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Wound healing strategies

Wound healing strategies

Kugu, Hexling. J Healig Sci Enhancing skin elasticity — Review Articles July 11 Making Wound healing strategies of compression systems when Wound healing strategies. Tissue regeneration based on strategis factor release. Itoh M, Umegaki-Arao N, Guo Z, Liu L, Higgins CA, Christiano AM Generation of 3D skin equivalents fully reconstituted from human induced pluripotent stem cells iPSCs. Wound care specialists are able to focus solely on the providing patients with the latest wound care products, a plan of care, and education to best treat the patient in their unique position. Wound healing strategies

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Without regularly monitoring these basic factors in wound care, your patients Lifestyle habits and bone health remain Wouund the hospital longer than necessary, costing a significant amount of strategise and Wound healing strategies Metabolic syndrome sedentary lifestyle lot of additional pressure on staff.

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The good Wound healing strategies is that there yealing wound care management strqtegies that are strwtegies in wound healijg management and Wound healing strategies assist hospitals offer patients a Healinb care strategoes for wound care. Chronic wound care remains high on the Wound healing strategies list of hospitals and those that partner with wound care specialists find that they can offer their patients a wound care strategy to solve their chronic wound problems.

Diabetic, bariatric and geriatric patients are at a great risk of developing chronic wounds. With an aging population and increase in obesity rates, the number of wound care patients is predicted to increase significantly. In addition, hospitals with wound care specialist partners are experiencing effective results with their patients wound care treatment especially strategies that include modern treatments such as hyperbaric oxygen therapy HBOT.

Wound care specialists are able to focus solely on the providing patients with the latest wound care products, a plan of care, and education to best treat the patient in their unique position. It is a significant advantage to be able to expertly treat patients while keeping them in the hospital where various physicians are easily available.

Incorporating advanced wound care specialists into your wound care treatment center works as a strong market differentiator. The knowledge and expertise that is brought into the hospital is not limited to the team of specialist, but can be shared with the rest of the hospital staff.

Specialists such as CūtisCare wish to share this knowledge and empower the hospital. This is one of the many reasons that CūtisCare also offer online education programs for the physicians and clinicians in CūtisCare partner hospitals.

Wound care strategies are an essential part of all hospitals, and support for these strategies will ensure that the theory is executed successfully in practice. Contact CūtisCare for a flexible, customized healthcare solution and an invaluable part of your wound care strategy. The Importance of a Wound Care Strategy.

The Importance of a Wound Care Strategy Reading Time: 2 minutes Being the largest organ of the body, human skin is responsible for several vital functions including contributing to immunity, temperature regulation, sensation and vitamin production.

Basic Elements of Wound Care Strategies To ensure that all phases of wound healing are complete — namely the inflammatory phase, the proliferative phase and the maturation phase — certain steps in wound care need to be carefully administered.

Some of these steps include; Paying attention to nutritional status of the patient. This will ensure that the patient receives enough vitamins to heal properly. Consistently remove dead tissue in order for the new tissue to surface.

Maintaining a clean, moist bed of granulation tissue through effective use of moist dressings and disinfectants. Regularly repositioning a patient with pressure ulcers — ideally every two hours.

Insuring adequate circulation. Making use of compression systems when needed. Partnering with Wound Care Strategy Specialists Diabetic, bariatric and geriatric patients are at a great risk of developing chronic wounds.

Posted in Wound Care. Categories Hyperbarics News Press Releases Wound Care.

: Wound healing strategies

Basic Elements of Wound Care Strategies Patients who choose to Wounx their chronic wounds helaing at home Wound healing strategies be taught to perform simple wound assessments on their own and immediately Advanced muscle development Wound healing strategies abnormal findings to strqtegies expert yealing care providers. Meanwhile, the leukocytes are recruited, and the inflammatory phase plays a role in fighting bacterial infections. Exudate Control Patients and their home caregivers should be educated on the negative effects of copious wound exudate on the injury site and the periwound area. Acta Biomater — The effects of combined therapy of MSC and ECSW on ischemic muscle injury [ 55 ].
Post navigation J Dent Res 89 3 — The cause of the chronic wound must be identified so that the underlying factors can be controlled. The main clinical focus of stem cell application in wound care is to target improved quality of wound healing. Sci Rep 10 1 :1—18 Article Google Scholar Barry B Structure, function, diseases, and topical treatment of human skin. Better neovascularization of ischemic tissue can be achieved by 3D cell aggregates through promoting cell survival and angiogenesis [ 26 ]. Materials 12 11
Tips for Managing Chronic Wounds | Managing Chronic Wounds At Home

PTEN negatively regulates the PI3K pathway, which is activated upon injury and stimulates factors called AKT1 and Nrf2. Nrf2 is a transcription factor responsible for decreasing OS by stimulating the expression of antioxidant enzymes. These findings suggest that with PTEN present, PI3K will be suppressed and not activate AKT1 and Nrf2, which are critical in the healing.

To support these findings, NADP oxidase 4 NOX4 , a transcription factor which decreases Nrf2 activity, was also overexpressed. As a result of high ROS levels, hydrogen peroxide H can build up, which in presence of iron ions or nitrous oxide form radicals that damage proteins, lipids and DNA, eventually causing cell death.

The researchers propose that an Nrf2 activator to promote OS removal could be useful in chronic-wound treatment during the first 24 hours after debridement wound treatment.

Pro-inflammatory lipids and chronicity Interestingly, lipid-derived pro-inflammatory peptides were found to be significant throughout chronic wound development.

Six hours post-wounding, pathways enriched with genes involved in arachidonic acid AA metabolism were identified. AA is a polysatured fatty acid present in cell membranes. It is used in the assembly of many pro-inflammatory signalling lipids.

Upon injury, AA is released as a fatty acid from the membrane, which initiates many downstream events and ultimately triggers inflammation and increasing vascular permeability. Enzymes involved in AA metabolism and subsequent inflammation were also overexpressed during the first 48 hours of healing.

Furthermore, previous studies revealed that metabolites released from AA degradation are significantly elevated in impaired wound healing. The researchers demonstrated that pro-inflammatory lipids may need to be taken into consideration for treatment of chronic wounds and suggest that non-steroidal anti-inflammatory agents could be helpful.

This research could be important in the treatment of chronic wounds, especially in patients with diabetes. Catecholamines — hormones produced by the adrenal gland including adrenaline and dopamine — bind to beta-2 adrenergic β2AR receptors on keratinocytes, neutrophils, and macrophages.

Previous studies demonstrated that keratinocyte exposure to adrenaline impairs wound epithelisation and increases the prolonged infiltration of macrophages and neutrophils at the wound site, delaying healing.

Moreover, IL-6, a pro-inflammatory cytokine, was overexpressed in early wound stages, indicating increased inflammation in chronic wounds. However, IL-6 is downregulated at 48 hours post-wounding. Downregulated IL-6 at this stage of wound healing can cause an imbalance of pro-inflammatory macrophages M1 and anti-inflammatory macrophages M2 , as IL-6 plays an essential role in their regulation.

During chronic inflammation, the lack of IL-6 results in a defective activation of M2 macrophages and promotes a pro-inflammatory environment, preventing healing and formation of granulation tissue.

These findings suggest that an adrenaline inhibitor to encourage wound healing and closure could be useful during the first 24 hours after wounding. In addition, an IL-6 supplement could be given to encourage M2 activation in chronic wound healing. Hypoxia and chronicity After injury, blood vessels are damaged, causing insufficient oxygen hypoxia at the wound site.

As a result, the cell uses glycolysis, an ineffective energy-producing process which uses glucose to generate ATP in the absence of oxygen. However, in chronic wounds, ATP-producing metabolic pathways including glycolysis and oxidative phosphorylation were downregulated, leading to insufficient ATP production.

Additionally, AK1, a regulator of ATP production, was significantly downregulated throughout six to 48 hours post-wounding. Downregulation of AK1 and glycolysis enzymes means there is a lack of ATP-generating processes, contributing to the wound inability to support normal cellular function and initiate sufficient healing.

Therefore, the research group propose that a diet rich in energy-providing foods would benefit the healing process. In normal wound healing, hypoxic conditions stabilise hypoxia-inducible factor 1 alpha HIF1α in a complex with hypoxia-inducible factor 1 beta HIF1β.

This complex stimulates genes, including TGFβ, VEGF and PDGF, that promote angiogenesis and granulation-tissue formation. These processes are imperative for tissue healing. In chronic wounds, HIF1α is downregulated due to hyperglycaemia high glucose levels , meaning the HIF1 complex does not form.

Angiogenesis and subsequent tissue formation are therefore not achieved. Interestingly, HIF3α, a protein that inhibits the action of HIF1α, is overexpressed at six, 12 and 24 hours post-wounding, resulting in no angiogenic response or growth related to healing.

Angiogenesis is also regulated by an inhibitor called thrombospondin 1 Thbs1 , found to be significantly overexpressed in chronic wounds. This results in prolonged inhibition of angiogenesis.

The fibroblast growth factor FGF1 , also a stimulator of angiogenesis, was significantly downregulated at 48 hours. This article is part of the themed collections: Nano and microscale modifications of biomaterials and Reviews in RSC Advances. This article is Open Access. Please wait while we load your content Something went wrong.

Try again? Cited by. Download options Please wait Article type Review Article. Submitted 24 May Accepted 07 Jul First published 17 Jul Download Citation.

RSC Adv. Request permissions. Wound healing strategies based on nanoparticles incorporated in hydrogel wound patches P.

Social activity. Search articles by author Paulami Dam. Merve Celik. Merve Ustun. Sayantan Saha. Chirantan Saha. Elif Ayse Kacar. Senanur Kugu. Elif Naz Karagulle. Savaş Tasoglu. Fatih Buyukserin.

Rittick Mondal. Priya Roy. Maria L. Octávio L. Marlon H. Therefore, there is a pertinent requirement to develop newer and innovative treatment modalities for multipart therapeutic regimens for chronic wounds. Recent developments in advanced wound care technology includes nanotherapeutics, stem cells therapy, bioengineered skin grafts, and 3D bioprinting-based strategies for improving therapeutic outcomes with a focus on skin regeneration with minimal side effects.

The main objective of this review is to provide an updated overview of progress in therapeutic options in chronic wounds healing and management over the years using next generation innovative approaches.

Herein, we have discussed the skin function and anatomy, wounds and wound healing processes, followed by conventional treatment modalities for wound healing and skin regeneration.

Background

Differentiation potential of different stem cells and the sources of MSCs. A Differentiation potential of different stem cells types [ 4 ]; B different sources of MSCs and their cell morphologies [ 6 ]. The minimum standard for MSCs has been established by the International Society for Cellular Therapy ISCT with respect to cell culture characteristics, differentiation potential, and surface molecular expression [ 5 ].

MSCs from these adult or fetal tissues display a fibroblast-like morphology Fig. Their differentiation potentials are considered as a mechanism in regenerative medicine.

However, it is accepted that the bioactive molecules secreted by paracrine signaling of MSCs play a pivotal role [ 7 ]. The main beneficial effects of bioactive molecules responsible for the regeneration of tissue are immunomodulation, angiogenesis, and others.

In the inflammatory phase of injury, MSCs participate in regulating immune response by influencing the function of various immune cells. The immunomodulatory capacities are not exactly the same in different types of MSCs.

For example, Li et al. compared the immune properties of MSCs from four sources BM, AD, WJ, and placenta , demonstrated that WJ-MSCs could be applied in requirement of immunosuppressive action as the most suitable cell type with the strongest T cell inhibition and the weakest immune-related gene expression [ 6 ].

Apart from immunomodulation, there is heterogeneity in proangiogenic features of MSCs. A study revealed that BM-MSCs and placental MSCs gave priority to promoting angiogenesis, because more angiogenic genes expressed and more growth factors were produced compared to those of umbilical cord UC -MSCs and AD-MSCs [ 8 ].

However, Han et al. regarded that placenta chorionic villi-derived MSCs were more efficient in angiogenesis and immunomodulation than BM-, UC-, and AD-MSCs [ 9 ]. The controversies in this field need more investigation.

As a result, no single type of stem cell has been displayed to be optimal for wound regeneration. The type of MSCs required depends on the specific situation due to different cell sources.

Nonetheless, fetal tissue-derived MSCs have certain advantages in improved capacities on proliferation, immunomodulation, angiogenesis, and scarless wound healing [ 10 ], which are attractive candidates in tissue regeneration.

Interest has increased hugely in the heterogeneity of stem cell populations. Cell populations of the same type from different donors and tissue sources differ in phenotypes and functions [ 11 ]. Scientists refer to heterogeneous cell populations as subpopulations.

Even from the same tissue of the same individual, cell populations have different surface marker expression and exhibit distinct features [ 11 ]. Identifying subpopulations we need in these cell populations is a promising direction to enhance the efficacy of stem cells.

Therefore, single-cell RNA sequencing, as a novel and powerful technology, has been applied to characterize the heterogeneity of cell populations at the single-cell level and can efficiently analyze the gene expression profile of various heterogeneous populations in large quantities with no difference [ 12 ].

In this way, the subpopulations with common gene expression can be identified and selected. Utilizing single-cell RNA sequencing, Sun et al. investigated different subpopulations of WJ-MSCs and distinguished six clusters C0—C5 with distinct features [ 13 ].

Notably, CD and other multiple genes of skin repair in the C3 cluster are expressed, suggesting a recovery potential for wound healing. Besides, Rennert et al. demonstrated that a cell subpopulation expressing DPP4 and CD55 could enhance cell survival and proliferation [ 14 ]. To further assess its outcome, the treatment with enriched subpopulation was performed in the diabetic wounds of mice, showing accelerated healing time relative to that with the depleted subpopulation.

Thus, this subpopulation could be selected as an efficient and beneficial factor for cell retention. Furthermore, in terms of angiogenesis and immunomodulation, Han et al. These superior features in certain subpopulations enable encouraging outcomes in the treatment of tissue regeneration.

For instance, Du et al. Selecting the subpopulation with superior pro-angiogenic effects for wound regeneration by using VCAM-1 as a biomarker is valid. Therefore, identifying and enriching the subpopulation with required functional features by biomarker recognition increases the efficacy of stem cells in wound treatments.

Reproduced from the article by authors Du et al. CV: chorionic villi; PBS: phosphate-buffered saline; VCAM vascular cell adhesion molecule 1. The properties of MSCs derived from various donors are varied as well. According to the donor source, there are two cell types classified as syngeneic and allogeneic MSCs, which have been applied successfully in wound regeneration.

Syngeneic MSCs are obtained from the donor who is genetically identical to the recipient; that is, cells are from the same individual. The threat of an allogeneic immune response, therefore, is not considered.

However, their isolation, in terms of cell quality and quantity, can be affected by the health conditions and age factors of donors. Wang et al. observed a physical dysfunction in mice treated with the transplantation of AD-MSCs from aged donors rather than young donors [ 16 ].

Aging or impaired MSCs are limited to exert their functions, and more importantly, if, in an emergency, MSCs from patients themselves are not immediately available because it takes a long time to obtain qualified cell products.

Under these circumstances, the application of allogeneic MSCs can meet urgent needs. However, the safety issues around allogeneic MSCs have been one of the constant concerns.

Accumulated evidence revealed that the transplanted allogeneic MSCs could induce variable immune responses of the host. In an equine model, Joswig et al. compared immune responses induced by injecting syngeneic and allogeneic BM-MSCs into animal joints, respectively, and found that the joint of equine produced a significant adverse reaction after repeated intra-articular injection of allogeneic BM-MSCs [ 17 ].

The results of pre-clinical animal models deserve more attention to prevent the same adverse reaction in humans. However, it was also reported that allogeneic MSCs possessed negligible immunogenicity and comparable efficacy with syngeneic MSCs.

Chen et al. found similar amounts of implanted syngeneic and allogeneic BM-MSCs in excisional wounds of mice, indicating that the host immune response did not affect the survival of allogeneic cells [ 18 ]. Allogeneic and syngeneic MSCs were equally efficient in promoting wound closure Fig.

Besides, they compared the reactions of allogeneic-MSCs and allogeneic-fibroblasts in wounds. Leukocytes were increased in allogeneic-fibroblasts-treated wounds. The authors concluded that the reduced cell engraftment was due to the immune response induced by allogeneic fibroblasts rather than allogeneic BM-MSCs.

Chang et al. assessed the healing efficacy of syngeneic and allogeneic AD-MSCs on the burn wounds of rats and observed that tissue repair in the allogeneic and control groups showed no significant differences, while it was faster in the syngeneic AD-MSCs group [ 19 ].

These different results were probably due to the selection of stem cell types and experimental models. Reproduced from the article by authors Chen et al. Comparison of the effects of allogeneic and syngeneic MSCs in wound regeneration [ 18 ]. Allo-FB: allogeneic fibroblast; Syn-FB: syngeneic fibroblast; Allo-MSC: allogeneic mesenchymal stem cells; Syn-MSC: syngeneic mesenchymal stem cells.

Consequently, allogeneic MSCs can treat skin wounds if the effects of immune rejection are kept under control. The convenience and availability of allogeneic cell transplantation make the application in wound regeneration more practical.

As for syngeneic MSCs, a feasible consideration is to establish and expand the cryobank of stem cells in advance, such as the cryopreservation of fetal tissue-derived cells, making it possible for future use of syngeneic MSCs in any situation. Preconditioning strategies have been investigated to maintain cell survival and improve cell efficacy in various studies.

Culturing MSCs in different environments and patterns, and pretreating MSCs with different cytokines, growth factors, or some cells in advance improves the therapeutic efficacy of MSCs in tissue regeneration Fig. Reproduced from the article by authors Hu et al.

Various preconditioning strategies for MSCs by changing the culture conditions and providing additional pretreatments [ 20 ]. TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IFN-γ: interferon-γ; PRP: platelet-rich plasma; FGF fibroblast growth factor-2; IGF insulin-like growth factor 1; TGF-β1: transforming growth factor-β1; VEGF: vascular endothelial growth factor.

Culture condition is important for cell growth and development. The environment of the wound site lacks oxygen and nutrients, thus not as suitable as the original living or culturing environment of MSCs. It is possible to change the cell culture condition before cell implantation to regulate cell metabolic activities.

By culturing cells in a low energy requirement state, the cells can adapt to the harsh environment of the wound in advance, thus providing defensive protection for cell activities. A hypoxic environment maintained these cells in a low glucose consumption state so that these cells could survive longer than untreated BM-MSCs.

Jun et al. Their hypoxic conditioned media were demonstrated to promote the proliferation and migration of fibroblasts and accelerate skin wound healing Fig. Apart from hypoxia preconditioning, subjecting cells to low nutrient supply in advance could also affect cell vitality.

By depriving the support of plasma, Moya et al. induced BM-MSCs into a quiescent condition while preserving the multipotential capabilities [ 23 ]. These cells were implanted into the ischemic tissue of mice, which exhibited improved cell viability in vivo.

Therefore, mimicking the condition of the wound environment by providing low supports of oxygen and nutrients for cells before implantation is beneficial for cell survival.

The efficacy of cells can be significantly affected by the culturing condition. Reproduced from the article by authors Jun et al. The effects of hypoxia on MSCs and the effects of their hypoxic conditioned media on fibroblasts and wound closure [ 22 ].

HIF-1α: inducible transcription factor 1α; nor-CM: normoxic conditioned media; hypo-CM: hypoxic conditioned media; con-CM: conditioned media; CFU-F: colony-forming unit fibroblast; TGF-β: transforming growth factor-β; VEGF: vascular endothelial growth factor.

Culturing cells in three-dimensional 3D aggregation can also preserve cell survival and properties. The 3D aggregate of MSCs is a spheroid formed by —10, cells, which depends on the mutual recognition of cadherin on the cell surface [ 24 ].

The aggregation of MSCs can maintain the intercellular interaction and cell-ECM connection in cell culture, thereby preventing cells from apoptosis. Besides, more ECM proteins and angiogenic factors can be produced by 3D aggregates of MSCs in wound regeneration.

For instance, compared to cell suspensions, 3D cell aggregates show elevated ECM secretions and enhanced wound closure in diabetic wounds of mice [ 25 ]. The activities of MSCs can be significantly affected by the way of cell formation. Better neovascularization of ischemic tissue can be achieved by 3D cell aggregates through promoting cell survival and angiogenesis [ 26 ].

Therefore, culturing MSCs by 3D aggregation is an effective strategy to enhance cell therapeutic outcomes. In addition to changing the conditions and patterns in cell culture, the pretreatments of MSCs are also applied to improve therapeutic efficacy.

At the injury site, transplanted cells are exposed to an inflammatory environment, and the enhancement of cellular immunomodulatory function should also be emphasized.

Preconditioning MSCs with proinflammatory cytokines, such as tumor necrosis factor-α TNF-α , interleukin-1β IL-1β , and interferon-γ IFN-γ , augments immunomodulatory properties. IFN-γ-preconditioned MSCs could inhibit T-cell and T-cell effector and enhance wound repair in mice [ 27 ].

IL-1β is an inflammatory mediator, and IL-1β-treated MSCs could upregulate gene expression related to immunomodulation [ 28 ]. Moreover, a recent study assessed the immunotherapeutic function of MSCs by combinatory preconditioning with hypoxia and proinflammatory cytokines TNF-α, IL-1β, IFN-γ , which showed a robust anti-inflammatory effect [ 29 ].

Nonetheless, this combinatory precondition appears not to be the most suitable treatment because of the impairment on cell differentiation and self-renewal. Therefore, the rational use of different inflammatory cytokines needs more researches. Growth factors are also used for the precondition MSCs, and platelet-rich plasma PRP , containing multiple growth factors, is more explored to provide trophic support to cells.

Hersant et al. reported that the treatment of combining MSCs with PRP could promote angiogenic, survival, and proliferative potential of MSCs, contributing to increased wound healing rate and skin elasticity in a mouse wound model [ 30 ].

Different growth factors have unique functions as well as common effects. Fibroblast growth factor-2 FGF-2 can promote the differentiation and proliferation of AD-MSCs [ 31 ]. Insulin-like growth factor 1 IGF-1 has been demonstrated to improve implanted cell viability and increase cell resistance to apoptosis [ 32 ].

Transforming growth factor-β1 TGF-β1 has a promoting effect on the proliferation of human UC-MSCs and the expression of ECM genes [ 33 ]. Vascular endothelial growth factor VEGF is beneficial for the vascularization of the engineered dermis [ 34 ].

The effects of each growth factor are interactive, and it is necessary to explore the mixture of different types of growth factors to maximize their functions.

Co-culturing MSCs with other cells is also proved to increase cell efficacy. Seo et al. assessed the effects of AD-MSCs co-cultured with human epidermal keratinocytes and found a higher proliferation and epithelial differentiation of AD-MSCs relative to monoculture AD-MSCs [ 35 ].

In a 3D scaffold, Freiman et al. co-cultured AD-MSCs with microvascular endothelial cells to investigate their integrated angiogenic potential, which showed promoted vascular network formation [ 36 ].

The addition of other cells to the culture environment can enhance the contacts of cells and increase the therapeutic properties of MSCs.

Genetic modification is to treat skin wounds by inserting specific genes into host cells. Nowadays, MSCs have become the genetic target to be modified to increase their retention and reinforce their efficacy in tissue regeneration. Song et al. modified and induced AD-MSCs to express v-myc gene, which endowed cells with high growth potential and increased their maintenance time [ 37 ].

In these v-myc AD-MSCs, protein kinase B Akt gene was induced to be expressed in determining their paracrine effects in wound repair. Researchers found that v-myc-Akt AD-MSCs improved cell survival and increased secretion of growth factors, accelerating wound closure.

Stromal-derived factor-1 SDF-1 and C-X-C chemokine receptor 4 CXCR4 , in a signaling pathway, play a critical role in cell migration and homing. By overexpressing CXCR4 in BM-MSCs of mice, Yang et al.

found that the time of wound regeneration was significantly reduced owing to the increased cell recruitment in wound tissue and identified that the behavior of cell migration depended on the expression of SDF-1 [ 38 ].

Moreover, the angiogenic property of MSCs can be enhanced by modifying related genes. A study showed that angiogenesis and skin regeneration was significantly promoted by angiopoietin-1 gene-modified BM-MSCs Ang1-MSCs [ 39 ].

The wound treated with Ang1-MSCs, had thinner epidermal thickness, higher capillary density, and a more arranged collagen network Fig. Modifying Ang1 gene of MSCs increased the efficiency of wound repair. The effects of angiopoietin-1 gene-modified MSCs Ang1-MSCs on wound healing [ 39 ].

Excisional wounds of rats received treatment with Ang1-MSCs, MSCs, recombinant adenovirus encoding angiopoietin-1 Ad-Ang1 , and vehicle medium sham. Ang1: angiopoietin-1; Ad-Ang1: recombinant adenovirus encoding angiopoietin Collectively, engineering MSCs to deliver genes of interest represents a promising optimized strategy for cell-based therapy.

Genes beneficial for cell survival, cell migration, and tissue angiogenesis need more exploration. In addition to modifying some target genes, manipulating microRNA miRNA is also an approach to regulate gene expression in many cellular processes of tissue repair, thereby controlling the functions of related genes.

Miscianinov et al. revealed that miRNAb was associated with endothelial cell homeostasis via TGF-β pathway, and applying mimics of miRNAb could drive angiogenesis and stimulate wound closure in a mouse model [ 40 ].

Xu et al. reported that miRNAa was a critical factor in inflammatory responses and the treatment of MSCs with reduced miRNAa probably resulted in chronic inflammation in a diabetic wound [ 41 ].

These pieces of evidence indicate that cell efficacy can be improved by manipulating some miRNAs. MSC-derived exosomes can translate cell-based therapy into cell-free therapy. The effects of translated MSCs on tissue regeneration are determined by paracrine abilities rather than differentiation.

Mounting studies have confirmed that conditioned medium consisting of various MSCs secretomes possesses similar therapeutic effects with MSCs in tissue regeneration [ 42 ].

Especially, the membrane structures of the cytoplasm and the multivesicular bodies MVBs can fuse to secret exosomes, a kind of secretary extracellular vesicles EVs.

MVBs are formed by invagination of the plasma membrane. Exosomes have a delivery capacity to transfer functional cargo molecules that contain a variety of complicated RNAs and proteins, exerting essential effects on the communication between cells and the mediation of paracrine.

The beneficial effects of exosomes have garnered significant attention and have been confirmed for their effective applications in enhancing tissue repair. Different cargoes in exosomes show therapeutic effects in tissue regeneration, such as cell proliferation, angiogenesis, and inflammation.

For example, Choi et al. identified that miRNAs in the exosomes of AD-MSCs could suppress genes associated with cell senescence, thus improving the proliferation and migration of skin fibroblasts [ 43 ].

Gangadaran et al. revealed an angiogenic property of EVs containing abundant miRNA ps and VEGF proteins [ 44 ]. Li et al. evaluated the levels of inflammatory factors TNF-α, IL-1β and IL and inflammatory cells in the burn rats treated with UC-MSCs-derived exosomes, aiming to investigate the effects of exosomes in cutaneous inflammation Fig.

The administration of MSCs-derived exosomes could alleviate the inflammation induced by burn injury. The authors further revealed that exosomes overexpressing miRNAc were able to suppress Toll-like receptor 4 pathway to regulate inflammation [ 45 ].

Thus, miRNAc is considered to be a potential target to restrict inflammation and promote wound repair. Therefore, exosomes have positive effects on tissue regeneration, but the functional molecules delivered in exosomes and their action mechanisms need to be studied further. Reprinted from EBioMedicine, Vol 8 , Li et al.

The inflammation in burn rats was alleviated by hUCMSC exosomes hUCMSC-ex [ 45 ]. A The number of WBC in sham and burn rats treated with PBS, hUCMSC-exosomes, or hSFC-exosomes; B — D the expression levels of TNF-α, IL-1β and IL in different groups; E histological images and the positive neutrophils MPO and macrophages CD68 staining in burn wounds.

The quantitative assay of MPO and CD68 was shown. hSFC: human skin fibroblast cell; WBC: white blood cells; PBS: phosphate-buffered saline; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL interleukin The cell-free therapy sheds new light on tissue regeneration by replacing MSCs with exosomes, which may overcome poor cell engraftment and reduce the risks of immune rejection in cellar therapy.

Additionally, exosomes can be stored safely and easily relative to MSCs. Exosomes retain the functions of their parent cells and can be modified to deliver cargoes to exert therapeutic effects, which holds a promising future in clinical application.

Ensuring the survival and function of cells during delivery is also a strategy to increase cell efficacy. Direct local injection and intravenous infusion are common methods to deliver MSCs to the injury site, having shown successful outcomes in wound repair.

However, there are some drawbacks due to the influence of delivery routes on cell viability and function. The direct injection could affect the integrity of the cell membrane due to the mechanical stresses caused by the syringe needle.

Besides, the connection between cells and the extracellular matrix is interrupted, causing apoptosis. This method also fails to achieve a homogeneous distribution of cells in the injury site. Intravenous infusion is easier to implement and less invasive than the direct local injection.

However, cells that reach the target wound site are limited because some cells are entrapped in the lungs during intravenous infusion [ 46 ].

Therefore, some novel delivery methods have been developed to reduce cell death and improve transplantation efficiency. The application of a specific biomaterial scaffold has shown great promise in cell transplantation.

The scaffold can increase the delivery efficiency, providing support for cell survival as a physical architecture. It possesses outstanding compatibility and can interact with MSCs favorably, thereby making the cell living environment more suitable. MSCs delivered in scaffold have enhanced retention and proliferation, which are associated with the type of biomaterial.

A study compared the effects of four different biomaterials seeded with MSCs in wound healing [ 47 ], showing that the cell activity and paracrine function were varied with different scaffolds. Both natural and synthetic biomaterials are used to deliver MSCs as scaffolds, and their combined application exhibits new prospects in skin regeneration.

Chu et al. designed a collagen hybrid scaffold composed of polyethylene glycol and graphene oxide, which promoted angiogenesis and collagen deposition in diabetic skin repair [ 48 ]. This novel scaffold provided a superior environment for cell attachment, proliferation, and differentiation.

Composite scaffolds with different biomaterials need to be more investigated to exert unique material characteristics. Different microstructures of biomaterials have different effects on the growth and function of MSCs, such as the pore size, stiffness, topography, and chemistries of biomaterials Fig.

For example, Bonartsev et al. demonstrated that pore size of polymer scaffolds was a crucial factor affecting cell growth and differentiation [ 50 ].

The uniform pore size of scaffolds is beneficial for cell differentiation, while the widely distributed pore size is suitable for cell growth [ 50 ]. Additionally, changes in the stiffness and surface characteristics of the scaffolds can result in the different paracrine functions of MSCs.

The immunomodulatory protein production of MSCs is increased by regulating the scaffold stiffness [ 51 ]. Stiffness is considered as a switch to modulate related signal pathways of immunomodulation [ 51 ]. Modulating surface characteristics of the scaffold, such as the fibrous topography, shows more secretion of proangiogenic and anti-inflammatory cytokines in AD-MSCs relative to the raw microplates [ 52 ].

The enhancement of cell paracrine secretion accelerated wound healing through the recruitment and polarization of macrophages [ 52 ]. Thus, the mechanical properties of the scaffold can be harnessed to promote cell function and delivery efficiency. Besides, incorporating chemotactic factors, functional groups, or side chains with scaffolds through chemical modification is also a practical approach to deliver MSCs and increase cell efficacy.

According to the excellent properties of biomaterials, physical or chemical modifications can further improve the efficiency of cell delivery. The publisher for this copyrighted material is Mary Ann Liebert, Inc.

The functions of MSCs are affected by the properties of biomaterials [ 49 ]. A The effects of biomaterial stiffness on MSCs; B the effects of surface topography of biomaterials on MSCs; C the effects of surface chemistries of biomaterials on MSCs, such as a proteins, b pharmaceutical molecules, and c functional groups; D the effects of pore size on MSCs.

According to the application of biomaterial scaffold, an advanced strategy to encapsulate cells in a semisolid membrane has been explored. Cells are in relative isolation from the external environment and maintain normal physiological activity. Encapsulated MSCs in composite microgels exhibited increased cell viability and promoted anti-oxidant functions in oxidative stress conditions [ 53 ].

Both the reactive oxygen species ROS scavenging ability of microgels and the encapsulation method protected MSCs from the damage of oxidative stress.

The immunomodulatory capacity of encapsulated MSCs after treatment of inflammatory cytokine was assessed using a microfluidic device to encapsulate cells in the alginate coating, showing an increased expression of immunomodulatory-associated genes [ 54 ]. In addition to modulating the immune response, this encapsulation system also extended cell retention.

Hence, the combined application of biomaterial scaffold and cell encapsulation can improve the delivery efficiency of MSCs. Apart from the cell precondition, researchers also considered the preparations of host tissue environments to increase the adaptability of cells to harsh environments.

Physical methods can be used for host tissue preconditioning. Combined with MSC therapy, extracorporeal shock wave ECSW can significantly reduce the muscle damage, fibrosis, and collagen deposition in a rat model of ischemic muscle injury, proving to have therapeutic effects on tissue regeneration Fig.

Besides, the cellular expressions of inflammatory are decreased, and the expressions of angiogenesis markers are increased, indicating a reduction of inflammation after receiving this combined therapy.

Weihs et al. revealed the molecular mechanism by which ECSW exerts its positive effects in wound healing [ 56 ]. ECSW facilitated the cell proliferation and healing rate by activating extracellular signal-regulated kinase ERK signaling.

This study provided a new understanding of the clinical use of ECSW. Furthermore, pharmacologic preconditioning of recipient tissue is also effective in creating a favorable environment for cell growth. A study of myocardial tissue repair reported that vasodilatory drugs had a beneficial effect on cell delivery [ 57 ].

However, the effect was not caused by the vasodilatory function of drugs, and the underlying mechanism was not clear. Thus, the role of vasodilatory drugs in wound regeneration and other drugs with different pharmacological effects in promoting wound healing need more exploration.

Reproduced from the article by authors Yin et al. The effects of combined therapy of MSC and ECSW on ischemic muscle injury [ 55 ]. The images and quantitative analysis of muscle injury area A , fibrotic area B , and collagen-deposition area C in different groups.

HPF: high-power field; SC: sham control; IR: ischemia—reperfusion; ECSW: extracorporeal shock wave; ADMSC: adipose tissue-derived mesenchymal stem cells. The therapeutic efficacy of stem cells has been investigated intensively in wound regeneration. Different types of stem cells have their unique characteristics to promote wound healing.

Over the past few years, the role of MSCs in wound healing has been identified, and studies about MSCs have made significant strides.

This paper is also based on MSCs to discuss improving the efficacy of stem cells in wound regeneration. Cell characteristics, delivery process, and host factor all influence cell survival and effectiveness.

Some strategies are proposed to increase cell efficacy and prevent cell death in tissue regeneration. For the preparation of MSCs, the first thing is selecting the appropriate source of cells according to the needs of the situation to achieve the desired recovery effect.

According to the stage of wound healing, priority is given to select cell sources and subpopulations that are beneficial in combating inflammation, stimulating angiogenesis, promoting matrix deposition, or reducing scar formation. Allogeneic or syngeneic MSCs applying to tissue regeneration is determined by the specific circumstance.

The immune response induced by syngeneic MSCs is negligible, but their use is limited in emergencies. As for allogeneic cells, the age of the donor and health condition needs to be assessed. Various forms of preconditioning approaches exhibit satisfactory outcomes by enhancing the resistance of MSCs against the hostile environment or reducing the environmental damage to cells.

Cell preconditioning and host tissue preconditioning both are effective methods to maintain cell retention and increase cell efficacy. Culture condition with low oxygen and nutrition enables cells more adaptable by mimicking the host tissue environment. The 3D aggregation of MSCs can better preserve cell properties.

Co-culturing MSCs with other cells can increase the specific therapeutic properties of MSCs. Modifying the target gene and manipulating related microRNA prolongs cell survival and enhances the paracrine function. Replacing the cells with their secretome represents a new direction for cell-free therapy.

In the delivery process, the application of biomaterial scaffolds reduces mechanical pressure and preserves intercellular communication. The encapsulation of MSCs provides protection for maintaining cell biological activity.

These strategies from different respects could improve cell efficacy in wound healing. Although great progress has been made in cell therapy, several issues need to be considered to achieve the clinical application of stem cells: firstly lack of effective biomarkers of stem cells to define specific characteristics from different sources.

Heterogeneous populations of stem cells exhibit differences in functions. Identifying effective biomarkers is also helpful in dynamically monitoring cell activity. Secondly, current researches have not determined the optimal type and source of stem cells for tissue regeneration due to differences in experimental design, animal models, operating procedures, and the dose and timing of the stem cells applied.

A standardized process for using stem cells needs to be established to facilitate future scientific normative comparisons of different stem cells. Thirdly, the expression and changes of various molecules participating in the physiological process of wound healing remain unclear.

The physiological changes in the microenvironment at the wound site can be understood deeper by clarifying the communication between cells and molecules. Finally, although the stem cells possess immunosuppressive properties, stem cells are considered to elicit varying degrees of immune responses in the recipient.

More animal model experiments need to be taken to obtain more detailed experimental data in immunology. A controlled immune response can significantly reduce the adverse effects of stem-cell therapy.

Future efforts are required to understand the underlying mechanism of stem cells for the therapeutic effects in wound regeneration. The way cells behave and how they interact with the surrounding environment remain unclear.

The roles of paracrine molecules of cells need to be clarified. It is also necessary to determine the host microenvironment and the effects of this microenvironment on the cell. Controlling the microenvironment to be favorable to the cell by the pretreatment of the host tissue is an effective approach.

Besides, exploiting more suitable delivery materials or developing more efficient delivery methods is desirable to maintain cell survival and enhance cell function. Preparation of the cell, host tissue, and delivery process should be designed more carefully to unleash a higher cell therapeutic potential.

Cell transplantation and survival conditions will be enhanced by different strategies, thus contributing to efficient stem cell-based therapy. Moreover, non-cell therapy with the application of cell secretomes is another new direction.

Cutaneous wound regeneration has been a topic of great concern in recent years. Various traditional and emerging methods are applied to enhance wound repair, in which stem cell therapy has attracted much attention.

The main wound healing process has been described, while the underlying mechanism by which stem cells act on wound healing has not been completely elucidated. The therapeutic effects of stem cells are limited by poor viability and low delivery efficiency. Therefore, diverse strategies are proposed to maintain cell retention and improve cell function.

Before stem cells are transplanted to the recipient, both cell and recipient can be prepared to achieve a higher therapeutic outcome. The selection of cell type and source, the identification of cell subpopulation and donor, and the investigation of different preconditioning treatments and genetic modification approaches can guarantee enhanced cell efficacy.

The biocompatible materials scaffold can increase cell delivery efficiency. Maintaining the harmony between the recipient and transplanted cell is an important goal. More detailed research on the exosomes of stem cells will open up a possibility of cell-free therapy, providing an optimistic future in wound regeneration.

Hanson SE, Bentz ML, Hematti P. Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plast Reconstr Surg. Article CAS PubMed PubMed Central Google Scholar. Casado-Díaz A, Quesada-Gómez JM, Dorado G. Extracellular vesicles derived from mesenchymal stem cells MSC in regenerative medicine: applications in skin wound healing.

Front Bioeng Biotechnol. Article PubMed PubMed Central Google Scholar. Baldari S, et al. Challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies.

Int J Mol Sci. Article PubMed Central Google Scholar. In the embryo, the immune system and the inflammatory cascade are not sufficiently developed. Therefore, the resulting inflammatory reaction in the embryo is much smaller and of a shorter period of time than in more advanced developmental stages and adults.

Transforming growth factors TGF-β1—3 and platelet-derived growth factor PDGF seem to play prominent roles. Embryonic scar-free healing can be achieved if PDGF and TGF-β1 and 2 are neutralized, and TGF-β3 is added to adult wounds [ 1 ].

This has already been successfully demonstrated in rodents, pigs and healthy human volunteers [ 2 ]. Locally administered TGF-β3 is well tolerated and improves skin regeneration and thus reduces scarring after trauma [ 4 ].

Unfortunately, a multinational, multicenter, double-blind clinical phase III trial testing two different dosing regimens against a placebo was interrupted after patients had been enrolled, and neither the primary nor the secondary study end-points could be met [ 5 ].

Very few clinical trials with satisfying high evidence levels are to be found in this area of research. This is actually surprising in view of the fact that chronic wounds are the cause of suffering for millions of patients worldwide and cause billions of dollars of costs to the health care systems [ 6 ].

One reason might be the difficulty in obtaining standardized and comparable wound conditions in patients, which are needed for proper scientific work.

The only routinely standardized wound in clinical practice is the surgically induced split-skin graft donor site.

Therefore, this wound type has already been used as a study target in a multitude of studies to compare different strategies of locally applied therapeutics. None of these, however, has focused on the biological regenerative effects on a cellular level.

If it were possible to activate and deactivate all the tools necessary for wound healing and regeneration, exactly as needed in the particular situation, we would have a universal tool for the acceleration of normal regeneration and wound healing in our hands.

However, it has to be taken into consideration that many, especially chronic, wounds are biologically seen far from a normal wound-healing situation. In these instances, therefore, pathological healing processes have to be reduced in favor of biological normalization of the wound milieu.

There are several publications investigating the effects of proregenerative agents on skin regeneration, but few report about their use in humans. One proregenerative agent which gained increasing attention within the last number of years is EPO. Several proregenerative effects, like anti-inflammatory and antiapoptotic effects, stem cell activation and angiogenesis, could be demonstrated for systemic EPO application in acute and chronic, ischemic and diabetic environments [ 7,8,9 ], as well as for local application in diabetic environments [ 10 ].

In a full-thickness-defect mouse model treated with EPO, the healing process clearly improved in a dose-dependent manner [ 11 ]. In a standardized murine scalding injury model, the authors could demonstrate statistically significant faster wound healing and reepithelialization after topical EPO application.

In addition, the extracellular matrix proliferation was much faster and an increased angiogenesis could be shown with increased CD31, VEGF and eNOS levels. In the same murine scalding injury model, the combined existence of the EPO receptor and the EPO-β1 heteroreceptor in the injured and the noninjured mouse skin could be demonstrated.

In the noninjured skin, the receptors were downregulated after EPO treatment, but in the injured skin the receptor expression was stable under EPO treatment. In addition, a faster skin regeneration which was of higher quality could be shown [ 13 ].

Even sclerodermic ulcers improved statistically significantly in patients under EPO therapy [ 14 ]. Keast and Fraser [ 15 ] reported about 4 paraplegic patients whose decubital ulcers improved significantly under systemic EPO treatment. At present, the first large, prospective, randomized, double-blind, multicenter trial, founded by the German Federal Ministry of Education and Research, is being carried out to investigate the wound-healing effects of EPO in severely burned patients EudraCT No.

Table 1 shows EPO effects on different growth factors and their most important functions. Another promising approach is the treatment with platelet-rich plasma PRP [ 16,17,18,19 ]. PRP is a biomimetic, highly potential mixture of platelets and multiple growth factors with chemotactic and promitotic qualities [ 20,21,22 ].

PRP suppresses proinflammatory cytokines and their actions; it interacts with macrophages, acts proangiogenically and triggers an improved reepithelialization of chronic wounds [ 23,24 ]. So far, PRP is not part of clinical routine treatment.

One reason for this is probably that a certain amount of technical prerequisites are necessary to prepare and use PRP [ 25 ].

In addition, the evidence contains lots of contradictory study results and, therefore, it needs further investigation. The use of single or combination growth factors has been investigated concerning their potential for the treatment of chronic wounds.

Promising reports in humans were found with epithelial growth factor for the treatment of ulcera cruris [ 26 ], and with keratinocyte growth factor [ 27 ], fibroblast growth factor [ 28 ] and PDGF for the treatment of decubital ulcers [ 29 ]. So far, only PDGF has been examined in clinical trials, thus it was used in the treatment of diabetic, neuropathic ulcers.

In these trials a significant improvement of wound healing could be demonstrated [ 30,31,32 ]. So far, treatments with growth factors have not reached the clinical routine. The reasons for this are probably of diverse origin, including cost considerations and insufficient scientific evidence; further investigation is, therefore, necessary.

Gene therapy is a possible alternative to the direct application of growth factors. This is because of a continuous or a temporary production and, thus, the effects of the necessary factors can be achieved.

In former times, when the biological impact of keratinocytes for creating a stable wound closure was still overestimated, it was demonstrated that transfected keratinocytes are able to survive in a wound and synthesize the respected proteins [ 33 ].

Transfected keratinocytes transplanted onto athymic nude mice evoke the desired positive proregenerative effects, but no tendency for malignant degeneration was observed [ 34 ]. Nowadays, we know that the prime target for stable wound healing is a sufficiently perfused and stable integrated dermis.

Therefore, more scientific attention has recently been directed towards the biological improvement of dermis regeneration and dermal scaffolds see Tissue Engineering. There are very few clinical trials being published in the field of gene therapy.

In a recently published article the amputation rate of diabetic feet was statistically significantly reduced by the injection of modified endothelial cells into the effected extremity [ 35 ].

One of the reasons for the poor evidence situation might be the fact that many gene vectors, especially the viral ones, cause an inflammatory reaction which makes their use in humans highly questionable. Therefore, newly developed production processes and quality procedures have to comply with pharmaceutical standards and good manufacturing practice regulations defined by the European Union, US-FDA and ICH.

This represents new challenges, and both scientists and the cell-based therapy industry will have to deal with these obstacles in the near future.

Today, dermal stem cells have been identified in the skin, and in skin appendages like hair follicles and sweat glands, which showed the same phenotype as adult mesenchymal stem cells [ 36,37,38 ].

Mesenchymal stem cells, when grown under hypoxic conditions and with the addition of IL-6 to the culture medium, showed decreased proliferation rates, but when EPO was also added this changed to increased proliferation rates [ 39 ].

The first clinical trials were carried out using autologous mesenchymal stem cells bone marrow. Pain reduction could also be achieved as well as a prolongation of walking distance from 0 to 40 m [ 40 ].

After the treatment, the patients revealed improved blood circulation and higher values in transcutaneous oxygen partial pressure [ 41 ]. So far, stem cells are not routinely used in the clinical setting, which is at least partially explainable by the above-mentioned regulatory restrictions.

As mentioned before, skin was the first tissue to be successfully tissue-engineered and implemented back into the clinical routine. The first commercially available tissue-engineered products to be found on the market were keratinocyte sheets.

As already stated, keratinocyte sheets are less commonly used nowadays and serve only as an additive in the therapy of severe full-thickness skin defects.

During the first enthusiastic phase, we learned that for the application of keratinocytes an existing dermis rest is an obligatory prerequisite, otherwise they cannot expel their biological effects, which causes impaired healing and scarring. Actually, the most commonly used variety is keratinocyte fibrin spray, which is used especially in dermis-preserved pediatric superficial thermal injuries.

Heterologous keratinocytes have additional disadvantages in that they are not only expensive, but they might also transmit infective diseases. Ideally, a tissue-engineered skin substitute is a multilayered, structurally fully functional skin substitute, which might fulfill all the different functions of the dermis and epidermis.

An interesting multilayer tissue-engineering approach to cover large full-thickness defects has already been described a few years ago. Autologous keratinocyte and fibroblast primer cell cultures were established, the cells were grown on special hyaluronic acid matrices, and the construct was transplanted in a single-step procedure.

A completely autologous and biological fully active epidermal-dermal substitute was realized, and in addition a thin split-skin graft could be transplanted if necessary [ 42 ].

Apligraft® is a tissue-engineered multilayered skin equivalent which is commercially available and approved by the legal authorities FDA and EMEA. It is a bilayered skin substitute consisting of allogenic neonatal fibroblasts and keratinocytes grown in and on a bovine collagen matrix.

Nevertheless, disadvantages are the allogenic origin of the cells and, therefore, the unclear infectiological status, the bovine origin of the collagen, the lack of dermal structures like sweat glands and hair follicles and the unclear fate of the graft after transplantation in general [ 43 ].

See table 2 for an overview of the literature, including preclinical and clinical trials. Regenerative therapies after skin injuries, especially with local topical approaches, have been studied for a long time, but in the majority of cases without focusing on the underling biological processes taking place.

Only recently, with a better molecular biological understanding of stem cell and protein-based principles, are we able to customize regenerative therapeutic strategies which respect such fundamental biological principles.

Perhaps the therapeutic use of proregenerative agents like EPO, which selectively triggers cell-protective and proregenerative effects, or stem cells or combinations of these methods, may play a key role in future developments of new therapeutics to enable and improve regeneration after skin injuries.

Full skin loss will still remain a therapeutic challenge for clinicians, since total skin loss necessitates skin transplantation or bioartificial generation of skin substitutes in such situations.

Three key problems need to be solved in the future to optimize skin tissue engineering and tissue regeneration: 1 creating a stable epidermo-dermal junction between the two major compartments dermis and epidermis ; 2 implementing a vascular supply in the dermal layer and 3 supporting the construct with its functional cells and appendices e.

melanocytes, sweat and sebaceous glands, hair bulges, etc. Today, evidence-based treatments for these patients are hardly possible because of insufficient scientific evidence due to the lack of a sufficient number of high-quality clinical trials.

To offer evidence-based, cost-effective and up-to-date therapies we need more high-quality clinical trials following the rules of good medical practice and high ethical, moral and scientific standards to be able to identify the most promising new therapeutic methods.

Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals European Surgical Research. Advanced Search. Skip Nav Destination Close navigation menu Article navigation.

Volume 49, Issue 1. Skin Wound Therapies. Innovative Approaches and Clinical Trials. Tissue Engineering. Conclusions and Future Perspectives on Skin Regenerative Therapies. Article Navigation. Review Articles July 11 New Strategies in Clinical Care of Skin Wound Healing Subject Area: Surgery.

Günter ; C. Clinic for Plastic and Hand Surgery, University Hospital rechts der Isar, Technische Universität München, Munich, Germany. This Site. Google Scholar. Machens H. Eur Surg Res 49 1 : 16— Article history Received:. Cite Icon Cite. toolbar search Search Dropdown Menu.

toolbar search search input Search input auto suggest. View large Download slide. Table 1 EPO effects on different growth factors and their most important functions.

View large. View Large. Table 2 Overview of the literature, preclinical and clinical trials. Shah M, et al: Neutralisation of TGF-β1 and TGF-β2 or exogenious addition of TGF-β3 to cutaneous rat wounds reduces scarring.

J Cell Sci ;— Ferguson MWJ, et al: Scar-free healing: from embryonic mechanisms to adult therapeutic intervention.

Philos Trans R Soc Lond B ;— Lancet ;— Occleston NL, et al: Prevention and reduction of scarring in the skin by Transforming Growth Factor beta 3 TGFbeta3 : from laboratory discovery to clinical pharmaceutical.

J Biomater Sci Polym Ed ;— Renovo: Juvista EU phase 3 trial results. Horch RE, et al: Ökonomische Aspekte in der chirurgischen Wundbehandlung. Chirurg ;— Galeano M, et al: Recombinant human EPO stimulates angiogenesis and wound healing in the genetically diabetic mouse.

Diabetes ;— Buemi M, et al: Recombinant human EPO stimulates angiogenesis and healing of ischemic skin wounds. Shock ;— Galeano M, et al: Recombinant human EPO improves angiogenesis and wound healing in experimental burn wounds. Crit Care Med ;— Hamed S, et al: Topical EPO promotes wound repair in diabetic rats.

J Invest Dermatol ; Sorg H, et al: Effects of EPO in skin wound healing are dose related. FASEB ; 1— Bader A, Machens HG: Recombinant human EPO plays a pivotal role as a topical stem cell activator to reverse effects of damage to the skin in aging and trauma.

Rejuvenation Res ; Bader A, et al: Skin regeneration with conical and hair follicle structure of deep second-degree scalding injuries via combined expression of the EPO receptor and beta common receptor by local subcutaneous injection of nanosized rhEPO.

Int J Nanomedicine ;— Ferri C, et al: Treatment of severe scleroderma skin ulcers with recombinant human EPO.

Clin Exp Dermatol ;— Keast DH, Fraser C: Treatment of chronic skin ulcers in individuals with anemia of chronic disease using rhEPO: a review of four cases.

Ostotomy Wound Manage ;— Driver VR, Hanft J, Fylling CP, Beriou JM, Autologel Diabetic Foot Ulcer Study Group: A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers.

Ostomy Wound Manage ;—70, 72, Pietrzak WS, et al: Platelet rich plasma: biology and new technology. J Cranoiofac Surg ;—

Publication types Snacking for better overall health occurs immediately after tissue hdaling, and the helaing aim of strtegies phase Woundd to prevent infection [ atrategies ]. We would Wound healing strategies to thank the Biotechnology Research Center, Shahrekord Branch, Islamic Ehaling University, Shahrekord Wound healing strategies southwest Iran for Wound healing strategies kindly cooperation. In this section About nursing guidelines Nursing guidelines index Developing and revising nursing guidelines Other useful clinical resources Nursing guideline disclaimer Contact nursing guidelines. This study suggested that PDGF supplementation could have altering effects on oxidative events depending on the duration of the wound-healing process [ 80 ]. Hepatocyte growth factor mediates enhanced wound healing responses and resistance to transforming growth factor- β 1 -driven myofibroblast differentiation in oral mucosal fibroblasts. Approved by the Clinical Effectiveness Committee.
Günter Wound healing strategies, H. Machens; New Strategies Wound healing strategies Clinical Care of Strxtegies Wound Healing. Eur Hsaling Res strategiss August ; 49 Emotional well-being and weight management : strateyies The prevalence of chronic wounds is closely correlated to the aging population and so-called civilizational diseases. Therefore, they are causing morbidity and mortality of millions of patients worldwide, with an unbroken upward trend. As a consequence, chronic wounds induce enormous and rapidly growing costs for our health care systems and society in general.

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Besides, the connection between cells and the extracellular matrix is interrupted, causing apoptosis. This method also fails to achieve a homogeneous distribution of cells in the injury site.

Intravenous infusion is easier to implement and less invasive than the direct local injection. However, cells that reach the target wound site are limited because some cells are entrapped in the lungs during intravenous infusion [ 46 ]. Therefore, some novel delivery methods have been developed to reduce cell death and improve transplantation efficiency.

The application of a specific biomaterial scaffold has shown great promise in cell transplantation. The scaffold can increase the delivery efficiency, providing support for cell survival as a physical architecture.

It possesses outstanding compatibility and can interact with MSCs favorably, thereby making the cell living environment more suitable. MSCs delivered in scaffold have enhanced retention and proliferation, which are associated with the type of biomaterial.

A study compared the effects of four different biomaterials seeded with MSCs in wound healing [ 47 ], showing that the cell activity and paracrine function were varied with different scaffolds. Both natural and synthetic biomaterials are used to deliver MSCs as scaffolds, and their combined application exhibits new prospects in skin regeneration.

Chu et al. designed a collagen hybrid scaffold composed of polyethylene glycol and graphene oxide, which promoted angiogenesis and collagen deposition in diabetic skin repair [ 48 ].

This novel scaffold provided a superior environment for cell attachment, proliferation, and differentiation. Composite scaffolds with different biomaterials need to be more investigated to exert unique material characteristics.

Different microstructures of biomaterials have different effects on the growth and function of MSCs, such as the pore size, stiffness, topography, and chemistries of biomaterials Fig.

For example, Bonartsev et al. demonstrated that pore size of polymer scaffolds was a crucial factor affecting cell growth and differentiation [ 50 ].

The uniform pore size of scaffolds is beneficial for cell differentiation, while the widely distributed pore size is suitable for cell growth [ 50 ]. Additionally, changes in the stiffness and surface characteristics of the scaffolds can result in the different paracrine functions of MSCs.

The immunomodulatory protein production of MSCs is increased by regulating the scaffold stiffness [ 51 ]. Stiffness is considered as a switch to modulate related signal pathways of immunomodulation [ 51 ]. Modulating surface characteristics of the scaffold, such as the fibrous topography, shows more secretion of proangiogenic and anti-inflammatory cytokines in AD-MSCs relative to the raw microplates [ 52 ].

The enhancement of cell paracrine secretion accelerated wound healing through the recruitment and polarization of macrophages [ 52 ]. Thus, the mechanical properties of the scaffold can be harnessed to promote cell function and delivery efficiency. Besides, incorporating chemotactic factors, functional groups, or side chains with scaffolds through chemical modification is also a practical approach to deliver MSCs and increase cell efficacy.

According to the excellent properties of biomaterials, physical or chemical modifications can further improve the efficiency of cell delivery.

The publisher for this copyrighted material is Mary Ann Liebert, Inc. The functions of MSCs are affected by the properties of biomaterials [ 49 ]. A The effects of biomaterial stiffness on MSCs; B the effects of surface topography of biomaterials on MSCs; C the effects of surface chemistries of biomaterials on MSCs, such as a proteins, b pharmaceutical molecules, and c functional groups; D the effects of pore size on MSCs.

According to the application of biomaterial scaffold, an advanced strategy to encapsulate cells in a semisolid membrane has been explored. Cells are in relative isolation from the external environment and maintain normal physiological activity. Encapsulated MSCs in composite microgels exhibited increased cell viability and promoted anti-oxidant functions in oxidative stress conditions [ 53 ].

Both the reactive oxygen species ROS scavenging ability of microgels and the encapsulation method protected MSCs from the damage of oxidative stress. The immunomodulatory capacity of encapsulated MSCs after treatment of inflammatory cytokine was assessed using a microfluidic device to encapsulate cells in the alginate coating, showing an increased expression of immunomodulatory-associated genes [ 54 ].

In addition to modulating the immune response, this encapsulation system also extended cell retention. Hence, the combined application of biomaterial scaffold and cell encapsulation can improve the delivery efficiency of MSCs.

Apart from the cell precondition, researchers also considered the preparations of host tissue environments to increase the adaptability of cells to harsh environments. Physical methods can be used for host tissue preconditioning. Combined with MSC therapy, extracorporeal shock wave ECSW can significantly reduce the muscle damage, fibrosis, and collagen deposition in a rat model of ischemic muscle injury, proving to have therapeutic effects on tissue regeneration Fig.

Besides, the cellular expressions of inflammatory are decreased, and the expressions of angiogenesis markers are increased, indicating a reduction of inflammation after receiving this combined therapy.

Weihs et al. revealed the molecular mechanism by which ECSW exerts its positive effects in wound healing [ 56 ]. ECSW facilitated the cell proliferation and healing rate by activating extracellular signal-regulated kinase ERK signaling.

This study provided a new understanding of the clinical use of ECSW. Furthermore, pharmacologic preconditioning of recipient tissue is also effective in creating a favorable environment for cell growth.

A study of myocardial tissue repair reported that vasodilatory drugs had a beneficial effect on cell delivery [ 57 ]. However, the effect was not caused by the vasodilatory function of drugs, and the underlying mechanism was not clear.

Thus, the role of vasodilatory drugs in wound regeneration and other drugs with different pharmacological effects in promoting wound healing need more exploration. Reproduced from the article by authors Yin et al.

The effects of combined therapy of MSC and ECSW on ischemic muscle injury [ 55 ]. The images and quantitative analysis of muscle injury area A , fibrotic area B , and collagen-deposition area C in different groups.

HPF: high-power field; SC: sham control; IR: ischemia—reperfusion; ECSW: extracorporeal shock wave; ADMSC: adipose tissue-derived mesenchymal stem cells. The therapeutic efficacy of stem cells has been investigated intensively in wound regeneration.

Different types of stem cells have their unique characteristics to promote wound healing. Over the past few years, the role of MSCs in wound healing has been identified, and studies about MSCs have made significant strides.

This paper is also based on MSCs to discuss improving the efficacy of stem cells in wound regeneration. Cell characteristics, delivery process, and host factor all influence cell survival and effectiveness. Some strategies are proposed to increase cell efficacy and prevent cell death in tissue regeneration.

For the preparation of MSCs, the first thing is selecting the appropriate source of cells according to the needs of the situation to achieve the desired recovery effect.

According to the stage of wound healing, priority is given to select cell sources and subpopulations that are beneficial in combating inflammation, stimulating angiogenesis, promoting matrix deposition, or reducing scar formation.

Allogeneic or syngeneic MSCs applying to tissue regeneration is determined by the specific circumstance. The immune response induced by syngeneic MSCs is negligible, but their use is limited in emergencies.

As for allogeneic cells, the age of the donor and health condition needs to be assessed. Various forms of preconditioning approaches exhibit satisfactory outcomes by enhancing the resistance of MSCs against the hostile environment or reducing the environmental damage to cells.

Cell preconditioning and host tissue preconditioning both are effective methods to maintain cell retention and increase cell efficacy.

Culture condition with low oxygen and nutrition enables cells more adaptable by mimicking the host tissue environment. The 3D aggregation of MSCs can better preserve cell properties.

Co-culturing MSCs with other cells can increase the specific therapeutic properties of MSCs. Modifying the target gene and manipulating related microRNA prolongs cell survival and enhances the paracrine function. Replacing the cells with their secretome represents a new direction for cell-free therapy.

In the delivery process, the application of biomaterial scaffolds reduces mechanical pressure and preserves intercellular communication. The encapsulation of MSCs provides protection for maintaining cell biological activity. These strategies from different respects could improve cell efficacy in wound healing.

Although great progress has been made in cell therapy, several issues need to be considered to achieve the clinical application of stem cells: firstly lack of effective biomarkers of stem cells to define specific characteristics from different sources.

Heterogeneous populations of stem cells exhibit differences in functions. Identifying effective biomarkers is also helpful in dynamically monitoring cell activity. Secondly, current researches have not determined the optimal type and source of stem cells for tissue regeneration due to differences in experimental design, animal models, operating procedures, and the dose and timing of the stem cells applied.

A standardized process for using stem cells needs to be established to facilitate future scientific normative comparisons of different stem cells.

Thirdly, the expression and changes of various molecules participating in the physiological process of wound healing remain unclear. The physiological changes in the microenvironment at the wound site can be understood deeper by clarifying the communication between cells and molecules.

Finally, although the stem cells possess immunosuppressive properties, stem cells are considered to elicit varying degrees of immune responses in the recipient. More animal model experiments need to be taken to obtain more detailed experimental data in immunology.

A controlled immune response can significantly reduce the adverse effects of stem-cell therapy. Future efforts are required to understand the underlying mechanism of stem cells for the therapeutic effects in wound regeneration.

The way cells behave and how they interact with the surrounding environment remain unclear. The roles of paracrine molecules of cells need to be clarified. It is also necessary to determine the host microenvironment and the effects of this microenvironment on the cell.

Controlling the microenvironment to be favorable to the cell by the pretreatment of the host tissue is an effective approach. Besides, exploiting more suitable delivery materials or developing more efficient delivery methods is desirable to maintain cell survival and enhance cell function.

Preparation of the cell, host tissue, and delivery process should be designed more carefully to unleash a higher cell therapeutic potential. Cell transplantation and survival conditions will be enhanced by different strategies, thus contributing to efficient stem cell-based therapy.

Moreover, non-cell therapy with the application of cell secretomes is another new direction. Cutaneous wound regeneration has been a topic of great concern in recent years. Various traditional and emerging methods are applied to enhance wound repair, in which stem cell therapy has attracted much attention.

The main wound healing process has been described, while the underlying mechanism by which stem cells act on wound healing has not been completely elucidated.

The therapeutic effects of stem cells are limited by poor viability and low delivery efficiency. Therefore, diverse strategies are proposed to maintain cell retention and improve cell function. Before stem cells are transplanted to the recipient, both cell and recipient can be prepared to achieve a higher therapeutic outcome.

The selection of cell type and source, the identification of cell subpopulation and donor, and the investigation of different preconditioning treatments and genetic modification approaches can guarantee enhanced cell efficacy.

The biocompatible materials scaffold can increase cell delivery efficiency. Maintaining the harmony between the recipient and transplanted cell is an important goal.

More detailed research on the exosomes of stem cells will open up a possibility of cell-free therapy, providing an optimistic future in wound regeneration.

Hanson SE, Bentz ML, Hematti P. Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plast Reconstr Surg. Article CAS PubMed PubMed Central Google Scholar. Casado-Díaz A, Quesada-Gómez JM, Dorado G. Extracellular vesicles derived from mesenchymal stem cells MSC in regenerative medicine: applications in skin wound healing.

Front Bioeng Biotechnol. Article PubMed PubMed Central Google Scholar. Baldari S, et al. Challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies.

Int J Mol Sci. Article PubMed Central Google Scholar. Duscher D, et al. Stem cells in wound healing: the future of regenerative medicine? A mini-review. Article CAS PubMed Google Scholar. Dominici M, et al. Minimal criteria for defining multipotent mesenchymal stromal cells.

The International Society for Cellular Therapy position statement. Li X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation.

Int J Mol Med. Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. Du WJ, et al. Heterogeneity of proangiogenic features in mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, and placenta.

Stem Cell Res Ther. Han ZC, et al. New insights into the heterogeneity and functional diversity of human mesenchymal stem cells. Biomed Mater Eng. CAS PubMed Google Scholar. Doi H, et al. Sci Rep. Zheng G, et al. Recent advances of single-cell RNA sequencing technology in mesenchymal stem cell research.

World J Stem Cells. Tanay A, Regev A. Scaling single-cell genomics from phenomenology to mechanism. Sun C, et al. Rennert RC, et al. Microfluidic single-cell transcriptional analysis rationally identifies novel surface marker profiles to enhance cell-based therapies.

Nat Commun. Du W, et al. Wang B, et al. Transplanting cells from old but not young donors causes physical dysfunction in older recipients. Aging Cell. Joswig AJ, et al.

Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model. Chen L, et al. Analysis of allogenicity of mesenchymal stem cells in engraftment and wound healing in mice. PLoS ONE. Chang YW, et al.

Autologous and not allogeneic adipose-derived stem cells improve acute burn wound healing. Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med. Beegle J, et al.

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Eur Heart J. Download references. This study was supported by grants from the Science and Technology Development Project of Jilin Province 3D , the Youth Program of the National Natural Science Foundation of China 3A , and the Education Project of Jilin University and D Department of General Surgery, The Second Hospital of Jilin University, No.

You can also search for this author in PubMed Google Scholar. ZYQ and WM drafted the review; LF generated the graphs; LJN guided the construction of the manuscript; LJN edited the review; LJN provided input on the scope and content of the review.

ZYQ and WM contributed equally to this work. All authors read and approved the final manuscript. Correspondence to Jiannan Li. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Stem Cell Res Ther 12 , Download citation. Received : 05 June Accepted : 03 November Published : 25 November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Skip to main content. Search all BMC articles Search. Download PDF. Abstract Skin wound healing is a multi-stage process that depends on the coordination of multiple cells and mediators. Introduction As a main organ of the human body, the skin is the first link between the human body and the outside world [ 1 ].

Full size image. Strategies to promote favorable effects of cell therapy Different types of stem cells A relatively effective stem cell source is the starting point for optimal outcomes because multiple types of stem cells have different wound healing effects.

Table 1 The main characteristics of ESC, iPSCs, and ASCs are compared from five aspects Full size table. MSC-derived exosomes MSC-derived exosomes can translate cell-based therapy into cell-free therapy.

Discussion The therapeutic efficacy of stem cells has been investigated intensively in wound regeneration. Conclusion Cutaneous wound regeneration has been a topic of great concern in recent years.

Availability of data and materials All data generated or analyzed during this study are included in this published article. References Hanson SE, Bentz ML, Hematti P. Article CAS PubMed PubMed Central Google Scholar Casado-Díaz A, Quesada-Gómez JM, Dorado G. Article PubMed PubMed Central Google Scholar Baldari S, et al.

Article PubMed Central Google Scholar Duscher D, et al. Article CAS PubMed Google Scholar Dominici M, et al. a Chemical Biology Laboratory, Department of Sericulture, Raiganj University, North Dinajpur, West Bengal, India E-mail: amitmandal08 gmail.

b Biomedical Engineering Graduate Program, TOBB University of Economics and Technology, Ankara, Turkey. c Graduate School of Sciences and Engineering, Koç University, Istanbul , Turkey.

d Graduate Program of Tissue Engineering, Institution of Health Sciences, University of Health Sciences Turkey, Istanbul, Turkey. e Mechanical Engineering Department, School of Engineering, Koç University, Istanbul, Turkey.

f Koç University Translational Medicine Research Center KUTTAM , Koç University, Istanbul, Turkey. g Department of Biomedical Engineering, TOBB University of Economics and Technology, Ankara, Turkey.

h Department of Law, Raiganj University, North Dinajpur, West Bengal, India. i Laboratório de Purificação de Proteínas e suas Funções Biológicas, Universidade Federal de Mato Grosso do Sul, Cidade Universitária, Campo Grande, Mato Grosso do Sul, Brazil.

j S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil. k Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil. l Experimental Medicine Research and Application Center, University of Health Sciences Turkey, Istanbul , Turkey E-mail: sevde.

altuntas sbu. m Department of Tissue Engineering, Institution of Health Sciences, University of Health Sciences Turkey, Istanbul, Turkey. n Centre for Nanotechnology Sciences CeNS , Raiganj University, North Dinajpur, West Bengal, India. The intricate, tightly controlled mechanism of wound healing that is a vital physiological mechanism is essential to maintaining the skin's natural barrier function.

Numerous studies have focused on wound healing as it is a massive burden on the healthcare system. Wound repair is a complicated process with various cell types and microenvironment conditions.

In wound healing studies, novel therapeutic approaches have been proposed to deliver an effective treatment. Nanoparticle-based materials are preferred due to their antibacterial activity, biocompatibility, and increased mechanical strength in wound healing.

They can be divided into six main groups: metal NPs, ceramic NPs, polymer NPs, self-assembled NPs, composite NPs, and nanoparticle-loaded hydrogels. Each group shows several advantages and disadvantages, and which material will be used depends on the type, depth, and area of the wound.

Bearing this in mind, here we reviewed current studies on which NPs have been used in wound healing and how this strategy has become a key biotechnological procedure to treat skin infections and wounds. Dam, M. Celik, M. Ustun, S. Saha, C. Saha, E. Kacar, S. Kugu, E. Karagulle, S.

Tasoglu, F. Buyukserin, R. Mondal, P. Roy, M. Macedo, O. Franco, M. Cardoso, S. Altuntas and A. Mandal, RSC Adv. This article is licensed under a Creative Commons Attribution-NonCommercial 3.

You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

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Metrics Wound healing strategies. Skin wound healing is strategis multi-stage process hdaling depends Wound healing strategies Organic mood regulator formula coordination of multiple strategkes and mediators. Chronic or Wond wounds resulting from the dysregulation of Wound healing strategies process represent a strateges for the healthcare system. For skin wound management, there are various approaches to tissue recovery. For decades, stem cell therapy has made outstanding achievements in wound regeneration. Three major types of stem cells, including embryonic stem cells, adult stem cells, and induced pluripotent stem cells, have been explored intensely. Mostly, mesenchymal stem cells are thought to be an extensive cell type for tissue repair.

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