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Terlinden A, Jacquet S, Manivong S, Cullier A, Cassé F, Legendre F, Garcia AA, Roullin G, Moldovan F, Sirois P, Banquy X, Galéra P, Audigié F, Demoor M, Bertoni L. Double-blinded, randomized tolerance study of a biologically enhanced Nanogel with endothelin-1 and bradykinin receptor antagonist peptides via intra-articular injection for osteoarthritis treatment in horses. BMC Vet Res 2024; 20:547. [PMID: 39633332 PMCID: PMC11616385 DOI: 10.1186/s12917-024-04352-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 10/23/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Osteoarthritis is a leading cause of pain and retirement in athletic horses. Hydro-expansive functionalized nanogels, acting as Drug Delivery Systems, constitute one of the current therapeutic prospects. These nanogels have the potential to combine mechanical benefits through polymers with the biological effect of prolonged release of bioactive molecules. The purpose of this double-blinded randomized tolerance study versus negative control was to evaluate the response of healthy joints to a single injection of the expected efficient dose (further referred to as the trial dose) and overdose of nanogels composed of chitosan and hyaluronic acid and featuring a type A endothelin receptor antagonist and a type B1 bradykinin receptor antagonist. The metacarpophalangeal joints of 8 healthy horses were randomly injected with 2.4 mL of functionalized nanogels and 2.4 mL of saline as control on the contralateral limb. Injections were repeated twice at one-week intervals, followed by injection of a triple dose of nanogel on week four. Clinical, ultrasonographic and synovial fluid cellular and biochemical follow-ups were performed up to three months following the first injection. RESULTS No change in general clinical parameters, lameness or sensitivity to passive flexion of the fetlocks was noted. Mild to moderate synovitis was noted on the day following injection in the treated group, with a significant difference (p < 0.05) compared to the control group. It spontaneously resolved on day 3 following the injections and did not increase with repeated injections. Similar effects were noted after injection of the triple dose but lasted for a week. Synovial fluid markers of inflammation also showed a transient significant increase in the treated group one week after each injection, but no differences were detected at the end of the study. CONCLUSIONS Injections of the expected therapeutic dose of functionalized nanogel in healthy joints induced a mild transient inflammatory response in the joint. Three injections of the trial dose at one-week intervals and injection of thrice the trial dose induce a mildly greater inflammation without harmful effects on joints. Functionalized nanogels are well tolerated prospects for the treatment of osteoarthritis in horses. Their beneficial effects on arthritic joints have yet to be evaluated to determine their therapeutic potential.
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Affiliation(s)
- Antoinette Terlinden
- CIRALE, USC 957, BPLC, Ecole Nationale Vétérinaire d'Alfort, 94700, Maisons-Alfort, France
| | - Sandrine Jacquet
- CIRALE, USC 957, BPLC, Ecole Nationale Vétérinaire d'Alfort, 94700, Maisons-Alfort, France
| | - Seng Manivong
- Research Center Azrieli, CHU Sainte Justine, Montréal, QC, H3T 1C5, Canada
- Faculty of Dentistry, Université de Montréal, Montréal, QC, H3T 1J4, Canada
- Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada
| | - Aurélie Cullier
- Université de Caen Normandie, BIOTARGEN UR 7450, Normandie Univ, 14000, Caen, France
| | - Frédéric Cassé
- Université de Caen Normandie, BIOTARGEN UR 7450, Normandie Univ, 14000, Caen, France
| | - Florence Legendre
- Université de Caen Normandie, BIOTARGEN UR 7450, Normandie Univ, 14000, Caen, France
| | - Araceli Ac Garcia
- Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada
- TransMedTech Institute (NanoBio Technology Platform), Montréal, QC, H3T 1J4, Canada
| | - Gaëlle Roullin
- Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada
| | - Florina Moldovan
- Research Center Azrieli, CHU Sainte Justine, Montréal, QC, H3T 1C5, Canada
- Faculty of Dentistry, Université de Montréal, Montréal, QC, H3T 1J4, Canada
| | - Pierre Sirois
- Department of Microbiology and Immunology, Faculty of Medicine, Université Laval, Quebec City, QC, G1V 4G2, Canada
| | - Xavier Banquy
- Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada
| | - Philippe Galéra
- Université de Caen Normandie, BIOTARGEN UR 7450, Normandie Univ, 14000, Caen, France
| | - Fabrice Audigié
- CIRALE, USC 957, BPLC, Ecole Nationale Vétérinaire d'Alfort, 94700, Maisons-Alfort, France
| | - Magali Demoor
- Université de Caen Normandie, BIOTARGEN UR 7450, Normandie Univ, 14000, Caen, France.
| | - Lélia Bertoni
- CIRALE, USC 957, BPLC, Ecole Nationale Vétérinaire d'Alfort, 94700, Maisons-Alfort, France
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Liao HJ, Chen HT, Chang CH. Peptides for Targeting Chondrogenic Induction and Cartilage Regeneration in Osteoarthritis. Cartilage 2024:19476035241276406. [PMID: 39291443 PMCID: PMC11556548 DOI: 10.1177/19476035241276406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/19/2024] Open
Abstract
OBJECTS Osteoarthritis (OA) is a widespread degenerative joint condition commonly occurring in older adults. Currently, no disease-modifying drugs are available, and safety concerns associated with commonly used traditional medications have been identified. In this review, a significant portion of research in this field is concentrated on cartilage, aiming to discover methods to halt cartilage breakdown or facilitate cartilage repair. METHODS Researchers have mainly investigated the cartilage, seeking methods to promote its repair. This review focuses on peptide-based molecules known for their ability to selectively bind to growth factor cytokines and components of the cartilage extracellular matrix. RESULTS Chondroinductive peptides, synthetically producible, boast superior reproducibility, stability, modifiability, and yield efficiency over natural biomaterials. This review outlines a chondroinductive peptide design, molecular mechanisms, and their application in cartilage tissue engineering and also compares their efficacy in chondrogenesis in vitro and in vivo. CONCLUSIONS In this paper, we will summarize the application of peptides engineered to regenerate cartilage by acting as scaffolds, functional molecules, or both and discuss additional possibilities for peptides. This review article provides an overview of our current understanding of chondroinductive peptides for treating OA-affected cartilage and explores the delivery systems used for regeneration. These advancements may hold promise for enhancing or even replacing current treatment methodologies.
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Affiliation(s)
- Hsiu-Jung Liao
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City
| | - Hui-Ting Chen
- Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei
- Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung
| | - Chih-Hung Chang
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan
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Goswami A, Ruhina Rahman SN, Ponneganti S, Gangipangi V, Vavialala H, Radhakrishnanand P, Selvaraju S, Mutheneni SR, Bharti S, Shunmugaperumal T. Intratympanic injections of emulsion-like dispersions to augment cinnarizine amount in a healthy rabbit inner ear model. Nanomedicine (Lond) 2024; 19:1717-1741. [PMID: 39041668 PMCID: PMC11418292 DOI: 10.1080/17435889.2024.2373042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Aim: To investigate eutectic liquid-based emulsion-like dispersions for intratympanic injections to augment cinnarizine permeability across round window membrane in a healthy rabbit inner ear model.Methods: Two-tier systematic optimization was used to get the injection formula. The drug concentrations in perilymph and plasma were analyzed via. Ultra-performance liquid chromatography-tandem mass spectrometry method after 30-, 60-, 90- and 120-min post intratympanic injection time points in rabbits.Results: A shear-thinning behavior, immediate drug release (∼98.80%, 10 min) and higher cell viability (>97.86%, 24 h) were observed in dispersions. The cinnarizine level of 8168.57 ± 1236.79 ng/ml was observed in perilymph at 30 min post intratympanic injection in rabbits.Conclusion: The emulsion-like dispersions can augment drug permeability through round window membrane.
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Affiliation(s)
- Abhinab Goswami
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
| | - Syed Nazrin Ruhina Rahman
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
| | - Srikanth Ponneganti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
| | - Vijayakumar Gangipangi
- Department of Biotechnology, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
| | - Hariprasad Vavialala
- Bioinformatics Group, Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana500007, India
| | - Pullapanthula Radhakrishnanand
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
| | - Sudhagar Selvaraju
- Department of Biotechnology, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
| | - Srinivasa Rao Mutheneni
- Bioinformatics Group, Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana500007, India
| | - Shreekant Bharti
- Department of Pathology/Lab Medicine, All India Institute of Medical Sciences Patna, Phulwarisarif, Patna, Bihar801507, India
| | - Tamilvanan Shunmugaperumal
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research- Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup, Assam781101, India
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Walvekar P, Lulinski P, Kumar P, Aminabhavi TM, Choonara YE. A review of hyaluronic acid-based therapeutics for the treatment and management of arthritis. Int J Biol Macromol 2024; 264:130645. [PMID: 38460633 DOI: 10.1016/j.ijbiomac.2024.130645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 02/25/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Hyaluronic acid (HA), a biodegradable, biocompatible and non-immunogenic therapeutic polymer is a key component of the cartilage extracellular matrix (ECM) and has been widely used to manage two major types of arthritis, osteoarthritis (OA) and rheumatoid arthritis (RA). OA joints are characterized by lower concentrations of depolymerized (low molecular weight) HA, resulting in reduced physiological viscoelasticity, while in RA, the associated immune cells are over-expressed with various cell surface receptors such as CD44. Due to HA's inherent viscoelastic property and its ability to target CD44, there has been a surge of interest in developing HA-based systems to deliver various bioactives (drugs and biologics) and manage arthritis. Considering therapeutic benefits of HA in arthritis management and potential advantages of novel delivery systems, bioactive delivery through HA-based systems is beginning to display improved outcomes over bioactive only treatment. The benefits include enhanced bioactive uptake due to receptor-mediated targeting, prolonged retention of bioactives in the synovium, reduced expressions of proinflammatory mediators, enhanced cartilage regeneration, reduced drug toxicity due to sustained release, and improved and cost-effective treatment. This review provides an underlying rationale to prepare and use HA-based bioactive delivery systems for arthritis applications. With special emphasis given to preclinical/clinical results, this article reviews various bioactive-loaded HA-based particulate carriers (organic and inorganic), gels, scaffolds and polymer-drug conjugates that have been reported to treat and manage OA and RA. Furthermore, the review identifies several key challenges and provides valuable suggestions to address them. Various developments, strategies and suggestions described in this review may guide the formulation scientists to optimize HA-based bioactive delivery systems as an effective approach to manage and treat arthritis effectively.
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Affiliation(s)
- Pavan Walvekar
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa; Department of Pharmaceutics, SET's College of Pharmacy, Dharwad 580 002, Karnataka, India
| | - Piotr Lulinski
- Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Pradeep Kumar
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Tejraj M Aminabhavi
- School of Advanced Sciences, KLE Technological University, Hubballi 580031, Karnataka, India.
| | - Yahya E Choonara
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa.
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Kearney CM, Korthagen NM, Plomp SGM, Labberté MC, de Grauw JC, van Weeren PR, Brama PAJ. A Translational Model for Repeated Episodes of Joint Inflammation: Welfare, Clinical and Synovial Fluid Biomarker Assessment. Animals (Basel) 2023; 13:3190. [PMID: 37893914 PMCID: PMC10603652 DOI: 10.3390/ani13203190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/28/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
This study investigates repeated low-dose lipopolysaccharide (LPS) injections in equine joints as a model for recurrent joint inflammation and its impact on animal welfare. Joint inflammation was induced in eight horses by injecting 0.25 ng of LPS three times at two-week intervals. Welfare scores and clinical parameters were recorded at baseline and over 168 h post-injection. Serial synoviocentesis was performed for the analysis of a panel of synovial fluid biomarkers of inflammation and cartilage turnover. Clinical parameters and a final synoviocentesis were also performed eight weeks after the last sampling point to assess the recovery of normal joint homeostasis. Statistical methods were used to compare the magnitude of response to each of the 3 LPS inductions and to compare the baseline and final measurements. Each LPS injection produced consistent clinical and biomarker responses, with minimal changes in welfare scores. General matrix metalloproteinase (MMP) activity and joint circumference showed greater response to the second LPS induction, but response to the third was comparable to the first. Gylcosaminoglycans (GAG) levels showed a significantly decreased response with each induction, while collagen-cleavage neoepitope of type II collagen (C2C) and carboxypropetide of type II collagen epitope (CPII) showed quicker responses to the second and third inductions. All parameters were comparable to baseline values at the final timepoint. In conclusion, a consistent, reliable intra-articular inflammatory response can be achieved with repeated injections of 0.25 ng LPS, with minimal impact on animal welfare, suggesting potential as a refined translational model of recurrent joint inflammation.
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Affiliation(s)
- Clodagh M. Kearney
- UCD School of Veterinary Medicine, University College Dublin, D04 W6F6 Dublin, Ireland (P.A.J.B.)
| | - Nicoline M. Korthagen
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands (S.G.M.P.); (P.R.v.W.)
| | - Saskia G. M. Plomp
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands (S.G.M.P.); (P.R.v.W.)
| | - Margot C. Labberté
- UCD School of Veterinary Medicine, University College Dublin, D04 W6F6 Dublin, Ireland (P.A.J.B.)
| | - Janny C. de Grauw
- Department of Clinical Sciences and Services, Royal Veterinary College, University of London, Hatfield AL9 7TA, UK
| | - P. René van Weeren
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands (S.G.M.P.); (P.R.v.W.)
| | - Pieter A. J. Brama
- UCD School of Veterinary Medicine, University College Dublin, D04 W6F6 Dublin, Ireland (P.A.J.B.)
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Kamar SS, ShamsEldeen AM, Hosny SA, El-Shafei AA, Rashid LA, Hassanein RT, Hassan RM. Comparing Effectiveness of Hyaluronic Acid-Chitosan Nanoparticles Encapsulation Versus Hyaluronic Acid Monotherapy in Osteoarthritis Rat Model: Microarray Screening for miR-140. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2023; 29:686-697. [PMID: 37749722 DOI: 10.1093/micmic/ozac048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 11/02/2022] [Accepted: 12/04/2022] [Indexed: 09/27/2023]
Abstract
Osteoarthritis is a debilitating, progressive joint disease linked to lower quality of life and higher health care costs. This study compared hyaluronic acid-chitosan nanoparticle encapsulation to hyaluronic-acid monotherapy in a rat model of knee osteoarthritis. Four groups of 40 adult male albino rats were designed. Group (Gp) I: control; Gp II (osteoarthritis model): intra-articular injection of monoiodoacetate; Gp III (hyaluronic acid-treated): intra-articular injections of hyaluronic-acid on days 14 and 21 after monoiodoacetate injection; and Gp IV (hyaluronic acid-chitosan nanoparticle-treated): intra-articular injections of hyaluronic acid-chitosan nanoparticle on days 14 and 21 after monoiodoacetate injection. After 28 days, knee joints were examined using H&E, Safranin O, and immunohistochemistry for nuclear factor kappa beta (NF-κB), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase (MMP)-13. Quantification for gene expression of collagen-II, aggrecan, and micro-RNA-140; ELISA for interleukin (IL)-1β and IL-8; and western blotting for IKBα and NF-κB was estimated. Osteoarthritis-knee joints showed a severe cartilage damage and synovial inflammation with increased NF-κB, iNOS, and MMP-13 immunostaining, decreased miR-140, collagen II, and aggrecan levels, and increased inflammatory markers' gene expressions. The hyaluronic acid-chitosan nanoparticle significantly improved knee joint structure and reduced inflammatory cytokines compared to hyaluronic acid monotherapy. Intra-articular injection of hyaluronic acid-chitosan nanoparticle encapsulation revealed a significant improvement in the knee joint structure compared to hyaluronic-acid in a rat model of osteoarthritis.
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Affiliation(s)
- Samaa Samir Kamar
- Histology Department, Kasr Al-ainy Faculty of Medicine, Cairo University, Cairo 11559, Egypt
| | | | - Sara Adel Hosny
- Histology Department, Kasr Al-ainy Faculty of Medicine, Cairo University, Cairo 11559, Egypt
| | - Asmaa Ahmed El-Shafei
- Histology Department, Kasr Al-ainy Faculty of Medicine, Cairo University, Cairo 11559, Egypt
| | - Laila Ahmad Rashid
- Biochemistry Department, Kasr Al-ainy Faculty of Medicine, Cairo University, Cairo 11559, Egypt
| | - Radwa Taha Hassanein
- Biochemistry Department, Kasr Al-ainy Faculty of Medicine, Cairo University, Cairo 11559, Egypt
| | - Rokia Mohamad Hassan
- Histology Department, Kasr Al-ainy Faculty of Medicine, Cairo University, Cairo 11559, Egypt
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Manivong S, Cullier A, Audigié F, Banquy X, Moldovan F, Demoor M, Roullin VG. New trends for osteoarthritis: Biomaterials, models and modeling. Drug Discov Today 2023; 28:103488. [PMID: 36623796 DOI: 10.1016/j.drudis.2023.103488] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 12/26/2022] [Accepted: 01/03/2023] [Indexed: 01/08/2023]
Abstract
The burden of osteoarthritis (OA), one of the major causes of functional disabilities in humans and animals, continues to increase worldwide while no disease-modifying OA drugs (DMOADs) that either slow down or reverse disease progression have been made available. Here, we provide a brief overview of recent advances in: designing new OA drug delivery approaches, focusing on lubrication-based biomaterials and drug delivery systems, such as hydrogels, liposomes, dendrimers, micro- and nanoparticles; using either large (horse) or small (zebrafish) relevant animal models to evaluate new therapeutic strategies; and OA in vitro modeling, focusing on 3D (organoid) models of cartilage regarding the Replace, Reduce and Refine (3R) principle of animal experimentation.
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Affiliation(s)
- Seng Manivong
- Faculty of Pharmacy, Faculty of Dentistry, and CHU Sainte-Justine Research Centre, Université de Montréal, Montréal, QC, Canada
| | | | - Fabrice Audigié
- Center of Imaging and Research in Locomotor Affections on Equines, Veterinary School of Alfort, Goustranville, France
| | - Xavier Banquy
- Faculty of Pharmacy, Faculty of Dentistry, and CHU Sainte-Justine Research Centre, Université de Montréal, Montréal, QC, Canada
| | - Florina Moldovan
- Faculty of Pharmacy, Faculty of Dentistry, and CHU Sainte-Justine Research Centre, Université de Montréal, Montréal, QC, Canada
| | - Magali Demoor
- Normandie University, UNICAEN, BIOTARGEN, Caen, France.
| | - V Gaëlle Roullin
- Faculty of Pharmacy, Faculty of Dentistry, and CHU Sainte-Justine Research Centre, Université de Montréal, Montréal, QC, Canada.
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Kearney CM, Khatab S, van Buul GM, Plomp SGM, Korthagen NM, Labberté MC, Goodrich LR, Kisiday JD, Van Weeren PR, van Osch GJVM, Brama PAJ. Treatment Effects of Intra-Articular Allogenic Mesenchymal Stem Cell Secretome in an Equine Model of Joint Inflammation. Front Vet Sci 2022; 9:907616. [PMID: 35812845 PMCID: PMC9257274 DOI: 10.3389/fvets.2022.907616] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/20/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundAllogenic mesenchymal stem cell (MSC) secretome is a novel intra-articular therapeutic that has shown promise in in vitro and small animal models and warrants further investigation.ObjectivesTo investigate if intra-articular allogenic MSC-secretome has anti-inflammatory effects using an equine model of joint inflammation.Study DesignRandomized positively and negatively controlled experimental study.MethodIn phase 1, joint inflammation was induced bilaterally in radiocarpal joints of eight horses by injecting 0.25 ng lipopolysaccharide (LPS). After 2 h, the secretome of INFy and TNFα stimulated allogeneic equine MSCs was injected in one randomly assigned joint, while the contralateral joint was injected with medium (negative control). Clinical parameters (composite welfare scores, joint effusion, joint circumference) were recorded, and synovial fluid samples were analyzed for biomarkers (total protein, WBCC; eicosanoid mediators, CCL2; TNFα; MMP; GAGs; C2C; CPII) at fixed post-injection hours (PIH 0, 8, 24, 72, and 168 h). The effects of time and treatment on clinical and synovial fluid parameters and the presence of time-treatment interactions were evaluated. For phase 2, allogeneic MSC-secretome vs. allogeneic equine MSCs (positive control) was tested using a similar methodology.ResultsIn phase 1, the joint circumference was significantly (p < 0.05) lower in the MSC-secretome treated group compared to the medium control group at PIH 24, and significantly higher peak synovial GAG values were noted at PIH 24 (p < 0.001). In phase 2, no significant differences were noted between the treatment effects of MSC-secretome and MSCs.Main LimitationsThis study is a controlled experimental study and therefore cannot fully reflect natural joint disease. In phase 2, two therapeutics are directly compared and there is no negative control.ConclusionsIn this model of joint inflammation, intra-articular MSC-secretome injection had some clinical anti-inflammatory effects. An effect on cartilage metabolism, evident as a rise in GAG levels was also noted, although it is unclear whether this could be considered a beneficial or detrimental effect. When directly comparing MSC-secretome to MSCs in this model results were comparable, indicating that MSC-secretome could be a viable off-the-shelf alternative to MSC treatment.
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Affiliation(s)
- Clodagh M. Kearney
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
- *Correspondence: Clodagh M. Kearney
| | - Sohrab Khatab
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Gerben M. van Buul
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
- Beacon Hospital, Dublin, Ireland
| | - Saskia G. M. Plomp
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Nicoline M. Korthagen
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Margot C. Labberté
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Laurie R. Goodrich
- Equine Orthopaedic Research Center, Colorado State University, Fort Collins, CO, United States
| | - John D. Kisiday
- Equine Orthopaedic Research Center, Colorado State University, Fort Collins, CO, United States
| | - P. R. Van Weeren
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Gerjo J. V. M. van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
- Department of Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Pieter A. J. Brama
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
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Huang H, Lou Z, Zheng S, Wu J, Yao Q, Chen R, Kou L, Chen D. Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage. Drug Deliv 2022; 29:767-791. [PMID: 35261301 PMCID: PMC8920370 DOI: 10.1080/10717544.2022.2048130] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a progressive chronic inflammation that leads to cartilage degeneration. OA Patients are commonly given pharmacological treatment, but the available treatments are not sufficiently effective. The development of sustained-release drug delivery systems (DDSs) for OA may be an attractive strategy to prevent rapid drug clearance and improve the half-life of a drug at the joint cavity. Such delivery systems will improve the therapeutic effects of anti-inflammatory effects in the joint cavity. Whereas, for disease-modifying OA drugs (DMOADs) which target chondrocytes or act on mesenchymal stem cells (MSCs), the cartilage-permeable DDSs are required to maximize their efficacy. This review provides an overview of joint structure in healthy and pathological conditions, introduces the advances of the sustained-release DDSs and the permeable DDSs, and discusses the rational design of the permeable DDSs for OA treatment. We hope that the ideas generated in this review will promote the development of effective OA drugs in the future.
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Affiliation(s)
- Huirong Huang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zijian Lou
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shimin Zheng
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jianing Wu
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing Yao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ruijie Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Longfa Kou
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Daosen Chen
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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10
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Kruel AVS, Ribeiro LL, Gusmão PD, Huber SC, Lana JFSD. Orthobiologics in the treatment of hip disorders. World J Stem Cells 2021; 13:304-316. [PMID: 33959220 PMCID: PMC8080542 DOI: 10.4252/wjsc.v13.i4.304] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/26/2020] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Orthobiologics are biological materials that are intended for the regeneration or healing of bone, cartilage and soft tissues. In this review we discuss the use of orthobiologics for hip disorders providing an update. The orthobiologics included in this article are hyaluronic acid, platelet rich plasma, bone marrow, adipose tissue and expanded mesenchymal stem cells. We explain the concepts and definitions of each orthobiological product, and the literature regarding its use in the hip joint. The paucity of guidelines for the production and characterization of the biological products leads to uneven results across the literature. Each biologic therapy has indications and benefits; however, noteworthy are the characterization of the orthobiologics, the application method and outcome analysis for further improvement of each technique.
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Affiliation(s)
| | - Lucas Leite Ribeiro
- Department of Orthopedics, Instituto Médico Salus, São Paulo, SP 01308-050, Brazil
| | - Paulo David Gusmão
- Department of Orthopedics, the Bone and Cartilage Institute, Porto Alegre, RS 90570-020, Brazil
| | - Stephany Cares Huber
- Department of Hematology, University of Campinas, Campinas, SP 13334-170, Brazil
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11
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Bittar IP, Neves CA, Araújo CT, Oliveira YVR, Silva SL, Borges NC, Franco LG. Dose-Finding in the Development of an LPS-Induced Model of Synovitis in Sheep. Comp Med 2021; 71:141-147. [PMID: 33568256 DOI: 10.30802/aalas-cm-20-000032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Models of transient synovitis that can be controlled with antiinflammatory and analgesic drugs have been used to study pain amelioration. To this end, we aimed to determine the dose of intraarticularly administered E. coli LPS that induced signs of synovitis without systemic signs in clinically healthy male castrated sheep (n = 14). In phase 1, a single dose of LPS (0.5, 1.0, 1.5, or 2.0 ng in a total volume of 0.5 mL) was administered into the right stifle joint. In phase 2, a dose of LPS (1.0 or 2.0 μg) in 0.3 mL was administered to 4 naïve sheep. In phase 3, 4 sheep from phase 1 were inoculated after a 60 d washout period with either 0.5 or 1.0 μg of LPS. During the first 48 h after LPS administration, the following were performed: assessment of clinical parameters; scoring for lameness, pain on limb flexion, and local swelling; and ultrasonography of the joints were performed. The doses tested during phase 1 produced subtle signs. During phase 2, mild to moderate lameness with no evidence of systemic signs occurred at both doses. In phase 3, clinical responses were similar between the 0.5- and 1-μg doses. Signs of swelling were not observed at any time. Therefore, we consider the 0.5-μg to be the most appropriate for this model, because it was the lowest dose tested capable of causing lameness without signs of systemic inflammation in all animals.
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Affiliation(s)
- Isabela P Bittar
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil;,
| | - Carla A Neves
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil
| | - Caroline T Araújo
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil
| | - Yan V R Oliveira
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil
| | - Suelen L Silva
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil
| | - Naida C Borges
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil
| | - Leandro G Franco
- Department of Veterinary Medicine, School of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia, Brazil
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12
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Egan S, Kearney CM, Brama PA, Parnell AC, McGrath D. Exploring stable-based behaviour and behaviour switching for the detection of bilateral pain in equines. Appl Anim Behav Sci 2021. [DOI: 10.1016/j.applanim.2021.105214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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13
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Kearney CM, Korthagen NM, Plomp SGM, Labberté MC, de Grauw JC, van Weeren PR, Brama PAJ. Treatment effects of intra-articular triamcinolone acetonide in an equine model of recurrent joint inflammation. Equine Vet J 2020; 53:1277-1286. [PMID: 33280164 DOI: 10.1111/evj.13396] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/17/2020] [Accepted: 11/19/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Intra-articular triamcinolone acetonide is a widely used treatment for joint inflammation despite limited scientific evidence of its efficacy. OBJECTIVES To investigate if intra-articular triamcinolone acetonide has sustained anti-inflammatory effects using an equine model of repeated joint inflammation. STUDY DESIGN Randomised controlled experimental study. METHOD For three consecutive cycles 2 weeks apart, inflammation was induced in both middle carpal joints of eight horses by injecting 0.25 ng lipopolysaccharide (LPS). After the first LPS injection only, treatment with 12 mg triamcinolone acetonide (TA) followed in one randomly assigned joint, while the contralateral joint was treated with sterile saline (control). Clinical parameters (composite welfare scores, joint effusion, joint circumference) were recorded and synovial fluid samples were analysed for various biomarkers (total protein, WBCC; PGE2 ; CCL2; TNFα; MMP; GAGs; C2C; CPII) at fixed timepoints (post injection hours 0, 8, 24, 72 and 168). The effects of time and treatment on clinical and synovial fluid parameters and the presence of time-treatment interactions were tested using a linear mixed model for repeated measures with horse as a random effect, and time and treatment as fixed effects. RESULTS The TA treated joints showed significantly higher peak synovial GAG concentrations (Difference in means 283.1875 µg/mL, 95% CI 179.8, 386.6, P < 0.000), and PGE2 levels (Difference in means 77.8025 pg/mL, 95% CI 21.2, 134.4, P < 0.007) after the first inflammation induction. Significantly lower TP levels were seen with TA treatment after the second induction (Difference in means -7.5 g/L, 95% CI -14.8, -0.20, P < 0.04) . Significantly lower WBCC levels were noted with TA treatment after the first (Difference in means -23.7125 × 109 cells/L, 95% CI -46.7, -0.7, P < 0.04) and second (Difference in means -35.95 × 109 cells/L, 95% CI -59.0, -12.9, P < 0.002) inflammation inductions. Significantly lower general MMP activity was also seen with TA treatment after the second inflammation inductions (Difference in means -51.65 RFU/s, 95% CI -92.4, -10.9, P < 0.01). MAIN LIMITATIONS This experimental study cannot fully reflect natural joint disease. CONCLUSIONS In this model, intra-articular TA seems to have some anti-inflammatory activity (demonstrated by reductions in TP, WBCC and general MMP activity) up to 2 weeks post treatment but not at 4 weeks. This anti-inflammatory effect appeared to outlast a shorter-lived, potentially detrimental effect illustrated by increased synovial GAG and PGE2 levels after the first induction.
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Affiliation(s)
- Clodagh M Kearney
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Nicoline M Korthagen
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Saskia G M Plomp
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Margot C Labberté
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Janny C de Grauw
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - P R van Weeren
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Pieter A J Brama
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland
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14
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Sladek S, McCartney F, Eskander M, Dunne DJ, Santos-Martinez MJ, Benetti F, Tajber L, Brayden DJ. An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations when Combined with a Permeation Enhancer. Pharmaceutics 2020; 12:pharmaceutics12030259. [PMID: 32178442 PMCID: PMC7151133 DOI: 10.3390/pharmaceutics12030259] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/03/2020] [Accepted: 03/10/2020] [Indexed: 12/16/2022] Open
Abstract
The use of nanocarriers is being researched to achieve oral peptide delivery. Insulin-associated anionic polyelectrolyte nanoparticle complexes (PECs) were formed that comprised hyaluronic acid and chitosan in an optimum mass mixing ratio of 5:1 (MR 5), followed by coating with a pH-dependent polymer. Free insulin was separated from PECs by size exclusion chromatography and then measured by HPLC. The association efficiency of insulin in PECs was >95% and the loading was ~83 µg/mg particles. Dynamic light scattering and nanoparticle tracking analysis of PECs revealed low polydispersity, a negative zeta potential range of −40 to −50 mV, and a diameter range of 95–200 nm. Dissolution studies in simulated small intestinal fluid (FaSSIF-V2) revealed that the PECs were colloidally stable. PECs that were coated with Eudragit® L-100 delayed insulin release in FaSSIF-V2 and protected insulin against pancreatin attack more than uncoated PECs. Uncoated anionic PECs interacted weakly with mucin in vitro and were non-cytotoxic to Caco-2 cells. The coated and uncoated PECs, both concentrated further by ultrafiltration, permitted dosing of 50 IU/kg in rat jejunal instillations, but they failed to reduce plasma glucose or deliver insulin to the blood. When ad-mixed with the permeation enhancer (PE), sucrose laurate (100 mM), the physicochemical parameters of coated PECs were relatively unchanged, however blood glucose was reduced by 70%. In conclusion, the use of a PE allowed for the PEC-released bioactive insulin to permeate the jejunum. This has implications for the design of orally delivered particles that can release the payload when formulated with enhancers.
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Affiliation(s)
- Svenja Sladek
- UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; (S.S.); (F.M.)
| | - Fiona McCartney
- UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; (S.S.); (F.M.)
| | - Mena Eskander
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; (M.E.); (D.J.D.); (M.J.S.-M.); (L.T.)
| | - David J. Dunne
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; (M.E.); (D.J.D.); (M.J.S.-M.); (L.T.)
| | - Maria Jose Santos-Martinez
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; (M.E.); (D.J.D.); (M.J.S.-M.); (L.T.)
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
| | - Federico Benetti
- ECSIN Laboratory–Ecamricert Srl, Corso Stati Uniti 4, I-35127 Padova, Italy;
| | - Lidia Tajber
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; (M.E.); (D.J.D.); (M.J.S.-M.); (L.T.)
| | - David J. Brayden
- UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; (S.S.); (F.M.)
- Correspondence: ; Tel.: +353-1716-6013
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15
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Yu P, Xie J, Chen Y, Liu J, Liu Y, Bi B, Luo J, Li S, Jiang X, Li J. A thermo-sensitive injectable hydroxypropyl chitin hydrogel for sustained salmon calcitonin release with enhanced osteogenesis and hypocalcemic effects. J Mater Chem B 2020; 8:270-281. [PMID: 31802093 DOI: 10.1039/c9tb02049g] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Pharmacotherapy towards hypercalcemia treatment mainly caused by osteoporosis and bone tumor is an effective method to regulate in vivo calcium equilibrium. As a clinical therapeutic peptide, salmon calcitonin (sCT) is considered as a quick-acting medicine but it is limited by the short half-life. To address this challenge, we designed an injectable thermo-sensitive hydrogel based on hydroxypropyl chitin (HPCH) and incorporated the complex of sCT and hyaluronic acid (HA) (sCT-HA) with high association efficiency up to 96.84 ± 7.25%. This composite hydrogel showed a tunable biodegradable property. In vitro sCT release profiles revealed that this hydrogel can achieve long-term sustained sCT release (28 days) with considerable structure stability. The cellular study illustrated outstanding compatibility and osteoconductive potential of this multi-component hydrogel according to the higher ALP activity (2.10-fold), calcium expression (2.30-fold) and extracellular calcium deposition (1.10-fold) compared to that of the sCT group. In vivo sCT release confirmed that this hydrogel system realized sustained sCT release and a continuous hypocalcemic effect for as long as 28 days, and there were no inflammation and immune responses according to the histological evaluations (H&E and IgG staining). These findings demonstrate that this osteoconductive hydrogel system can provide a promising method for therapy of bone related disease.
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Affiliation(s)
- Peng Yu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China.
| | - Jing Xie
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China.
| | - Yu Chen
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China.
| | - Jinming Liu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China.
| | - Yanpeng Liu
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Research Center for Clinical Pharmacy, First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, P. R. China
| | - Bo Bi
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Jun Luo
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China.
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
| | - Xulin Jiang
- Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Jianshu Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, P. R. China.
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