For best results change frequently more than once daily. Stop using when wound is granulating or epithelising. It is an expectation that all aspects of wound care, including assessment, treatment and management plans are documented clearly and comprehensively.

Documentation of wound assessment and management is completed in the EMR under the Flowsheet activity utilising the LDA tab or Avatar activity , on the Rover device, hub, or planned for in the Orders tab.

For more information follow the Parkville EMR Nursing — Documenting Wound Assessments phs. Clinical images are a valuable assessment tool that should be utilised to track the progress of wound management.

See Clinical Images- Photography Videography Audio Recordings policy for more information regarding collection of clinical images.

Wound management follow up should be arranged with families prior to discharge e. Hospital in the Home, Specialist Clinics or GP follow up. The evidence table for this guideline can be viewed here. Please remember to read the disclaimer.

The revision of this clinical guideline was coordinated by Mica Schneider, RN, Platypus. Approved by the Clinical Effectiveness Committee. Updated February Stay informed with the latest updates on coronavirus COVID The Royal Children's Hospital Melbourne. Health Professionals Patients and Families Departments and Services Research Health Professionals Departments and Services Patients and Families Research Home About News Careers Support us Contact.

Nursing guidelines Toggle section navigation In this section About nursing guidelines Nursing guidelines index Developing and revising nursing guidelines Other useful clinical resources Nursing guideline disclaimer Contact nursing guidelines.

In this section About nursing guidelines Nursing guidelines index Developing and revising nursing guidelines Other useful clinical resources Nursing guideline disclaimer Contact nursing guidelines. Wound assessment and management. Silver dressing.

cavities -Ideal for bleeding wounds due to haemostatic properties. Change every days depending on exudate. Stop using once wound bed is dry. Needs to be bigger than the wound as it will shrink in size -Prevents peri wound maceration.

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.

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Issue 31, From the journal: RSC Advances. A typical example would be sunburn. In a situation like this basically no specialized therapy is needed. Nevertheless, a variety of therapeutic options exist. Most available products just have a cooling affect, some also have a local analgesic affect and others just help to keep the wound moist.

Superficial dermal thermal injuries display blister formation. If the blister ground is exposed to air it is extremely painful. It includes the removal of the blisters and occlusive local therapy. There exist several treatment options and products silver nitrate, marfenide, vinegar, iodine, silver sulfadiazine, etc.

which enable microbiological control, but some of these lack enough moisturizing capacity for the wound surface. A widely used product is Flammacine® silver sulfadiazine , which is simple to handle and has a favorable cost-effectiveness ratio.

The disadvantage of this is the painful daily dressing change and the drying out of the wound area. In the occlusive method, closure of the wound surface is realized with synthetic membranes under strictly sterile conditions e. Biobrane® or Suprathel. The advantage of these products is that they stay in place until complete wound healing, thus painful dressing changes are no longer needed; nevertheless, frequent wound controls are necessary.

After a deep dermal injury a deep second-degree burn , the necrotic superficial layers of the skin have to be removed either biologically or surgically until vital layers are exposed.

After bleeding control, keratinocytes as solution or as sheets can be transplanted if enough dermal tissue is preserved and the regenerative capacity of the patient is postulated to be sufficient.

Split-skin grafts are used if deeper layers of the dermis are involved. If, after extensive thermal trauma, the remaining nondamaged body surface does not allow for sufficient amounts of split-skin grafts to be taken, temporary skin substitutes such as heterologous or xeno split-skin grafts, or amnion, can be used for a short period of time to prevent both infection and hypertrophic granulation and later scar tissue formation.

If an acute full-thickness skin defect has occurred e. a third-degree burn , the wound has to be cleaned carefully and all remnants of necrotic skin or foreign bodies have to be removed. In a condition like this the underlying tissue is subjected to infection and trauma since the protecting barriers, dermis and epidermis are lost.

Therefore, wound closure is the most important aim. This can be achieved with split-skin graft transplantation or, after pretreatment with a dermis substitute e.

Integra® and neodermis formation, keratinocytes may be transplanted. If a chronic full-thickness skin defect exists we need a different therapeutic strategy. In addition, chronic wounds are usually colonized with a multitude of microorganisms and are sometimes even infected.

These microorganisms have to be, at least grossly, removed before a wound closure attempt can be made. After cleaning the wound and removing necrotic tissue remnants the wound environment has to be changed from antiproliferate to proproliferate.

Therefore, antiproliferative factors such as metalloproteinases and TNF-α have to be antagonized and the concentrations and effectiveness of proproliferative factors such as erythropoietin EPO or transforming growth factor TGF-β3 have to be increased. Granulation tissue formation can then take over or a neodermis can be grown using a dermis substitute.

Later split-skin grafts can be transplanted on the prepared new wound bed if necessary. If a proproliferative environment cannot be created, for example due to advanced loss of vital and vascularized tissue, plastic surgical techniques have to be employed by using local or free tissue transfers to substitute the previous tissue loss in an adequate manner.

Figure 1 shows the four stages of thermal injury to the skin. Four stages of thermal injury to the skin. This section will focus on innovative treatment approaches which are at the stage of clinical phase I—III trials or even only in the preclinical phase, but which seem to have a special promising potential.

One very interesting fact is the scar-free healing of mammalian embryos. So far, several investigations have been carried out to investigate adult and embryonic wound healing and scarring reaction in adults.

Nowadays, many factors involved in adult and embryonic skin regeneration are being described. 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 ].

To prevent wounds from developing into a larger problem, wound care strategies need to be implemented. 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;. Without regularly monitoring these basic factors in wound care, your patients will remain in the hospital longer than necessary, costing a significant amount of money and putting a lot of additional pressure on staff. However, what happens when your staff is limited?

This is a reality for many hospitals in the United States as the nursing shortage has put strain on the health care system.

The good news is that there are wound care management companies that are trained in wound care management and can assist hospitals offer patients a health care solution for wound care.

Chronic wound care remains high on the priority 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. 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.

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Wu Y, Wang J, Scott PG, Tredget EE. Bone marrow-derived stem cells in wound healing: a review. Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow—derived cells. Arch Dermatol. Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells.

Rejuvenation Res. Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wan J, Xia L, Liang W, Liu Y, Cai Q.

Transplantation of bone marrow-derived mesenchymal stem cells promotes delayed wound healing in diabetic rats. J Diabetes Res. Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, Shrayer D, Carson P. Autologous bone marrow—derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds.

Ravari H, Hamidi-Almadari D, Salimifar M, Bonakdaran S, Parizadeh MR, Koliakos G. Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix.

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Chin Med J , 2 — Jung JA, Yoon YD, Lee HW, Kang SR, Han SK. Comparison of human umbilical cord blood-derived mesenchymal stem cells with healthy fibroblasts on wound-healing activity of diabetic fibroblasts.

Int Wound J. Shrestha C, Zhao L, Chen K, He H, Mo Z. Enhanced healing of diabetic wounds by subcutaneous administration of human umbilical cord derived stem cells and their conditioned media. Int J Endocrinol. Kocan B, Maziarz A, Tabarkiewicz J, Ochiya T, Banaś-Ząbczyk A. Trophic activity and phenotype of adipose tissue-derived mesenchymal stem cells as a background of their regenerative potential.

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Arterioscler Thromb Vasc Biol. Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, Kim KJ, Park BS, Sung JH. Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF.

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Dermal fibroblasts display similar phenotypic and differentiation capacity to fat-derived mesenchymal stem cells, but differ in anti-inflammatory and angiogenic potential.

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As inflammation diminishes, epithelial cells begin to proliferate and keratinocytes migrate to promote epithelialization. In the final remodeling phase, the extracellular matrix ECM is constantly reconstructed and the proportion of various kinds of collagen changes to strengthen the skin resilience.

Reproduced from the article by authors Casado-Díaz et al. Reproduced from the article by authors Baldari et al. Wound healing process and different ways for stem cells to enhance the treatment efficacy of wound healing. A Timeline of skin wound healing [ 2 ]; B different ways of stem cells to enhance the treatment efficacy of wound healing [ 3 ].

In fact, unadvanced wound healing can occur in any phase of skin recovery due to abnormal factors. Confined to a prolonged inflammatory stage, chronic wound is exposed to persistent bacterial infections and excessive proinflammatory cytokine stimulation, which requires constant treatment.

Chronic wound, such as pressure sores, diabetic ulcers, and arteriovenous ulcers, not only lowers the living quality of patients but also imposes a huge economic burden on society. In addition, the poor appearance of wounds and the inconveniency of movements both bother patients.

Therefore, various therapies have been developed to manage chronic wounds, of which traditional therapies are favored for debriding necrotic tissue, applying wound dressings, using antibiotics, and performing skin graft if necessary.

As for emerging therapies, some biophysical modalities, such as electrical stimulation and shock wave therapy, are used to faster wound regeneration. Besides, engineered skin substitutes are popular in the tissue regeneration.

Recently, stem cell therapy has received increasing attention in wound healing due to its excellent abilities in self-renewal, differentiation, and immunomodulation.

Although significant progress has been made on stem cell treatment for cutaneous wound healing, the potentials of stem cells remain to be unleashed. The transplanted stem cells have a short duration of existence and a low survival rate at the wound site.

When the cell loses its original supportive environment, apoptotic signaling is activated, leading to the death of cells. Besides, the mechanical stress exerted on the cells during delivery, and the harsh conditions of host after translation both affect the cell viability.

Therefore, one of the aims to optimize cell therapy is to increase cell survival. Additionally, promoting cell functionality is another goal.

In this study, we summarize current optimizing strategies to enhance the wound healing efficacy of stem cells Fig. A relatively effective stem cell source is the starting point for optimal outcomes because multiple types of stem cells have different wound healing effects.

Besides, advantages and limitations both exist in each type of stem cells. Stem cells are classified into embryonic stem cells ESCs , adult stem cells ASCs and induced pluripotent stem cells iPSCs. These stem cells show different differentiation potential, among which ESC and iPSCs have higher differentiation potential compared to ASCs Fig.

ASCs include multiple types of stem cells, such as mesenchymal stem cells MSCs , hematopoietic stem cells, and umbilical cord stem cells.

A brief comparison of the characteristics of ESC, iPSCs, and ASCs mainly MSCs is presented in Table 1. Among ASCs, MSCs have been applied more widely and successfully for the treatment of many kinds of diseases, including wound healing.

As a result, we mainly highlight the comparison of MSCs from different sources in the treatment of wound repair. Reproduced from the article by authors Duscher et al. Reproduced from the article by authors Li et al. 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. Differential response of fetal and adult fibroblasts to cytokines: cell migration and hyaluronan synthesis.

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