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Topical Lineage-Negative Progenitor-Cell Therapy for Diabetic Wounds (Invited Discussion)

Gurtner, Geoffrey C. M.D.; Longaker, Michael T. M.D., M.B.A.

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Plastic and Reconstructive Surgery: January 2009 - Volume 123 - Issue 1 - p 421-423
doi: 10.1097/PRS.0b013e318194d2b8
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The following communication is an invited discussion of the article “Topical Lineage-Negative Progenitor-Cell Therapy for Diabetic Wounds,” but it was not received in time to be printed in the November issue.

Sir:

In their November 2008 study, Lin et al. (Plast Reconstr Surg. 2008;122:1341–1351) describe the use of bone marrow stem cells to improve cutaneous wound healing in diabetic animals. The population used from the bone marrow was selected to exclude any differentiated cells, such as red blood cells, neutrophils, or lymphocytes, and would conceivably contain both hematopoietic and mesenchymal stem cells. Since these cells were harvested from nondiabetic but genetically identical donors, clinical translation of this approach does not appear on the horizon. However, the article adds to the growing literature demonstrating that bone marrow cells applied to nonhealing wounds may have an effect in accelerating wound closure.1–4

One of the more interesting aspects of the study was the observation that the accelerated wound healing was associated with an increase in both vascular density and blood vessel area. This observation supports a wealth of published studies suggesting that vascular growth and proliferation are important for normal wound healing. This concept has been validated in a number of clinical studies. One recent validation of this can be found in the data supporting the use of negative pressure treatment for difficult and nonhealing wounds. Along with the clinical improvement, one constant finding in the literature supporting the Vacuum-Assisted Closure device and other negative pressure wound-healing modalities is the stimulation of granulation tissue depth and surface area. Granulation tissue consists of tangled loops of blood vessels, cells, and connective tissue matrix. In the experience of many clinicians, the appearance of granulation tissue is a harbinger of healing in a difficult wound.

In both aesthetic and reconstructive plastic surgery, vascular biology is a critical determinant for the ultimate success or failure of a procedure. Perhaps no field of medicine is more experienced with the consequences and natural history of tissue ischemia. After all, in cardiovascular or vascular surgery, the sequence of events following vascular occlusion unfurls in the depths of the chest or muscle compartments. In plastic surgery, the consequences of inadequate perfusion are plainly visible on the surface of the skin, where we can observe the sequence of events that occur when a tissue is deprived of perfusion. Thus, it is timely that plastic surgery is evolving into a surgical discipline with real clinical and scientific expertise in vascular biology.

Plastic surgeons are confronted with problems caused by blood vessels every day. These problems can vary from situations with too many blood vessels to scenarios with a paucity of blood vessels (Fig. 1). Although it is not the most common issue confronting plastic surgeons, one serious condition characterized by too many blood vessels is cancer. Most tumors start as a small clump of transformed cells, but as these cells grow, their increasing mass can no longer be supported by diffusion alone. Thus, solid tumors must recruit and build a vascular network to support their continued growth. They do so by hijacking the pathways of neovascularization that are operative during normal wound healing. However, these processes are altered by the tumor milieu and result in vessels that are deformed and leaky. The importance of these vessels is confirmed by the efficacy of strategies, pioneered by the late Judah Folkman, that impair vascular growth to slow solid tumor growth. Agents such as Avastin (Genentech) and Erbitux (Imclone) have become billion dollar drugs by targeting and killing blood vessels, an approach referred to as antiangiogenesis.

Fig. 1.
Fig. 1.:
Clinical scenarios in plastic surgery involving “too few” or “too many” blood vessels.

An area characterized by too many blood vessels that is more familiar to plastic surgeons is the field of vascular anomalies. This collection of different diseases is unified by the presence of chaotic and abnormal vascular growth. The etiology of these diseases is obscure, but for the common hemangioma of infancy, new insights from the laboratory are bringing its etiology into focus. For hemangioma, it appears that cells responsible for their explosive growth are very closely related to blood vessel precursors that are the building blocks for the vasculature in the developing embryo. Although the exact sequence of events is still being worked out, it seems likely that a few of these errant precursor cells become activated following birth by either environmental factors5 or somatic mutations.6 Uncontrolled vascular growth subsequently occurs and leads to the compromise of aesthetically delicate structures, such as the lip, nose, or orbit, and ultimately to treatment by the plastic surgeon. However, the day is not too far off when we might be able to effectively control hemangioma growth biologically, thereby eliminating the need for a surgical procedure.

Without question, the most common vascular problems encountered by plastic surgeons are the difficulties presented by inadequate perfusion in the microcirculation. The retroauricular skin slough in a smoker or the challenges presented by mastectomy flap necrosis over a tissue expander are all the consequence of inadequate blood supply. At present, we do not have good tools to determine the perfusion (and ultimately the viability) of a piece of skin or soft tissue, and we do not have robust ways to treat or prevent ischemic necrosis. Thus, we are left with clinical judgment and “watchful waiting” when we are faced with the question of compromise at the microcirculatory level. Over the next few years, new technologies will come onto the market that hold the promise to both diagnose and treat vascular insufficiency at the microcirculatory level. Similarly, many of the wounds we see have an underlying vascular etiology, whether it be diabetes7 or external pressure. Biotechnological approaches, including augmentation of vascular growth factors,8 are currently being examined in the United States and abroad, and it is likely that in the near future we will have new tools to manipulate blood vessels to prevent and treat wounds in vulnerable populations.

One of the final frontiers for plastic surgery (and indeed all of medicine) is the broader clinical application of tissue engineering principles. At present, the entire field of tissue engineering is hampered by difficulties in vascularizing tissue-engineered constructs. The relatively unimpressive results of currently available skin substitutes are in part attributable to poor neovascularization of the tissue-engineered matrix. Until this problem is solved, the possibility of creating larger, more complex organs, such as livers and hearts, must remain a fantasy. Given our human expertise, it is not surprising that some of the most innovative approaches to this issue are coming out of plastic surgery research centers.9 The payoff for our investment in understanding vascular biology will be in facilitating tissue engineering's ability to create and employ replacement parts to more effectively treat human diseases.

DISCLOSURE

The authors have no financial interest to disclose.

Geoffrey C. Gurtner, M.D.

Michael T. Longaker, M.D., M.B.A.

Division of Plastic and Reconstructive Surgery

Department of Surgery

Stanford University School of Medicine

Stanford, Calif.

REFERENCES

1. Javazon EH, Sundeep GB, Andrea T, et al. Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells. Wound Repair Regen. 2007;15:350–359.
2. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:2648–2659.
3. Awad O, Dedkov EI, Jiao C, et al. Differential healing activities of CD34+ and CD14+ endothelial cell progenitors. Arterioscler Thromb Vasc Biol. 2006;26:758–764.
4. Sivan-Loukianova E, Awad OA, Stepanovic V, et al. CD34+ blood cells accelerate vascularization and healing of diabetic mouse skin wounds. J Vasc Res. 2003;40:368–377.
5. Kleinman ME, Greives MR, Churgin SS, et al. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol. 2007;27:2664–2670.
6. Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008;118:2592–2599.
7. Ceradini DJ, Yao D, Grogan RH, et al. Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J Biol Chem. 2008;283:10930–10938.
8. Galiano RD, Tepper OM, Pelo CR, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol. 2004;164:1935–1947.
9. Chang EI, Bonillas R, El-ftesi S, et al. Tissue engineering using autologous microcirculatory beds as bioscaffolds. FASEB J. (in press).

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©2009American Society of Plastic Surgeons