H2O2-responsive short peptide hydrogel for joint cavity drug delivery开题报告

1. 研究目的与意义（文献综述包含参考文献）

H2O2 responsive short peptide hydrogel for joint cavity drug deliveryProposalOsteoarthritis is the most common form of arthritis that affects millions across the world today. It happens when over time the protective cartilage which cushions the ends of your bones wears down. While osteoarthritis can damage any joint, your hands, knees, hips and spine are most commonly affected by the disease. The most frequently affected joint is the knee, which causes significant weakness in 10 per cent of patients over 55 years of age. The key and first form of treatment for osteoarthritis is conservative therapies, including acetaminophen, nonsteroidal anti-inflammatory drugs, exercise, and weight loss; intraarticular injections have become more popular in recent years. The decline in intra-articular concentration and molecular weight of endogenous hyaluronic acid (HA) in osteoarthritis induces alterations in synovial fluid properties, which in turn triggers cartilage degeneration and symptom aggravation. Intra-articular HA injections were recommended for patients with osteoarthritis. In recent years, in particular in Asia, polyacrylamide hydrogels (PAH) have also gained popularity as an alternative.The joint cartilage is classified into the superficial, middle, deep and calcified areas. Such areas include different cell morphologies, configurations, ECM structural structures, and mechanical properties. Clinically, osteochondral injury with involvement of both the cartilage and subchondral layers is the most symptomatic cartilage damage. To model the intricate zonal architecture of the cartilage and the areas expected to be affected in the joint by osteochondral defects. The goal is develop a simple form of a multilayer matrix and investigated bilayer hydrogels by both 3D printing and projection of stereolithography to drug delivery. There are designed a PEG-based tri-layer hydrogel by Nguyen . Such tri-layer scaffolds contributed to the regeneration of osteochondral tissue with a cartilage surface rich in lubricin, similar to that of the native tissue.Hydrogels are cross-linked with 3D polymeric networks, they are especially swollen and porous, where different solutes and nutrients can be found and diffuse and with high water content. The ability to tune the gels' mechanical properties has become an increasingly important factor in the consideration of gel design. For biomedical applications, hydrogels are used in tissue engineering alone or in combination with cells. Hydrogels can be made of these polymers from natural, synthetic, or a combination of them. Injectable hydrogels can not only provide a biocompatible, biodegradable and highly hydrated 3D structure analogous to cartilaginous ECM and improve the supply of nutrients and cellular metabolites via elastic properties, but also encapsulate cells and deliver bioactive molecules efficiently and effectively through stimuli-responsive release mechanisms to targeted sites for cartilage regeneration. The main components of the extracellular matrix in cartilage are hyaluronic acid (HA), chondroitin sulfate (CS), and collagen. Also readily available are other natural polymers such as gelatin, alginate, and chitosan. Many naturally derived polymers, however, are mechanically poor, and are rapidly degraded. Biodegradable and biocompatible synthetic polymers such as poly(ethylene glycol) (PEG), polyvinyl alcohol (PVA), and poly(DL-lactic-co-glycolic acid) (PLGA) are, thus, often widely used in cartilage tissue engineering. These synthetic polymers are typically degraded by covalent bond hydrolysis; hydrolytic cleavage resistance varies, depending on the cleavage site's steric hindrance. Polycaprolactone, for example, can take as long as 24 months to undergo complete degradation. They also have comprehensive chemical modification possibilities for tuning the biological (e.g., cell-adhesive peptide conjugation), physical (e.g., pore size and swelling ratio), and mechanical properties of the hydrogels. Scientists are gradually endowing hydrogels with properties such as injectability and adhesivity to promote use in regeneration of cartilage tissue. Polyacrylamide hydrogels are biocompatible, high grade, synthetic polymers containing silver ions used as filling materials.From the latter half of the 20th century, the potential of hydrogels as efficient biomaterials has been documented, beginning with the use of non-degradable methacrylate gels to create soft contact lenses. People then researched hydrogels for various biomedical applications, including drug delivery, wound healing, and tissue engineering. Based on the source material (natural or synthetic) and biodegradability (biodegradable or non-biodegradable) hydrogels can be loosely categorized. Natural hydrophilic macromolecules which are used to make hydrogel scaffolds are often biodegradable and consist mainly of proteins and polysaccharides. Molecular hydrogels hold big potential for tissue engineering and controlled drug delivery. Our labfocuses on short-peptide-based molecular hydrogels formed by biocompatible methods and theirapplications in tissue engineering (especially, 3D cell culture) and controlled drug delivery. Molecular hydrogels hold great importance for tissue engineering and drug delivery control. Short-peptide molecular hydrogels developed through biocompatible methods and tissue engineering applications (especially 3D cell culture) and controlled drug delivery. It was showed that self-assembled structures based on peptides could be used as immune adjuvants and also initiated the use of peptide-based hydrogels in cell transplantation and regenerative medicine. Molecular hydrogels have been widely used as carriers for the delivery of therapeutic agents. Therapeutic agents may be physically stuck in hydrogels in the matrix of self-assembled nanofibers, or covalently bonded to hydrogelators via hydrolysable bonds. Hydrolysis of hydrolysable chemical bonds, diffusion, and enzymatic degradation of the gels can then extract the encapsulated therapeutic agents from the gels. In addition to the use of molecular hydrogels as carriers for the supply of therapeutic agents, molecular hydrogels of therapeutic agents or therapeutic agent derivatives have been identified as novel carrier-free self-delivery systems.Because of the accelerated release of the medications in joints, many treatments have limited effectiveness. On the other hand, injectable scaffolds of hydrogels can survive product release and improve the manufacturing time for the drug. Numerous studies have examined natural and synthetic biomaterials to build scaffolds with unique properties, such as enhanced joint articular dwelling with continuous drug release while enhancing delivery systems' biodegradation.Many approaches to intraarticular drug delivery have been investigated to maximize the shared residence time of local therapies. There is an explanation that even an autonomous drug delivery system, titrating drug release to current joint disease activity, could boost the therapeutic outcomes. The idea of hydrogel development has been to generate an intra-articular drug reservoir which releases drug in response to overexpressed enzymes in inflamed joints.According to their inherent advantages, such as ease of design and synthesis, good biocompatibility and degradability, peptide-based supramolecular hydrogels have drawn significant research interest in the last few decades. Therefore, because supramolecular hydrogels are formed by non-covalent interactions (hydrogen bond, ππ, hydrophobic, and charging interactions), they are extremely sensitive to external stimuli, including pH, light, enzymes, ions, and redox agents. Increasing numbers of intelligent responsive supramolecular hydrogels have been produced so far and have shown great promise in drug delivery applications, cancer cell inhibition, vaccine adjuvants, and essential analyte detection.Hydrogen peroxide (H2O2), as a second intracellular signal transduction messenger, is typically the product of molecular oxygen cell metabolism. It is retained at well-balanced concentration levels in most cases, and plays key roles in cell proliferation, cell differentiation, and cell migration. Overproduction of H2O2 can result in high oxidative stress and hence degradation of cellular structures. Many studies have shown that a variety of pathologies are associated with elevated H2O2 levels including asthma, cancer, cardiovascular disorders and neurodegenerative diseases. As a result, considerable efforts have been made to build H2O2 active nano-systems for controlled release of drugs to treat these diseases or to detect their over-production. These nano-systems are based mostly on the traditional peroxalate ester, which can react with H2O2. There are also several reports regarding H2O2 responsive supramolecular hydrogels. There is a report that Responsive peptide-based hydrogels containing a group of H2O2-reactive boronoarylmethoxycarbonyl and capable of maintaining encapsulated enzyme activity. It has been shown that the programmable hybridization of the hydrogel and oxidases allows the resulting materials to react not only to H2O2 molecules but also to a range of biomarkers related to disease.A novel H2O2 sensitive peptide hydrogelator containing the thiazolidinone group is developed and synthesized. Using a heating cooling process, a supramolecular hydrogel based on peptide self-assembly was prepared and its gel sol phase transformation could be activated by eliminating thiazolidinone groups upon oxidation of H2O2. LC-MS, rheology, and TEM studied the excellent H2O2 sensitive properties of the supramolecular hydrogel. A analysis of drug release in vitro showed that gel sol phase transition could be extended to sustainably and controllably release gemcitabine. It is useful for the H2O2 responsive property of our hydrogel suggested its potential application in controlled drug release. It can be used for possible application of controlled drug release, therefore, it might be used as potential delivery system for anticancer drug delivery to tumor sites.According to some researches, the hydrogel demonstrated an outstanding property that was sensitive to H2O2 and could release gemcitabine sustainably and controllably. The gelator can prevent the cleavage of ubiquitous in vivo esterases. However, because of a small improvement in the structure of the thiazolidinone-modified hydrogelator at H2O2 oxidation, the H2O2-response sensitivity of the hydrogelator produced by us was not as high as that of the peroxalate ester and boronoaryl groups and should be further enhanced in future research. Because of the significant importance of hydrogen peroxide (H2O2) in the metabolism, aging and disease of living organisms, enormous efforts have been made to establish H2O2 active materials to detect its over-production or controlled release of drugs. Although designing H2O2 sensitive supramolecular hydrogels is still difficult. The purpose is to develop a system that releases the drug on demand in response exclusively to inflammation with limited release under non-inflammatory conditions. The preparation method for hydrogel and drug encapsulation may be changed to minimize the amount of surface-absorbed drug or eliminate it before injection.To date, injectable scaffolds of hydrogels have provided a successful forum for cartilage regeneration therapy. As noted above, a variety of short peptide hydrogel scaffolds with intrinsic cartilaginous tissue engineering capabilities and adequate mechanical properties to heal cartilage defects have been established to restore normal joint function. Firstly, to increase the mechanical properties of scaffolds, conventional single-network hydrogels were augmented with either additional networks or polymer mixtures, and many nanocomposites were used to change the mechanical properties of scaffolds. These techniques have also been used to produce hydrogels that can enhance interaction with the underlying cartilage while facilitating the chondrogenesis of in vivo hydrogel encapsulated stem cells. Second, innovative formulations such as MPs and NPs have been studied in scaffolds for controlled drug distribution to improve the quality and length of delivery of growth factors or other medicinal substances. Such developments have spurred interest in the controllable analysis of biochemical signs.References: Shu Hui Hiew, Harini Mohanram, Lulu Ning, Jingjing Guo, Antoni Snchez-Ferrer, Xiangyan Shi, Konstantin Pervushin, Yuguang Mu, Raffaele Mezzenga, and Ali Miserez , A Short Peptide Hydrogel with High Stiffness Induced by 310‐Helices to β‐Sheet Transition in Water, (2019), https://doi.org/10.1002/advs.201901173 Li J, Chen G, Xu X, Abdou P, Jiang Q, Shi D, Gu Z. Advances of injectable hydrogel-based scaffolds for cartilage regeneration. Regen Biomater. 2019 Jun;6(3):129-140. doi: 10.1093/rb/rbz022. Epub 2019 May 25. PMID: 31198581; PMCID: PMC6547311. Wang, Huaimin Yang, Zhimou. (2012). Short-peptide-based molecular hydrogels: Novel gelation strategies and applications for tissue engineering and drug delivery. Nanoscale. 4. 5259-67. 10.1039/c2nr31149f. Chunhua Ren, Liping Chu, Fan Huang, Lijun Yang, Huirong Fan,* Jianfeng Liu and Cuihong Yang* (2017, 7, 1313) A novel H2O2 responsive supramolecular hydrogel for controllable drug release DOI: 10.1039/C6RA26536G (Paper) RSC Adv., 2017, 7, 1313-1317 Rachel H. Koh 1, , Yinji Jin 1, , Jisoo Kim 1 and Nathaniel S. Hwang, (2020) Inflammation-Modulating Hydrogels for Osteoarthritis Cartilage Tissue Engineering, Cells 2020, 9, 419; doi:10.3390/cells9020419 Tonbul M, Adas M, Bekmezci T, Kara AD. Intra-articular polyacrylamide hydrogel injections are not innocent. Case Rep Orthop. 2014;2014:150709. doi: 10.1155/2014/150709. Epub 2014 Aug 13. PMID: 25197596; PMCID: PMC4147293.

2. 研究的基本内容、问题解决措施及方案

Purpose: increase drug delivery in joint cavity through H2O2 short peptide hydrogel. To maximize the shared residence time of local therapies.The idea of hydrogel development has been to generate an intra-articular drug reservoir which releases drug in response to overexpressed enzymes in inflamed joints.Method: Using a heating cooling process, a supramolecular hydrogel based on peptide self-assembly was prepared and its gel sol phase transformation could be activated by eliminating thiazolidinone groups upon oxidation of H2O2.The preparation method for hydrogel and drug encapsulation: may be changed to minimize the amount of surface-absorbed drug or eliminate it before injection.