Wound Healing

Chronic or non-healing skin wounds present an ongoing challenge in advanced wound care, particularly as the number of patients increases while technology aimed at stimulating wound healing in these cases remains inefficient. Mesenchymal stem cells (MSCs) have proved to be an attractive cell type for various cell therapies due to their ability to differentiate into various cell lineages, multiple donor tissue types, and relative resilience in ex-vivo expansion, as well as immunomodulatory effects during transplants. More recently, these cells have been targeted for use in strategies to improve chronic wound healing in patients with diabetic ulcers or other stasis wounds. Here, we outline several mechanisms by which MSCs can improve healing outcomes in these cases, including reducing tissue inflammation, inducing angiogenesis in the wound bed, and reducing scarring following the repair process. Approaches to extend MSC life span in implant sites are also examined.

 Introduction

Wound healing is a complex multi-stage process that orchestrates the reconstitution of the dermal and epidermal layers of the skin. In many pathological circumstances such as diabetes or severe burns, the normal wound healing process fails to adequately restore function to the skin, leading to potentially severe complications from ulcers or resulting infections. As the incidence of obesity and resulting diabetes continues to increase in the western world, the prevalence of chronic wounds related to these conditions continues to be a major focus of wound care research. In fact, non-healing wounds from these conditions have produced a multi-billion dollar advanced wound care market for technologies aimed at stimulating wound healing in patients that suffer from dysfunctional wound repair, with large projected growth in the near future. Most current biological technologies for advanced wound care aim to provide antimicrobial support to the open wound and a matrix scaffold (collagen-based in many cases) for invading cells to reestablish the skin, with some focus on growth factor support of the healing process. However, patient outcomes in this area remain marginal and novel bioengineered approaches to chronic wound repair remain a topic of high interest.

Chronic wound healing technologies

Mesenchymal stem cells (MSCs) are important cells in orchestrating the three main phases of normal wound healing (inflammatory/proliferative/remodeling), directing inflammation and antimicrobial activity and promoting cell migration during epithelial remodeling. However, recently due to advances in understanding of MSC immunosuppression and secretion of pro-angiogenic factors, MSC-based cell therapy in combination with matrix scaffold approaches to improve wound healing outcomes has become a potential strategy in treatment of non-healing wounds.

 Traditionally, MSCs have long been identified for their ability to migrate to sites of injury in the body and differentiate into a variety of cell lineages such as bone, fat, and cartilage,making them attractive candidates for a variety of cell therapies in recent studies. A variety of easy means of isolating and expanding these cells ex-vivo (bone marrow, adipose tissue, placenta, peripheral blood,and others) also makes MSCs useful cells for therapeutic approaches to supplementing tissue regeneration. Additionally, these cells have been shown to have notable immunomodulatory effects on the surrounding environment following transplantation and can support native cells with the secretion of a variety of pro-survival and pro-migratory cytokines and growth factors. As a major problem in chronic wounding is unmitigated inflammation, this characteristic of MSCs has made them good candidates for approaches to cell therapy for chronic wounds in particular.

Clinical sources of MSCs

In this review, we examine current trends in MSC therapy for chronic wound healing, including several major areas of MSC benefit to the wound repair process. Additionally, potential further MSC applications in wound healing and novel technologies are discussed.

Chronic Skin Wounds

The normal wound healing process is characterized by three main phases that lead to efficient reconstitution of a functional dermis/epidermis and revascularized tissue. Briefly, the inflammatory phase immediately follows wounding, serving to stop bleeding in the wound bed via platelet aggregation and fibrin clot formation. This is followed by invasion of neutrophils and mast cells that follow a chemotactic gradient to clear the wound of dead cells, debris, and residual ECM. The proliferative phase then proceeds, including fibroblast migration into the wound bed and deposition of new ECM (collagen). VEGF and B-FGF also stimulate de novo angiogenesis in the skin. Finally, the remodeling process resolves the wound by organizing collagen fibers that formed during fibroblast proliferation in parallel with further removal of fibronectin to increase the strength of the new skin.

A chronic or non-healing wound is essentially a wound that does not progress normally through the wound healing process, resulting in an open laceration of varying degrees of severity. These conditions can be cause by a number of various pathophysiological conditions (diabetes, venous stasis ulcer progression, nd others), though all causes generally lead to a hyper-inflammatory environment, particularly evidenced by the characteristic presence of neutrophils/high MMP activity that leads to high breakdown of new collagen during the wound healing process and inhibition of pro-healing factors (PDGF, TGF-B, and others). This excessive inflammation phenotype leads to wounds that cannot resolve under normal circumstances, especially until the inflammation in the wound bed is controlled to a normal level and fibroblasts are able to effectively migrate into the wound space and synthesize new matrix.

Clinically, these wounds present a large problem for wound care specialists globally, with approximately 1–2% prevalence and a greater than 50% recurrence rate for diabetic patients. This need has generated a large interest in new treatments for improving patient outcomes in chronic wound therapies. Mesenchymal stem cells, given their immunomodulatory and angiogenic properties, have therefore been studied extensively with regards to cell therapy to supplement wound dressings. With over 350 listed clinical trials for MSC therapies (clinicaltrials.gov), many include studies utilizing MSCs for healing ischemic/diabetic foot ulcers and similar wounds.

Clinical trials for MSCs and chronic wounds

 Ultimately, this interest in MSCs for cell therapies in wound healing revolves around several key aspects, including immunosuppression, angiogenesis stimulation, and scar reduction. As MSCs play a normal role in the wound healing process, they are an obvious candidate for study in this context as opposed to embryonic stem cells or other regenerative sources. Recent studies have outlined some successful approaches to promoting wound healing with MSCs, including autologous bone marrow-derived MSCs in fibrin matrix or, more recently, intramuscular injection of autologous MSCs to improve diabetic wound closure. While some trials have been aimed primarily at safety of MSC use for wound healing, several clinical trials have shown the potential benefit of MSCs for inclusion in wound healing devices, including improved average rate of wound healing and general limb perfusion after treatment and also improved acute wound healing correlating to the number of injected cells.Despite any effects on healing, there was some doubt as to any reduction in limb amputation rate or relative pain levels among groups, a major consideration for effective therapy in chronic wounds. In general, the consensus from completed trials has been an overall improvement in chronic wound closure with application of mesenchymal stem cells, particularly as a part of a matrix delivery system (wound gel, etc.).

 Mesenchymal Stem Cell Therapy in Multiple System Atrophy

Randomized clinical trials

The purpose of this study is to determine whether mesenchymal stem cells (MSCs) can be safely delivered to the cerebrospinal fluid (CSF) of patients with multiple system atrophy (MSA). Funding Source – FDA OOPD.

Primary Outcome Measures : Adverse event frequency (by severity, type, attribution, and intervention dose). [ Time Frame: 14 months ] Secondary Outcome Measures : Rate of change of Unified Multiple System Atrophy Rating Scale (UMSARS) I score from baseline to 12 months (or last available date), compared with placebo limb of Rifampicin trial (historical control cohort). [ Time Frame: 12 months ] Rate of change from baseline to 12 months (or last available date) in UMSARS II score. [ Time Frame: 12 months ] Rate of change from baseline to 12 months (or last available date) in UMSARS total score. [ Time Frame: 12 months ] Rate of change in COMPASS-select score from baseline to 12 months. [ Time Frame: 12 months ] Change in CASS score and thermoregulatory sweat test (TST) % from baseline to 12 months. [ Time Frame: 12 months ] MRI morphometric changes using dedicated algorithms to evaluate rate of atrophy of defined areas of brain from baseline to 12 months. [ Time Frame: 12 months ] Change in CSF biomarkers from baseline to 2 months. [ Time Frame: 2 months ]

The most recent, and by far, the larger clinical trial performed (60 cases and 60 controls) infused intravenously 2.9 × 106 CD34+ obtained by HSC in subacute stroke patients (median of 18.5 days after stroke).111 Even though safety was met, no changes were observed as to functional improvements. This contrasts with results obtained by the same research group a few years back, where they used either HSC or MSC in chronic patients (n treated = 20), and found statically significant improvements in BI, as well as increased number of cluster activation in motor cortex area, suggesting neuroplasticity.

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