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Ding X, Xie S, Zhang W, Zhu Y, Xu D, Xian S, Sun H, Guo X, Li Y, Lu J, Tong X, Huang R, Ji S, Xia Z. Current application of tissue-engineered dermal scaffolds mimicking the extracellular matrix microenvironment in wound healing. Regen Ther 2025; 28:371-382. [PMID: 39896445 PMCID: PMC11786805 DOI: 10.1016/j.reth.2024.12.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/09/2024] [Accepted: 12/26/2024] [Indexed: 02/04/2025] Open
Abstract
With the continuous advancement of materials science, cell biology, and biotechnology, tissue engineering has introduced novel solutions to traditional wound healing approaches, particularly demonstrating significant potential in addressing complex or non-healing wounds. One of the key technologies in this field, dermal scaffolds, serve as wound coverage materials that mimic the structural framework of the dermis. They primarily assume the function of extracellular matrix, providing space for cell attachment, migration, and proliferation, thus supporting cellular growth and regulating multiple biological processes in healing. Tissue engineering utilizes combinations of natural or synthetic scaffolds, seeded cells, or growth factors to induce distinct effects in angiogenesis, extracellular matrix deposition, and functional recovery. Therefore, various bioengineered dermal scaffolds hold significant potential for clinical translation in wound healing. This review outlines various extracellular matrix molecules utilized in the development of dermal scaffolds, emphasizes recent progress in cell- and growth factor-modified scaffolds, and discusses the challenges and future perspectives in this evolving field.
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Affiliation(s)
| | | | | | - Yushu Zhu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Dayuan Xu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Shuyuan Xian
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Hanlin Sun
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Xinya Guo
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Yixu Li
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Jianyu Lu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Xirui Tong
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Runzhi Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Shizhao Ji
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
| | - Zhaofan Xia
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, People's Republic of China, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, No. 168 Changhai Road, Shanghai 200433, China
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Chen H, Sun J, Liu W. Injectable ADM temperature-sensitive hydrogel loaded with bFGF in diabetic rat wound healing study. J Biomater Appl 2025:8853282251321943. [PMID: 39967017 DOI: 10.1177/08853282251321943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Background: Diabetic wound is one of the most common diabetic chronic complications. Effective treatments of diabetic wound remain limited. Here, we explored the effects of basic fibroblast growth factor (bFGF)-acellular dermal matrix (ADM) hydrogel on the diabetic wound. Methods: The bFGF-ADM hydrogel was manufactured by mixing 180 µL ADM hydrogel and 20 µL bFGF aqueous solution (10 mg/mL). The morphology of ADM hydrogel and bFGF-ADM hydrogel was observed under scanning electron microscope. The release property of bFGF-ADM hydrogel was determined by ELISA. CCK-8 assay was utilized to estimate the cell viability of mouse skin fibroblasts. The diabetes mellitus (DM) model was established in rats. The four wounds on the back of each DM rat were treated with the ADM hydrogel, bFGF-ADM hydrogel, bFGF aqueous solution and no solution (control), respectively. The wound healing rate of each rat was estimated. The traumatized skin tissue of each rat was observed by H&E staining and Sirius red staining. Results: The bFGF-ADM hydrogel displayed an interconnected pore structure and bFGF was gradually released from the bFGF-ADM hydrogel over time. The bFGF-ADM hydrogel could enhance the cell viability of skin fibroblasts and promote the wound healing rate, the re-epithelialization of wound and increase the collagen fiber content of dermis. And the bFGF-ADM hydrogel exhibited better therapeutic effects of diabetic wound than either bFGF or ADM alone. Conclusions: Our study revealed that the bFGF-ADM hydrogel could promote diabetic wound healing.
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Affiliation(s)
- Haojiao Chen
- Department of Burn Plastic and wound Repair, Shaoxing Second Hospital, Shaoxing, China
| | - Jianping Sun
- Department of Burn Plastic and wound Repair, Shaoxing Second Hospital, Shaoxing, China
| | - Wenyang Liu
- Department of Burn Plastic and wound Repair, Shaoxing Second Hospital, Shaoxing, China
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Wang X, Que H. Diagnostic Significance of Serum VEGF, bFGF, and Wound Tissue EGFR in Diabetic Chronic Refractory Wounds. INT J LOW EXTR WOUND 2025:15347346241313010. [PMID: 39819228 DOI: 10.1177/15347346241313010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
BACKGROUND Patients with diabetes mellitus (DM) face a higher risk of developing chronic refractory wounds. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epidermal growth factor receptor (EGFR) plays an important role in diabetes-related complications. This study aims to analyze the correlation between the 3 indicators and diabetic chronic refractory wounds, in order to establish the diagnostic value of these 3 indicators and provide reference for the treatment. MATERIAL AND METHODS We selected 168 patients, with 84 in healing group and 84 in refractory group. The levels of serum VEGF, bFGF, and wound tissue EGFR were compared before treatment, and the correlation between the 3 indicators and the refractory wounds was analyzed. After the specific treatment in refractory group, the clinical efficacy and wound closure index was recorded, and the correlation between them and the 3 indicators were analyzed. RESULTS The 3 indicators were all protective factors for diabetic chronic refractory wounds (p < .05). The serum VEGF and bFGF had relatively low diagnostic value for diabetic chronic refractory wounds, while wound tissue EGFR demonstrated higher diagnostic value (p < .05). The 3 indicators had a positive correlation with both the clinical efficacy and the wound closure index (p < .05). CONCLUSION Higher levels of serum VEGF, bFGF, and wound tissue EGFR are conducive to reducing the incidence of diabetic chronic refractory wounds. The combined measurement of these indicators holds high diagnostic value for the disease. Moreover, the higher the expression levels of these 3 indicators, the more favorable the clinical outcomes.
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Affiliation(s)
- Xuanyu Wang
- Department of Traditional Chinese Medicine Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huafa Que
- Department of Traditional Chinese Medicine Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Bigham A, Zarepour A, Khosravi A, Iravani S, Zarrabi A. Microneedle patches: a new vantage point for diabetic wound treatments. Biomater Sci 2025; 13:379-407. [PMID: 39620710 DOI: 10.1039/d4bm01229a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Microneedle patches have emerged as a promising approach for diabetic wound healing by enabling the targeted delivery of therapeutic agents such as stem cells and their derived exosomes, as well as localized delivery of bioactive moieties. These patches offer a non-invasive and efficient method for administering therapeutic payloads directly to the site of the wound, bypassing systemic circulation and minimizing potential side effects. The targeted delivery of stem cells holds immense potential for promoting tissue regeneration and accelerating wound healing in diabetic patients. Similarly, the localized delivery of stem cell-derived exosomes, which are known for their regenerative and anti-inflammatory properties, can enhance the healing process. Furthermore, microneedle patches enable the precise and controlled release of bioactive moieties, such as growth factors and cytokines, directly to the wound site, creating a conducive microenvironment for tissue repair and regeneration. The challenges associated with microneedle patches for diabetic wound healing are multifaceted. Biocompatibility issues, variability in skin characteristics among diabetic patients, regulatory hurdles, scalability, cost considerations, long-term stability, and patient acceptance and compliance all present significant barriers to the widespread adoption and optimization of microneedle technology in clinical practice. Overcoming these challenges will require collaborative efforts from various stakeholders to advance the field and address critical gaps in research and development. Ongoing research focuses on enhancing the biocompatibility and mechanical properties of microneedle materials, developing customizable technologies for personalized treatment approaches, integrating advanced functionalities such as sensors for real-time monitoring, and improving patient engagement and adherence through education and support mechanisms. These advancements have the potential to improve diabetic wound management by providing tailored and precise therapies that promote faster healing and reduce complications. This review explores the current landscape of microneedle patches in the context of diabetic wound management, highlighting both the challenges that need to be addressed and future perspectives for this innovative treatment modality.
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Affiliation(s)
- Ashkan Bigham
- Institute of Polymers, Composites, and Biomaterials, National Research Council (IPCB-CNR), Naples 80125, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Piazzale V. Tecchio 80, 80125 Naples, Italy
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Türkiye
| | - Siavash Iravani
- Independent Researcher, W Nazar ST, Boostan Ave, Isfahan, Iran.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye.
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
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Saleem M, Syed Khaja AS, Moursi S, Altamimi TA, Alharbi MS, Usman K, Khan MS, Alaskar A, Alam MJ. Narrative review on nanoparticles based on current evidence: therapeutic agents for diabetic foot infection. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6275-6297. [PMID: 38639898 DOI: 10.1007/s00210-024-03094-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 04/11/2024] [Indexed: 04/20/2024]
Abstract
Diabetes's effects on wound healing present a major treatment challenge and increase the risk of amputation. When traditional therapies fail, new approaches must be investigated. With their submicron size and improved cellular internalisation, nanoparticles present a viable way to improve diabetic wound healing. They are attractive options because of their innate antibacterial qualities, biocompatibility, and biodegradability. Nanoparticles loaded with organic or inorganic compounds, or embedded in biomimetic matrices such as hydrogels, chitosan, and hyaluronic acid, exhibit excellent anti-inflammatory, antibacterial, and antioxidant properties. Drug delivery systems (DDSs)-more precisely, nanodrug delivery systems (NDDSs)-use the advantages of nanotechnology to get around some of the drawbacks of traditional DDSs. Recent developments show how expertly designed nanocarriers can carry a variety of chemicals, transforming the treatment of diabetic wounds. Biomaterials that deliver customised medications to the wound microenvironment demonstrate potential. Delivery techniques for nanomedicines become more potent than ever, overcoming conventional constraints. Therapeutics for diabetes-induced non-healing wounds are entering a revolutionary era thanks to precisely calibrated nanocarriers that effectively distribute chemicals. This review highlights the therapeutic potential of nanoparticles and outlines the multifunctional nanoparticles of the future that will be used for complete wound healing in diabetics. The investigation of novel nanodrug delivery systems has the potential to revolutionise diabetic wound therapy and provide hope for more efficient and focused therapeutic approaches.
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Affiliation(s)
- Mohd Saleem
- Department of Pathology, College of Medicine, University of Hail, 55211, Hail, Saudi Arabia.
| | | | - Soha Moursi
- Department of Pathology, College of Medicine, University of Hail, 55211, Hail, Saudi Arabia
| | - Tahani Almofeed Altamimi
- Department of Family Medicine, College of Medicine, University of Hail, 55211, Hail, Saudi Arabia
| | - Mohammed Salem Alharbi
- Department of Internal Medicine, College of Medicine, University of Hail, 55211, Hail, Saudi Arabia
| | - Kauser Usman
- Department of Internal Medicine, King George's Medical University, Lucknow, India
| | - Mohd Shahid Khan
- Department of Microbiology, Integral Institute of Medical Sciences and Research, Lucknow, India
| | - Alwaleed Alaskar
- Department of Diabetes and Endocrinology, King Salman Specialist Hospital, 55211, Hail, Saudi Arabia
| | - Mohammad Jahoor Alam
- Department of Biology, College of Science, University of Hail, 55211, Hail, Saudi Arabia
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Chen YC, Chuang EY, Tu YK, Hsu CL, Cheng NC. Human platelet lysate-cultured adipose-derived stem cell sheets promote angiogenesis and accelerate wound healing via CCL5 modulation. Stem Cell Res Ther 2024; 15:163. [PMID: 38853252 PMCID: PMC11163789 DOI: 10.1186/s13287-024-03762-9] [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: 01/25/2024] [Accepted: 05/15/2024] [Indexed: 06/11/2024] Open
Abstract
BACKGROUND A rising population faces challenges with healing-impaired cutaneous wounds, often leading to physical disabilities. Adipose-derived stem cells (ASCs), specifically in the cell sheet format, have emerged as a promising remedy for impaired wound healing. Human platelet lysate (HPL) provides an attractive alternative to fetal bovine serum (FBS) for culturing clinical-grade ASCs. However, the potential of HPL sheets in promoting wound healing has not been fully investigated. This study aimed to explore the anti-fibrotic and pro-angiogenic capabilities of HPL-cultured ASC sheets and delve into the molecular mechanism. METHODS A rat burn model was utilized to evaluate the efficacy of HPL-cultured ASC sheets in promoting wound healing. ASC sheets were fabricated with HPL, and those with FBS were included for comparison. Various analyses were conducted to assess the impact of HPL sheets on wound healing. Histological examination of wound tissues provided insights into aspects such as wound closure, collagen deposition, and overall tissue regeneration. Immunofluorescence was employed to assess the presence and distribution of transplanted ASCs after treatment. Further in vitro studies were conducted to decipher the specific factors in HPL sheets contributing to angiogenesis. RESULTS HPL-cultured ASC sheets significantly accelerated wound closure, fostering ample and organized collagen deposition in the neo-dermis. Significantly more retained ASCs were observed in wound tissues treated with HPL sheets compared to the FBS counterparts. Moreover, HPL sheets mitigated macrophage recruitment and decreased subsequent wound tissue fibrosis in vivo. Immunohistochemistry also indicated enhanced angiogenesis in the HPL sheet group. The in vitro analyses showed upregulation of C-C motif chemokine ligand 5 (CCL5) and angiogenin in HPL sheets, including both gene expression and protein secretion. Culturing endothelial cells in the conditioned media compared to media supplemented with CCL5 or angiogenin suggested a correlation between CCL5 and the pro-angiogenic effect of HPL sheets. Additionally, through neutralizing antibody experiments, we further validated the crucial role of CCL5 in HPL sheet-mediated angiogenesis in vitro. CONCLUSIONS The present study underscores CCL5 as an essential factor in the pro-angiogenic effect of HPL-cultured ASC sheets during the wound healing process. These findings highlight the potential of HPL-cultured ASC sheets as a promising therapeutic option for healing-impaired cutaneous wounds in clinical settings. Furthermore, the mechanism exploration yields valuable information for optimizing regenerative strategies with ASC products. BRIEF ACKNOWLEDGMENT This research was supported by the National Science and Technology Council, Taiwan (NSTC112-2321-B-002-018), National Taiwan University Hospital (111C-007), and E-Da Hospital-National Taiwan University Hospital Joint Research Program (111-EDN0001, 112-EDN0002).
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Affiliation(s)
- Yueh-Chen Chen
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd, Taipei, 100, Taiwan
| | - Er-Yuan Chuang
- International Ph.D. Program in Biomedical Engineering, Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei, Taiwan
| | - Yuan-Kun Tu
- Department of Orthopedics, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Nai-Chen Cheng
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd, Taipei, 100, Taiwan.
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
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Ju CC, Liu XX, Liu LH, Guo N, Guan LW, Wu JX, Liu DW. Epigenetic modification: A novel insight into diabetic wound healing. Heliyon 2024; 10:e28086. [PMID: 38533007 PMCID: PMC10963386 DOI: 10.1016/j.heliyon.2024.e28086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 03/04/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Wound healing is an intricate and fine regulatory process. In diabetic patients, advanced glycation end products (AGEs), excessive reactive oxygen species (ROS), biofilm formation, persistent inflammation, and angiogenesis regression contribute to delayed wound healing. Epigenetics, the fast-moving science in the 21st century, has been up to date and associated with diabetic wound repair. In this review, we go over the functions of epigenetics in diabetic wound repair in retrospect, covering transcriptional and posttranscriptional regulation. Among these, we found that histone modification is widely involved in inflammation and angiogenesis by affecting macrophages and endothelial cells. DNA methylation is involved in factors regulation in wound repair but also affects the differentiation phenotype of cells in hyperglycemia. In addition, noncodingRNA regulation and RNA modification in diabetic wound repair were also generalized. The future prospects for epigenetic applications are discussed in the end. In conclusion, the study suggests that epigenetics is an integral regulatory mechanism in diabetic wound healing.
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Affiliation(s)
- Cong-Cong Ju
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, PR China
| | - Xiao-Xiao Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Li-hua Liu
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, PR China
| | - Nan Guo
- Nanchang University, Nanchang, Jiangxi, PR China
| | - Le-wei Guan
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, PR China
| | - Jun-xian Wu
- Nanchang University, Nanchang, Jiangxi, PR China
| | - De-Wu Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
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Zhang T, Shi X, Li M, Hu J, Lu H. Optimized Allogenic Decellularized Meniscal Scaffold Modified by Collagen Affinity Stromal Cell-Derived Factor SDF1α for Meniscal Regeneration: A 6- and 12-Week Animal Study in a Rabbit Model. Am J Sports Med 2024; 52:124-139. [PMID: 38164676 DOI: 10.1177/03635465231210950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
BACKGROUND Total meniscectomy for treating massive meniscal tears may lead to joint instability, cartilage degeneration, and even progressive osteoarthritis. The meniscal substitution strategies for advancing reconstruction of the meniscus deserve further investigation. HYPOTHESIS A decellularized meniscal scaffold (DMS) modified with collagen affinity stromal cell-derived factor (C-SDF1α) may facilitate meniscal regeneration and protect cartilage from abrasion. STUDY DESIGN Controlled laboratory study. METHODS The authors first modified DMS with C-SDF1α to fabricate a new meniscal graft (DMS-CBD [collagen-binding domain]). Second, they performed in vitro studies to evaluate the release dynamics, biocompatibility, and differentiation inducibility (osteogenic, chondrogenic, and tenogenic differentiation) on human bone marrow mesenchymal stem cells. Using in vivo studies, they subjected rabbits that received medial meniscectomy to a transplantation procedure to implement their meniscal graft. At postoperative weeks 6 and 12, the meniscal regeneration outcomes and chondroprotective efficacy of the new meniscal graft were evaluated by macroscopic observation, histology, micromechanics, and immunohistochemistry tests. RESULTS In in vitro studies, the optimized DMS-CBD graft showed notable biocompatibility, releasing efficiency, and chondrogenic inducibility. In in vivo studies, the implanted DMS-CBD graft after total meniscectomy promoted the migration of cells and extracellular matrix deposition in transplantation and further facilitated meniscal regeneration and protected articular cartilage from degeneration. CONCLUSION The new meniscal graft (DMS-CBD) accelerated extracellular matrix deposition and meniscal regeneration and protected articular cartilage from degeneration. CLINICAL RELEVANCE The results demonstrate that the DMS-CBD graft can serve as a potential meniscal substitution after meniscectomy.
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Affiliation(s)
- Tao Zhang
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Xin Shi
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Muzhi Li
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Jianzhong Hu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Hongbin Lu
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
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Zhang HM, Yang ML, Xi JZ, Yang GY, Wu QN. Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer: A review. World J Diabetes 2023; 14:1585-1602. [DOI: 10.4239/wjd.v14.i11.1585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/16/2023] [Accepted: 09/11/2023] [Indexed: 11/14/2023] Open
Abstract
The complication of diabetes, which is known as diabetic foot ulcer (DFU), is a significant concern due to its association with high rates of disability and mortality. It not only severely affects patients’ quality of life, but also imposes a substantial burden on the healthcare system. In spite of efforts made in clinical practice, treating DFU remains a challenging task. While mesenchymal stem cell (MSC) therapy has been extensively studied in treating DFU, the current efficacy of DFU healing using this method is still inadequate. However, in recent years, several MSCs-based drug delivery systems have emerged, which have shown to increase the efficacy of MSC therapy, especially in treating DFU. This review summarized the application of diverse MSCs-based drug delivery systems in treating DFU and suggested potential prospects for the future research.
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Affiliation(s)
- Hong-Min Zhang
- Department of Endocrinology, People’s Hospital of Chongqing Liangjiang New Area, Chongqing 400030, China
| | - Meng-Liu Yang
- Department of Endocrinology, The Second Affiliated Hospital of The Chongqing Medical University, Chongqing 400030, China
| | - Jia-Zhuang Xi
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing 406230, China
| | - Gang-Yi Yang
- Department of Endocrinology, The Second Affiliated Hospital of The Chongqing Medical University, Chongqing 400030, China
| | - Qi-Nan Wu
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing 406230, China
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Liu M, Wei X, Zheng Z, Li Y, Li M, Lin J, Yang L. Recent Advances in Nano-Drug Delivery Systems for the Treatment of Diabetic Wound Healing. Int J Nanomedicine 2023; 18:1537-1560. [PMID: 37007988 PMCID: PMC10065433 DOI: 10.2147/ijn.s395438] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
Diabetes mellitus (DM) induced wound healing impairment remains a serious health problem and burden on the clinical obligation for high amputation rates. Based on the features of wound microenvironment, biomaterials loading specific drugs can benefit diabetic wound treatment. Drug delivery systems (DDSs) can carry diverse functional substances to the wound site. Nano-drug delivery systems (NDDSs), benefiting from their features related to nano size, overcome limitations of conventional DDSs application and are considered as a developing process in the wound treatment field. Recently, a number of finely designed nanocarriers efficiently loading various substances (bioactive and non-bioactive factors) have emerged to circumvent constraints faced by traditional DDSs. This review describes various recent advances of nano-drug delivery systems involved in mitigating diabetes mellitus-based non-healing wounds.
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Affiliation(s)
- Mengqian Liu
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xuerong Wei
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Zijun Zheng
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yicheng Li
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Mengyao Li
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jiabao Lin
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Lei Yang
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- Correspondence: Lei Yang, Department of Burns, Nanfang Hospital, Southern Medical University, Jingxi Street, Baiyun District, Guangzhou, 510515, People’s Republic of China, Tel +86-20-6164-1841, Email
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Brembilla NC, Vuagnat H, Boehncke WH, Krause KH, Preynat-Seauve O. Adipose-Derived Stromal Cells for Chronic Wounds: Scientific Evidence and Roadmap Toward Clinical Practice. Stem Cells Transl Med 2022; 12:17-25. [PMID: 36571216 PMCID: PMC9887085 DOI: 10.1093/stcltm/szac081] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/16/2022] [Indexed: 12/27/2022] Open
Abstract
Chronic wounds, ie, non-healing ulcers, have a prevalence of ~1% in the general population. Chronic wounds strongly affect the quality of life and generate considerable medical costs. A fraction of chronic wounds will heal within months of appropriate treatment; however, a significant fraction of patients will develop therapy-refractory chronic wounds, leading to chronic pain, infection, and amputation. Given the paucity of therapeutic options for refractory wounds, cell therapy and in particular the use of adipose-derived stromal cells (ASC) has emerged as a promising concept. ASC can be used as autologous or allogeneic cells. They can be delivered in suspension or in 3D cultures within scaffolds. ASC can be used without further processing (stromal vascular fraction of the adipose tissue) or can be expanded in vitro. ASC-derived non-cellular components, such as conditioned media or exosomes, have also been investigated. Many in vitro and preclinical studies in animals have demonstrated the ASC efficacy on wounds. ASC efficiency appears to occurs mainly through their regenerative secretome. Hitherto, the majority of clinical trials focused mainly on safety issues. However more recently, a small number of randomized, well-controlled trials provided first convincing evidences for a clinical efficacy of ASC-based chronic wound therapies in humans. This brief review summarizes the current knowledge on the mechanism of action, delivery and efficacy of ASC in chronic wound therapy. It also discusses the scientific and pharmaceutical challenges to be solved before ASC-based wound therapy enters clinical reality.
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Affiliation(s)
- Nicolo C Brembilla
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland,Division of Dermatology and Venereology, Geneva University Hospitals, Geneva, Switzerland
| | - Hubert Vuagnat
- Program for Wounds and Wound Healing, Care Directorate, Geneva University Hospitals, Geneva, Switzerland
| | - Wolf-Henning Boehncke
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland,Division of Dermatology and Venereology, Geneva University Hospitals, Geneva, Switzerland
| | - Karl-Heinz Krause
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland,Laboratory of Therapy and Stem Cells, Geneva University Hospitals, Geneva, Switzerland
| | - Olivier Preynat-Seauve
- Corresponding author: Olivier Preynat-Seauve, PATIM, 1 rue Michel Servet CH-1211 Geneva 4, Switzerland. Tel: +41223794139;
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12
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Stability Enhancement of Freeze-Dried Gelatin/Alginate Coacervates for bFGF Delivery. Pharmaceutics 2022; 14:pharmaceutics14122548. [PMID: 36559042 PMCID: PMC9781200 DOI: 10.3390/pharmaceutics14122548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/11/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022] Open
Abstract
Chronic wound sites have elevated levels of proteolytic enzymes that negate the activity of topically applied growth factors. bFGF encapsulated in gelatin/alginate coacervates was protected from protease and showed better activity than bFGF in solution; however, its activity decreased with particle size and PDI increase after freeze-drying and rehydration. In this study, we aim to improve the stability of bFGF coacervates during freeze-drying to enable a topically applied growth factor delivery system for diabetic foot ulcer. Trehalose, mannitol, and Tween 80 at various concentrations were tested as cryoprotectant candidates. Trehalose improved the mechanical property of freeze-dried coacervates and physical properties after rehydration, resulting in stable size and PDI values. It also enhanced the bFGF activity in hyperglycemic human dermal fibroblasts with better cell viability, migration, and procollagen synthesis compared to the coacervates without trehalose. Hydrogen bonding interactions between trehalose and polymers probed by ATR-FTIR contribute to the stability of coacervates during freeze-drying. In conclusion, the freeze-dried gelatin/alginate coacervates encapsulating bFGF was effectively stabilized with trehalose, and the resulting coacervate composition is suggested as a potential therapeutic modality for chronic wounds including diabetic foot ulcer.
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Liu H, Wu B, Shi X, Cao Y, Zhao X, Liang D, Qin Q, Liang X, Lu W, Wang D, Liu J. Aerobic exercise-induced circulating extracellular vesicle combined decellularized dermal matrix hydrogel facilitates diabetic wound healing by promoting angiogenesis. Front Bioeng Biotechnol 2022; 10:903779. [PMID: 36082169 PMCID: PMC9445842 DOI: 10.3389/fbioe.2022.903779] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Insufficient blood supply results in unsatisfactory wound healing, especially for challenging wound repair such as diabetic wound defects. Regular exercise training brings a lot of benefits to cardiovascular fitness and metabolic health including attenuation of T2DM progression. Circulating extracellular vesicles (EVs) are postulated to carry a variety of signals involved in tissue crosstalk by their modified cargoes, representing novel mechanisms for the effects of exercise. Prominently, both acute and chronic aerobic exercise training can promote the release of exercise-induced cytokines and enhance the angiogenic function of circulating angiogenic cell–derived EVs.Methods: We investigated the possible angiogenesis potential of aerobic exercise-induced circulating EVs (EXE-EVs) on diabetic wound healing. Circulating EVs were isolated from the plasma of rats subjected to 4 weeks of moderate aerobic exercise or sedentariness 24 h after the last training session. The therapeutic effect of circulating EVs was evaluated in vitro by proliferation, migration, and tube formation assays of human umbilical vein endothelial cells (HUVECs), as well as in vivo by quantification of angiogenesis and cutaneous wound healing in diabetic rats.Results: The number of circulating EVs did not change significantly in exercised rats 24 h post-exercise in comparison with the sedentary rats. Nevertheless, EXE-EVs showed remarkable pro-angiogenic effect by augmenting proliferation, migration, and tube formation of HUVECs. Furthermore, the findings of animal experiments revealed that the EXE-EVs delivered by decellularized dermal matrix hydrogel (DDMH) could significantly promote the repair of skin defects through stimulating the regeneration of vascularized skin.Discussion: The present study is the first attempt to demonstrate that aerobic exercise-induced circulating EVs could be utilized as a cell-free therapy to activate angiogenesis and promote diabetic wound healing. Our findings suggest that EXE-EVs may stand for a potential strategy for diabetic soft tissue wound repair.
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Affiliation(s)
- Haifeng Liu
- Guangzhou Medical University, Guangzhou, China
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Bing Wu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Xin Shi
- Department of Limbs (Foot and Hand) Microsurgery, Affiliated Chenzhou Hospital, Hengyang Medical School, University of South China, Chenzhou, China
| | - Yanpeng Cao
- Department of Limbs (Foot and Hand) Microsurgery, Affiliated Chenzhou Hospital, Hengyang Medical School, University of South China, Chenzhou, China
| | - Xin Zhao
- Department of Limbs (Foot and Hand) Microsurgery, Affiliated Chenzhou Hospital, Hengyang Medical School, University of South China, Chenzhou, China
| | - Daqiang Liang
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Qihuang Qin
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Xinzhi Liang
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Wei Lu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Daping Wang
- Guangzhou Medical University, Guangzhou, China
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- *Correspondence: Daping Wang, ; Jun Liu,
| | - Jun Liu
- Department of Limbs (Foot and Hand) Microsurgery, Affiliated Chenzhou Hospital, Hengyang Medical School, University of South China, Chenzhou, China
- *Correspondence: Daping Wang, ; Jun Liu,
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14
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Liu R, Dong R, Chang M, Liang X, Wang HC. Adipose-Derived Stem Cells for the Treatment of Diabetic Wound: From Basic Study to Clinical Application. Front Endocrinol (Lausanne) 2022; 13:882469. [PMID: 35898452 PMCID: PMC9309392 DOI: 10.3389/fendo.2022.882469] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/19/2022] [Indexed: 12/27/2022] Open
Abstract
Diabetic wounds significantly affect the life quality of patients and may cause amputation and mortality if poorly managed. Recently, a wide range of cell-based methods has emerged as novel therapeutic methods in treating diabetic wounds. Adipose-derived stem cells (ASCs) are considered to have the potential for widespread clinical application of diabetic wounds treatment in the future. This review summarized the mechanisms of ASCs to promote diabetic wound healing, including the promotion of immunomodulation, neovascularization, and fibro synthesis. We also review the current progress and limitations of clinical studies using ASCs to intervene in diabetic wound healing. New methods of ASC delivery have been raised in recent years to provide a standardized and convenient use of ASCs.
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Affiliation(s)
- Runzhu Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ruijia Dong
- Department of Plastic Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Mengling Chang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiao Liang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hayson Chenyu Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Yu J, Hsu YC, Lee JK, Cheng NC. Enhanced angiogenic potential of adipose-derived stem cell sheets by integration with cell spheroids of the same source. Stem Cell Res Ther 2022; 13:276. [PMID: 35765015 PMCID: PMC9241243 DOI: 10.1186/s13287-022-02948-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 06/09/2022] [Indexed: 11/24/2022] Open
Abstract
Background Adipose-derived stem cell (ASC) has been considered as a desirable source for cell therapy. In contrast to combining scaffold materials with cells, ASCs can be fabricated into scaffold-free three-dimensional (3D) constructs to promote regeneration at tissue level. However, previous reports have found decreased expression of vascular endothelial growth factor (VEGF) in ASC sheets. In this study, we aimed to integrate ASC spheroids into ASC sheets to enhance the angiogenic capability of cell sheets. Methods ASCs were seeded in agarose microwells to generate uniform cell spheroids with adjustable size, while extracellular matrix deposition could be stimulated by ascorbic acid 2-phosphate to form ASC sheets. RNA sequencing was performed to identify the transcriptomic profiles of ASC spheroids and sheets relative to monolayer ASCs. By transferring ASC spheroids onto ASC sheets, the spheroid sheet composites could be successfully fabricated after a short-term co-culture, and their angiogenic potential was evaluated in vitro and in ovo. Results RNA sequencing analysis revealed that upregulation of angiogenesis-related genes was found only in ASC spheroids. The stimulating effect of spheroid formation on ASCs toward endothelial lineage was demonstrated by enhanced CD31 expression, which maintained after ASC spheroids were seeded on cell sheets. Relative to ASC sheets, enhanced expression of VEGF and hepatocyte growth factor was also noted in ASC spheroid sheets, and conditioned medium of ASC spheroid sheets significantly enhanced tube formation of endothelial cells in vitro. Moreover, chick embryo chorioallantoic membrane assay showed a significantly higher capillary density with more branch points after applying ASC spheroid sheets, and immunohistochemistry also revealed a significantly higher ratio of CD31-positive area. Conclusion In the spheroid sheet construct, ASC spheroids can augment the pro-angiogenesis capability of ASC sheets without the use of exogenous biomaterial or genetic manipulation. The strategy of this composite system holds promise as an advance in 3D culture technique of ASCs for future application in angiogenesis and regeneration therapies. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02948-3.
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Affiliation(s)
- Jiashing Yu
- Department of Chemical Engineering, College of Engineering, National Taiwan University, 1 Sec. 4, Roosevelt Rd., Taipei 106, Taiwan
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central University, 300 Zhongda Rd., Taoyuan 320, Taiwan
| | - Jen-Kuang Lee
- Department of Medicine, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd., Taipei 100, Taiwan
| | - Nai-Chen Cheng
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd., Taipei 100, Taiwan.
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16
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Xu Z, Cao J, Zhao Z, Qiao Y, Liu X, Zhong J, Wang B, Suo G. A functional extracellular matrix biomaterial enriched with VEGFA and bFGF as vehicle of human umbilical cord mesenchymal stem cells in skin wound healing. Biomed Mater 2021; 17. [PMID: 34749352 DOI: 10.1088/1748-605x/ac37b0] [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: 09/11/2021] [Accepted: 11/08/2021] [Indexed: 11/12/2022]
Abstract
The construction of microvascular network is one of the greatest challenges for tissue engineering and cell therapy. Endothelial cells are essential for the construction of network of blood vessels. However, their application meets challenges in clinic due to the limited resource of autologous endothelium. Mesenchymal stem cells can effectively promote the angiogenesis in ischemic tissues for their abilities of endothelial differentiation and paracrine, and abundant sources. Extracellular matrix (ECM) has been widely used as an ideal biomaterial to mimic cellular microenvironment for tissue engineering due to its merits of neutrality, good biocompatibility, degradability, and controllability. In this study, a functional cell derived ECM biomaterial enriched with VEGFA and bFGF by expressing the collagen-binding domain fused factor genes in host cells was prepared. This material could induce endothelial differentiation of human umbilical cord mesenchymal stem cells (hUCMSCs) and promote angiogenesis, which may improve the healing effect of skin injury. Our research not only provides a functional ECM material to inducing angiogenesis by inducing endothelial differentiation of hUCMSCs, but also shed light on the ubiquitous approaches to endow ECM materials different functions by enriching different factors. This study will benefit tissue engineering and regenerative medicine researches.
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Affiliation(s)
- Zhongjuan Xu
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, Anhui, People's Republic of China.,CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu, People's Republic of China
| | - Junjun Cao
- Livingchip Lnc., Nanjing 211112, Jiangsu, People's Republic of China
| | - Zhe Zhao
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu, People's Republic of China
| | - Yong Qiao
- Livingchip Lnc., Nanjing 211112, Jiangsu, People's Republic of China
| | - Xingzhi Liu
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, Anhui, People's Republic of China.,CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu, People's Republic of China
| | - Junjie Zhong
- Department of Neurosurgery, Fudan University Huashan Hospital, National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200041, People's Republic of China
| | - Bin Wang
- Center for Clinic Stem Cell Research, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, People's Republic of China
| | - Guangli Suo
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu, People's Republic of China
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