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  1. Fulltext Electrospun Collagen Nanofibers and Their Applications in Skin Tissue Engineering
    Law JX, Liau LL, Saim A, Yang Y, Idrus R
    Tissue Eng Regen Med, 2017 Dec;14(6):699-718.
    PMID: 30603521 DOI: 10.1007/s13770-017-0075-9
    Electrospinning is a simple and versatile technique to fabricate continuous fibers with diameter ranging from micrometers to a few nanometers. To date, the number of polymers that have been electrospun has exceeded 200. In recent years, electrospinning has become one of the most popular scaffold fabrication techniques to prepare nanofiber mesh for tissue engineering applications. Collagen, the most abundant extracellular matrix protein in the human body, has been electrospun to fabricate biomimetic scaffolds that imitate the architecture of native human tissues. As collagen nanofibers are mechanically weak in nature, it is commonly cross-linked or blended with synthetic polymers to improve the mechanical strength without compromising the biological activity. Electrospun collagen nanofiber mesh has high surface area to volume ratio, tunable diameter and porosity, and excellent biological activity to regulate cell function and tissue formation. Due to these advantages, collagen nanofibers have been tested for the regeneration of a myriad of tissues and organs. In this review, we gave an overview of electrospinning, encompassing the history, the instrument settings, the spinning process and the parameters that affect fiber formation, with emphasis given to collagen nanofibers' fabrication and application, especially the use of collagen nanofibers in skin tissue engineering.
  2. Fulltext Physicochemical Properties and Biocompatibility of Electrospun Polycaprolactone/Gelatin Nanofibers
    Lim WL, Chowdhury SR, Ng MH, Law JX
    Int J Environ Res Public Health, 2021 04 29;18(9).
    PMID: 33947053 DOI: 10.3390/ijerph18094764
    Tissue-engineered substitutes have shown great promise as a potential replacement for current tissue grafts to treat tendon/ligament injury. Herein, we have fabricated aligned polycaprolactone (PCL) and gelatin (GT) nanofibers and further evaluated their physicochemical properties and biocompatibility. PCL and GT were mixed at a ratio of 100:0, 70:30, 50:50, 30:70, 0:100, and electrospun to generate aligned nanofibers. The PCL/GT nanofibers were assessed to determine the diameter, alignment, water contact angle, degradation, and surface chemical analysis. The effects on cells were evaluated through Wharton's jelly-derived mesenchymal stem cell (WJ-MSC) viability, alignment and tenogenic differentiation. The PCL/GT nanofibers were aligned and had a mean fiber diameter within 200-800 nm. Increasing the GT concentration reduced the water contact angle of the nanofibers. GT nanofibers alone degraded fastest, observed only within 2 days. Chemical composition analysis confirmed the presence of PCL and GT in the nanofibers. The WJ-MSCs were aligned and remained viable after 7 days with the PCL/GT nanofibers. Additionally, the PCL/GT nanofibers supported tenogenic differentiation of WJ-MSCs. The fabricated PCL/GT nanofibers have a diameter that closely resembles the native tissue's collagen fibrils and have good biocompatibility. Thus, our study demonstrated the suitability of PCL/GT nanofibers for tendon/ligament tissue engineering applications.
  3. Characteristics and clinical applications of Wharton's jelly-derived mesenchymal stromal cells
    Liau LL, Ruszymah BHI, Ng MH, Law JX
    Curr Res Transl Med, 2020 01;68(1):5-16.
    PMID: 31543433 DOI: 10.1016/j.retram.2019.09.001
    Mesenchymal stromal cells (MSCs) are widely used in the clinic because they involve fewer ethical issues and safety concerns compared to other stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). MSCs derived from umbilical cord Wharton's jelly (WJ-MSCs) have excellent proliferative potential and a faster growth rate and can retain their multipotency for more passages in vitro compared to adult MSCs from bone marrow or adipose tissue. WJ-MSCs are used clinically for repairing tissue injuries of the spinal cord, liver and heart with the aim of regenerating tissue. On the other hand, WJ-MSCs are also used clinically to ameliorate immune-mediated diseases based on their ability to modulate immune responses. In the field of tissue engineering, WJ-MSCs capable of differentiating into multiple cell lineages have been used to produce a variety of engineered tissues in vitro that can then be transplanted in vivo. This review discusses the characteristics of WJ-MSCs, the differences between WJ-MSCs and adult MSCs, clinical studies involving WJ-MSCs and future perspectives of WJ-MSC research and clinical applications. To summarize, WJ-MSCs have shown promise in treating a variety of diseases clinically. However, most clinical trials/studies reported thus far are relatively smaller in scale. The collected evidence is insufficient to support the routine use of WJ-MSC therapy in the clinic. Thus, rigorous clinical trials are needed in the future to obtain more information on WJ-MSC therapy safety and efficacy.
  4. Tissue-engineered trachea: A review
    Law JX, Liau LL, Aminuddin BS, Ruszymah BH
    Int J Pediatr Otorhinolaryngol, 2016 Dec;91:55-63.
    PMID: 27863642 DOI: 10.1016/j.ijporl.2016.10.012
    Tracheal replacement is performed after resection of a portion of the trachea that was impossible to reconnect via direct anastomosis. A tissue-engineered trachea is one of the available options that offer many advantages compared to other types of graft. Fabrication of a functional tissue-engineered trachea for grafting is very challenging, as it is a complex organ with important components, including cartilage, epithelium and vasculature. A number of studies have been reported on the preparation of a graftable trachea. A laterally rigid but longitudinally flexible hollow cylindrical scaffold which supports cartilage and epithelial tissue formation is the key element. The scaffold can be prepared via decellularization of an allograft or fabricated using biodegradable or non-biodegradable biomaterials. Commonly, the scaffold is seeded with chondrocytes and epithelial cells at the outer and luminal surfaces, respectively, to hasten tissue formation and improve functionality. To date, several clinical trials of tracheal replacement with tissue-engineered trachea have been performed. This article reviews the formation of cartilage tissue, epithelium and neovascularization of tissue-engineered trachea, together with the obstacles, possible solutions and future. Furthermore, the role of the bioreactor for in vitro tracheal graft formation and recently reported clinical applications of tracheal graft were also discussed. Generally, although encouraging results have been achieved, however, some obstacles remain to be resolved before the tissue-engineered trachea can be widely used in clinical settings.
  5. Platelet-rich plasma with keratinocytes and fibroblasts enhance healing of full-thickness wounds
    Law JX, Chowdhury SR, Saim AB, Idrus RBH
    J Tissue Viability, 2017 Aug;26(3):208-215.
    PMID: 28615133 DOI: 10.1016/j.jtv.2017.05.003
    Advances in tissue engineering led to the development of various tissue-engineered skin substitutes (TESS) for the treatment of skin injuries. The majority of the autologous TESS required lengthy and costly cell expansion process to fabricate. In this study, we determine the possibility of using a low density of human skin cells suspended in platelet-rich plasma (PRP)-enriched medium to promote the healing of full-thickness skin wounds. To achieve this, full-thickness wounds of size 1.767 cm2 were created at the dorsum part of nude mice and treated with keratinocytes (2 × 104 cells/cm2) and fibroblasts (3 × 104 cells/cm2) suspended in 10% PRP-enriched medium. Wound examination was conducted weekly and the animals were euthanized after 2 weeks. Gross examination showed that re-epithelialization was fastest in the PRP+cells group at both day 7 and 14, followed by the PRP group and NT group receiving no treatment. Only the PRP+cells group achieved complete wound closure by 2 weeks. Epidermal layer was presence in the central region of the wound of the PRP+cells and PRP groups but absence in the NT group. Comparison between the PRP+cells and PRP groups showed that the PRP+cells-treated wound was more mature as indicated by the presence of thinner epidermis with single cell layer thick basal keratinocytes and less cellular dermis. In summary, the combination of low cell density and diluted PRP creates a synergistic effect which expedites the healing of full-thickness wounds. This combination has the potential to be developed as a rapid wound therapy via the direct application of freshly harvested skin cells in diluted PRP.
  6. Role of plasma-derived fibrin on keratinocyte and fibroblast wound healing
    Law JX, Chowdhury SR, Aminuddin BS, Ruszymah BHI
    Cell Tissue Bank, 2017 Dec;18(4):585-595.
    PMID: 28748415 DOI: 10.1007/s10561-017-9645-2
    Fibrin has excellent biocompatibility and biological properties to support tissue regeneration and promote wound healing. However, the role of diluted fibrin in wound healing has yet to be elucidated as it is commonly used in high concentration. This study was aimed to examine the effects of diluted plasma-derived fibrin (PDF) on keratinocyte and fibroblast wound healing in term of cell proliferation, migration, extracellular matrix (ECM) production and soluble factor secretion. Two PDF concentrations, 10 and 20% (v/v) were tested on keratinocytes and fibroblasts indirectly co-cultured in the transwell system. The control group was cultured with 5% FBS. Results showed that PDF reduced the keratinocyte growth rate and fibroblast migration, and increased the fibroblast ECM gene expression whereby significant differences were found between the 20% PDF group and the 5% FBS group. Similar trend was seen for the 10% PDF group but the differences were not significant. Comparison of the soluble factors between the PDF groups demonstrated that the level of growth-related oncogene alpha, interleukin-8 and epithelial neutrophil-activating peptide-78 were significantly higher in the 10% PDF group, whilst interleukin-1 alpha and granulocyte-macrophage colony stimulating factor were significantly more concentrated in the 20% PDF group. Our results suggested that PDF selectively elevated the expression of collagen type 1 and collagen type 3 in fibroblasts but slowed down the migration in concentration-dependent manner. These novel findings provide new insight into the role of PDF in wound healing and may have important implications for the use of fibrin in skin tissue engineering.
  7. Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty
    Mahindran E, Law JX, Ng MH, Nordin F
    Int J Mol Sci, 2021 Sep 29;22(19).
    PMID: 34638883 DOI: 10.3390/ijms221910542
    Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies leading to rapid growth of geriatric population. Thus, age-associated diseases especially in the musculoskeletal system are becoming more common. Loss of bone (osteoporosis) and muscle (sarcopenia) mass are conditions whose prevalence is increasing because of the change in population distribution in the world towards an older mean age. The deterioration in the bone and muscle functions can cause severe disability and seriously affects the patients' quality of life. Currently, there is no treatment to prevent and reverse age-related musculoskeletal frailty. Existing interventions are mainly to slow down and control the signs and symptoms. Mesenchymal stem cell (MSC) transplantation is a promising approach to attenuate age-related musculoskeletal frailty. This review compiles the present knowledge of the causes and changes of the musculoskeletal frailty and the potential of MSC transplantation as a regenerative therapy for age-related musculoskeletal frailty.
  8. Fulltext Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System
    Yeo GEC, Ng MH, Nordin FB, Law JX
    Int J Mol Sci, 2021 May 27;22(11).
    PMID: 34072224 DOI: 10.3390/ijms22115749
    Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.
  9. Fulltext The Role of Calcium in Wound Healing
    Subramaniam T, Fauzi MB, Lokanathan Y, Law JX
    Int J Mol Sci, 2021 Jun 17;22(12).
    PMID: 34204292 DOI: 10.3390/ijms22126486
    Skin injury is quite common, and the wound healing is a complex process involving many types of cells, the extracellular matrix, and soluble mediators. Cell differentiation, migration, and proliferation are essential in restoring the integrity of the injured tissue. Despite the advances in science and technology, we have yet to find the ideal dressing that can support the healing of cutaneous wounds effectively, particularly for difficult-to-heal chronic wounds such as diabetic foot ulcers, bed sores, and venous ulcers. Hence, there is a need to identify and incorporate new ideas and methods to design a more effective dressing that not only can expedite wound healing but also can reduce scarring. Calcium has been identified to influence the wound healing process. This review explores the functions and roles of calcium in skin regeneration and reconstruction during would healing. Furthermore, this review also investigates the possibility of incorporating calcium into scaffolds and examines how it modulates cutaneous wound healing. In summary, the preliminary findings are promising. However, some challenges remain to be addressed before calcium can be used for cutaneous wound healing in clinical settings.
  10. Fulltext Unseen Weapons: Bacterial Extracellular Vesicles and the Spread of Antibiotic Resistance in Aquatic Environments
    Barathan M, Ng SL, Lokanathan Y, Ng MH, Law JX
    Int J Mol Sci, 2024 Mar 07;25(6).
    PMID: 38542054 DOI: 10.3390/ijms25063080
    This paper sheds light on the alarming issue of antibiotic resistance (ABR) in aquatic environments, exploring its detrimental effects on ecosystems and public health. It examines the multifaceted role of antibiotic use in aquaculture, agricultural runoff, and industrial waste in fostering the development and dissemination of resistant bacteria. The intricate interplay between various environmental factors, horizontal gene transfer, and bacterial extracellular vesicles (BEVs) in accelerating the spread of ABR is comprehensively discussed. Various BEVs carrying resistance genes like blaCTX-M, tetA, floR, and sul/I, as well as their contribution to the dominance of multidrug-resistant bacteria, are highlighted. The potential of BEVs as both a threat and a tool in combating ABR is explored, with promising strategies like targeted antimicrobial delivery systems and probiotic-derived EVs holding significant promise. This paper underscores the urgency of understanding the intricate interplay between BEVs and ABR in aquatic environments. By unraveling these unseen weapons, we pave the way for developing effective strategies to mitigate the spread of ABR, advocating for a multidisciplinary approach that includes stringent regulations, enhanced wastewater treatment, and the adoption of sustainable practices in aquaculture.
  11. Fulltext The Profound Influence of Gut Microbiome and Extracellular Vesicles on Animal Health and Disease
    Barathan M, Ng SL, Lokanathan Y, Ng MH, Law JX
    Int J Mol Sci, 2024 Apr 04;25(7).
    PMID: 38612834 DOI: 10.3390/ijms25074024
    The animal gut microbiota, comprising a diverse array of microorganisms, plays a pivotal role in shaping host health and physiology. This review explores the intricate dynamics of the gut microbiome in animals, focusing on its composition, function, and impact on host-microbe interactions. The composition of the intestinal microbiota in animals is influenced by the host ecology, including factors such as temperature, pH, oxygen levels, and nutrient availability, as well as genetic makeup, diet, habitat, stressors, and husbandry practices. Dysbiosis can lead to various gastrointestinal and immune-related issues in animals, impacting overall health and productivity. Extracellular vesicles (EVs), particularly exosomes derived from gut microbiota, play a crucial role in intercellular communication, influencing host health by transporting bioactive molecules across barriers like the intestinal and brain barriers. Dysregulation of the gut-brain axis has implications for various disorders in animals, highlighting the potential role of microbiota-derived EVs in disease progression. Therapeutic approaches to modulate gut microbiota, such as probiotics, prebiotics, microbial transplants, and phage therapy, offer promising strategies for enhancing animal health and performance. Studies investigating the effects of phage therapy on gut microbiota composition have shown promising results, with potential implications for improving animal health and food safety in poultry production systems. Understanding the complex interactions between host ecology, gut microbiota, and EVs provides valuable insights into the mechanisms underlying host-microbe interactions and their impact on animal health and productivity. Further research in this field is essential for developing effective therapeutic interventions and management strategies to promote gut health and overall well-being in animals.
  12. Secretion of wound healing mediators by single and bi-layer skin substitutes
    Maarof M, Law JX, Chowdhury SR, Khairoji KA, Saim AB, Idrus RB
    Cytotechnology, 2016 Oct;68(5):1873-84.
    PMID: 26768914 DOI: 10.1007/s10616-015-9940-3
    Limitations of current treatments for skin loss caused by major injuries leads to the use of skin substitutes. It is assumed that secretion of wound healing mediators by these skin substitutes plays a role in treating skin loss. In our previous study, single layer keratinocytes (SK), single layer fibroblast (SF) and bilayer (BL; containing keratinocytes and fibroblasts layers) skin substitutes were fabricated using fibrin that had shown potential to heal wounds in preclinical studies. This study aimed to quantify the secretion of wound healing mediators, and compare between single and bi-layer skin substitutes. Skin samples were digested to harvest fibroblasts and keratinocytes, and expanded to obtain sufficient cells for the construction of skin substitutes. Acellular fibrin (AF) construct was used as control. Substitutes i.e. AF, SK, SF and BL were cultured for 2 days, and culture supernatant was collected to analyze secretion of wound healing mediators via multiplex ELISA. Among 19 wound healing mediators tested, BL substitute secreted significantly higher amounts of CXCL1 and GCSF compared to SF and AF substitute but this was not significant with respect to SK substitute. The BL substitute also secreted significantly higher amounts of CXCL5 and IL-6 compared to other substitutes. In contrast, the SK substitute secreted significantly higher amounts of VCAM-1 compared to other substitutes. However, all three skin substitutes also secreted CCL2, CCL5, CCL11, GM-CSF, IL8, IL-1α, TNF-α, ICAM-1, FGF-β, TGF-β, HGF, VEGF-α and PDGF-BB factors, but no significant difference was seen. Secretion of these mediators after transplantation may play a significant role in promoting wound healing process for the treatment of skin loss.
  13. Fulltext Treatment of spinal cord injury with mesenchymal stem cells
    Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX
    Cell Biosci, 2020;10:112.
    PMID: 32983406 DOI: 10.1186/s13578-020-00475-3
    Background: Spinal cord injury (SCI) is the damage to the spinal cord that can lead to temporary or permanent loss of function due to injury to the nerve. The SCI patients are often associated with poor quality of life.

    Results: This review discusses the current status of mesenchymal stem cell (MSC) therapy for SCI, criteria to considering for the application of MSC therapy and novel biological therapies that can be applied together with MSCs to enhance its efficacy. Bone marrow-derived MSCs (BMSCs), umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (ADSCs) have been trialed for the treatment of SCI. Application of MSCs may minimize secondary injury to the spinal cord and protect the neural elements that survived the initial mechanical insult by suppressing the inflammation. Additionally, MSCs have been shown to differentiate into neuron-like cells and stimulate neural stem cell proliferation to rebuild the damaged nerve tissue.

    Conclusion: These characteristics are crucial for the restoration of spinal cord function upon SCI as damaged cord has limited regenerative capacity and it is also something that cannot be achieved by pharmacological and physiotherapy interventions. New biological therapies including stem cell secretome therapy, immunotherapy and scaffolds can be combined with MSC therapy to enhance its therapeutic effects.

  14. Fulltext Feasibility of Human Platelet Lysate as an Alternative to Foetal Bovine Serum for In Vitro Expansion of Chondrocytes
    Liau LL, Hassan MNFB, Tang YL, Ng MH, Law JX
    Int J Mol Sci, 2021 Jan 28;22(3).
    PMID: 33525349 DOI: 10.3390/ijms22031269
    Osteoarthritis (OA) is a degenerative joint disease that affects a lot of people worldwide. Current treatment for OA mainly focuses on halting or slowing down the disease progress and to improve the patient's quality of life and functionality. Autologous chondrocyte implantation (ACI) is a new treatment modality with the potential to promote regeneration of worn cartilage. Traditionally, foetal bovine serum (FBS) is used to expand the chondrocytes. However, the use of FBS is not ideal for the expansion of cells mean for clinical applications as it possesses the risk of animal pathogen transmission and animal protein transfer to host. Human platelet lysate (HPL) appears to be a suitable alternative to FBS as it is rich in biological factors that enhance cell proliferation. Thus far, HPL has been found to be superior in promoting chondrocyte proliferation compared to FBS. However, both HPL and FBS cannot prevent chondrocyte dedifferentiation. Discrepant results have been reported for the maintenance of chondrocyte redifferentiation potential by HPL. These differences are likely due to the diversity in the HPL preparation methods. In the future, more studies on HPL need to be performed to develop a standardized technique which is capable of producing HPL that can maintain the chondrocyte redifferentiation potential reproducibly. This review discusses the in vitro expansion of chondrocytes with FBS and HPL, focusing on its capability to promote the proliferation and maintain the chondrogenic characteristics of chondrocytes.
  15. Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes
    Hafez P, Chowdhury SR, Jose S, Law JX, Ruszymah BHI, Mohd Ramzisham AR, et al.
    Cardiovasc Eng Technol, 2018 09;9(3):529-538.
    PMID: 29948837 DOI: 10.1007/s13239-018-0368-8
    Developing experimental models to study ischemic heart disease is necessary for understanding of biological mechanisms to improve the therapeutic approaches for restoring cardiomyocytes function following injury. The aim of this study was to develop an in vitro hypoxic/re-oxygenation model of ischemia using primary human cardiomyocytes (HCM) and define subsequent cytotoxic effects. HCM were cultured in serum and glucose free medium in hypoxic condition with 1% O2 ranging from 30 min to 12 h. The optimal hypoxic exposure time was determined using Hypoxia Inducible Factor 1α (HIF-1α) as the hypoxic marker. Subsequently, the cells were moved to normoxic condition for 3, 6 and 9 h to replicate the re-oxygenation phase. Optimal period of hypoxic/re-oxygenation was determined based on 50% mitochondrial injury via 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and cytotoxicity via lactate dehydrogenase (LDH) assay. It was found that the number of cells expressing HIF-1α increased with hypoxic time and 3 h was sufficient to stimulate the expression of this marker in all the cells. Upon re-oxygenation, mitochondrial activity reduced significantly whereas the cytotoxicity increased significantly with time. Six hours of re-oxygenation was optimal to induce reversible cell injury. The injury became irreversible after 9 h as indicated by > 60% LDH leakage compared to the control group cultured in normal condition. Under optimized hypoxic reoxygenation experimental conditions, mesenchymal stem cells formed nanotube with ischemic HCM and facilitated transfer of mitochondria suggesting the feasibility of using this as a model system to study molecular mechanisms of myocardial injury and rescue.
  16. Fulltext Three dimensional microcarrier system in mesenchymal stem cell culture: a systematic review
    Koh B, Sulaiman N, Fauzi MB, Law JX, Ng MH, Idrus RBH, et al.
    Cell Biosci, 2020;10:75.
    PMID: 32518618 DOI: 10.1186/s13578-020-00438-8
    Stem cell-based regenerative medicine is a promising approach for tissue reconstruction. However, a large number of cells are needed in a typical clinical study, where conventional monolayer cultures might pose a limitation for scale-up. The purpose of this review was to systematically assess the application of microcarriers in Mesenchymal Stem Cell cultures. A comprehensive search was conducted in Medline via Ebscohost, Pubmed, and Scopus, and relevant studies published between 2015 and 2019 were selected. The literature search identified 53 related studies, but only 14 articles met the inclusion criteria. These include 7 utilised commercially available microcarriers, while the rest were formulated based on different surface characteristics, all of which are discussed in this review. Current applications of microcarriers were focused on MSC expansion and induction of MSCs into different lineages. These studies demonstrated that MSCs could proliferate in a microcarrier culture system in-fold compared to monolayer cultures, and the culture system could simulate a three-dimensional environment which induces cell differentiation. However, detailed studies are still required before this system were to be adapted into the scale of GMP manufacturing.
  17. Fulltext Potential of Exosomes as Cell-Free Therapy in Articular Cartilage Regeneration: A Review
    Ng CY, Chai JY, Foo JB, Mohamad Yahaya NH, Yang Y, Ng MH, et al.
    Int J Nanomedicine, 2021;16:6749-6781.
    PMID: 34621125 DOI: 10.2147/IJN.S327059
    Treatment of cartilage defects such as osteoarthritis (OA) and osteochondral defect (OCD) remains a huge clinical challenge in orthopedics. OA is one of the most common chronic health conditions and is mainly characterized by the degeneration of articular cartilage, shown in the limited capacity for intrinsic repair. OCD refers to the focal defects affecting cartilage and the underlying bone. The current OA and OCD management modalities focus on symptom control and on improving joint functionality and the patient's quality of life. Cell-based therapy has been evaluated for managing OA and OCD, and its chondroprotective efficacy is recognized mainly through paracrine action. Hence, there is growing interest in exploiting extracellular vesicles to induce cartilage regeneration. In this review, we explore the in vivo evidence of exosomes on cartilage regeneration. A total of 29 in vivo studies from the PubMed and Scopus databases were identified and analyzed. The studies reported promising results in terms of in vivo exosome delivery and uptake; improved cartilage morphological, histological, and biochemical outcomes; enhanced subchondral bone regeneration; and improved pain behavior following exosome treatment. In addition, exosome therapy is safe, as the included studies documented no significant complications. Modifying exosomal cargos further increased the cartilage and subchondral bone regeneration capacity of exosomes. We conclude that exosome administration is a potent cell-free therapy for alleviating OA and OCD. However, additional studies are needed to confirm the therapeutic potential of exosomes and to identify the standard protocol for exosome-based therapy in OA and OCD management.
  18. A comparative study of skin cell activities in collagen and fibrin constructs
    Law JX, Musa F, Ruszymah BH, El Haj AJ, Yang Y
    Med Eng Phys, 2016 Sep;38(9):854-61.
    PMID: 27349492 DOI: 10.1016/j.medengphy.2016.05.017
    Collagen and fibrin are widely used in tissue engineering due to their excellent biocompatibility and bioactivities that support in vivo tissue formation. These two hydrogels naturally present in different wound healing stages with different regulatory effects on cells, and both of them are mechanically weak in the reconstructed hydrogels. We conducted a comparative study by the growth of rat dermal fibroblasts or dermal fibroblasts and epidermal keratinocytes together in collagen and fibrin constructs respectively with and without the reinforcement of electrospun poly(lactic acid) nanofiber mesh. Cell proliferation, gel contraction and elastic modulus of the constructs were measured on the same gels at multiple time points during the 22 day culturing period using multiple non-destructive techniques. The results demonstrated considerably different cellular activities within the two types of constructs. Co-culturing keratinocytes with fibroblasts in the collagen constructs reduced the fibroblast proliferation, collagen contraction and mechanical strength at late culture point regardless of the presence of nanofibers. Co-culturing keratinocytes with fibroblasts in the fibrin constructs promoted fibroblast proliferation but exerted no influence on fibrin contraction and mechanical strength. The presence of nanofibers in the collagen and fibrin constructs played a favorable role on the fibroblast proliferation when keratinocytes were absent. Thus, this study exhibited new evidence of the strong cross-talk between keratinocytes and fibroblasts, which can be used to control fibroblast proliferation and construct contraction. This cross-talk activity is extracellular matrix-dependent in terms of the fibrous network morphology, density and strength.
  19. Fulltext Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review
    Chan AML, Cheah JM, Lokanathan Y, Ng MH, Law JX
    Int J Mol Sci, 2023 Feb 16;24(4).
    PMID: 36835438 DOI: 10.3390/ijms24044026
    Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis and resistance. Currently, chemotherapy and radiotherapy are the standard treatments for cancers. However, these treatments cause a significant number of side effects, as they damage both the cancer cells and the actively dividing normal cells indiscriminately. Hence, a new generation of immunotherapy using natural killer (NK) cells, cytotoxic CD8+ T-lymphocytes or macrophages was developed to achieve tumor-specific targeting and circumvent the adverse effects. However, the progression of cell-based immunotherapy is hindered by the combined action of TME and TD-EVs, which render the cancer cells less immunogenic. Recently, there has been an increase in interest in using immune cell derivatives to treat cancers. One of the highly potential immune cell derivatives is the NK cell-derived EVs (NK-EVs). As an acellular product, NK-EVs are resistant to the influence of TME and TD-EVs, and can be designed for "off-the-shelf" use. In this systematic review, we examine the safety and efficacy of NK-EVs to treat various cancers in vitro and in vivo.
  20. Fulltext Current Progress in Tendon and Ligament Tissue Engineering
    Lim WL, Liau LL, Ng MH, Chowdhury SR, Law JX
    Tissue Eng Regen Med, 2019 Dec;16(6):549-571.
    PMID: 31824819 DOI: 10.1007/s13770-019-00196-w
    BACKGROUND: Tendon and ligament injuries accounted for 30% of all musculoskeletal consultations with 4 million new incidences worldwide each year and thus imposed a significant burden to the society and the economy. Damaged tendon and ligament can severely affect the normal body movement and might lead to many complications if not treated promptly and adequately. Current conventional treatment through surgical repair and tissue graft are ineffective with a high rate of recurrence.

    METHODS: In this review, we first discussed the anatomy, physiology and pathophysiology of tendon and ligament injuries and its current treatment. Secondly, we explored the current role of tendon and ligament tissue engineering, describing its recent advances. After that, we also described stem cell and cell secreted product approaches in tendon and ligament injuries. Lastly, we examined the role of the bioreactor and mechanical loading in in vitro maturation of engineered tendon and ligament.

    RESULTS: Tissue engineering offers various alternative ways of treatment from biological tissue constructs to stem cell therapy and cell secreted products. Bioreactor with mechanical stimulation is instrumental in preparing mature engineered tendon and ligament substitutes in vitro.

    CONCLUSIONS: Tissue engineering showed great promise in replacing the damaged tendon and ligament. However, more study is needed to develop ideal engineered tendon and ligament.

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