Stem Cells (ADSCS) for Wound Healing

Acute Wound Healing (last 4-6 weeks)

Surgical wounds, bites, burns, abrasions, traumatic wounds

The Four Phases of Wound Healing:

The phases of wound healing begin with some type of incision or trauma. There are 4 phases of wound healing, and there are factors that can impact the rate at which these phases occur, such as age, smoking, nutrition, other health issues such as diabetes and size of the wound.

First Phase: Haemostasis & Coagulation (seconds to hours)

Stop bleeding

The shortest phase and it is an immediate process by which the body attempts to control bleeding by creating blood clot

This phase started immediately after the incision or the trauma that exposes the extracellular matrix protein to platelets. Platelets respond by degranulation leading to 2 major effects: haemostasis and vasoconstriction. Taking medications such as blood thinners or NSAIDS can affect the body’s ability to control bleeding.

Second Phase: Inflammation (hours to day 6)

New frame work for blood vessels growth

The inflammatory phase of wound healing typically begins 10-15 minutes after the initial insult and end of haemostasis.  Under ideal circumstances, and assuming proper progression through the phases of healing, this phase last 2-3 days but it can be up to 6 days. In this phase, nutrient rich blood is sent to the wound, which causes swelling and warmth or redness at the site of the wound. The body also signals cells, growth factors and proteins needed to begin the healing process, and to fight infection. This also begins a process called angiogenesis whereby blood vessels begin to reform.

Ultimately the purpose of this phase is to establish a clean wound bed and set up the next phase of wound healing.  Unfortunately, the inflammatory phases been identified as the most common sticking point in the wound healing cascade.  In this stage where the wound convert to chronic or delay wound healing.

Third Phase: Proliferative Phase (day 4 to week 3)

Pull the wound closed

During this phase of the wound healing process (3-24 days), fibroblast move into wound days 2-3, dominant cell at 7 days. Fibroblast at work to produce collagen to aid in healing.  Skin cells arranged in specific way to reform a new surface layer of skin. high rate of collagen synthesis from day 5 to weeks 3, tensile strength start to increase at days 4-5. Granulation tissue that is pink to red in appearance, is a necessary component of wound healing. However, it can be problematic if it becomes elevated above the surrounding plane of skin, making it difficult for skin cells to continue the its arrangement over others, and thus can delay wound healing. Too much granulation tissue can be caused by excessive amounts of moisture, whereas not enough granulation tissue can be the result of a lack of moisture.  and thus, making it difficult for skin cells to centime the collagen formation and tensile strength of the wound increases, while at the same time contraction of the wound begins to finally repair the defect.  

Forth Phase: Remodelling or Maturation phase (week 3 to 1 year)

Final proper tissue

After 3-5 weeks, mostly start by day 24th and continue up to 1 year. The trigger for the initiation maturation is when equilibrium reached between collagen breakdown and synthesis, at this point the maturation phase begins, replacing provisional type III collagen performed during the proliferative phase with type I collagen restoring normal 4:1 ratio. subsequently no net changes in quantity plus This takes a disorganized collagen structure and rearranges and cross-links the fibers along tension lines forming a more durable, strong and organized closure. Decreased in water content, vascularity and cell population as scar tissue decreases granulation tissue gets stronger and changes from reddish to pale scar colour. Scar tissue is an acceptable outcome for wound healing but is associated with a decrease in tensile strength having approximately 80% strength of normal regenerated skin by 60 days. A scar formed and collagen remodels over a period of a 24 months. Think of a stretch mark. Initially, it is red purple , but over tie it fades to while . This is what happens as result of the remodelling phase.

Chronic Wound Healing (longer than 6 weeks)

Chronic wounds is the wound that does not enter the healing cascade in the classic manner. The surgical model depends on a trauma/incision to activate platelets through interaction with extracellular matrix proteins, but what happens if there is not an incision or trauma to activate the cascade. A simple example of that problem is the pressure ulcer, in which the ulcer is generated by local pressure and ischemic tissue injury as chronic wound mostly caused by endogenous mechanisms related to a predisposing condition or risk factors (diabetes, obesity, smoking, AIDS, chemotherapy) which eventually compromised dermal and epidermal tissue structures e.g. leg/foot ulcers and pressure sores likely from vascular insufficiency or neuropathy.

Any abnormalities in the progress through the phases may lead to an inappropriately healing wound.  Wound fails to progress in a predicted fashion through the phases of wound healing, and in a timely manner the wound is considered to be a chronic wound.

Stem Cells (ADSCs) for Wound Healing

Since ADSCs were first isolated by Zuk et al., (2001), stem cell therapy has gained a prominent and promising role in the future of wound healing and much has been done to thoroughly understand ADSC biology. To date, ADSCs have mainly been studied in vitro and in vivo in animal models, and only a few clinical trials have been reported in the literature. The preliminary results reported so far are promising, and from a practical standpoint the clinical application of ADSCs in wound healing seems effective & safe, even if it is currently in its early stages. However, further research is needed: the mechanism of action of ADSCs is still not completely understood, and the isolation protocol and delivery system must be improved.

Up-to-date, the studies reported the effect of mesenchymal stem cells in wound healing, in preclinical and clinical settings and demonstrated that mesenchymal stem cells stimulate re-epithelialization, suppress the inflammatory process, and has an anti–scarring effect. However, their exact mechanism involved is still not elucidated.

Adipose-derived mesenchymal stem cells (ASCs), which participate in normal wound healing, are trophic mediators of tissue repair. These cells participate in attenuating inflammation in the wound and reprogramming the resident immune and wound healing cells to favour tissue regeneration and inhibit fibrotic tissue formation. As a result, these cells have been considered and tested by researchers as a likely candidate for a cellular therapy to promote scar-less wound healing.

A growing body of evidence by recent studies and trials clearly demonstrated that lipofilling and ADSCs influence significantly processes associated with dermal wound healing as they:

  1. Accelerate the rate of wound reepithelialisation, and thus the wound closure
  2. Improve the quality and strength of the regenerated tissue then, improve the quality of tissue tension
  3. Recover wound healing pathologies that might otherwise result in a chronic, non-healing wound, and 
  4. Minimize the visual appear scar tissue.

So, ADSCs are characterized by their regenerative capacity and have been recognized as a legitimate player accelerating the wound healing process.

Mechanism of Stem Cells Effect in Wound Healing

It is well known fact today that human Mesenchymal Stem Cells (MSCs) can accelerate the wound healing process by their self-renewing ability. Mesenchymal stem cells have been used in several studies, which showed that;

  • Regeneration of full-thickness wounds can be enhanced by application of MSCs. Fu et al. (2006) reported that BmMSCs cells improved the quality of wound healing, such as the reepithelialisation process, the regeneration of the epidermis, and the amount of microvasculature, fibroblasts and collagen.
  • Same finding with Adipose-Derived MSCs increased the structure of epithelial in wound healing process of full-thickness donor wounds during the period of proliferative phase and maturation phase. The mesenchymal stem cells regulate the density of collagen in the proliferative phase and the initial phase of maturation in full-thickness wounds donor. Therefore, adipose-derived mesenchymal stem cells can be used in the process of full-thickness wound healing.

There is a high interest in using stem cells for wound healing, since they can migrate to the wound site, and become part of the micro-environment. Besides that, stem cells can increase growth factors reduce inflammation, and inhibit hypertrophic scar formation. Therefore, mesenchymal stem cells are expected to become helpful in accelerating healing of full-thickness wounds. However, the underlying mechanism is still not fully understood.

Stem Cells Therapy (ADSCs) Role in Chronic Wound Healing

The phases of wound healing in chronic wound is flawed for many reasons. The first argument is that the wound in a “multi-co-morbid” patient such as those treated in a wound care centre already have features of chronicity built in to them. Meaning an acute wound in a patient with significant co-morbidities at its initiation has behaviour and biochemistry that makes it behave in a chronic fashion.

Another challenge that physician face in the arena of chronic wounds is the wound that does not enter the healing cascade in the classic manner. That mean no wound or trauma to activate the cascade of wound healing. Currently, ASCs are being investigated as a therapeutic strategy for a diverse group of pathological conditions, including hard-to-heal wounds. Wound healing is not a series of individual and independent progressive steps, but a complex process involving inflammation, epithelialization, neoangiogenesis, proliferation, and collagen matrix formation. This complex process is carried out and regulated by numerous growth factors, cytokines, and chemokines. A reduction in the cytokines released by local inflammatory cells & decreased neo-vascularization are the main obstacles to healing processes. BmSCs and ADSCs have been studied as potential solutions for these major issues. Both types of MSC (Bone marrow-derived & Adipose-derived stem cells) have been shown to be effective in enhancing wound healing by modulating the immune response, secreting paracrine factors, and promoting therapeutic angiogenesis, thereby providing the building blocks for wound regeneration. Given their higher isolation yield, ease of harvest and abundance, ADSCs are more clinically attractive and have generated interest as the most favoured cell type for wound repair and regeneration. It has been demonstrated that ADSCs not only have potential for stimulating angiogenesis, but may also function in situ as pericytes providing vascular stability, and can communicate with endothelial cells in response to environmental stimuli. As a consequence of a newly re-established blood supply, hard-to-heal wounds can obtain the necessary support for wound recovery.

ADSCs Role in Full Thickness Wound Healing

Wounds that exist after harvesting a full thickness graft in the donor area can cause wound healing problems. This results in bad scars, which can even become hypertrophic in patients with dark skin complexion and this will lead to less aesthetic outcomes. Multifactorial processes take place in the proliferation phase of wound healing, such as angiogenesis, epithelialization, collagen deposition, and wound contraction and several important factors are responsible for the alteration in wound healing function. Administration of mesenchymal stem cells in the donor wound area, after excision of a full-thickness graft, can regulate the number of layers of epithelial. Dososaputro et al., (2017). The number of epithelial layers in the MSCs group exceeded even two times the number of epithelial layers in the structure of the normal skin-group (p=<0.001) also, showed that mesenchymal stem cells are capable of controlling the density of collagen in the maturation phase. Therefore, adipose-derived mesenchymal stem cells ADSCs can be used in the process of full-thickness wound healing.

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