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In vitro lesion repair assay. Lesion closure (expressed as % of the area at day 0) in an in vitro lesion repair assay. Nontransduced AT-SCs (NT) or transduced with an adenoviral vector expressing GFP (Ad-GFP) or expressing SDF-1 and GFP (Ad-SDF-1) were maintained in serum-free medium supplemented by 0.1% BSA. Control cells were grown in complete medium (DMEM-20% FCS). Data are expressed as mean ± SEM, and experiment was performed in triplicate. Statistical significance level was set at P < .05. No statistically significant difference was assessed between the NT and Ad-GFP-transduced groups. At 48 hours, lesion repair in the Ad-SDF-1 group was improved in comparison with both NT group (P = .018) and Ad-GFP (*P = .006). Representative fluorescence micrographs of lesion area (dotted lines) at day 2. Original magnification 40X.
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Chronic ulcers represent a major health problem in diabetic patients resulting in pain and discomfort. Conventional therapy does not guarantee adequate wound repair. In diabetes, impaired healing is partly due to poor endothelial progenitor cells mobilisation and homing, with altered levels of the chemokine stromal-derived factor-1 (SDF-1) at the w...
Citations
... Scaffolds made by fibrin (Stolzing et al., 2011), collagen (Assi et al., 2016), hydrogels (Wong et al., 2011;Dong et al., 2018) or acellular dermal matrix (Fu et al., 2019) were adopted for MSC delivery and to enhance their therapeutic potential. MSCs cultured in the presence of selective growth factors or engineered to overexpress them showed enhanced key healing functions, particularly angiogenesis and progenitor cell recruitment, in diabetic preclinical settings (Di Rocco et al., 2010;Li et al., 2013;Penna et al., 2013;Yang et al., 2013;Capilla-González et al., 2018;Dhoke et al., 2020;Srifa et al., 2020). Hypoxia pretreatment also enhanced MSC survival in the diabetic wound environment by minimizing ROS accumulation and improving angiogenesis (Liu et al., 2015). ...
Cutaneous chronic wounds are a major global health burden in continuous growth, because of population aging and the higher incidence of chronic diseases, such as diabetes. Different treatments have been proposed: biological, surgical, and physical. However, most of these treatments are palliative and none of them can be considered fully satisfactory. During a spontaneous wound healing, endogenous regeneration mechanisms and resident cell activity are triggered by the released platelet content. Activated stem and progenitor cells are key factors for ulcer healing, and they can be either recruited to the wound site from the tissue itself (resident cells) or from elsewhere. Transplant of skin substitutes, and of stem cells derived from tissues such as bone marrow or adipose tissue, together with platelet-rich plasma (PRP) treatments have been proposed as therapeutic options, and they represent the today most promising tools to promote ulcer healing in diabetes. Although stem cells can directly participate to skin repair, they primarily contribute to the tissue remodeling by releasing biomolecules and microvesicles able to stimulate the endogenous regeneration mechanisms. Stem cells and PRP can be obtained from patients as autologous preparations. However, in the diabetic condition, poor cell number, reduced cell activity or impaired PRP efficacy may limit their use. Administration of allogeneic preparations from healthy and/or younger donors is regarded with increasing interest to overcome such limitation. This review summarizes the results obtained when these innovative treatments were adopted in preclinical animal models of diabetes and in diabetic patients, with a focus on allogeneic preparations.
... However, low engraftment and poor survival of stem cells after transplantation significantly limit their effect for skin wound healing [18][19][20]. To address the challenges, a combination of stem cells and bioactive materials, which are used as a protective cell delivery vehicle, has been proposed for wound treatment [21,22]. ...
Chronic nonhealing wounds are one of the most common and serious complications of diabetes, which can lead to disability of patients. Adipose-derived stem cells (ADSCs) have emerged as a promising tool for skin wound healing, but the therapeutic potential depends considerably on the cell delivery system. Small intestinal submucosa (SIS) is an extracellular matrix-based membranous scaffold with outstanding repair potential for skin wounds. In this study, we first fabricated a bioactive wound dressing, termed the SIS+ADSCs composite, by using human ADSCs as the seed cell and porcine SIS as the cell delivery vehicle. Then, we systematically investigated, for the first time, the healing potential of this wound dressing in a rat model of type 2 diabetes. In vitro studies revealed that SIS provided a favorable microenvironment for ADSCs and significantly promoted the expression of growth factors critical for chronic wound healing. After implantation in the full-thickness skin wounds of diabetic rats, the SIS+ADSCs composite showed a higher wound healing rate and wound healing quality than those in the PBS, ADSCs, and SIS groups. Along with the ability to modulate the polarization of macrophages in vivo, the SIS+ADSCs composite was potent at promoting wound angiogenesis, reepithelialization, and skin appendage regeneration. Taken together, these results indicate that the SIS+ADSCs composite has good therapeutic potential and high translational value for diabetic wound treatment.
... Moreover, they followed the biodistribution and the kinetics of engraftment, survival, and the proliferation of administered cells, which proved relatively permanent in the regenerated tissue even after complete healing. 52 In this context, Kue et al, in a streptozotocin-induced DM rodent model in which subcutaneously adipose-derived stem cells had been injected, showed a significant reduction in the pro-inflammatory reaction, with significantly increased levels of epidermal growth factor, VEGF, prolyl 4-hydroxylase, and proliferating cell nuclear antigen (Ki-67) expression compared with controls. This suggested that this treatment stimulated neoangiogenesis and increased tissue regeneration through paracrine and autocrine mechanisms. ...
This review provides an outline of the use of adipose-derived mesenchymal stem cells (AMSCs) in the treatment of diabetic foot ulcers (DFUs). A systematic search of PubMed and the Cochrane database was performed on October 2, 2019. Eighteen studies were identified (14 preclinical and 4 clinical). Studies in animal models have demonstrated that AMSCs enhance diabetic wound healing, accelerate granulation tissue formation, and increase reepithelialization and neovascularization. Only 1 randomized control trial has been published so far. Patients (n = 25) with DFUs were treated using an allogeneic AMSC directly on the wound bed as a primary dressing, and improvements were found in complete wound closure in the treatment group (n = 16). Three clinical studies showed that autologous AMSC might be a safe alternative to achieve therapeutic angiogenesis in patients with diabetes and peripheral arterial disease. Based on the available evidence, AMSCs hold promise in the treatment of DFUs. However, this evidence requires confirmation by well-designed trials. Additional studies are also required to understand some issues regarding this treatment for DFUs. For example, the potential application of autologous or allogeneic AMSCs in different types of DFUs, optimal dose/infusion schedules, safety evaluations, and cost-effectiveness.
... A few years later, silicone in scar treatment was adopted and tested by different researchers [15,16] . The mechanisms of silicone therapy in scars treatment have been suggested by different researchers and the possible suggested effects of silicone include increased skin temperature, hydration of scars, and polarization of scar tissue [17][18][19][20][21] . In practice, pressure therapy is typically used to treat burn victims by providing a continuous pressure of about 25 mmHg to inhibit the growth of HS and encourage its maturation through pressure garments, face masks, casts, splints, or conformers [22][23][24][25][26] . ...
Hypertrophic scars (HS) are considered to be the greatest unmet challenge in wound and burn rehabilitation. The most common treatment for HS is pressure therapy, but pressure garments may not be able to exert adequate pressure onto HS due to the complexity of the human body. However, the development of three-dimensional (3D) scanning and direct digital manufacturing technologies has facilitated the customized placement of additively manufactured silicone gel onto fabric as a component of the pressure therapy garment. This study provides an introduction on a novel and customized fabrication approach to treat HS and discusses the mechanical properties of 3D printed fabric reinforced with a silicone composite. For further demonstration of the suggested HS therapy with customized silicone insert, silicone inserts for the finger webs and HS were additively manufactured onto the fabric. Through the pressure evaluation by Pliance X system, it proved that silicone insert increases the pressure exerted to the HS. Moreover, the mechanical properties of the additively manufactured fabric silicone composites were characterized. The findings suggest that as compared with single viscosity print materials, the adhesive force of the additively manufactured silicone and fabric showed a remarkable improvement of 600% when print materials with different viscosities were applied onto elevated fabric
... A few years later, silicone in scar treatment was adopted and tested by different researchers [15,16] . The mechanisms of silicone therapy in scars treatment have been suggested by different researchers and the possible suggested effects of silicone include increased skin temperature, hydration of scars, and polarization of scar tissue [17][18][19][20][21] . In practice, pressure therapy is typically used to treat burn victims by providing a continuous pressure of about 25 mmHg to inhibit the growth of HS and encourage its maturation through pressure garments, face masks, casts, splints, or conformers [22][23][24][25][26] . ...
Hypertrophic scars (HS) are considered to be the greatest unmet challenge in wound and burn rehabilitation. The most common treatment for HS is pressure therapy, but pressure garments may not be able to exert adequate pressure onto HS due to the complexity of the human body. However, the development of three-dimensional (3D) scanning and direct digital manufacturing technologies has facilitated the customized placement of additively manufactured silicone gel onto fabric as a component of the pressure therapy garment. This study provides an introduction on a novel and customized fabrication approach to treat HS and discusses the mechanical properties of 3D printed fabric reinforced with a silicone composite. For further demonstration of the suggested HS therapy with customized silicone insert, silicone inserts for the finger webs and HS were additively manufactured onto the fabric. Through the pressure evaluation by Pliance X system, it proved that silicone insert increases the pressure exerted to the HS. Moreover, the mechanical properties of the additively manufactured fabric silicone composites were characterized. The findings suggest that as compared with single viscosity print materials, the adhesive force of the additively manufactured silicone and fabric showed a remarkable improvement of 600% when print materials with different viscosities were applied onto elevated fabric.
... 76 MSCs have been shown to express low levels of molecules including the homing factor stromal cell-derived factor-1 and chemokine receptors (i.e., CXCR4 and CCR1 receptors). 77 Genetic manipulation of pro-survival or anti-apoptotic genes including Bcl-2, protein kinase B (Akt/PBK), HGF, and survivin increased MSC survival in vivo. [78][79][80][81] It is also known that miRNA can regulate mRNAs, modulating the cellular gene networks, including those involved in cell survival. ...
Mesenchymal stem cell transplantation is an emerging therapy for treating chronic liver diseases. The potential of this treatment has been evaluated in preclinical and clinical studies. Although the mechanisms of mesenchymal stem cell transplantation are still not completely understood, accumulating evidence has revealed that their immunomodulation, differentiation, and antifibrotic properties play a crucial role in liver regeneration. The safety and therapeutic effects of mesenchymal stem cells in patients with chronic liver disease have been observed in many clinical studies. However, only modest improvements have been seen, partly because of the limited feasibility of transplanted cells at present. Here, we discuss several strategies targeted at improving viable cell engraftment and the potential challenges in the use of extracellular vesicle-based therapies for liver disease in the future.
... Although systemic administration of cytokines induces EPC homing to the peripheral circulation from bone marrow, the non-specific mobilization of other cell populations, such as white blood cells or platelets, makes this therapy unsuitable for non-healing diabetic wounds. A recent attempt has been made to improve conventional therapies by administering ex vivo EPCs modified by over-expressing SDF-1, which enhanced wound healing by cell differentiation and increased EPC recruitment to the wound site and paracrine secretion of cytokines locally [122]. EPC-mediated transplantation or gene thera-pyÀbased strategies have shown its pre-clinical potential in ameliorating diabetic wound healing but have yet to set their therapeutic mark clinically. ...
Despite advancements in wound care, healing of chronic diabetic wounds remains a great challenge for the clinical fraternity because of the intricacies of the healing process. Due to the limitations of existing treatment strategies for chronic wounds, stem/progenitor cell transplantation therapies have been explored as an alternative for tissue regeneration at the wound site. The non-healing phenotype of chronic wounds is directly associated with lack of vascularization. Therefore, endothelial progenitor cell (EPC) transplantation is proving to be a promising approach for the treatment of hypo-vascular chronic wounds. With the existing knowledge in EPC biology, significant efforts have been made to enrich EPCs at the chronic wound site, generating EPCs from somatic cells, induced pluripotent stem cells (iPSCs) using transcription factors, or from adult stem cells using chemicals/drugs for use in transplantation, as well as modulating the endogenous dysfunctional/compromised EPCs under diabetic conditions. This review mainly focuses on the pre-clinical and clinical approaches undertaken to date with EPC-based translational therapy for chronic diabetic as well as non-diabetic wounds to evaluate their vascularity-mediated regeneration potential.
... Evidence from animal studies suggests that the local delivery of ex vivo expanded ADSCs to cutaneous lesions of varying etiologies improves wound healing outcomes (Table 3). [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] However, these studies differ significantly with respect to ADSC harvest, culture conditions and administration methods. ...
There is growing interest in the regenerative potential of adipose-derived stem cells (ADSCs) for wound healing applications. ADSCs have been shown to promote revascularization, activate local stem cell niches, reduce oxidative stress, and modulate immune responses. Combined with the fact that they can be harvested in large numbers with minimal donor site morbidity, ADSC products represent promising regenerative cell therapies. This article provides a detailed description of the defining characteristics and therapeutic potential of ADSCs, with a focus on understanding how ADSCs promote tissue regeneration and repair. It summarizes the current regulatory environment governing use of ADSC products across Europe and the United States and examines how various adipose-derived products conform to the current United Kingdom legislative framework. Advice is given to clinicians and researchers on how novel ADSC therapeutics may be developed in accordance with regulatory guidelines.
... They can be isolated from the patient/animal himself, in which case they are called "Autologous ADSCs". These cells are isolated from the subcutaneous adipose tissue, either from the inguinal [11][12][13][14][15] or abdominal areas [16,17]. They can also be obtained from another individual in the same species "Allogenic" or from a different species "Xenogenic ADSCs" [18][19][20][21]. ...
... Di-Rocco et al. demonstrated that topical administration of genetically-modified ADSCs induced overexpression of Stromal derived factor-1 (SDF-1) that promoted wound healing in hyperglycemic mice [12]. Another study used ADSCs-containing atelocollagen matrix and found significantly increased capillary number, both in the first and second weeks of injection. ...
... Stimulation of this receptor increased cell survival, migration, and proliferation. Moreover, they recorded the role of ADSCs-SDF-1 in augmenting the pro-healing effects of dermal fibroblasts and enhancing their proliferation under anoxic conditions in-vivo and in-vitro [12]. ...
With the increasing global prevalence of diabetes mellitus, a significant rise in the number of patients suffering from non-healing wounds is expected. However, available treatments, such as revascularization surgery and foot care education are often insufficient to ensure satisfactory wound healing. One therapeutic strategy that has been identified as particularly promising utilizes adipose-derived stem cells (ADSCs). Through a comprehensive literature search of published and ongoing studies, we aimed to provide an overview of the experimental basis, the scientific background, and advances in the delivery of ADSCs for treating non-healing diabetic wounds. ADSCs have the capacity to differentiate into multiple cell lineages and are considered an alternative to bone marrow-derived mesenchymal stem cells. They can be easily extracted from the adipose tissue and are capable of in-vitro expansion. The reviewed experimental studies showed that ADSCs can enhance diabetic wound healing through increasing epithelialization and granulation tissue formation, anti-inflammatory and anti-apoptotic effects, and release of angiogenic cytokines. Moreover, few small clinical trials showed that ADSCs treatment in patients with diabetic ulcers caused enhanced ulcer evolution, lower pain scores, and improved claudication walking distances with no reported complications. In conclusion, ADSCs have a promising potential in the regenerative therapy of chronic diabetic wounds. However, larger studies should confirm their efficacy and long-term safety in diabetic patients.
... They have also shown that VEGF overexpressing ADSCs decreased the healing time of mouse excisional wounds in comparison with ADSCs alone or saline-treated groups. Moreover, SDF-1 transduced ADSC transplantation significantly reduced the wound area and epithelial gap in diabetic wounds by direct cell differentiation, enhanced cellular recruitment at the wound area, and paracrine signaling [91]. These studies and others conducted with genetically engineered MSCs (other than ADSCs) undeniably present promising advances for future chronic wound healing modalities but there are critical issues to be solved before realizing the use of genetically modified stem cells in clinics. ...
Adipose tissue serves as an alternative mesenchymal cell source with comparable proliferation, growth factor expression, and differentiation capacity. A large body of work has suggested that adipose-derived stem cells (ADSCs) would be used in various regeneration applications. Due to having remarkable therapeutic potential, ADSCs would also be a putative therapy for non-healing wounds, which is a growing clinical concern for especially aged populations with systemic diseases such as obesity and diabetes. This chapter aims to highlight beneficial effects of ADSCs on acute and chronic wound healing by reviewing preclinical studies and clinical trials from the perspective of direct differentiation, paracrine signaling, cell recruitment, scaffold combination, and preconditioning. In addition, possible action of a mechanism for wound healing promoting activity of ADSCs will be explained in detail along with addressing efficacy and safety issues.
