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Hense D, Strube OI. Glutaraldehyde Cross-Linking of Salt-Induced Fibrinogen Hydrogels. ACS Biomater Sci Eng 2024; 10:6927-6937. [PMID: 39422201 PMCID: PMC11558561 DOI: 10.1021/acsbiomaterials.4c01412] [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: 07/30/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/19/2024]
Abstract
Covalent cross-linking is a common strategy to improve the mechanical properties of biological polymers. The most prominent field of application of such materials is in medicine, for example, in the form of bioprinting, drug delivery, and wound sealants. One biological polymer of particular interest is the blood clotting protein fibrinogen. In the natural process, fibrinogen polymerizes to fibrous hydrogel fibrin. Although the material shows great potential, its costs are very high due to the required enzyme thrombin. Recently, we introduced several approaches to trigger a thrombin-free fibrillogenesis of fibrinogen to a fibrin-like material. Inspired by the natural pathway of blood clotting in which covalent cross-linking stabilizes the clot, this "pseudofibrin" is now developed even further by covalently cross-linking the fibers. In particular, the effect of inexpensive glutaraldehyde on fiber morphology, rheological properties, and irreversible gel dissolution is investigated. Additionally, new insights into the reaction kinetics between fibrinogen and glutaraldehyde are gained. It could be shown that the fibrous structure of pseudofibrin can be retained during cross-linking and that glutaraldehyde significantly improves rheological properties of the hydrogels. Even more important, cross-linking with glutaraldehyde can prevent dissolution of the gels at elevated temperatures.
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Affiliation(s)
- Dominik Hense
- Institute for Chemical Engineering, University of Innsbruck, Innrain 80-82, Innsbruck, AT 6020, Austria
| | - Oliver I. Strube
- Institute for Chemical Engineering, University of Innsbruck, Innrain 80-82, Innsbruck, AT 6020, Austria
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2
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Nguyen DV, Yuan Y, Kukumberg M, Wang L, Lim SH, Hassanbhai AM, Chong M, Kofidis T, Tan ECK, Seliktar D, Kang L, Rufaihah AJ. Controlled release of vancomycin from PEGylated fibrinogen polyethylene glycol diacrylate hydrogel. BIOMATERIALS ADVANCES 2024; 161:213896. [PMID: 38795473 DOI: 10.1016/j.bioadv.2024.213896] [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: 12/22/2023] [Revised: 04/29/2024] [Accepted: 05/14/2024] [Indexed: 05/28/2024]
Abstract
Surgical site infection (SSI) is a common issue post-surgery which often prolongs hospitalization and can lead to serious complications such as sternal wound infection following cardiac surgery via median sternotomy. Controlled release of suitable antibiotics could allow maximizing drug efficacy and safety, and therefore achieving a desired therapeutic response. In this study, we have developed a vancomycin laden PEGylated fibrinogen-polyethylene glycol diacrylate (PF-PEGDA) hydrogel system that can release vancomycin at a controlled and predictable rate to be applied in SSI prevention. Two configurations were developed to study effect of the hydrogel on drug release, namely, vancomycin laden hydrogel and vancomycin solution on top of blank hydrogel. The relationship between the rigidity of the hydrogel and drug diffusion was found to comply with a universal power law, i.e., softer hydrogels result in a greater diffusion coefficient hence faster release rate. Besides, vancomycin laden hydrogels exhibited burst release, whereas the vancomycin solution on top of blank hydrogels exhibited lag release. A mathematical model was developed to simulate vancomycin permeation through the hydrogels. The permeation of vancomycin can be predicted accurately by using the mathematical model, which provided a useful tool to customize drug loading, hydrogel thickness and stiffness for personalized medication to manage SSI. To evaluate the potential of hydrogels for bone healing applications in cardiovascular medicine, we performed a proof-of-concept median sternotomy in rabbits and applied the hydrogels. The hydrogel formulations accelerated the onset of osteo-genetic processes in rabbits, demonstrating its potential to be used in human.
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Affiliation(s)
- Duc-Viet Nguyen
- Nusmetics Pte Ltd., 3791 Jalan Bukit Merah, E-Centre@Redhill, Singapore 159471, Singapore
| | - Yunong Yuan
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, Science Road, NSW 2006, Australia
| | - Marek Kukumberg
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 8, Singapore 119228, Singapore; Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 12, Singapore 119228, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Lingxin Wang
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, Science Road, NSW 2006, Australia
| | - Seng Han Lim
- Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Block S4A, Level 3, Singapore 117543, Singapore
| | - Ammar Mansoor Hassanbhai
- Osteopore International Pte Ltd, 2 Tukang Innovation Grove #09-06, MedTech Hub, Singapore 618305, Singapore
| | - Mark Chong
- College of Design and Engineering, National University of Singapore, 5 Engineering Drive 2, Block E2A, #04-05, Singapore 117579, Singapore
| | - Theodoros Kofidis
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 8, Singapore 119228, Singapore
| | - Edwin C K Tan
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, Science Road, NSW 2006, Australia
| | - Dror Seliktar
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Lifeng Kang
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, Science Road, NSW 2006, Australia.
| | - Abdul Jalil Rufaihah
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 8, Singapore 119228, Singapore; School of Applied Science, Temasek Polytechnic, 21 Tampines Avenue 1, Block 8, Level 3, Singapore 529757, Singapore.
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3
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Acebes-Huerta A, Martínez-Botía P, Carbajo-Argüelles G, Fernández-Fuertes J, Muñoz-Turrillas MC, Ojea-Pérez AM, López-Vázquez A, Eble JA, Gutiérrez L. Characterization of the molecular composition and in vitro regenerative capacity of platelet-based bioproducts and related subfractions. Acta Biomater 2024; 177:132-147. [PMID: 38311196 DOI: 10.1016/j.actbio.2024.01.029] [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: 03/13/2023] [Revised: 12/29/2023] [Accepted: 01/19/2024] [Indexed: 02/10/2024]
Abstract
The use and demand of platelet-based bioproducts in regenerative medicine is steadily increasing. However, it is very difficult to establish the real clinical benefits of these therapies, as the lack of characterization and detailed production methods of platelet-based bioproducts persists in the literature and precludes cross-study comparisons. We characterized the molecular composition and in vitro regenerative capacity of platelet-rich plasma (PRP) produced in a closed-system. Furthermore, we performed a parallel characterization on different PRP subfractions (plasma and plasma-free platelet lysate), identifying that the fractions containing platelet-derived cargo exert the most potent regenerative capacity. This observation led us to develop a method to obtain a platelet secretome highly enriched in growth factors, free of plasma and cellular components (PCT/IB2022/057936), with the aim of establishing a superior bioproduct. The molecular characterization of secretomes revealed agonist-dependent differences, which correlates with beneficial grades of regenerative capacity. Importantly, secretomes showed general superiority to PRP in vitro. We discuss the variables influencing the bioproduct quality (inter-donor variation, platelet source and processing methods). Finally, we propose that the characteristics of secretomes circumvents certain limitations of PRP (autologous vs allogeneic), and envision that optimizing post-processing protocols (nanoencapsulation, lyophilization), would allow their clinical application even beyond regenerative medicine. STATEMENT OF SIGNIFICANCE: The use and demand of platelet-based bioproducts in regenerative medicine is steadily increasing. However, it is very difficult to establish the real clinical benefits of these therapies, or to improve/personalize them, as the lack of characterization of the bioproducts and their production methods is a constant in the literature, reason that precludes cross-study comparisons. In the present manuscript, we provide a comprehensive molecular and functional characterization of platelet-based bioproducts and subfractions, including platelet rich plasma, plasma fractions and platelet secretomes produced with a methodology developed by our group. Our results show that the molecular composition of each fraction correlates with its regenerative capacity in vitro. Thus, a rigorous characterization of platelet-derived bioproducts will potentially allow universal use, customizing and new applications.
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Affiliation(s)
- Andrea Acebes-Huerta
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Department of Medicine, University of Oviedo, Spain
| | - Patricia Martínez-Botía
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Graciela Carbajo-Argüelles
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Judit Fernández-Fuertes
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Department of Orthopedics and Trauma Surgery, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain; Department of Surgery and Medical Surgical Specialties, University of Oviedo, Spain
| | - María Carmen Muñoz-Turrillas
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Centro Regional de Transfusión de Toledo-Guadalajara, Spain
| | | | - Antonio López-Vázquez
- Department of Immunology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Johannes A Eble
- Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Germany
| | - Laura Gutiérrez
- Platelet Research Lab, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Department of Medicine, University of Oviedo, Spain.
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Morey M, Larrañaga A, Abbah SA, Bohara R, Aljaabary A, Pandit A. Glucose-Responsive Fibrin Hydrogel-Based Multimodal Nucleic Acid Delivery System. Adv Biol (Weinh) 2023; 7:e2300161. [PMID: 37401646 DOI: 10.1002/adbi.202300161] [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: 04/27/2023] [Indexed: 07/05/2023]
Abstract
Nucleic acid therapy has emerged as a potential alternative for promoting wound healing by gene expression modification. On the other hand, protecting the nucleic acid payload from degradation, efficient bioresponsive delivery and effective transfection into cells remain challenging. A glucose-responsive gene delivery system for treating diabetic wounds would be advantageous as it would be responsive to the underlying pathology giving a regulated payload delivery with fewer side effects. Herein a GOx-based glucose-responsive delivery system is designed based on fibrin-coated polymeric microcapsules (FCPMC) using the layer-by-layer (LbL) approach that simultaneously delivers two nucleic acids in diabetic wounds. The designed FCPMC displays an ability to effectively load many nucleic acids in polyplexes and release it over a prolonged period with no cytotoxic effects seen in in vitro studies. Furthermore, the developed system does not show any undesired effects in vivo. When applied to wounds in genetically diabetic db/db mice, the fabricated system on its own improves reepithelialization and angiogenesis while decreasing inflammation. Also, key proteins involved in the wound healing process, i.e., Actn2, MYBPC1, and desmin, are upregulated in the glucose-responsive fibrin hydrogel (GRFHG) treated group of animals. In conclusion, the fabricated hydrogel promotes wound healing. Furthermore, the system may be encapsulated with various therapeutic nucleic acids that aid wound healing.
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Affiliation(s)
- Mangesh Morey
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Aitor Larrañaga
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Sunny Akogwu Abbah
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Raghvendra Bohara
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Amal Aljaabary
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Abhay Pandit
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
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5
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Afzal Z, Huguet EL. Bioengineering liver tissue by repopulation of decellularised scaffolds. World J Hepatol 2023; 15:151-179. [PMID: 36926238 PMCID: PMC10011915 DOI: 10.4254/wjh.v15.i2.151] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/22/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Liver transplantation is the only curative therapy for end stage liver disease, but is limited by the organ shortage, and is associated with the adverse consequences of immunosuppression. Repopulation of decellularised whole organ scaffolds with appropriate cells of recipient origin offers a theoretically attractive solution, allowing reliable and timely organ sourcing without the need for immunosuppression. Decellularisation methodologies vary widely but seek to address the conflicting objectives of removing the cellular component of tissues whilst keeping the 3D structure of the extra-cellular matrix intact, as well as retaining the instructive cell fate determining biochemicals contained therein. Liver scaffold recellularisation has progressed from small rodent in vitro studies to large animal in vivo perfusion models, using a wide range of cell types including primary cells, cell lines, foetal stem cells, and induced pluripotent stem cells. Within these models, a limited but measurable degree of physiologically significant hepatocyte function has been reported with demonstrable ammonia metabolism in vivo. Biliary repopulation and function have been restricted by challenges relating to the culture and propagations of cholangiocytes, though advances in organoid culture may help address this. Hepatic vasculature repopulation has enabled sustainable blood perfusion in vivo, but with cell types that would limit clinical applications, and which have not been shown to have the specific functions of liver sinusoidal endothelial cells. Minority cell groups such as Kupffer cells and stellate cells have not been repopulated. Bioengineering by repopulation of decellularised scaffolds has significantly progressed, but there remain significant experimental challenges to be addressed before therapeutic applications may be envisaged.
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Affiliation(s)
- Zeeshan Afzal
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Laurent Huguet
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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6
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Ngarande E, Doubell E, Tamgue O, Mano M, Human P, Giacca M, Davies NH. Modified fibrin hydrogel for sustained delivery of RNAi lipopolyplexes in skeletal muscle. Regen Biomater 2022; 10:rbac101. [PMID: 36726610 PMCID: PMC9887344 DOI: 10.1093/rb/rbac101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 11/02/2022] [Accepted: 11/24/2022] [Indexed: 12/15/2022] Open
Abstract
RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues. Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers. Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine® 3.0, a lipid nonviral transfection vector, for local and sustained release. PEGylation of fibrin allowed for controlled release of small interfering RNA (siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo. A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days. Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth. Thus, the increased efficacy observed here for the combination of a lipid nanoparticle, the only type of nonviral vector approved for the clinic, with fibrin, might allow for more rapid translation of injectable hydrogel-based RNA interference.
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Affiliation(s)
- Ellen Ngarande
- Cardiovascular Research Unit, Department of Surgery, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Emma Doubell
- Cardiovascular Research Unit, Department of Surgery, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
| | | | - Manuel Mano
- King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, WC2R 2LS, London, UK
| | - Paul Human
- Cardiovascular Research Unit, Department of Surgery, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Mauro Giacca
- King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, WC2R 2LS, London, UK
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7
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Abdelrahman TA, Motawea A, El-Dahhan MS, Abdelghani GM. Chitosan-dipotassium orthophosphate lyophilizate: a novel in situ thermogel carrier system of allogeneic platelet lysate growth factors. Drug Deliv 2022; 29:413-426. [PMID: 35098833 PMCID: PMC8812773 DOI: 10.1080/10717544.2022.2030429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The clinical success of platelet-rich plasma (PRP) is constrained by its limited mechanical strength, rapid disintegration by lytic enzymes, and the consequent short-term release of bioactive growth factors (GFs). Recently, attempts to formulate PRP and other hemoderivatives, such as platelet lysate (PL) have been underway. The current study aimed to formulate allogeneic freeze-dried human platelet lysate (HPL) onto lyophilized chitosan - dipotassium hydrogen orthophosphate (CS/DHO) thermo-sensitive scaffolds. A systemic approach was employed to optimize freeze-drying (FD) procedures targeting predefined critical quality attributes (CQAs). Thermal behavior, vibrational spectroscopy, morphological and moisture content analyses were used to detect possible protein destabilization during formulation and suboptimal cake properties. The effect of CS/DHO concentrations on thermo-responsiveness and release kinetics were investigated. Finally, six-months stability and cytotoxicity studies were carried out. An optimized lyophilizate was attainable with residual moisture of less than 5% and thermoresponsive to 33 °C in less than 3 min. HPL proteins were sustainedly released over five days in a pH-sensitive manner. The stability study indicated plausible physical and biochemical stability. Cell viability testing supported the cytocompatibility of the system. Finally, the lyophilizate variant of CS/DHO thermogel overcomes limited storage stability previously posed as a challenge in freshly prepared thermogels. The developed system overcomes the drawbacks of currently used PRP treatment and provides a novel GF-rich scaffold for wound repair.
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Affiliation(s)
- Toaa A Abdelrahman
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Amira Motawea
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Marwa S El-Dahhan
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Galal M Abdelghani
- Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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8
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Zastosowanie fibryny w inżynierii tkankowej. Osiągnięcia i perspektywy. POSTEP HIG MED DOSW 2021. [DOI: 10.2478/ahem-2021-0017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstrakt
W ostatnich latach istotnym obszarem zastosowania fibryny stała się inżynieria tkankowa, w której wykorzystuje się naturalne właściwości biostatyczne i bioaktywne fibryny, a także możliwość pułapkowania i wiązania w jej strukturze czynników wzrostu. Fibryna jest najczęściej stosowana w postaci żeli i dysków. Jednak każda postać wskutek pochłaniania wody docelowo przyjmuje postać żelu. Białko to w warunkach in vivo spełnia rolę rusztowania dla komórek, a także może być aplikowane w miejsca trudno dostępne – może wypełniać ubytki tkanek i podtrzymywać tkanki okalające, zapobiegając ich zapadaniu się. Ponadto fibryna hamuje krwawienie i inicjuje proces odnowy, jak również pełni rolę stymulatora wzrostu komórek. Przez modyfikacje struktury fibryny cząsteczkami adhezyjnymi, można przyspieszyć odbudowę prawidłowej struktury tkanek. Jej właściwości strukturalne mogą być także wykorzystywane jako rezerwuar czynników wzrostu i system ich przedłużonego uwalniania. Fibryna jest materiałem biodegradowalnym, umożliwiając skorelowanie ubytku matrycy fibrynowej z odbudową tkanek własnych pacjenta. Wprowadzenie metod druku 3D i elektroprzędzenia umożliwia formulację dopasowanych do uszkodzeń kształtek oraz włóknin bez utraty bioaktywnych funkcji fibryny. Metody te umożliwiają także poprawę właściwości mechanicznych przez otrzymywanie m.in. włóknin fibryny z innymi polimerami, co jest szczególnie uzasadnione w przypadku materiałów stosowanych w odbudowie takich struktur jak ścięgna czy kości. Biotechnologiczna synteza fibrynogenu może w przyszłości uniezależnić pozyskiwanie go z krwi i zwiększyć popularność wyrobów medycznych otrzymywanych z fibryny.
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9
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Catanzano O, Quaglia F, Boateng JS. Wound dressings as growth factor delivery platforms for chronic wound healing. Expert Opin Drug Deliv 2021; 18:737-759. [PMID: 33338386 DOI: 10.1080/17425247.2021.1867096] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Years of tissue engineering research have clearly demonstrated the potential of integrating growth factors (GFs) into scaffolds for tissue regeneration, a concept that has recently been applied to wound dressings. The old concept of wound dressings that only take a passive role in wound healing has now been overtaken, and advanced dressings which can take an active part in wound healing, are of current research interest.Areas covered: In this review we will focus on the recent strategies for the delivery of GFs to wound sites with an emphasis on the different approaches used to achieve fine tuning of spatial and temporal concentrations to achieve therapeutic efficacy.Expert opinion: The use of GFs to accelerate wound healing and reduce scar formation is now considered a feasible therapeutic approach in patients with a high risk of infections and complications. The integration of micro - and nanotechnologies into wound dressings could be the key to overcome the inherent instability of GFs and offer adequate control over the release rate. Many investigations have led to encouraging outcomes in various in vitro and in vivo wound models, and it is expected that some of these technologies will satisfy clinical needs and will enter commercialization.
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Affiliation(s)
- Ovidio Catanzano
- Institute for Polymers Composites and Biomaterials (IPCB) - CNR, Pozzuoli, Italy
| | - Fabiana Quaglia
- Drug Delivery Laboratory, Department of Pharmacy, University of Napoli Federico II, Naples, Italy
| | - Joshua S Boateng
- School of Science, Faculty of Engineering and Science, University of Greenwich, Medway, Central Avenue, Chatham Maritime, Kent, UK
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10
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Yang Q, Fang J, Lei Z, Sluijter JPG, Schiffelers R. Repairing the heart: State-of the art delivery strategies for biological therapeutics. Adv Drug Deliv Rev 2020; 160:1-18. [PMID: 33039498 DOI: 10.1016/j.addr.2020.10.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 10/01/2020] [Accepted: 10/03/2020] [Indexed: 12/23/2022]
Abstract
Myocardial infarction (MI) is one of the leading causes of mortality worldwide. It is caused by an acute imbalance between oxygen supply and demand in the myocardium, usually caused by an obstruction in the coronary arteries. The conventional therapy is based on the application of (a combination of) anti-thrombotics, reperfusion strategies to open the occluded artery, stents and bypass surgery. However, numerous patients cannot fully recover after these interventions. In this context, new therapeutic methods are explored. Three decades ago, the first biologicals were tested to improve cardiac regeneration. Angiogenic proteins gained popularity as potential therapeutics. This is not straightforward as proteins are delicate molecules that in order to have a reasonably long time of activity need to be stabilized and released in a controlled fashion requiring advanced delivery systems. To ensure long-term expression, DNA vectors-encoding for therapeutic proteins have been developed. Here, the nuclear membrane proved to be a formidable barrier for efficient expression. Moreover, the development of delivery systems that can ensure entry in the target cell, and also correct intracellular trafficking towards the nucleus are essential. The recent introduction of mRNA as a therapeutic entity has provided an attractive intermediate: prolonged but transient expression from a cytoplasmic site of action. However, protection of the sensitive mRNA and correct delivery within the cell remains a challenge. This review focuses on the application of synthetic delivery systems that target the myocardium to stimulate cardiac repair using proteins, DNA or RNA.
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Affiliation(s)
- Qiangbing Yang
- Division LAB, CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Juntao Fang
- Division Heart & Lungs, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Zhiyong Lei
- Division LAB, CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands; Division Heart & Lungs, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Joost P G Sluijter
- Division Heart & Lungs, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Utrecht, Circulatory Health Laboratory, Utrecht University, Utrecht, the Netherlands
| | - Raymond Schiffelers
- Division LAB, CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands.
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11
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Hu J, Tao L, Deng W, Liu L. Fabrication and sustained‐release property of vinyl silica hollow spheres as a delivery system for aroma compounds. FLAVOUR FRAG J 2020. [DOI: 10.1002/ffj.3616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Jing Hu
- School of Perfume and Aroma Technology Shanghai Institute of Technology Shanghai P. R. China
- Department of Chemical Engineering The University of Melbourne Parkville Vic. Australia
| | - Li Tao
- School of Perfume and Aroma Technology Shanghai Institute of Technology Shanghai P. R. China
| | - Weijun Deng
- School of Chemical and Environmental Engineering Shanghai Institute of Technology Shanghai P. R. China
| | - Liqin Liu
- School of Perfume and Aroma Technology Shanghai Institute of Technology Shanghai P. R. China
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12
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Ao Q, Wang S, He Q, Ten H, Oyama K, Ito A, He J, Javed R, Wang A, Matsuno A. Fibrin Glue/Fibronectin/Heparin-Based Delivery System of BMP2 Induces Osteogenesis in MC3T3-E1 Cells and Bone Formation in Rat Calvarial Critical-Sized Defects. ACS APPLIED MATERIALS & INTERFACES 2020; 12:13400-13410. [PMID: 32091872 DOI: 10.1021/acsami.0c01371] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Bone morphogenetic proteins (BMPs) have been used to promote bone formation in many clinical scenarios. However, the BMPs are inherently unstable in vivo and therefore need to be combined with carriers for controlled delivery. In this study, an innovative and efficient fibrin glue/fibronectin/heparin (FG/Fn/Hep)-based delivery system was developed for controlled release of BMP2. The incorporation of heparin can significantly slow the release of BMP2 without substantially affecting the structure and stiffness of the FG/Fn. The BMP2 release from the FG/Fn/Hep-BMP2 hydrogel is largely dominated by hydrogel degradation rather than simple diffusion. In vitro release experiments and MC3T3-E1 cell induction experiments showed that BMP2 can be released steadily and can induce MC3T3-E1 cells to differentiate into osteoblasts efficiently. This process is characterized by the significantly increased expression of calcium deposits, alkaline phosphatase, runt-related transcription factor-2, osteopontin, osteocalcin, and collagen I in comparison with the negative control. In vivo assessments revealed that the FG/Fn/Hep-BMP2 hydrogel significantly promotes bone regeneration in a rat calvarial critical-sized defect model. Our investigation indicates that FG/Fn/Hep-BMP2 hydrogel holds promise to be used as an alternative biomaterial for the repair of bone defects.
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Affiliation(s)
- Qiang Ao
- Department of Tissue Engineering, China Medical University, Shenyang 110122, China
- Institute of Regulatory Science for Medical Device, National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Shilin Wang
- Department of Tissue Engineering, China Medical University, Shenyang 110122, China
| | - Qing He
- State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Hirotomo Ten
- Department of Neurosurgery, Teikyo University School of Medicine, Tokyo 163-8001, Japan
| | - Kenichi Oyama
- Department of Neurosurgery, Teikyo University School of Medicine, Tokyo 163-8001, Japan
| | - Akihiro Ito
- Department of Neurosurgery, Teikyo University School of Medicine, Tokyo 163-8001, Japan
| | - Jing He
- Department of Tissue Engineering, China Medical University, Shenyang 110122, China
| | - Rabia Javed
- Department of Tissue Engineering, China Medical University, Shenyang 110122, China
| | - Aijun Wang
- Surgical Bioengineering Laboratory, Department of Surgery, School of Medicine, University of California, Davis, Sacramento, California 95817, United States
| | - Akira Matsuno
- Department of Neurosurgery, Teikyo University School of Medicine, Tokyo 163-8001, Japan
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13
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Ding Y, Johnson R, Sharma S, Ding X, Bryant SJ, Tan W. Tethering transforming growth factor β1 to soft hydrogels guides vascular smooth muscle commitment from human mesenchymal stem cells. Acta Biomater 2020; 105:68-77. [PMID: 31982589 DOI: 10.1016/j.actbio.2020.01.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 01/10/2020] [Accepted: 01/21/2020] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) hold great promise for vascular smooth muscle regeneration. However, most studies have mainly relied on extended supplementation of sophisticated biochemical regimen to drive MSC differentiation towards vascular smooth muscle cells (vSMCs). Herein we demonstrate a concomitant method that exploits the advantages of biomimetic matrix stiffness and tethered transforming growth factor β1 (TGF-β1) to guide vSMC commitment from human MSCs. Our designed poly(ethylene glycol) hydrogels, presenting a biomimetic stiffness and tethered TGF-β1, provide an instructive environment to potently upregulate smooth muscle marker expression in vitro and in vivo. Importantly, it significantly enhances the functional contractility of vSMCs derived from MSCs within 3 days. Interestingly, compared to non-tethered one, tethered TGF-β1 enhanced the potency of vSMC commitment on hydrogels. We provide compelling evidence that combining stiffness and tethered TGF-β1 on poly(ethylene glycol) hydrogels can be a promising approach to drastically enhance maturation and function of vSMCs from stem cell differentiation in vitro and in vivo. STATEMENT OF SIGNIFICANCE: A fast, reliable and safe regeneration of vascular smooth muscle cells (vSMCs) from stem cell differentiation is promising for vascular tissue engineering and regenerative medicine applications, but remains challenging. Herein, a photo-click hydrogel platform is devised to recapitulate the stiffness of vascular tissue and appropriate presentation of transforming growth factor β1 (TGF-β1) to guide vSMC commitment from mesenchymal stem cells (MSCs). We demonstrate that such concomitant method drastically enhanced regeneration of mature, functional vSMCs from MSCs in vitro and in vivo within only a 3-days span. This work is not only of fundamental scientific importance, revealing how physiochemical factors and the manner of their presentation direct stem cell differentiation, but also attacks the long-standing difficulty in regenerating highly functional vSMCs within a short period.
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14
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Bijl I, Vlig M, Middelkoop E, Korte D. Allogeneic platelet‐rich plasma (PRP) is superior to platelets or plasma alone in stimulating fibroblast proliferation and migration, angiogenesis, and chemotaxis as relevant processes for wound healing. Transfusion 2019; 59:3492-3500. [DOI: 10.1111/trf.15535] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/16/2019] [Accepted: 08/01/2019] [Indexed: 12/19/2022]
Affiliation(s)
- Ivo Bijl
- Department of Blood Cell Research Sanquin Research Amsterdam The Netherlands
| | - Marcel Vlig
- Association of Dutch Burn Centres, Red Cross Hospital Beverwijk The Netherlands
| | - Esther Middelkoop
- Association of Dutch Burn Centres, Red Cross Hospital Beverwijk The Netherlands
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Plastic, Reconstructive and Hand Surgery Amsterdam Movement Sciences Amsterdam The Netherlands
| | - Dirk Korte
- Department of Blood Cell Research Sanquin Research Amsterdam The Netherlands
- Department of Product and Process Development Sanquin Blood Bank Amsterdam The Netherlands
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15
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Ghosh S, Girigoswami K, Girigoswami A. Membrane-encapsulated camouflaged nanomedicines in drug delivery. Nanomedicine (Lond) 2019; 14:2067-2082. [DOI: 10.2217/nnm-2019-0155] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Owing to the limitations of conventional therapies, there has been an increasing need for nanomedicines for real-time diagnosis and effective treatment of life-threatening diseases. Despite the conceptual and technological success achieved by researchers worldwide, the complexities of biological systems, efficient engineering and formulation of monodispersed nanomedicines, inadequate information on bio–nano interactions, issues on health hazards, clinical trials and commercialization have set new challenges in biomedical research. This review highlights how the biological membrane improves the performance of nanomedicines in drug delivery. With the list of nanomedicines getting longer gradually to overcome the drawbacks of conventional therapeutics, it is important to concentrate on the interactions between nanostructures and living systems in order to improve the biocompatibility and therapeutic efficacy of functional nanomedicines.
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Affiliation(s)
- Suparna Ghosh
- Medical Bionanotechnology, Faculty of Allied Health Sciences, Chettinad Hospital & Research Institute (CHRI), Chettinad Academy of Research & Education (CARE), Kelambakkam, Chennai 603103, India
| | - Koyeli Girigoswami
- Medical Bionanotechnology, Faculty of Allied Health Sciences, Chettinad Hospital & Research Institute (CHRI), Chettinad Academy of Research & Education (CARE), Kelambakkam, Chennai 603103, India
| | - Agnishwar Girigoswami
- Medical Bionanotechnology, Faculty of Allied Health Sciences, Chettinad Hospital & Research Institute (CHRI), Chettinad Academy of Research & Education (CARE), Kelambakkam, Chennai 603103, India
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16
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Preparation of fibrin hydrogels to promote the recruitment of anti-inflammatory macrophages. Acta Biomater 2019; 89:152-165. [PMID: 30862554 DOI: 10.1016/j.actbio.2019.03.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 12/31/2022]
Abstract
Macrophages play an important role in regulating inflammation and tissue regeneration. In the present study, uniform fibrin hydrogel scaffolds were engineered in millimeters. These scaffolds induced anti-inflammatory macrophages to digest and infiltrate the scaffold. The culture conditions of the fibrin hydrogels decreased the secretion of tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, and increased the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, in mouse bone marrow-derived macrophages. Similar results were also observed in human monocyte-derived macrophages (HMDMs). In addition, most of cells that infiltrated the fibrin hydrogels were macrophages expressing CD163, CD204, and CD206, which are anti-inflammatory macrophages markers, both in mice and in human cells. Therefore, to induce increased macrophage infiltration, we attempted to combine fibrin hydrogels with SEW2871, a monocyte/macrophage recruitment agent that is known to be a sphingosine-1 phosphate receptor 1 agonist, solubilized in water by micelle formation with a cholesterol-grafted gelatin. However, the fibrin hydrogels alone retained the same monocyte migration activity as the hydrogels with SEW2871-incorporated micelles in the hydrogel-bearing mouse model. These findings indicate that fibrin hydrogels have a strong promoting effect on the recruitment of anti-inflammatory macrophages. Therefore, fibrin hydrogels may be an optimal biomaterial in the design of medicines for macrophage-induced regenerative therapies. STATEMENT OF SIGNIFICANCE: The immune response to tissue injury is important for determining the speed and the result of the regeneration. Alternatively activated macrophages (M2 macrophages) resolve inflammatory response and promote tissue repair by producing anti-inflammatory factors. Promoting the recruitment of macrophages is a hopeful strategy in the design of biomaterials for tissue regeneration. In the present study, we combined the fibrin hydrogel, which promotes anti-inflammatory polarization, with a macrophage recruitment agent. We revealed that the fibrin hydrogel significantly promoted anti-inflammatory polarization in mouse in vivo and human in vitro. Moreover, macrophages significantly infiltrated into the fibrin hydrogel regardless of the agent combination. Fibrin hydrogels may become a reliable biomaterial for tissue regeneration, and the present study is believed to provide information for many researchers.
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17
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Rastogi SK, Anderson HE, Lamas J, Barret S, Cantu T, Zauscher S, Brittain WJ, Betancourt T. Enhanced Release of Molecules upon Ultraviolet (UV) Light Irradiation from Photoresponsive Hydrogels Prepared from Bifunctional Azobenzene and Four-Arm Poly(ethylene glycol). ACS APPLIED MATERIALS & INTERFACES 2018; 10:30071-30080. [PMID: 28222261 DOI: 10.1021/acsami.6b16183] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Advances in biosensors and drug delivery are dependent on hydrogels that respond to external stimuli. In this work, we describe the preparation and characterization of photoresponsive hydrogels prepared by cross-linking of di-NHS ester of azobenzoic acid and four-armed, amine-terminated poly(ethylene glycol). The porous structure and composition of the hydrogels were confirmed by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. The reversible photoisomerization of the azobenzene-containing hydrogel cross-linkers in the gels was confirmed by absorption spectroscopy. Specifically, the photoisomerization of the cross-linkers between their trans and cis configurations was observed by monitoring the absorbance of the hydrogels at the two characteristic peaks of azobenzene (π-π* at 330 nm and n-π* at 435 nm). The effect of photoisomerization on the hydrogel structure was investigated by microscopy. Ultraviolet (UV) irradiation-induced reduction in hydrogel size was observed, which may be a result of the inherently smaller footprint of the cis azobenzene conformation, as well as dipole-dipole interactions between the polar cis azobenzene and the polymer network. The UV-triggered reduction in hydrogel size was accompanied by enhanced release of the near-infrared fluorescent dye Alexa Fluor 750 (AF750). Enhanced release of AF750 was observed in samples irradiated with UV versus dark control. Together, these data demonstrate the potential of these systems as reversible photoresponsive biomaterials.
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Affiliation(s)
- Shiva K Rastogi
- Department of Chemistry and Biochemistry , Texas State University , San Marcos , Texas 78666 , United States
| | - Hailee E Anderson
- Department of Chemistry and Biochemistry , Texas State University , San Marcos , Texas 78666 , United States
| | - Joseph Lamas
- Department of Mechanical Engineering and Materials Science , Duke University , Durham , North Carolina 27708 , United States
| | - Scott Barret
- Department of Chemistry and Biochemistry , Texas State University , San Marcos , Texas 78666 , United States
| | - Travis Cantu
- Materials Science, Engineering, and Commercialization Program , Texas State University , San Marcos , Texas 78666 , United States
| | - Stefan Zauscher
- Department of Mechanical Engineering and Materials Science , Duke University , Durham , North Carolina 27708 , United States
| | - William J Brittain
- Department of Chemistry and Biochemistry , Texas State University , San Marcos , Texas 78666 , United States
| | - Tania Betancourt
- Department of Chemistry and Biochemistry , Texas State University , San Marcos , Texas 78666 , United States
- Materials Science, Engineering, and Commercialization Program , Texas State University , San Marcos , Texas 78666 , United States
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18
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Heher P, Mühleder S, Mittermayr R, Redl H, Slezak P. Fibrin-based delivery strategies for acute and chronic wound healing. Adv Drug Deliv Rev 2018; 129:134-147. [PMID: 29247766 DOI: 10.1016/j.addr.2017.12.007] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/24/2017] [Accepted: 12/09/2017] [Indexed: 12/17/2022]
Abstract
Fibrin, a natural hydrogel, is the end product of the physiological blood coagulation cascade and naturally involved in wound healing. Beyond its role in hemostasis, it acts as a local reservoir for growth factors and as a provisional matrix for invading cells that drive the regenerative process. Its unique intrinsic features do not only promote wound healing directly via modulation of cell behavior but it can also be fine-tuned to evolve into a delivery system for sustained release of therapeutic biomolecules, cells and gene vectors. To further augment tissue regeneration potential, current strategies exploit and modify the chemical and physical characteristics of fibrin to employ combined incorporation of several factors and their timed release. In this work we show advanced therapeutic approaches employing fibrin matrices in wound healing and cover the many possibilities fibrin offers to the field of regenerative medicine.
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19
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Rybalko VY, Pham CB, Hsieh PL, Hammers DW, Merscham-Banda M, Suggs LJ, Farrar RP. Controlled delivery of SDF-1α and IGF-1: CXCR4(+) cell recruitment and functional skeletal muscle recovery. Biomater Sci 2017; 3:1475-86. [PMID: 26247892 DOI: 10.1039/c5bm00233h] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1α) alone or in combination with insulin-like growth factor-I (SDF-1α/IGF-I) for the treatment of tourniquet-induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1α will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1α alone (PEG-Fib/SDF-1α) or in combination with IGF-I (PEG-Fib/SDF-1α/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1α treatment, functional analysis showed no benefit from PEG-Fib/SDF-1α therapy, while dual delivery of PEG-Fib/SDF-1α/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1α-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient.
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Affiliation(s)
- Viktoriya Y Rybalko
- Department of Kinesiology, The University of Texas at Austin, 1 University Station D3700, Austin, TX 78712, USA
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20
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Wu H, Liu S, Xiao L, Dong X, Lu Q, Kaplan DL. Injectable and pH-Responsive Silk Nanofiber Hydrogels for Sustained Anticancer Drug Delivery. ACS APPLIED MATERIALS & INTERFACES 2016; 8:17118-26. [PMID: 27315327 DOI: 10.1021/acsami.6b04424] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Silk is useful as a drug carrier due to its biocompatibility, tunable degradation, and outstanding capacity in maintaining the function of drugs. Injectable silk hydrogels could deliver doxorubicin (DOX) for localized chemotherapy for breast cancer. To improve hydrogel properties, thixotropic silk nanofiber hydrogels in an all-aqueous solution were prepared and used to locally deliver DOX. The silk hydrogels displayed thixotropic capacity, allowing for easy injectability followed by solidification in situ. The hydrogels were loaded with DOX and released the drug over eight weeks with pH- and concentration-dependent release kinetics. In vitro and in vivo studies demonstrated that DOX-loaded silk hydrogels had good antitumor response, outperforming the equivalent dose of free DOX administered intravenously. Thixotropic silk hydrogels provide improved injectability to support sustained release, suggesting promising applications for localized chemotherapy.
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Affiliation(s)
- Hongchun Wu
- Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University , Suzhou 215123, P.R. China
| | - Shanshan Liu
- Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University , Suzhou 215123, P.R. China
| | - Liying Xiao
- Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University , Suzhou 215123, P.R. China
- National Engineering Laboratory for Modern Silk, Soochow University , Suzhou 215123, P.R. China
| | - Xiaodan Dong
- Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University , Suzhou 215123, P.R. China
- National Engineering Laboratory for Modern Silk, Soochow University , Suzhou 215123, P.R. China
| | - Qiang Lu
- Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University , Suzhou 215123, P.R. China
- National Engineering Laboratory for Modern Silk, Soochow University , Suzhou 215123, P.R. China
| | - David L Kaplan
- Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University , Suzhou 215123, P.R. China
- Department of Biomedical Engineering, Tufts University , Medford, Massachusetts 02155, United States
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21
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Barker K, Rastogi SK, Dominguez J, Cantu T, Brittain W, Irvin J, Betancourt T. Biodegradable DNA-enabled poly(ethylene glycol) hydrogels prepared by copper-free click chemistry. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2015; 27:22-39. [DOI: 10.1080/09205063.2015.1103590] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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22
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Jungst T, Smolan W, Schacht K, Scheibel T, Groll J. Strategies and Molecular Design Criteria for 3D Printable Hydrogels. Chem Rev 2015; 116:1496-539. [PMID: 26492834 DOI: 10.1021/acs.chemrev.5b00303] [Citation(s) in RCA: 437] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Tomasz Jungst
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg , Pleicherwall 2, 97070 Würzburg, Germany
| | - Willi Smolan
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg , Pleicherwall 2, 97070 Würzburg, Germany
| | - Kristin Schacht
- Chair of Biomaterials, Faculty of Engineering Science, University of Bayreuth , Universitätsstrasse 30, 95447 Bayreuth, Germany
| | - Thomas Scheibel
- Chair of Biomaterials, Faculty of Engineering Science, University of Bayreuth , Universitätsstrasse 30, 95447 Bayreuth, Germany
| | - Jürgen Groll
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg , Pleicherwall 2, 97070 Würzburg, Germany
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23
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Goldshmid R, Cohen S, Shachaf Y, Kupershmit I, Sarig-Nadir O, Seliktar D, Wechsler R. Steric Interference of Adhesion Supports In-Vitro Chondrogenesis of Mesenchymal Stem Cells on Hydrogels for Cartilage Repair. Sci Rep 2015; 5:12607. [PMID: 26411496 PMCID: PMC4585928 DOI: 10.1038/srep12607] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 06/11/2015] [Indexed: 02/02/2023] Open
Abstract
Recent studies suggest the presence of cell adhesion motifs found in structural proteins can inhibit chondrogenesis. In this context, the current study aims to determine if a polyethylene glycol (PEG)-modified fibrinogen matrix could support better chondrogenesis of human bone marrow mesenchymal stem cells (BM-MSC) based on steric interference of adhesion, when compared to a natural fibrin matrix. Hydrogels used as substrates for two-dimensional (2D) BM-MSC cultures under chondrogenic conditions were made from cross-linked PEG-fibrinogen (PF) and compared to thrombin-activated fibrin. Cell morphology, protein expression, DNA and sulfated proteoglycan (GAG) content were correlated to substrate properties such as stiffness and adhesiveness. Cell aggregation and chondrogenic markers, including collagen II and aggrecan, were observed on all PF substrates but not on fibrin. Shielding fibrinogen's adhesion domains and increasing stiffness of the material are likely contributing factors that cause the BM-MSCs to display a more chondrogenic phenotype. One composition of PF corresponding to GelrinC™--a product cleared in the EU for cartilage repair--was found to be optimal for supporting chondrogenic differentiation of BM-MSC while minimizing hypertrophy (collagen X). These findings suggest that semi-synthetic biomaterials based on ECM proteins can be designed to favourably affect BM-MSC towards repair processes involving chondrogenesis.
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Affiliation(s)
- Revital Goldshmid
- The Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | | | | | | | | | - Dror Seliktar
- The Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
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24
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Ahadian S, Sadeghian RB, Salehi S, Ostrovidov S, Bae H, Ramalingam M, Khademhosseini A. Bioconjugated Hydrogels for Tissue Engineering and Regenerative Medicine. Bioconjug Chem 2015; 26:1984-2001. [PMID: 26280942 DOI: 10.1021/acs.bioconjchem.5b00360] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Samad Ahadian
- WPI-Advanced
Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
| | - Ramin Banan Sadeghian
- WPI-Advanced
Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
| | - Sahar Salehi
- WPI-Advanced
Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
| | - Serge Ostrovidov
- WPI-Advanced
Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
| | - Hojae Bae
- College
of Animal Bioscience and Technology, Department of Bioindustrial Technologies, Konkuk University, Hwayang-dong,
Kwangjin-gu, Seoul 143-701, Republic of Korea
| | - Murugan Ramalingam
- WPI-Advanced
Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
- Centre
for Stem Cell Research, Institute for Stem Cell Biology and Regenerative Medicine, Christian Medical College Campus, Vellore 632002, India
| | - Ali Khademhosseini
- WPI-Advanced
Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
- College
of Animal Bioscience and Technology, Department of Bioindustrial Technologies, Konkuk University, Hwayang-dong,
Kwangjin-gu, Seoul 143-701, Republic of Korea
- Department
of Medicine, Center for Biomedical Engineering, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States
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25
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Awada HK, Johnson NR, Wang Y. Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction. J Control Release 2015; 207:7-17. [PMID: 25836592 PMCID: PMC4430430 DOI: 10.1016/j.jconrel.2015.03.034] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 02/17/2015] [Accepted: 03/30/2015] [Indexed: 12/28/2022]
Abstract
Treatment of ischemia through therapeutic angiogenesis faces significant challenges. Growth factor (GF)-based therapies can be more effective when concerns such as GF spatiotemporal presentation, bioactivity, bioavailability, and localization are addressed. During angiogenesis, vascular endothelial GF (VEGF) is required early to initiate neovessel formation while platelet-derived GF (PDGF-BB) is needed later to stabilize the neovessels. The spatiotemporal delivery of multiple bioactive GFs involved in angiogenesis, in a close mimic to physiological cues, holds great potential to treat ischemic diseases. To achieve sequential release of VEGF and PDGF, we embed VEGF in fibrin gel and PDGF in a heparin-based coacervate that is distributed in the same fibrin gel. In vitro, we show the benefits of this controlled delivery approach on cell proliferation, chemotaxis, and capillary formation. A rat myocardial infarction (MI) model demonstrated the effectiveness of this delivery system in improving cardiac function, ventricular wall thickness, angiogenesis, cardiac muscle survival, and reducing fibrosis and inflammation in the infarct zone compared to saline, empty vehicle, and free GFs. Collectively, our results show that this delivery approach mitigated the injury caused by MI and may serve as a new therapy to treat ischemic hearts pending further examination.
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Affiliation(s)
- Hassan K Awada
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Noah R Johnson
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Yadong Wang
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
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26
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Minardi S, Sandri M, Martinez JO, Yazdi IK, Liu X, Ferrari M, Weiner BK, Tampieri A, Tasciotti E. Multiscale patterning of a biomimetic scaffold integrated with composite microspheres. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2014; 10:3943-53. [PMID: 24867543 PMCID: PMC4192098 DOI: 10.1002/smll.201401211] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Indexed: 05/02/2023]
Abstract
The ideal scaffold for regenerative medicine should concurrently mimic the structure of the original tissue from the nano- up to the macroscale and recapitulate the biochemical composition of the extracellular matrix (ECM) in space and time. In this study, a multiscale approach is followed to selectively integrate different types of nanostructured composite microspheres loaded with reporter proteins, in a multi-compartment collagen scaffold. Through the preservation of the structural cues of the functionalized collagen scaffold at the nano- and microscale, its macroscopic features (pore size, porosity, and swelling) are not altered. Additionally, the spatial confinement of the microspheres allows the release of the reporter proteins in each of the layers of the scaffold. Finally, the staged and zero-order release kinetics enables the temporal biochemical patterning of the scaffold. The versatile manufacturing of each component of the scaffold results in the ability to customize it to better mimic the architecture and composition of the tissues and biological systems.
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Affiliation(s)
- Silvia Minardi
- Department of Bioceramics and Bio-hybrid materials, National Research Council of Italy – ISTEC, Via Granarolo 64, 48018, Faenza RA, Italy
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
| | - Monica Sandri
- Department of Bioceramics and Bio-hybrid materials, National Research Council of Italy – ISTEC, Via Granarolo 64, 48018, Faenza RA, Italy
| | - Jonathan O. Martinez
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
- Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, 6767 Bertner Ave; Houston, TX 77030 (USA), Houston, TX USA
| | - Iman K. Yazdi
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
- Department of Biomedical Engineering, University of Houston, Houston, TX USA
| | - Xeuwu Liu
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
| | - Mauro Ferrari
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
| | - Bradley K. Weiner
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
- Department of Orthopedic Surgery Weill Cornell Medical College, The Methodist Hospital, 6550 Fannin St. 77030, Houston TX, USA
| | - Anna Tampieri
- Department of Bioceramics and Bio-hybrid materials, National Research Council of Italy – ISTEC, Via Granarolo 64, 48018, Faenza RA, Italy
| | - Ennio Tasciotti
- Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX 77030 (USA)
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Fibrin as a delivery system in wound healing tissue engineering applications. J Control Release 2014; 196:1-8. [PMID: 25284479 DOI: 10.1016/j.jconrel.2014.09.023] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/22/2014] [Accepted: 09/23/2014] [Indexed: 12/21/2022]
Abstract
Fibrin is formed in the body upon initiation of the clotting cascade and is produced commercially for use as a tissue sealant and hemostasis device during surgical procedures. Experimentally fibrin is being increasingly used as a vector to deliver growth factors, cells, drugs and genes in tissue engineering applications mimicking aspects of the extra cellular matrix. Growth factors (GFs) are central to wound healing, inducing cell proliferation, migration and differentiation. Attempts have been made to augment wound healing with GFs, however widespread clinical use has been hindered in vivo due to their rapid metabolism within the body. Fibrin hydrogels protect GFs from rapid degradation and the composition of which can be altered to achieve their optimal release. This article reviews the use of fibrin for the delivery of GFs and details the various strategies that have evolved to alter the release rate so as to enhance the regenerative process, including bi-domain peptides, plasmin degradation sequences and heparin incorporation. This paper also reviews other recent advances in this field, such as dual delivery of cells and GF or sequential release of multiple GF.
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Nafea EH, Poole-Warren LA, Martens PJ. Structural and permeability characterization of biosynthetic PVA hydrogels designed for cell-based therapy. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2014; 25:1771-90. [DOI: 10.1080/09205063.2014.950033] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Zhang J, Sen A, Cho E, Lee JS, Webb K. Poloxamine/fibrin hybrid hydrogels for non-viral gene delivery. J Tissue Eng Regen Med 2014; 11:246-255. [PMID: 24889259 DOI: 10.1002/term.1906] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 01/06/2014] [Accepted: 04/20/2014] [Indexed: 11/10/2022]
Abstract
Hydrogels have been widely investigated for localized, sustained gene delivery because of the similarity of their physical properties to native extracellular matrix and their ability to be formed under mild conditions amenable to the incorporation of bioactive molecules. The objective of this study was to develop bioactive hydrogels composed of macromolecules capable of enhancing the efficiency of non-viral vectors. Hybrid hydrogels were prepared by simultaneous enzymatic and Michael-type addition crosslinking of reduced fibrinogen and an acrylated amphiphilic block copolymer, Tetronic T904, in the presence of dithiothreitol (DTT) and thrombin. T904/fibrin hydrogels degraded by surface erosion in the presence of plasmin and provided sustained release of polyplex vectors up to an order of magnitude longer than pure fibrin gel control. In addition, the rate of gel degradation and time-course of polyplex vector release were readily controlled by varying the T904/fibrinogen ratio in the gel composition. When added to transfected neuroblastoma (N2A) cells, both native T904 itself and hydrogel degradation products significantly increased polyplex transfection efficiency with minimal effect on cell viability. To evaluate gel-based transfection, N2A cells encapsulated in small fibrin clusters were covered by or suspended within polyplex-loaded hydrogels. Cells progressively degraded and invaded the hybrid hydrogels, exhibiting increasing gene expression over 2 weeks and then diminishing but persistent gene expression for over 1 month. In conclusion, these results demonstrate that T904/fibrin hybrid hydrogels can be promising tissue engineering scaffolds that provide local, controlled release of non-viral vectors in combination with the generation of bioactive gel degradation products that actively enhance vector efficiency. Copyright © 2014 John Wiley & Sons, Ltd.
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Affiliation(s)
- Jeremy Zhang
- Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, USA
| | - Atanu Sen
- Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, USA
| | - Eunhee Cho
- Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, USA.,St Jude Medical, St Paul, MN, USA
| | - Jeoung Soo Lee
- Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, USA
| | - Ken Webb
- Microenvironmental Engineering Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, USA
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Brown AC, Barker TH. Fibrin-based biomaterials: modulation of macroscopic properties through rational design at the molecular level. Acta Biomater 2014; 10:1502-14. [PMID: 24056097 DOI: 10.1016/j.actbio.2013.09.008] [Citation(s) in RCA: 182] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 08/14/2013] [Accepted: 09/06/2013] [Indexed: 01/06/2023]
Abstract
Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach it can now be somewhat easily modified through alterations of molecular interactions key to the protein's polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials.
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Skorb EV, Möhwald H. 25th anniversary article: Dynamic interfaces for responsive encapsulation systems. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2013; 25:5029-5043. [PMID: 24000161 DOI: 10.1002/adma.201302142] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Indexed: 06/02/2023]
Abstract
Encapsulation systems are urgently needed both as micrometer and sub-micrometer capsules for active chemicals' delivery, to encapsulate biological objects and capsules immobilized on surfaces for a wide variety of advanced applications. Methods for encapsulation, prolonged storage and controllable release are discussed in this review. Formation of stimuli responsive systems via layer-by-layer (LbL) assembly, as well as via mobile chemical bonding (hydrogen bonds, chemisorptions) and formation of special dynamic stoppers are presented. The most essential advances of the systems presented are multifunctionality and responsiveness to a multitude of stimuli - the possibility of formation of multi-modal systems. Specific examples of advanced applications - drug delivery, diagnostics, tissue engineering, lab-on-chip and organ-on-chip, bio-sensors, membranes, templates for synthesis, optical systems, and antifouling, self-healing materials and coatings - are provided. Finally, we try to outline emerging developments.
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Affiliation(s)
- Ekaterina V Skorb
- Max Planck Institute of Colloids and Interfaces, Wissenschaftspark Golm, Am Mühlenberg 1, Golm, 14424, Germany; Chemistry Department Belarusian State University, Leningradskaya str. 14, Minsk, 220030, Belarus
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Sadava EE, Krpata DM, Gao Y, Rosen MJ, Novitsky YW. Wound healing process and mediators: Implications for modulations for hernia repair and mesh integration. J Biomed Mater Res A 2013; 102:295-302. [DOI: 10.1002/jbm.a.34676] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 02/15/2013] [Accepted: 02/17/2013] [Indexed: 11/06/2022]
Affiliation(s)
- Emmanuel E. Sadava
- Case Comprehensive Hernia Center; Department of Surgery; University Hospitals Case Medical Center; 11100 Euclid Avenue Cleveland Ohio 44106-5047
| | - David M. Krpata
- Case Comprehensive Hernia Center; Department of Surgery; University Hospitals Case Medical Center; 11100 Euclid Avenue Cleveland Ohio 44106-5047
| | - Yue Gao
- Case Comprehensive Hernia Center; Department of Surgery; University Hospitals Case Medical Center; 11100 Euclid Avenue Cleveland Ohio 44106-5047
| | - Michael J. Rosen
- Case Comprehensive Hernia Center; Department of Surgery; University Hospitals Case Medical Center; 11100 Euclid Avenue Cleveland Ohio 44106-5047
| | - Yuri W. Novitsky
- Case Comprehensive Hernia Center; Department of Surgery; University Hospitals Case Medical Center; 11100 Euclid Avenue Cleveland Ohio 44106-5047
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Anitua E, Zalduendo MM, Alkhraisat MH, Orive G. Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors. Ann Anat 2013; 195:461-6. [PMID: 23722041 DOI: 10.1016/j.aanat.2013.04.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 03/01/2013] [Accepted: 04/02/2013] [Indexed: 10/26/2022]
Abstract
Many studies have evaluated the biological effects of platelet rich plasma reporting the final outcomes on cell and tissues. However, few studies have dealt with the kinetics of growth factor delivery by plasma rich in growth factors. Venous blood was obtained from three healthy volunteers and processed with PRGF-Endoret technology to prepare autologous plasma rich in growth factors. The gel-like fibrin scaffolds were then incubated in triplicate, in a cell culture medium to monitor the release of PDGF-AB, VEGF, HGF and IGF-I during 8 days of incubation. A leukocyte-platelet rich plasma was prepared employing the same technology and the concentrations of growth factors and interleukin-1β were determined after 24h of incubation. After each period, the medium was collected, fibrin clot was destroyed and the supernatants were stored at -80°C until analysis. The growth factor delivery is diffusion controlled with a rapid initial release by 30% of the bioactive content after 1h of incubation and a steady state release when almost 70% of the growth factor content has been delivered. Autologous fibrin matrix retained almost 30% of the amount of the growth factors after 8 days of incubation. The addition of leukocytes to the formula of platelet rich plasma did not increase the concentration of the growth factors, while it drastically increased the presence of pro-inflammatory IL-1β. Further studies employing an in vitro inflammatory model would be interesting to study the difference in growth factors and pro-inflammatory cytokines between leukocyte-free and leukocyte-rich platelet rich plasma.
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Affiliation(s)
- Eduardo Anitua
- Eduardo Anitua Foundation, c/Jose Maria Cagigal 19, 01007 Vitoria, Spain; BTI Biotechnology Institute, c/Jacinto Quincoces 39, 01007 Vitoria, Spain.
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Stowers RS, Drinnan CT, Chung E, Suggs LJ. Mesenchymal stem cell response to TGF-β1 in both 2D and 3D environments. Biomater Sci 2013; 1:860-869. [DOI: 10.1039/c3bm60057b] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Chung E, Ricles LM, Stowers RS, Nam SY, Emelianov SY, Suggs LJ. Multifunctional nanoscale strategies for enhancing and monitoring blood vessel regeneration. NANO TODAY 2012; 7:514-531. [PMID: 28989343 PMCID: PMC5630157 DOI: 10.1016/j.nantod.2012.10.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Nanomedicine has great potential in biomedical applications, and specifically in regenerative medicine and vascular tissue engineering. Designing nanometer-sized therapeutic and diagnostic devices for tissue engineering applications is critical because cells experience and respond to stimuli on this spatial scale. For example, nanoscaffolds, including nanoscalestructured or nanoscale surface-modified vascular scaffolds, can influence cell alignment, adhesion, and differentiation to promote better endothelization. Furthermore, nanoscale contrast agents can be extended to the field of biomedical imaging to monitor and track stem cells to better understand the process of neovascularization. In addition, nanoscale systems capable of delivering biomolecules (e.g. peptides and angiogenic genes/proteins) can influence cell behavior, function, and phenotype to promote blood vessel regeneration. This review will focus on nanomedicine and nanoscale strategies applied to vascular tissue engineering. In particular, some of the latest research and potential applications pertaining to nanoscaffolds, biomedical imaging and cell tracking using nanoscale contrast agents, and nanodelivery systems of bioactive molecules applied to blood vessel regeneration will be discussed. In addition, the overlap between these three areas and their synergistic effects will be examined as related to vascular tissue engineering.
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Affiliation(s)
- Eunna Chung
- Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712-0238, USA
| | - Laura M. Ricles
- Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712-0238, USA
| | - Ryan S. Stowers
- Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712-0238, USA
| | - Seung Yun Nam
- Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712-0238, USA
- Department of Electrical and Computer Engineering, The University of Texas at Austin, Austin, TX 78712-0238, USA
| | - Stanislav Y. Emelianov
- Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712-0238, USA
- Department of Electrical and Computer Engineering, The University of Texas at Austin, Austin, TX 78712-0238, USA
| | - Laura J. Suggs
- Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712-0238, USA
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Jiang B, Waller TM, Larson JC, Appel AA, Brey EM. Fibrin-loaded porous poly(ethylene glycol) hydrogels as scaffold materials for vascularized tissue formation. Tissue Eng Part A 2012; 19:224-34. [PMID: 23003671 DOI: 10.1089/ten.tea.2012.0120] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Vascular network formation within biomaterial scaffolds is essential for the generation of properly functioning engineered tissues. In this study, a method is described for generating composite hydrogels in which porous poly(ethylene glycol) (PEG) hydrogels serve as scaffolds for mechanical and structural support, and fibrin is loaded within the pores to induce vascularized tissue formation. Porous PEG hydrogels were generated by a salt leaching technique with 100-150-μm pore size and thrombin (Tb) preloaded within the scaffold. Fibrinogen (Fg) was loaded into pores with varying concentrations and polymerized into fibrin due to the presence of Tb, with loading efficiencies ranging from 79.9% to 82.4%. Fibrin was distributed throughout the entire porous hydrogels, lasted for greater than 20 days, and increased hydrogel mechanical stiffness. A rodent subcutaneous implant model was used to evaluate the influence of fibrin loading on in vivo response. At weeks 1, 2, and 3, all hydrogels had significant tissue invasion, but no difference in the depth of invasion was found with the Fg concentration. Hydrogels with fibrin loading induced more vascularization, with a significantly higher vascular density at 20 mg/mL (week 1) and 40 mg/mL (weeks 2 and 3) Fg concentration compared to hydrogels without fibrin. In conclusion, we have developed a composite hydrogel that supports rapid vascularized tissue ingrowth, and thus holds great potential for tissue engineering applications.
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Affiliation(s)
- Bin Jiang
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA
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Abstract
Therapeutic angiogenesis aims at treating ischemic diseases by generating new blood vessels from existing vasculature. It relies on delivery of exogenous factors to stimulate neovasculature formation. Current strategies using genes, proteins and cells have demonstrated efficacy in animal models. However, clinical translation of any of the three approaches has proved to be challenging for various reasons. Administration of angiogenic factors is generally considered safe, according to accumulated trials, and offers off-the-shelf availability. However, many hurdles must be overcome before therapeutic angiogenesis can become a true human therapy. This article will highlight protein-based therapeutic angiogenesis, concisely review recent progress and examine critical challenges. We will discuss growth factors that have been widely utilized in promoting angiogenesis and compare their targets and functions. Lastly, since bolus injection of free proteins usually result in poor outcomes, we will focus on controlled release of proteins.
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Li Y, Rodrigues J, Tomás H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chem Soc Rev 2012; 41:2193-2221. [PMID: 22116474 DOI: 10.1039/c1cs15203c] [Citation(s) in RCA: 1189] [Impact Index Per Article: 91.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Injectable hydrogels with biodegradability have in situ formability which in vitro/in vivo allows an effective and homogeneous encapsulation of drugs/cells, and convenient in vivo surgical operation in a minimally invasive way, causing smaller scar size and less pain for patients. Therefore, they have found a variety of biomedical applications, such as drug delivery, cell encapsulation, and tissue engineering. This critical review systematically summarizes the recent progresses on biodegradable and injectable hydrogels fabricated from natural polymers (chitosan, hyaluronic acid, alginates, gelatin, heparin, chondroitin sulfate, etc.) and biodegradable synthetic polymers (polypeptides, polyesters, polyphosphazenes, etc.). The review includes the novel naturally based hydrogels with high potential for biomedical applications developed in the past five years which integrate the excellent biocompatibility of natural polymers/synthetic polypeptides with structural controllability via chemical modification. The gelation and biodegradation which are two key factors to affect the cell fate or drug delivery are highlighted. A brief outlook on the future of injectable and biodegradable hydrogels is also presented (326 references).
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Affiliation(s)
- Yulin Li
- CQM-Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada 9020-105 Funchal, Portugal.
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Censi R, Di Martino P, Vermonden T, Hennink WE. Hydrogels for protein delivery in tissue engineering. J Control Release 2012; 161:680-92. [PMID: 22421425 DOI: 10.1016/j.jconrel.2012.03.002] [Citation(s) in RCA: 250] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 02/29/2012] [Accepted: 03/02/2012] [Indexed: 12/17/2022]
Abstract
Tissue defects caused by diseases or trauma present enormous challenges in regenerative medicine. Recently, a better understanding of the biological processes underlying tissue repair led to the establishment of new approaches in tissue engineering which comprise the combination of biodegradable scaffolds and appropriate cells together with specific environmental cues, such as growth or adhesive factors. These factors (in fact proteins) have to be loaded and sustainably released from the scaffolds in time. This review provides an overview of the various hydrogel technologies that have been proposed to control the release of bioactive molecules of interest for tissue engineering applications. In particular, after a brief introduction on bioactive protein drugs that have remarkable relevance for tissue engineering, this review will discuss their release mechanisms from hydrogels, their encapsulation and immobilization methods and will overview the main classes of hydrogel forming biomaterials used in vitro and in vivo to release them. Finally, an outlook on future directions and a glimpse into the current clinical developments are provided.
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Affiliation(s)
- Roberta Censi
- School of Pharmacy, University of Camerino, via S. Agostino 1, 62032, Camerino (MC), Italy.
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40
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Current World Literature. Curr Opin Nephrol Hypertens 2012; 21:106-18. [DOI: 10.1097/mnh.0b013e32834ee42b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hammers DW, Sarathy A, Pham CB, Drinnan CT, Farrar RP, Suggs LJ. Controlled release of IGF-I from a biodegradable matrix improves functional recovery of skeletal muscle from ischemia/reperfusion. Biotechnol Bioeng 2011; 109:1051-9. [PMID: 22095096 DOI: 10.1002/bit.24382] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 11/10/2011] [Accepted: 11/11/2011] [Indexed: 11/06/2022]
Abstract
Ischemia/reperfusion (I/R) injury is a considerable insult to skeletal muscle, often resulting in prolonged functional deficits. The purpose of the current study was to evaluate the controlled release of the pro-regenerative growth factor, insulin-like growth factor-I (IGF-I), from a biodegradable polyethylene glycol (PEG)ylated fibrin gel matrix and the subsequent recovery of skeletal muscle from I/R. To accomplish this, the hind limbs of male Sprague-Dawley rats were subjected to 2-h tourniquet-induced I/R then treated with saline, bolus IGF-I (bIGF), PEGylated fibrin gel (PEG-Fib), or IGF-I conjugated PEGylated fibrin gel (PEG-Fib-IGF). Functional and histological evaluations were performed following 14 days of reperfusion, and muscles from 4-day reperfusion animals were analyzed by Western blotting and histological assessments. There was no difference in functional recovery between saline, bIGF, or PEG-Fib groups. However, PEG-Fib-IGF treatment resulted in significant improvement of muscle function and structure, as observed histologically. Activation of the PI3K/Akt pathway was significantly elevated in PEG-Fib-IGF muscles, compared to PEG-Fib treatment, at 4 days of reperfusion, suggesting involvement of the pathway PI3K/Akt as a mediator of the improved function. Surprisingly, myoblast activity was not evident as a result of PEG-Fib-IGF treatment. Taken together, these data give evidence for a protective role for the delivered IGF. These results indicate that PEG-Fib-IGF is a viable therapeutic technique in the treatment of skeletal muscle I/R injury.
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Affiliation(s)
- David W Hammers
- Department of Kinesiology, The University of Texas at Austin, Austin, Texas 78712, USA
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Liang MS, Andreadis ST. Engineering fibrin-binding TGF-β1 for sustained signaling and contractile function of MSC based vascular constructs. Biomaterials 2011; 32:8684-93. [PMID: 21864893 DOI: 10.1016/j.biomaterials.2011.07.079] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Accepted: 07/27/2011] [Indexed: 01/02/2023]
Abstract
We present a strategy to conjugate TGF-β1 into fibrin hydrogels to mimic the in vivo presentation of the growth factor in a 3D context. To this end, we engineered fusion proteins between TGF-β1 and a bi-functional peptide composed of a Factor XIII domain and a plasmin cleavage site. In another version the protease cleavage site was omitted to examine whether the growth factor that could not be released from the scaffold by cells had different effects on tissue constructs. The optimal insertion site which yielded correctly processed, functional protein was found between the latency associated peptide and mature TGF-β1 domains. In solution the fusion proteins exhibited similar biological activity as native TGF-β1 as evidenced by inhibition of cell proliferation and promoter activity assays. Immunoprecipitation experiments demonstrated that the fusion TGF-β1 protein bound to fibrinogen in a Factor XIII dependent manner and could be released from the peptide by the action of plasmin. In contrast to bolus delivery, immobilized TGF-β1 induced sustained signaling in fibrin-embedded cells for several days as evidenced by Smad2 phosphorylation. Prolonged pathway activation correlated with enhanced contractile function of vascular constructs prepared from hair follicle mesenchymal stem cells or bone marrow derived smooth muscle cells. Our results suggest that fibrin-immobilized TGF-β1 may be used to enhance the local microenvironment and improve the function of engineered tissues in vitro and potentially also after implantation in vivo where growth factor delivery faces overwhelming challenges.
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Affiliation(s)
- Mao-Shih Liang
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260-4200, USA
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Galler KM, Cavender AC, Koeklue U, Suggs LJ, Schmalz G, D'Souza RN. Bioengineering of dental stem cells in a PEGylated fibrin gel. Regen Med 2011; 6:191-200. [PMID: 21391853 DOI: 10.2217/rme.11.3] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
AIM Postnatal stem cells can generate tooth-specific structures after transplantation in vivo, which makes them a valuable tool for dental tissue engineering. Scaffold materials that are compatible with dental stem cells, injectable and tunable for targeted regeneration are needed. A candidate material is fibrin, a biopolymer critical to hemostasis and wound healing. Rapid degradation of fibrin can be decelerated by modification with polyethylene glycol (PEG), thus creating a hybrid material for cell delivery. The aim of this study was to evaluate the suitability of PEGylated fibrin as a scaffold for dental stem cells. METHODS A PEGylated fibrin hydrogel was combined with stem cells derived from dental pulp or periodontal ligament. Cell proliferation was assessed over a 4-week period, and alkaline phosphatase activity and expression levels of mineralization-associated genes after osteogenic induction were analyzed. Cell morphology, matrix degradation, collagen production and mineral deposition were evaluated by histology. Constructs of PEGylated fibrin with dental pulp stem cells in dentin disks were transplanted in immunocompromised mice for 5 weeks and examined for new tissue formation. RESULTS All cell types proliferated in PEGylated fibrin. After osteogenic induction, alkaline phosphatase activity was higher and osteoblast-specific genes were upregulated. Dentin-specific markers increased in pulp-derived stem cells. Histologic analysis revealed degradation of fibrin, production of a collagenous matrix and mineral deposition. In vivo transplantation rendered a vascularized soft connective tissue similar to dental pulp. CONCLUSION Fibrin allows for the growth and differentiation of dental stem cells, can be inserted into small defects and thus appears to be a promising biomaterial for tissue regeneration in the oral cavity.
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Affiliation(s)
- Kerstin M Galler
- Department of Restorative Dentistry & Periodontology, University of Regensburg, Regensburg, Germany
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Gonen-Wadmany M, Goldshmid R, Seliktar D. Biological and mechanical implications of PEGylating proteins into hydrogel biomaterials. Biomaterials 2011; 32:6025-33. [PMID: 21669457 DOI: 10.1016/j.biomaterials.2011.04.055] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 04/20/2011] [Indexed: 11/19/2022]
Abstract
Protein PEGylation has been successfully applied in pharmaceuticals and more recently in biomaterials development for making bioactive and structurally versatile hydrogels. Despite many advantages in this regard, PEGylation of proteins is also known to alter biological activity and modify biophysical characteristics in ways that may be detrimental to cells. The aim of this study was to evaluate the relative loss of biological compatibility associated with PEGylating a fibrinogen precursor into a hydrogel scaffold, in comparison to thrombin cross-linked fibrin hydrogels. Specifically, we investigated the consequences of conjugating fibrinogen with linear polyethtylene glycol (PEG) polymer chains (10 kDa) on the ability to cultivate neonatal human foreskin fibroblasts (HFFs) in 3-D. For this purpose, thrombin cross-linked fibrin (TCL-Fib) and PEGylated fibrinogen (PEG-Fib) gels were prepared with HFFs and cultured for up to seven days. The benchmark biological compatibility test was based on a combined assessment of cellular morphology, proliferation, actin expression, and matrix metalloproteinase (MMP) expression in the 3-D culture systems. The results showed correlations between modulus and proteolytic biodegradation in both materials, but no correlation between the mechanical properties and the ability of HFFs to remodel the microenvironment. A slight reduction of actin, MMPs, and spindled morphology of the cells in the PEG-Fib hydrogels indicated that the PEGylation process altered the biological compatibility of the fibrin. Nevertheless, the overall benchmark performance of the two materials demonstrated that PEGylated fibrinogen hydrogels still retains much to the inherent biofunctionality of the fibrin precursor when used as a scaffold for 3-D cell cultivation.
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Affiliation(s)
- Maya Gonen-Wadmany
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Technion city, Haifa 32000, Israel
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McCall JD, Lin CC, Anseth KS. Affinity peptides protect transforming growth factor beta during encapsulation in poly(ethylene glycol) hydrogels. Biomacromolecules 2011; 12:1051-7. [PMID: 21375234 PMCID: PMC3074572 DOI: 10.1021/bm101379v] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Revised: 01/19/2011] [Indexed: 11/29/2022]
Abstract
Transforming growth factor beta (TGFβ(1)) influences a host of cellular fates, including proliferation, migration, and differentiation. Due to its short half-life and cross reactivity with a variety of cells, clinical application of TGFβ(1) may benefit from a localized delivery strategy. Photoencapsulation of proteins in polymeric matrices offers such an opportunity; however, the reactions forming polymer networks often result in lowered protein bioactivity. Here, PEG-based gels formed from the chain polymerization of acrylated monomers were studied as a model system for TGFβ(1) delivery. Concentrations of acrylate group ranging from 0 to 50 mM and photopolymerization conditions were systematically altered to study their effects on TGFβ(1) bioactivity. In addition, two peptide sequences, WSHW (K(D) = 8.20 nM) and KRIWFIPRSSWY (K(D) = 10.41 nM), that exhibit binding affinity for TGFβ(1) were introduced into the monomer solution prior to encapsulation to determine if affinity binders would increase the activity and release of the encapsulated growth factor. The addition of affinity peptides enhanced the bioactivity of TGFβ(1) in vitro from 1.3- to 2.9-fold, compared to hydrogels with no peptide. Further, increasing the concentration of affinity peptides by a factor of 100-10000 relative to the TGFβ(1) concentration increased fractional recovery of the protein from PEG hydrogels.
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Affiliation(s)
- Joshua D. McCall
- Department of Chemical and Biological Engineering and Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0424, United States
| | - Chien-Chi Lin
- Department of Chemical and Biological Engineering and Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0424, United States
| | - Kristi S. Anseth
- Department of Chemical and Biological Engineering and Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0424, United States
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Preparation of well-defined poly(ether-ester) macromers: photogelation and biodegradability. Acta Biomater 2011; 7:1496-503. [PMID: 21095246 DOI: 10.1016/j.actbio.2010.11.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 11/12/2010] [Accepted: 11/17/2010] [Indexed: 11/23/2022]
Abstract
Two series of poly(ether-ester)-based bis-functional macromers terminated with acrylate groups and a well-defined number of ester bonds were synthesized. One series had a chain of 1, 3 or 5 ester bonds at both ends of the central poly(ethylene glycol) block (molecular weight, about 1000), while the other had an alternating structure of oligo(ethylene glycol) each of them linked to two ester bonds, in which 6 or 10 ester bonds were incorporated equally in the macromer molecules and the total molecular weight was adjusted by about 1000. Irradiation of all poly(ether-ester) macromers mixed with camphorquinone resulted in the formation of gels. Gel yield increased and hydrophilic properties of the gels produced decreased with irradiation time. The elastic modulus of the gels decreased with the number of ester bonds. Upon incubation in a PBS solution (pH 8.04), all gels were gradually degraded with time. At 3 weeks of incubation, the degradation ratio increased linearly with the number of ester bonds per unit of molecular weight of the macromers. The order of in vivo degradation rates determined from weight loss was similar to that of the in vitro study. Thus, these poly(ether-ester) macromers may be useful for biodegradable biomaterials or tissue engineering scaffolds.
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Chen FM, An Y, Zhang R, Zhang M. New insights into and novel applications of release technology for periodontal reconstructive therapies. J Control Release 2011; 149:92-110. [DOI: 10.1016/j.jconrel.2010.10.021] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Accepted: 10/13/2010] [Indexed: 02/09/2023]
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Spicer PP, Mikos AG. Fibrin glue as a drug delivery system. J Control Release 2010; 148:49-55. [PMID: 20637815 PMCID: PMC3005546 DOI: 10.1016/j.jconrel.2010.06.025] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 06/20/2010] [Accepted: 06/29/2010] [Indexed: 11/17/2022]
Abstract
Fibrin glue has been used surgically for decades for hemostasis as well as a sealant. It has also been researched as both a gel for cell delivery and a vehicle for drug delivery. The drug delivery applications for fibrin glue span tissue engineering to chemotherapy and involve several mechanisms for drug matrix interactions and control of release kinetics. Additionally, drugs or factors can be loaded in the gel via impregnation and tethering to the gel through covalent linkages or affinity-based systems. This review highlights recent research of fibrin glue as a drug delivery vehicle.
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Affiliation(s)
| | - Antonios G Mikos
- Department of Bioengineering, Rice University, Houston, TX, USA.
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Kretlow JD, Spicer PP, Jansen JA, Vacanti CA, Kasper FK, Mikos AG. Uncultured marrow mononuclear cells delivered within fibrin glue hydrogels to porous scaffolds enhance bone regeneration within critical-sized rat cranial defects. Tissue Eng Part A 2010; 16:3555-68. [PMID: 20715884 DOI: 10.1089/ten.tea.2010.0471] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
For bone tissue engineering, the benefits of incorporating mesenchymal stem cells (MSCs) into porous scaffolds are well established. There is, however, little consensus on the effects of or need for MSC handling ex vivo. Culture and expansion of MSCs adds length and cost, and likely increases risk associated with treatment. We evaluated the effect of using uncultured bone marrow mononuclear cells (bmMNCs) encapsulated within fibrin glue hydrogels and seeded into porous scaffolds to regenerate bone over 12 weeks in an 8-mm-diameter, critical-sized rat cranial defect. A full factorial experimental design was used to evaluate bone formation within model poly(L-lactic acid) and corraline hydroxyapatite scaffolds with or without platelet-rich plasma (PRP) and bmMNCs. Mechanical push-out testing, microcomputed tomographical analyses, and histology were performed. PRP showed no benefit for bone formation. Cell-laden poly(L-lactic acid) scaffolds without PRP required significantly greater force to displace from surrounding tissues than control (cell-free) scaffolds, but no differences were observed during push-out testing of coral scaffolds. For bone volume formation as analyzed by microcomputed tomography, significant positive overall effects were observed with bmMNC incorporation. These data suggest that bmMNCs may provide therapeutic advantages in bone tissue engineering applications without the need for culture, expansion, and purification.
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Affiliation(s)
- James D Kretlow
- Department of Bioengineering, Rice University, Houston, Texas, USA
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