hyperbaric oxygen and act as an injectable and dynamic matrix. We designed gelatin-based HOG hydrogels that can form hydrogel networks in situ through a CaO2-mediated oxidative cross-linking reaction with oxygen generation. The HOG hydrogel has controllable physicochemical properties and oxygen generation by varying the CaO2 content. The HDFs and HUVECs treated with HOG hydrogels showed enhanced cell proliferative activities.
Author contributions
S.P. designed and performed research, analyzed data and wrote the paper; K.M.Park designed research, analyzed data and wrote the paper.
Disclosures
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2018M3A9E2023257) and by Incheon National University Research Grant in 2015.
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2023, Acta BiomaterialiaCitation Excerpt :Hyperbaric oxygen therapy (HBO2) has been extensively explored for direct oxygen delivery. This approach has been used clinically and also in an attempt to increase cellular oxygen concentration within engineered structures for several applications, such as wound healing and bone grafting [16,37,45–47]. Uncontrolled oxygen delivery via HBO2 limits its use for tissue engineering purposes, together with the fact that does not allow for the self-renew of oxygen production and cannot be used to target a specific site [37].