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Cai Y, Liu J, Han R, Ma Z, Yu K, Wu P, Li X, Wang Z, Wang J. Novel application of CHUANG BI FU biologic protein sponge in promoting peripheral nerve injury repair by regulating vascular regeneration. Eur J Med Res 2025; 30:380. [PMID: 40369654 PMCID: PMC12076905 DOI: 10.1186/s40001-025-02552-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Accepted: 04/04/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND The search for effective drugs that promote regeneration after peripheral nerve injury (PNI) has received widespread attention, but little attention has been paid to the potential secondary damage to nerves during neurosurgical procedures. CHUANG BI FU Biologic Protein Sponge (CHUANG BI FU) is a composite biological sponge loaded with basic fibroblast growth factor (bFGF) that has been effectively applied to clinical wounds, but has never been used for repairing peripheral nerves. METHODS This study used a 3.5-mm nerve defect model in mice, and wrap CHUANG BI FU around the nerve defect site, connecting the distal and proximal ends of the damaged nerve without suturing the nerve. The repair function of the nerve by the wound was tested by detecting mouse footprints, electrophysiology, NF200 staining, CD31 staining, and gastrocnemius muscle Masson staining. RESULTS It was found that CHUANG BI FU can promote axonal elongation, promote neuromuscular reinnervation function, and promote angiogenesis of regenerating nerves, thereby achieving the function of promoting damaged nerve regeneration. And through cellular level research, it was found that CHUANG BI FU may promote vascular regeneration through the PI3 K-AKT pathway. CONCLUSIONS Using CHUANG BI FU to repair peripheral nerves can promote vascular regeneration through the PI3 K-AKT pathway and it can greatly reduce the technical difficulty and operation time required by surgical operators.
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Affiliation(s)
- Yunhao Cai
- Department of Wound Repair, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, Zhejiang, China
| | - Jiahao Liu
- Department of Wound Repair, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, Zhejiang, China
| | - Renwei Han
- Department of Wound Repair, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, Zhejiang, China
| | - Zizhao Ma
- Department of Wound Repair, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, Zhejiang, China
| | - Kaihang Yu
- Department of Wound Repair, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, Zhejiang, China
| | - Ping Wu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xiaokun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Zhouguang Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Jian Wang
- Department of Wound Repair, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325005, Zhejiang, China.
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Takematsu E, Massidda M, Howe G, Goldman J, Felli P, Mei L, Callahan G, Sligar AD, Smalling R, Baker AB. Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits. Sci Rep 2024; 14:2352. [PMID: 38287067 PMCID: PMC10825164 DOI: 10.1038/s41598-024-52888-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 01/24/2024] [Indexed: 01/31/2024] Open
Abstract
Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.
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Affiliation(s)
- Eri Takematsu
- Department of Biomedical Engineering, University of Texas at Austin, 1 University Station, BME 5.202D, C0800, Austin, TX, 78712, USA
- School of Medicine, Surgery, Stanford University, Stanford, CA, USA
| | - Miles Massidda
- Department of Biomedical Engineering, University of Texas at Austin, 1 University Station, BME 5.202D, C0800, Austin, TX, 78712, USA
| | - Gretchen Howe
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA
| | - Julia Goldman
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA
- Center for Laboratory Animal Medicine and Care, UT Health Science Center at Houston, Houston, TX, USA
| | - Patricia Felli
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA
- Center for Laboratory Animal Medicine and Care, UT Health Science Center at Houston, Houston, TX, USA
| | - Lei Mei
- Department of Biomedical Engineering, University of Texas at Austin, 1 University Station, BME 5.202D, C0800, Austin, TX, 78712, USA
| | - Gregory Callahan
- Department of Biomedical Engineering, University of Texas at Austin, 1 University Station, BME 5.202D, C0800, Austin, TX, 78712, USA
| | - Andrew D Sligar
- Department of Biomedical Engineering, University of Texas at Austin, 1 University Station, BME 5.202D, C0800, Austin, TX, 78712, USA
| | - Richard Smalling
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA
- Memorial Hermann Heart and Vascular Institute, Houston, TX, USA
| | - Aaron B Baker
- Department of Biomedical Engineering, University of Texas at Austin, 1 University Station, BME 5.202D, C0800, Austin, TX, 78712, USA.
- Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
- The Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA.
- Institute for Biomaterials, Drug Delivery and Regenerative Medicine, University of Texas at Austin, Austin, TX, USA.
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Takematsu E, Massidda M, Howe G, Goldman J, Felli P, Mei L, Callahan G, Sligar A, Smalling R, Baker A. Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits. RESEARCH SQUARE 2023:rs.3.rs-2997323. [PMID: 37398327 PMCID: PMC10312936 DOI: 10.21203/rs.3.rs-2997323/v1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.
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Affiliation(s)
| | | | - Gretchen Howe
- The University of Texas Health Science Center at Houston
| | - Julia Goldman
- The University of Texas Health Science Center at Houston
| | - Patricia Felli
- The University of Texas Health Science Center at Houston
| | - Lei Mei
- The University of Texas at Austin
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Sligar AD, Howe G, Goldman J, Felli P, Gómez-Hernández A, Takematsu E, Veith A, Desai S, Riley WJ, Singeetham R, Mei L, Callahan G, Ashirov D, Smalling R, Baker AB. Syndecan-4 Proteoliposomes Enhance Revascularization in a Rabbit Hind Limb Ischemia Model of Peripheral Ischemia. Acta Biomater 2023:S1742-7061(23)00331-8. [PMID: 37321528 DOI: 10.1016/j.actbio.2023.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 06/07/2023] [Accepted: 06/08/2023] [Indexed: 06/17/2023]
Abstract
Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes.
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Affiliation(s)
- Andrew D Sligar
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Gretchen Howe
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, TX
| | - Julia Goldman
- Center for Laboratory Animal Medicine and Care, UT Health Science Center at Houston
| | - Patricia Felli
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, TX
| | - Almudena Gómez-Hernández
- Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Eri Takematsu
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Austin Veith
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Shubh Desai
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - William J Riley
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Rohan Singeetham
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Lei Mei
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Gregory Callahan
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - David Ashirov
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX
| | - Richard Smalling
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Medical School at Houston, TX; Memorial Hermann Heart and Vascular Institute, Houston, TX
| | - Aaron B Baker
- University of Texas at Austin, Department of Biomedical Engineering, Austin, TX; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX; The Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX; Institute for Biomaterials, Drug Delivery and Regenerative Medicine, University of Texas at Austin, Austin, TX.
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Takematsu E, Massidda M, Howe G, Goldman J, Felli P, Mei L, Callahan G, Sligar AD, Smalling R, Baker AB. Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.20.533550. [PMID: 36993249 PMCID: PMC10055194 DOI: 10.1101/2023.03.20.533550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.
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Xiao L, Hui F, Tian T, Yan R, Xin J, Zhao X, Jiang Y, Zhang Z, Kuang Y, Li N, Zhao Y, Lin Q. A Novel Conductive Antibacterial Nanocomposite Hydrogel Dressing for Healing of Severely Infected Wounds. Front Chem 2021; 9:787886. [PMID: 34900945 PMCID: PMC8652251 DOI: 10.3389/fchem.2021.787886] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/09/2021] [Indexed: 01/01/2023] Open
Abstract
Wound infections are serious medical complications that can endanger human health. Latest researches show that conductive composite materials may make endogenous/exogenous electrical stimulation more effective, guide/comb cell migration to the wound, and subsequently promote wound healing. To accelerate infected wound healing, a novel medical silver nanoparticle-doped conductive polymer-based hydrogel system (Ag NPs/CPH) dressing with good conductivity, biocompatibility, and mechanical and antibacterial properties was fabricated. For the hydrogel dressing, Ag NPs/CPH, polyvinyl alcohol (PVA), and gelatin were used as the host matrix materials, and phytic acid (PA) was used as the cross-linking agent to introduce conductive polyaniline into the matrix, with antibacterial Ag NPs loaded via impregnation. After a series of analyses, the material containing 5 wt% of PVA by concentration, 1.5 wt% gelatin, 600 μL of AN reactive volume, and 600 μL of PA reactive volume was chosen for Ag NPs/CPH preparation. XPS and FTIR analysis had been further used to characterize the composition of the prepared Ag NPs/CPH. The test on the swelling property showed that the hydrogels had abundant pores with good water absorption (≈140% within 12 h). They can be loaded and continuously release Ag NPs. Thus, the prepared Ag NPs/CPH showed excellent antibacterial property with increasing duration of immersion of Ag NPs. Additionally, to evaluate in vivo safety, CCK-8 experiments of HaCat, LO2 and 293T cells were treated with different concentrations of the Ag NPs/CPH hydrogel soaking solution. The experimental results showed the Ag NPs/CPH had no significant inhibitory effect on any of the cells. Finally, an innovative infection and inflammation model was designed to evaluate the prepared Ag NPs/CPH hydrogel dressing for the treatment of severely infected wounds. The results showed that even when infected with bacteria for long periods of time (more than 20 h), the proposed conductive antibacterial hydrogel could treat severely infected wounds.
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Affiliation(s)
- Lizhi Xiao
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Fang Hui
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Tenghui Tian
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Ruyue Yan
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jingwei Xin
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Chinese-Japan Union Hospital of Jilin University, Jilin University, Changchun, China
| | - Xinyu Zhao
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yingnan Jiang
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Zhe Zhang
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yulan Kuang
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Na Li
- Key Laboratory of Songliao Aquatic Environment of Ministry of Education, Jilin Jianzhu University, Changchun, China
| | - Yu Zhao
- Jilin Ginseng Academy, Hospital of Affiliated Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Quan Lin
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Chinese-Japan Union Hospital of Jilin University, Jilin University, Changchun, China
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Cationic, anionic and neutral polysaccharides for skin tissue engineering and wound healing applications. Int J Biol Macromol 2021; 192:298-322. [PMID: 34634326 DOI: 10.1016/j.ijbiomac.2021.10.013] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/25/2021] [Accepted: 10/03/2021] [Indexed: 12/17/2022]
Abstract
Today, chronic wound care and management can be regarded as a clinically critical issue. However, the limitations of current approaches for wound healing have encouraged researchers and physicians to develop more efficient alternative approaches. Advances in tissue engineering and regenerative medicine have resulted in the development of promising approaches that can accelerate wound healing and improve the skin regeneration rate and quality. The design and fabrication of scaffolds that can address the multifactorial nature of chronic wound occurrence and provide support for the healing process can be considered an important area requiring improvement. In this regard, polysaccharide-based scaffolds have distinctive properties such as biocompatibility, biodegradability, high water retention capacity and nontoxicity, making them ideal for wound healing applications. Their tunable structure and networked morphology could facilitate a number of functions, such as controlling their diffusion, maintaining wound moisture, absorbing a large amount of exudates and facilitating gas exchange. In this review, the wound healing process and the influential factors, structure and properties of carbohydrate polymers, physical and chemical crosslinking of polysaccharides, scaffold fabrication techniques, and the use of polysaccharide-based scaffolds in skin tissue engineering and wound healing applications are discussed.
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Haas G, Dunn A, Madsen J, Genovese P, Chauvin H, Au J, Ziemkiewicz N, Johnson D, Paoli A, Lin A, Pullen N, Garg K. Biomimetic sponges improve muscle structure and function following volumetric muscle loss. J Biomed Mater Res A 2021; 109:2280-2293. [PMID: 33960118 PMCID: PMC9838030 DOI: 10.1002/jbm.a.37212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/15/2021] [Accepted: 04/23/2021] [Indexed: 01/17/2023]
Abstract
Skeletal muscle is inept in regenerating after traumatic injuries such as volumetric muscle loss (VML) due to significant loss of various cellular and acellular components. Currently, there are no approved therapies for the treatment of muscle tissue following trauma. In this study, biomimetic sponges composed of gelatin, collagen, laminin-111, and FK-506 were used for the treatment of VML in a rodent model. We observed that biomimetic sponge treatment improved muscle structure and function while modulating inflammation and limiting the extent of fibrotic tissue deposition. Specifically, sponge treatment increased the total number of myofibers, type 2B fiber cross-sectional area, myosin: collagen ratio, myofibers with central nuclei, and peak isometric torque compared to untreated VML injured muscles. As an acellular scaffold, biomimetic sponges may provide a promising clinical therapy for VML.
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Affiliation(s)
- Gabriel Haas
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Andrew Dunn
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Josh Madsen
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Peter Genovese
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Hannah Chauvin
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Jeffrey Au
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Natalia Ziemkiewicz
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - David Johnson
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Allison Paoli
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Andrew Lin
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
| | - Nicholas Pullen
- School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, Colorado
| | - Koyal Garg
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri
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Eugenis I, Wu D, Rando TA. Cells, scaffolds, and bioactive factors: Engineering strategies for improving regeneration following volumetric muscle loss. Biomaterials 2021; 278:121173. [PMID: 34619561 PMCID: PMC8556323 DOI: 10.1016/j.biomaterials.2021.121173] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 08/01/2021] [Accepted: 08/14/2021] [Indexed: 12/20/2022]
Abstract
Severe traumatic skeletal muscle injuries, such as volumetric muscle loss (VML), result in the obliteration of large amounts of skeletal muscle and lead to permanent functional impairment. Current clinical treatments are limited in their capacity to regenerate damaged muscle and restore tissue function, promoting the need for novel muscle regeneration strategies. Advances in tissue engineering, including cell therapy, scaffold design, and bioactive factor delivery, are promising solutions for VML therapy. Herein, we review tissue engineering strategies for regeneration of skeletal muscle, development of vasculature and nerve within the damaged muscle, and achievements in immunomodulation following VML. In addition, we discuss the limitations of current state of the art technologies and perspectives of tissue-engineered bioconstructs for muscle regeneration and functional recovery following VML.
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Affiliation(s)
- Ioannis Eugenis
- Department of Bioengineering, Stanford University, Stanford, CA, USA; Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - Di Wu
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - Thomas A Rando
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA; Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
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Marsico G, Martin‐Saldaña S, Pandit A. Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003119. [PMID: 33854887 PMCID: PMC8025020 DOI: 10.1002/advs.202003119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/24/2020] [Indexed: 05/14/2023]
Abstract
Chronic limb threatening ischemia (CLTI) is a severe condition defined by the blockage of arteries in the lower extremities that leads to the degeneration of blood vessels and is characterized by the formation of non-healing ulcers and necrosis. The gold standard therapies such as bypass and endovascular surgery aim at the removal of the blockage. These therapies are not suitable for the so-called "no option patients" which present multiple artery occlusions with a likelihood of significant limb amputation. Therefore, CLTI represents a significant clinical challenge, and the efforts of developing new treatments have been focused on stimulating angiogenesis in the ischemic muscle. The delivery of pro-angiogenic nucleic acid, protein, and stem cell-based interventions have limited efficacy due to their short survival. Engineered biomaterials have emerged as a promising method to improve the effectiveness of these latter strategies. Several synthetic and natural biomaterials are tested in different formulations aiming to incorporate nucleic acid, proteins, stem cells, macrophages, or endothelial cells in supportive matrices. In this review, an overview of the biomaterials used alone and in combination with growth factors, nucleic acid, and cells in preclinical models is provided and their potential to induce revascularization and regeneration for CLTI applications is discussed.
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Affiliation(s)
- Grazia Marsico
- CÚRAM SFI Research Centre for Medical DevicesNational University of IrelandGalwayIreland
| | - Sergio Martin‐Saldaña
- CÚRAM SFI Research Centre for Medical DevicesNational University of IrelandGalwayIreland
| | - Abhay Pandit
- CÚRAM SFI Research Centre for Medical DevicesNational University of IrelandGalwayIreland
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Nosrati H, Aramideh Khouy R, Nosrati A, Khodaei M, Banitalebi-Dehkordi M, Ashrafi-Dehkordi K, Sanami S, Alizadeh Z. Nanocomposite scaffolds for accelerating chronic wound healing by enhancing angiogenesis. J Nanobiotechnology 2021; 19:1. [PMID: 33397416 PMCID: PMC7784275 DOI: 10.1186/s12951-020-00755-7] [Citation(s) in RCA: 345] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/12/2020] [Indexed: 12/23/2022] Open
Abstract
Skin is the body's first barrier against external pathogens that maintains the homeostasis of the body. Any serious damage to the skin could have an impact on human health and quality of life. Tissue engineering aims to improve the quality of damaged tissue regeneration. One of the most effective treatments for skin tissue regeneration is to improve angiogenesis during the healing period. Over the last decade, there has been an impressive growth of new potential applications for nanobiomaterials in tissue engineering. Various approaches have been developed to improve the rate and quality of the healing process using angiogenic nanomaterials. In this review, we focused on molecular mechanisms and key factors in angiogenesis, the role of nanobiomaterials in angiogenesis, and scaffold-based tissue engineering approaches for accelerated wound healing based on improved angiogenesis.
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Affiliation(s)
- Hamed Nosrati
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | | | - Ali Nosrati
- School of Mechanical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Mohammad Khodaei
- Department of Materials Science and Engineering, Golpayegan University of Technology, Golpayegan, Iran
| | - Mehdi Banitalebi-Dehkordi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Korosh Ashrafi-Dehkordi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Samira Sanami
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zohreh Alizadeh
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Anatomical Sciences, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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12
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Kobayashi M, Kadota J, Hashimoto Y, Fujisato T, Nakamura N, Kimura T, Kishida A. Elastic Modulus of ECM Hydrogels Derived from Decellularized Tissue Affects Capillary Network Formation in Endothelial Cells. Int J Mol Sci 2020; 21:E6304. [PMID: 32878178 PMCID: PMC7503911 DOI: 10.3390/ijms21176304] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/07/2020] [Accepted: 08/27/2020] [Indexed: 12/23/2022] Open
Abstract
Recent applications of decellularized tissue have included the use of hydrogels for injectable materials and three-dimensional (3D) bioprinting bioink for tissue regeneration. Microvascular formation is required for the delivery of oxygen and nutrients to support cell growth and regeneration in tissues and organs. The aim of the present study was to evaluate the formation of capillary networks in decellularized extracellular matrix (d-ECM) hydrogels. The d-ECM hydrogels were obtained from the small intestine submucosa (SIS) and the urinary bladder matrix (UBM) after decellularizing with sodium deoxycholate (SDC) and high hydrostatic pressure (HHP). The SDC d-ECM hydrogel gradually gelated, while the HHP d-ECM hydrogel immediately gelated. All d-ECM hydrogels had low matrix stiffness compared to that of the collagen hydrogel, according to a compression test. D-ECM hydrogels with various elastic moduli were obtained, irrespective of the decellularization method or tissue source. Microvascular-derived endothelial cells were seeded on d-ECM hydrogels. Few cells attached to the SDC d-ECM hydrogel with no network formation, while on the HHP d-ECM hydrogel, a capillary network structure formed between elongated cells. Long, branched networks formed on d-ECM hydrogels with lower matrix stiffness. This suggests that the capillary network structure that forms on d-ECM hydrogels is closely related to the matrix stiffness of the hydrogel.
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Affiliation(s)
- Mako Kobayashi
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; (M.K.); (J.K.); (Y.H.); (A.K.)
| | - Junpei Kadota
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; (M.K.); (J.K.); (Y.H.); (A.K.)
| | - Yoshihide Hashimoto
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; (M.K.); (J.K.); (Y.H.); (A.K.)
| | - Toshiya Fujisato
- Department of Biomedical Engineering, Osaka Institute of Technology, Osaka 535-8585, Japan;
| | - Naoko Nakamura
- Department of Bioscience and Engineering, Shibaura Institute of Technology, Saitama 337-8570, Japan;
| | - Tsuyoshi Kimura
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; (M.K.); (J.K.); (Y.H.); (A.K.)
| | - Akio Kishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; (M.K.); (J.K.); (Y.H.); (A.K.)
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13
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Skeletal Muscle Tissue Engineering: Biomaterials-Based Strategies for the Treatment of Volumetric Muscle Loss. Bioengineering (Basel) 2020; 7:bioengineering7030085. [PMID: 32751847 PMCID: PMC7552659 DOI: 10.3390/bioengineering7030085] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
Millions of Americans suffer from skeletal muscle injuries annually that can result in volumetric muscle loss (VML), where extensive musculoskeletal damage and tissue loss result in permanent functional deficits. In the case of small-scale injury skeletal muscle is capable of endogenous regeneration through activation of resident satellite cells (SCs). However, this is greatly reduced in VML injuries, which remove native biophysical and biochemical signaling cues and hinder the damaged tissue's ability to direct regeneration. The current clinical treatment for VML is autologous tissue transfer, but graft failure and scar tissue formation leave patients with limited functional recovery. Tissue engineering of instructive biomaterial scaffolds offers a promising approach for treating VML injuries. Herein, we review the strategic engineering of biophysical and biochemical cues in current scaffold designs that aid in restoring function to these preclinical VML injuries. We also discuss the successes and limitations of the three main biomaterial-based strategies to treat VML injuries: acellular scaffolds, cell-delivery scaffolds, and in vitro tissue engineered constructs. Finally, we examine several innovative approaches to enhancing the design of the next generation of engineered scaffolds to improve the functional regeneration of skeletal muscle following VML injuries.
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14
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Ferrini A, Stevens MM, Sattler S, Rosenthal N. Toward Regeneration of the Heart: Bioengineering Strategies for Immunomodulation. Front Cardiovasc Med 2019; 6:26. [PMID: 30949485 PMCID: PMC6437044 DOI: 10.3389/fcvm.2019.00026] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/26/2019] [Indexed: 01/10/2023] Open
Abstract
Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF development. Two newly emerging fields of biomedical research, immunomodulatory therapies and cardiac bioengineering, provide potential options to target the causative mechanisms underlying HF development. Combining these two fields to develop biomaterials for delivery of immunomodulatory bioactive molecules holds great promise for HF therapy. Specifically, minimally invasive delivery of injectable hydrogels, loaded with bioactive factors with angiogenic, proliferative, anti-apoptotic and immunomodulatory functions, is a promising route for influencing the cascade of immune events post-MI, preventing adverse left ventricular remodeling, and offering protection from early inflammation to fibrosis. Here we provide an updated overview on the main injectable hydrogel systems and bioactive factors that have been tested in animal models with promising results and discuss the challenges to be addressed for accelerating the development of these novel therapeutic strategies.
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Affiliation(s)
- Arianna Ferrini
- Department of Materials, Imperial College London, London, United Kingdom,National Heart and Lung Institute and BHF Centre for Research Excellence, Imperial College London, London, United Kingdom
| | - Molly M. Stevens
- Department of Materials, Imperial College London, London, United Kingdom,Department of Bioengineering, Imperial College London, London, United Kingdom,Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
| | - Susanne Sattler
- National Heart and Lung Institute and BHF Centre for Research Excellence, Imperial College London, London, United Kingdom
| | - Nadia Rosenthal
- National Heart and Lung Institute and BHF Centre for Research Excellence, Imperial College London, London, United Kingdom,The Jackson Laboratory, Bar Harbor, ME, United States,*Correspondence: Nadia Rosenthal
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15
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Chen CF, Liao HT. Platelet-rich plasma enhances adipose-derived stem cell-mediated angiogenesis in a mouse ischemic hindlimb model. World J Stem Cells 2018; 10:212-227. [PMID: 30613314 PMCID: PMC6306556 DOI: 10.4252/wjsc.v10.i12.212] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/18/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the angiogenic effect of platelet-rich plasma (PRP)-preconditioned adipose-derived stem cells (ADSCs) both in vitro and in a mouse ischemic hindlimb model.
METHODS ADSCs were divided based on culture medium: 2.5% PRP, 5% PRP, 7.5% PRP, and 10% PRP. Cell proliferation rate was analyzed using the MTS assay. The gene expression of CD31, vascular endothelial growth factor, hypoxia-inducible factors, and endothelial cell nitric oxide synthase was analyzed using reverse transcription polymerase chain reaction. Cell markers and structural changes were assessed through immunofluorescence staining and the tube formation assay. Subsequently, we studied the in vivo angiogenic capabilities of ADSCs by a mouse ischemic hindlimb model.
RESULTS The proliferation rate of ADSCs was higher in the 2.5%, 5%, and 7.5% PRP groups. The expression of hypoxia-inducible factor, CD31, vascular endothelial growth factor, and endothelial cell nitric oxide synthase in the 5% and 7.5% PRP groups increased. The 5%, 7.5%, and 10% PRP groups showed higher abilities to promote both CD31 and vascular endothelial growth factor production and tubular structure formation in ADSCs. According to laser Doppler perfusion scan, the perfusion ratios of ischemic limb to normal limb were significantly higher in 5% PRP, 7.5% PRP, and human umbilical vein endothelial cells groups compared with the negative control and fetal bovine serum (FBS) groups (0.88 ± 0.08, 0.85 ± 0.07 and 0.81 ± 0.06 for 5%, 7.5% PRP and human umbilical vein endothelial cells compared with 0.42 ± 0.17 and 0.54 ± 0.14 for the negative control and FBS, P < 0.01).
CONCLUSION PRP-preconditioned ADSCs presented endothelial cell characteristics in vitro and significantly improved neovascularization in ischemic hindlimbs. The optimal angiogenic effect occurred in 5% PRP- and 7.5% PRP-preconditioned ADSCs.
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Affiliation(s)
- Chia-Fang Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Han-Tsung Liao
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Craniofacial Research Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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16
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Jia Z, Guo H, Xie H, Bao X, Huang Y, Yang G, Chen F. Harvesting prevascularized smooth muscle cell sheets from common polystyrene culture dishes. PLoS One 2018; 13:e0204677. [PMID: 30256839 PMCID: PMC6157888 DOI: 10.1371/journal.pone.0204677] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 09/12/2018] [Indexed: 02/07/2023] Open
Abstract
Cell sheet engineering has recently emerged as a promising strategy for scaffold-free tissue engineering. However, the primary method of harvesting cell sheets using temperature-responsive dishes has potential limitations. Here we report a novel cell sheet technology based on a coculture system in which SMCs are cocultured with EPCs on common polystyrene dishes. We found that an intact and highly viable cell sheet could be harvested using mechanical methods when SMCs and EPCs were cocultured on common polystyrene dishes at a ratio of 6:1 for 5 to 6 days; the method is simple, cost-effective and highly repeatable. Moreover, the cocultured cell sheet contained capillary-like networks and could secrete a variety of angiogenic factors. Finally, in vivo studies proved that the cocultured cell sheets were more favorable for the fabrication of vascularized smooth muscle tissues compared to single SMC sheets. This study provides a promising avenue for smooth muscle tissue engineering.
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Affiliation(s)
- Zhiming Jia
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hailin Guo
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hua Xie
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xingqi Bao
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yichen Huang
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ganggang Yang
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Fang Chen
- Department of Urology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
- * E-mail:
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17
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Tanaka A, Nakamura H, Tabata Y, Fujimori Y, Kumasawa K, Kimura T. Effect of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogels on frozen-thawed human ovarian tissue in a xenograft model. J Obstet Gynaecol Res 2018; 44:1947-1955. [PMID: 29998469 DOI: 10.1111/jog.13726] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 06/07/2018] [Indexed: 01/08/2023]
Abstract
AIM Ovarian tissue cryopreservation before cancer treatment is the only option to preserve fertility under some circumstances. However, tissue ischemia after transplantation while awaiting angiogenesis induces dysfunctional folliculogenesis and reduces ovarian reserve and is one of the disadvantages of frozen-thawed ovarian tissue transplantation. Basic fibroblast growth factor (bFGF) is a major regulator of angiogenesis. However, bFGF rapidly loses biological activity when its free form is injected in vivo. This study investigated whether administration of active bFGF helps establish a nurturing environment for follicular survival. METHODS A sheet form of a sustained release drug delivery system for bFGF was developed using biodegradable acidic gelatin hydrogel (bFGF sheet). The bFGF sheets or phosphate-buffered saline sheets, as a negative control, were transplanted with frozen-thawed human ovarian tissues subcutaneously into the backs of severe combined immunodeficient mice. Neovascularization, cell proliferation, fibrosis and follicular survival of ovarian grafts were analyzed at 6 weeks after xenografting. RESULTS The bFGF sheets were optimized to release bFGF for at least 10 days. The transplantation of bFGF sheets with frozen-thawed ovarian tissues significantly increased human and mouse CD31-positive areas and stromal and endothelial cell proliferations. The administration of bFGF also significantly decreased the percentage of the fibrotic area in the graft, resulting in a significant increase in primordial and primary follicular density. CONCLUSION Local administration of a sustained release of biologically active bFGF induced neovascularization in frozen-thawed ovarian tissue grafts, which could establish the nurturing environment required for follicular survival in heterotopic xenografts.
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Affiliation(s)
- Ayaka Tanaka
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hitomi Nakamura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yuka Fujimori
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Keiichi Kumasawa
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
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18
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Kumagai M, Minakata K, Masumoto H, Yamamoto M, Yonezawa A, Ikeda T, Uehara K, Yamazaki K, Ikeda T, Matsubara K, Yokode M, Shimizu A, Tabata Y, Sakata R, Minatoya K. A therapeutic angiogenesis of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel sheets in a canine chronic myocardial infarction model. Heart Vessels 2018; 33:1251-1257. [DOI: 10.1007/s00380-018-1185-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 05/11/2018] [Indexed: 10/16/2022]
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19
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αvβ3 and α5β1 integrin-specific ligands: From tumor angiogenesis inhibitors to vascularization promoters in regenerative medicine? Biotechnol Adv 2017; 36:208-227. [PMID: 29155160 DOI: 10.1016/j.biotechadv.2017.11.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/07/2017] [Accepted: 11/13/2017] [Indexed: 12/30/2022]
Abstract
Integrins are cell adhesion receptors predominantly important during normal and tumor angiogenesis. A sequence present on several extracellular matrix proteins composed of Arg-Gly-Asp (RGD) has attracted attention due to its role in cell adhesion mediated by integrins. The development of ligands that can bind to integrins involved in tumor angiogenesis and brake disease progression has resulted in new investigational drug entities reaching the clinical trial phase in humans. The use of integrin-specific ligands can be useful for the vascularization of regenerative medicine constructs, which remains a major limitation for translation into clinical practice. In order to enhance vascularization, immobilization of integrin-specific RGD peptidomimetics within constructs is a recommended approach, due to their high specificity and selectivity towards certain desired integrins. This review endeavours to address the potential of peptidomimetic-coated biomaterials as vascular network promoters for regenerative medicine purposes. Clinical studies involving molecules tracking active integrins in cancer angiogenesis and reasons for their failure are also addressed.
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20
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Hernandez MJ, Christman KL. Designing Acellular Injectable Biomaterial Therapeutics for Treating Myocardial Infarction and Peripheral Artery Disease. JACC Basic Transl Sci 2017; 2:212-226. [PMID: 29057375 PMCID: PMC5646282 DOI: 10.1016/j.jacbts.2016.11.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 02/07/2023]
Abstract
As the number of global deaths attributed to cardiovascular disease continues to rise, viable treatments for cardiovascular events such as myocardial infarction (MI) or conditions like peripheral artery disease (PAD) are critical. Recent studies investigating injectable biomaterials have shown promise in promoting tissue regeneration and functional improvement, and in some cases, incorporating other therapeutics further augments the beneficial effects of these biomaterials. In this review, we aim to emphasize the advantages of acellular injectable biomaterial-based therapies, specifically material-alone approaches or delivery of acellular biologics, in regards to manufacturability and the capacity of these biomaterials to regenerate or repair diseased tissue. We will focus on design parameters and mechanisms that maximize therapeutic efficacy, particularly, improved functional perfusion and neovascularization regarding PAD and improved cardiac function and reduced negative left ventricular (LV) remodeling post-MI. We will then discuss the rationale and challenges of designing new injectable biomaterial-based therapies for the clinic.
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Affiliation(s)
| | - Karen L. Christman
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California
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21
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Passipieri JA, Christ GJ. The Potential of Combination Therapeutics for More Complete Repair of Volumetric Muscle Loss Injuries: The Role of Exogenous Growth Factors and/or Progenitor Cells in Implantable Skeletal Muscle Tissue Engineering Technologies. Cells Tissues Organs 2016; 202:202-213. [PMID: 27825153 DOI: 10.1159/000447323] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2016] [Indexed: 11/19/2022] Open
Abstract
Despite the robust regenerative capacity of skeletal muscle, there are a variety of congenital and acquired conditions in which the volume of skeletal muscle loss results in major permanent functional and cosmetic deficits. These latter injuries are referred to as volumetric muscle loss (VML) injuries or VML-like conditions, and they are characterized by the simultaneous absence of multiple tissue components (i.e., nerves, vessels, muscles, satellite cells, and matrix). There are currently no effective treatment options. Regenerative medicine/tissue engineering technologies hold great potential for repair of these otherwise irrecoverable VML injuries. In this regard, three-dimensional scaffolds have been used to deliver sustained amounts of growth factors into a variety of injury models, to modulate host cell recruitment and extracellular matrix remodeling. However, this is a nascent field of research, and more complete functional improvements require more precise control of the spatiotemporal distribution of critical growth factors over a physiologically relevant range. This is especially true for VML injuries where incorporation of a cellular component into the scaffolds might provide not only a source of new tissue formation but also additional signals for host cell migration, recruitment, and survival. To this end, we review the major features of muscle repair and regeneration for largely recoverable injuries, and then discuss recent cell- and/or growth factor-based approaches to repair the more profound and irreversible VML and VML-like injuries. The underlying supposition is that more rationale incorporation of exogenous growth factors and/or cellular components will be required to optimize the regenerative capacity of implantable therapeutics for VML repair.
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Abstract
All tissue-engineered substitutes (with the exception of cornea and cartilage) require a vascular network to provide the nutrient and oxygen supply needed for their survival in vivo. Unfortunately the process of vascular ingrowth into an engineered tissue can take weeks to occur naturally and during this time the tissues become starved of essential nutrients, leading to tissue death. This review initially gives a brief overview of the processes and factors involved in the formation of new vasculature. It then summarizes the different approaches that are being applied or developed to overcome the issue of slow neovascularization in a range of tissue-engineered substitutes. Some potential future strategies are then discussed.
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Affiliation(s)
- Lindsey Dew
- Department of Materials Science & Engineering, Kroto Research Institute, North Campus, University of Sheffield, Broad Lane, Sheffield S3 7HQ, UK
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23
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Horikoshi-Ishihara H, Tobita M, Tajima S, Tanaka R, Oshita T, Tabata Y, Mizuno H. Coadministration of adipose-derived stem cells and control-released basic fibroblast growth factor facilitates angiogenesis in a murine ischemic hind limb model. J Vasc Surg 2015; 64:1825-1834.e1. [PMID: 26597457 DOI: 10.1016/j.jvs.2015.09.054] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 09/18/2015] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Adipose-derived stem cells (ASCs) have angiogenic potential owing to their differentiation into endothelial cells and their release of angiogenic growth factors to elicit paracrine effects. In addition, control-released basic fibroblast growth factor (bFGF) sustained with a gelatin hydrogel also supports effective angiogenesis. We sought to determine if coadministration of ASCs and control-released bFGF into murine ischemic limbs facilitates angiogenesis. METHODS Levels of growth factors in the conditioned media of ASCs cultured with or without control-released bFGF were measured by enzyme-linked immunosorbent assays. A murine ischemic hind limb model was generated and intramuscularly injected with the following: gelatin hydrogel (group 1), a high number of ASCs (group 2), control-released bFGF (group 3), a small number of ASCs and control-released bFGF (group 4), and a high number of ASCs and control-released bFGF (group 5). Macroscopic and microscopic vascular changes were evaluated until day 7 by laser Doppler perfusion imaging and histologic analyses, respectively. RESULTS Secretion of hepatocyte growth factor, vascular endothelial growth factor, and transforming growth factor-β1 was enhanced by control-released bFGF. Vascular improvement was achieved in groups 4 and 5 according to laser Doppler perfusion imaging. Hematoxylin and eosin staining and CD31 immunohistochemical staining demonstrated an increase in the vascular density, vessel diameter, and thickness of vessel walls in groups 4 and 5. Cells positively stained for CD146, α-smooth muscle actin, and transforming growth factor-β1 were observed around vessel walls in groups 4 and 5. CONCLUSIONS These findings suggest that coadministration of ASCs and control-released bFGF facilitates angiogenesis in terms of vessel maturation in a murine ischemic hind limb model.
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Affiliation(s)
- Hisako Horikoshi-Ishihara
- Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Morikuni Tobita
- Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Satoshi Tajima
- Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Rica Tanaka
- Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Oshita
- Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Yasuhiko Tabata
- Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hiroshi Mizuno
- Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan.
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Kumagai M, Marui A, Tabata Y, Takeda T, Yamamoto M, Yonezawa A, Tanaka S, Yanagi S, Ito-Ihara T, Ikeda T, Murayama T, Teramukai S, Katsura T, Matsubara K, Kawakami K, Yokode M, Shimizu A, Sakata R. Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia. Heart Vessels 2015; 31:713-21. [PMID: 25861983 DOI: 10.1007/s00380-015-0677-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 04/01/2015] [Indexed: 12/22/2022]
Abstract
As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I-IIa study that analyzed 10 CLI patients following a 200-μg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger's disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.
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Affiliation(s)
- Motoyuki Kumagai
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Akira Marui
- Division of Cardiovascular Surgery, Tenri Hospital, Nara, Japan.,Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Yasuhiko Tabata
- Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Takahide Takeda
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Masaya Yamamoto
- Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Atsushi Yonezawa
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Shiro Tanaka
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.,Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Shigeki Yanagi
- Department of Cardiovascular Surgery, Kumamoto Central Hospital, Kumamoto, Japan
| | - Toshiko Ito-Ihara
- Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Takafumi Ikeda
- Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Toshinori Murayama
- Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Satoshi Teramukai
- Department of Biostatistics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiya Katsura
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Kazuo Matsubara
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Koji Kawakami
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.,Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Masayuki Yokode
- Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Akira Shimizu
- Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Ryuzo Sakata
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
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25
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Wolf MT, Dearth CL, Sonnenberg SB, Loboa EG, Badylak SF. Naturally derived and synthetic scaffolds for skeletal muscle reconstruction. Adv Drug Deliv Rev 2015; 84:208-21. [PMID: 25174309 DOI: 10.1016/j.addr.2014.08.011] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 07/22/2014] [Accepted: 08/20/2014] [Indexed: 12/15/2022]
Abstract
Skeletal muscle tissue has an inherent capacity for regeneration following injury. However, severe trauma, such as volumetric muscle loss, overwhelms these natural muscle repair mechanisms prompting the search for a tissue engineering/regenerative medicine approach to promote functional skeletal muscle restoration. A desirable approach involves a bioscaffold that simultaneously acts as an inductive microenvironment and as a cell/drug delivery vehicle to encourage muscle ingrowth. Both biologically active, naturally derived materials (such as extracellular matrix) and carefully engineered synthetic polymers have been developed to provide such a muscle regenerative environment. Next generation naturally derived/synthetic "hybrid materials" would combine the advantageous properties of these materials to create an optimal platform for cell/drug delivery and possess inherent bioactive properties. Advances in scaffolds using muscle tissue engineering are reviewed herein.
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Affiliation(s)
- Matthew T Wolf
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Christopher L Dearth
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Sonya B Sonnenberg
- Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA
| | - Elizabeth G Loboa
- Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA; Department of Materials Science & Engineering, North Carolina State University, Raleigh, NC 27695, USA
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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26
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Mulyasasmita W, Cai L, Dewi RE, Jha A, Ullmann SD, Luong RH, Huang NF, Heilshorn SC. Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J Control Release 2014; 191:71-81. [PMID: 24848744 DOI: 10.1016/j.jconrel.2014.05.015] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 05/02/2014] [Accepted: 05/08/2014] [Indexed: 12/20/2022]
Abstract
To translate recent advances in induced pluripotent stem cell biology to clinical regenerative medicine therapies, new strategies to control the co-delivery of cells and growth factors are needed. Building on our previous work designing Mixing-Induced Two-Component Hydrogels (MITCHs) from engineered proteins, here we develop protein-polyethylene glycol (PEG) hybrid hydrogels, MITCH-PEG, which form physical gels upon mixing for cell and growth factor co-delivery. MITCH-PEG is a mixture of C7, which is a linear, engineered protein containing seven repeats of the CC43 WW peptide domain (C), and 8-arm star-shaped PEG conjugated with either one or two repeats of a proline-rich peptide to each arm (P1 or P2, respectively). Both 20kDa and 40kDa star-shaped PEG variants were investigated, and all four PEG-peptide variants were able to undergo a sol-gel phase transition when mixed with the linear C7 protein at constant physiological conditions due to noncovalent hetero-dimerization between the C and P domains. Due to the dynamic nature of the C-P physical crosslinks, all four gels were observed to be reversibly shear-thinning and self-healing. The P2 variants exhibited higher storage moduli than the P1 variants, demonstrating the ability to tune the hydrogel bulk properties through a biomimetic peptide-avidity strategy. The 20kDa PEG variants exhibited slower release of encapsulated vascular endothelial growth factor (VEGF), due to a decrease in hydrogel mesh size relative to the 40kDa variants. Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) adopted a well-spread morphology within three-dimensional MITCH-PEG cultures, and MITCH-PEG provided significant protection from cell damage during ejection through a fine-gauge syringe needle. In a mouse hindlimb ischemia model of peripheral arterial disease, MITCH-PEG co-delivery of hiPSC-ECs and VEGF was found to reduce inflammation and promote muscle tissue regeneration compared to a saline control.
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Affiliation(s)
| | - Lei Cai
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
| | - Ruby E Dewi
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA
| | - Arshi Jha
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | | | - Richard H Luong
- Department of Comparative Medicine, Stanford University, Stanford, CA, USA
| | - Ngan F Huang
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
| | - Sarah C Heilshorn
- Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
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27
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Pardue EL, Ibrahim S, Ramamurthi A. Role of hyaluronan in angiogenesis and its utility to angiogenic tissue engineering. Organogenesis 2012; 4:203-14. [PMID: 19337400 DOI: 10.4161/org.4.4.6926] [Citation(s) in RCA: 140] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Accepted: 09/08/2008] [Indexed: 01/30/2023] Open
Abstract
Angiogenesis represents the outgrowth of new blood vessels from existing ones, a physiologic process that is vital to supply nourishment to newly forming tissues during development and tissue remodeling and repair (wound healing). Regulation of angiogenesis in the healthy body occurs through a fine balance of angiogenesis-stimulating factors and angiogenesis inhibitors. When this balance is disturbed, excessive or deficient angiogenesis can result and contribute to development of a wide variety of pathological conditions. The therapeutic stimulation or suppression of angiogenesis could be the key to abrogating these diseases. In recent years, tissue engineering has emerged as a promising technology for regenerating tissues or organs that are diseased beyond repair. Among the critical challenges that deter the practical realization of the vision of regenerating functional tissues for clinical implantation, is how tissues of finite size can be regenerated and maintained viable in the long-term. Since the diffusion of nutrients and essential gases to cells, and removal of metabolic wastes is typically limited to a depth of 150-250 microm from a capillary (3-10 cells thick), tissue constructs must mandatorily permit in-growth of a blood capillary network to nourish and sustain the viability of cells within. The purpose of this article is to provide an overview of the role and significance of hyaluronan (HA), a glycosaminoglycan (GAG) component of connective tissues, in physiologic and pathological angiogenesis, its applicability as a therapeutic to stimulate or suppress angiogenesis in situ within necrotic tissues in vivo, and the factors determining its potential utility as a pro-angiogenic stimulus that will enable tissue engineering of neo-vascularized and functional tissue constructs for clinical use.
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Affiliation(s)
- Erin L Pardue
- Clemson University; Medical University of South Carolina Bioengineering Program; Charleston, South Carolina USA
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28
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Guo X, Elliott CG, Li Z, Xu Y, Hamilton DW, Guan J. Creating 3D angiogenic growth factor gradients in fibrous constructs to guide fast angiogenesis. Biomacromolecules 2012; 13:3262-71. [PMID: 22924876 DOI: 10.1021/bm301029a] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Fast angiogenesis in 3D fibrous constructs that mimic the morphology of the extracellular matrix remains challenging due to limited porosity in the densely packed constructs. We investigated whether mimicking the in vivo chemotaxis microenvironment for native blood vessel formation would stimulate angiogenesis in the fibrous constructs. The chemotaxis microenvironment was created by introducing 3D angiogenic growth factor gradients into the constructs. We have developed a technique that can quickly fabricate (∼40 min) such 3D gradients by simultaneously electrospinning polycaprolactone (PCL) fibers, encapsulating gradient amount of bFGF (stabilized by heparin) into poly(lactide-co-glycolide) (PLGA) microspheres, and electrospraying the microspheres into PCL fibers. Gradient formation was confirmed by fluorescence microscopy. Gradients with different steepnesses were obtained by modulating the initial concentration of the bFGF solution. All of the constructs were able to sustainedly release bioactive bFGF over a 28 day period. The release kinetics was dependent on the bFGF loading and steepness of the gradient. In vitro cell migration study demonstrated that bFGF gradients significantly increased the depth of cell migration. To assess the efficacy of bFGF gradients in inducing angiogenesis, we implanted constructs subcutaneously using mouse model. bFGF gradients significantly promoted cell penetration into the constructs. After 10 days of implantation, a high density of mature blood vessels (positive to both CD31 and α-SMA) were formed in the constructs. Vessel density was increased with the increase in steepness of the bFGF gradient. These gradient constructs may have potential to engineer vascularized tissues for various applications.
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Affiliation(s)
- Xiaolei Guo
- Department of Materials Science & Engineering, The Ohio State University, Columbus, OH, USA
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29
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Zhou J, Zhao Y, Wang J, Zhang S, Liu Z, Zhen M, Liu Y, Liu P, Yin Z, Wang X. Therapeutic angiogenesis using basic fibroblast growth factor in combination with a collagen matrix in chronic hindlimb ischemia. ScientificWorldJournal 2012; 2012:652794. [PMID: 22666143 PMCID: PMC3362026 DOI: 10.1100/2012/652794] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 02/23/2012] [Indexed: 11/26/2022] Open
Abstract
Although therapeutic angiogenesis by angiogenic cytokines is a feasible strategy to improve regional blood flow in ischemic regions, the optimal delivery mode needs to be established. Here we designed a complex of collagen matrix (CM) and basic fibroblast growth factor (bFGF) and evaluated its proangiogenic effect in ischemic hindlimbs. The bFGF-CM was prepared using lyophilization. The morphology, porosity and toxicity of CM were examined. The bFGF releasing profile and bioactivity of released bFGF were assessed. bFGF-CM was intramuscularly implanted into the rabbit ischemic hindlimb model. Oxygen saturation parameters (OSP) of ischemic hindlimbs was measured to evaluate the extremity perfusion at intervals. Histological examination was performed to evaluate the level of angiogenesis. The CM and bFGF-CM were of identical multiporous structure lacking cytotoxicity. The releasing profile lasted 10 days and the released bFGF remained bioactive. OSP in bFGF-CM group was significantly higher
than that in CM, bFGF and ischemic groups at 2 and 4 weeks. The number of capillaries and mature vessels in bFGF-CM group were significantly greater than that in untreated control, CM and bFGF groups. Therefore, bFGF-CM enables the safe and effective long-term release of bFGF with improved angiogenesis in ischemic hindlimbs compared with CM devoid of bFGF.
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Affiliation(s)
- Jianyin Zhou
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Xiamen 361001, China
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30
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Tara S, Takagi G, Miyamoto M, Kirinoki-Ichikawa S, Yamamoto T, Takano H, Takagi I, Yasutake M, Tabata Y, Mizuno K. Novel approach to ischemic skin ulcer in systemic lupus erythematosus: therapeutic angiogenesis by controlled-release basic fibroblast growth factor. Geriatr Gerontol Int 2012; 11:527-30. [PMID: 21951777 DOI: 10.1111/j.1447-0594.2011.00695.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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31
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Yoshii T, Harada F, Saito I, Nozawa-Inoue K, Kawano Y, Maeda T. Immunoexpression of aquaporin-1 in the rat periodontal ligament during experimental tooth movement. Biomed Res 2012; 33:225-33. [DOI: 10.2220/biomedres.33.225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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32
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Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats. PLoS One 2011; 6:e19192. [PMID: 21547081 PMCID: PMC3081850 DOI: 10.1371/journal.pone.0019192] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 03/22/2011] [Indexed: 11/26/2022] Open
Abstract
Background Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia-related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral growth and re-establishment of circulation in ischemic limbs using double transplantation of gene nucleofected primary cultures of fibroblasts, which were isolated from rat receiving such therapy. Methods and Results Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8±2.3 vs. 10.1±2.6; p<0.05). Moreover, improved collateral proliferation (BrdU incorporation: 0.48±0.05 vs. 0.57±0.05; p<0.05) and increase in blood perfusion (microspheres ratio: gastrocnemius: 0.41±0.10 vs. 0.50±0.11; p<0.05; soleus ratio: soleus: 0.42±0.08 vs. 0.60±0.08; p<0.01) in the lower hindlimb were also observed. Conclusions These results demonstrate the feasibility and effectiveness of double transplantation of gene nucleofected primary fibroblasts in producing growth factors and promoting the formation of collateral circulation in ischemic hindlimb, suggesting that isolation and preparation of gene nucleofected cells from individual accepting gene therapy may be an alternative strategy for treating limb ischemia related diseases.
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Kaully T, Kaufman-Francis K, Lesman A, Levenberg S. Vascularization--the conduit to viable engineered tissues. TISSUE ENGINEERING PART B-REVIEWS 2010; 15:159-69. [PMID: 19309238 DOI: 10.1089/ten.teb.2008.0193] [Citation(s) in RCA: 210] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Long-term viability of thick three-dimensional engineered tissue constructs is a major challenge. Addressing it requires development of vessel-like network that will allow the survival of the construct in vitro and its integration in vivo owing to improved vascularization after implantation. Resulting from work of various research groups, several approaches were developed aiming engineered tissue vascularization: (1) embodiment of angiogenesis growth factors in the polymeric scaffolds for prolonged release, (2) coculture of endothelial cells with target tissue cells and angiogenesis signaling cells, (3) use of microfabrication methods for creating designed channels for allowing nutrients to flow and/or for directing endothelial cells attachment, and (4) decellularization of organs and blood vessels for creating extracellular matrix. A synergistic effect is expected by combining several of these approaches as already demonstrated in some of the latest studies. Current paper reviews the progress in each approach and recent achievements toward vascularization of engineered tissues.
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Affiliation(s)
- Tamar Kaully
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
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34
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Ran X, Wang H, Chen Y, Zeng Z, Zhou Q, Zheng R, Sun J, Wang B, Lv X, Liang Y, Zhang K, Liu W. Aquaporin-1 expression and angiogenesis in rabbit chronic myocardial ischemia is decreased by acetazolamide. Heart Vessels 2010; 25:237-47. [PMID: 20512452 DOI: 10.1007/s00380-009-1179-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2009] [Accepted: 06/12/2009] [Indexed: 02/05/2023]
Abstract
Aquaporin-1 (AQP1) is a water channel protein expressed in endothelial and epithelial cells of many tissues, including the vasculature, where it serves to increase water permeability of the cell membrane. Prior studies have also reported that AQP1 plays a central role in tumor angiogenesis by promoting endothelial cell migration. To investigate whether AQP1 might also influence vascular angiogenesis in ischemic myocardium, the expression level of AQP1 for 21 days post myocardial infarction in rabbit hearts was observed. Aquaporin-1 mRNA and protein levels in day 3, and peaked on day 7 post surgery. This correlated well with the pattern of neovascularization and increased water content of infarct border tissue, and suggested that AQP1 may be involved in myocardial angiogenesis in response to ischemia injury. These AQP1-induced changes were tempered by acetazolamide, a carbonic anhydrase inhibitor, which acted by downregulating AQP1 expression. Acetazolamide treatment did not significantly affect the expression of vascular endothelial growth factor in the tissues studied. Our findings indicate a novel role for AQP1 in postnatal angiogenesis, which has implications in diverse pathophysiological conditions including wound healing, tumor metastasis, and organ regeneration.
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Affiliation(s)
- Xun Ran
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
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35
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Abstract
Basic fibroblast growth factor and vascular endothelial growth factor are thought to play a synergistic role in angiogenesis. They are released into the wound bed during haemostasis and promote the formation of new blood vessels.
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Affiliation(s)
- M Przybylski
- Wound Healing Research Unit, Cardiff Universtity, UK.
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36
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Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 2009; 24:321-8. [PMID: 19784813 DOI: 10.1007/s00380-008-1140-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Accepted: 12/19/2008] [Indexed: 01/31/2023]
Abstract
We aim to determine the efficacy and safety of gene and cell angiogenic therapies in the treatment of peripheral arterial disease (PAD) and evaluate them for the first time by a meta-analysis. We include in the formal meta-analysis only the randomized placebo-controlled phase 2 studies with any angiogenic gene or cell therapy modality to treat patients with PAD (intermittent claudication, ulcer or critical ischemia) identified by electronic search in MEDLINE and EMBASE databases (1980 to date). Altogether, 543 patients are analyzed from six randomized, controlled trials that are comparable with regard to patient selection, study design, and endpoints. We perform the meta-analysis regarding clinical improvement (improvement of peak walk time, relief in rest pain, ulcer healing or limb salvage) and rate of adverse events. At the end of treatment, therapeutic angiogenesis shows a significantly clinical improvement as compared to placebo in patients with PAD (odds ratio [OR] = 1.437; 95% confidence interval [CI] = 1.03-2.00; P = 0.033). The response rate (improvement of peak walk time) of the pooled groups according to clinical severity does not significantly differ for gene therapy as compared with placebo in the treatment of claudicating patients (OR = 1.304; 95% CI = 0.90-1.89; P = 0.16). Otherwise, we find significant efficacy of the treatment in critical ischemia (OR = 2.20; 95% CI = 1.01-4.79; P = 0.046). The adverse events rates show a slightly significantly higher risk of potential nonserious adverse events (edema, hypotension, proteinuria) in the treated group (OR = 1.81; 95% CI = 1.01-3.38; P = 0.045). We find no differences in mortality from any cause, malignancy, or retinopathy. The patients with PAD, and particularly those with critical ischemia, improve their symptoms when treated with angiogenic gene and cell therapy with acceptable tolerability.
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37
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Combined delivery of heme oxygenase-1 gene and fibroblast growth factor-2 protein for therapeutic angiogenesis. Biomaterials 2009; 30:6247-56. [PMID: 19682740 DOI: 10.1016/j.biomaterials.2009.07.058] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 07/27/2009] [Indexed: 01/31/2023]
Abstract
Ectopic expression of heme oxygenase-1 (HO-1) in ischemic tissue protects the tissue from apoptosis and necrosis and promotes angiogenesis. However, apoptosis and necrosis will decrease HO-1 gene transfection efficacy. We hypothesized that fibroblast growth factor-2 (FGF2) would attenuate ischemic damage during the incipient period, improve HO-1 gene transfection and, in turn, enhance neovascularization. To test this hypothesis, we employed a mouse model of hindlimb ischemia and treated the mice with HO-1 gene therapy alone, FGF2 alone, or HO-1 gene therapy plus FGF2. As controls, a group of mice was left untreated. At 12h, prior to the expression of exogenously delivered HO-1, apoptosis was significantly reduced in mice treated with FGF2, either alone or in combination with HO-1 gene therapy. At 3 days, HO-1 expression was greater in mice that also received FGF2 than in mice treated with HO-1 gene therapy alone. The expression of angiogenic growth factors and angiogenesis was greater in mice treated with HO-1 gene therapy plus FGF2 than in mice treated with HO-1 gene therapy alone. These data indicate that FGF2 rescued muscle necrosis prior to the exogenous expression of HO-1 and enhanced HO-1 gene transfection in ischemic murine limbs.
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38
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Esaki J, Sakaguchi H, Marui A, Bir SC, Arai Y, Huang Y, Tsubota H, Kanaji T, Ikeda T, Sakata R. Local Sustained Release of Prostaglandin E1 Induces Neovascularization in Murine Hindlimb Ischemia. Circ J 2009; 73:1330-6. [DOI: 10.1253/circj.cj-08-0999] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Jiro Esaki
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Hisashi Sakaguchi
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Akira Marui
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Shyamal Chandra Bir
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Yoshio Arai
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Yuhong Huang
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Hideki Tsubota
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | | | - Tadashi Ikeda
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
| | - Ryuzo Sakata
- Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine
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39
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Esaki J, Marui A, Tabata Y, Komeda M. Controlled release systems of angiogenic growth factors for cardiovascular diseases. Expert Opin Drug Deliv 2007; 4:635-49. [DOI: 10.1517/17425247.4.6.635] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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