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Chapter 3

Innovations in the Treatment of Chronic Wounds

Robert E. Bowen, M.D., FCCP, FSLMS

Clinical Associate Professor, WVU-East

Medical Director, The Center for Positive Aging, Martinsburg, WV

ABSTRACT

Healing of wounds is a complex process that most often proceeds in an orchestrated fashion resulting in repair of the injured area. When this orchestration proceeds in a disordered fashion then the healing process may result in an over-expression of fibroblasts (resulting in a hypertrophic scar or keloid) or inability to form new tissue (chronic wound). Hypertrophic scars are commonly seen as sequelae of thermal injuries (burns) and chronic wounds are often seen in patients with arterial and venous insufficiency and diabetes.

Previous approaches to these problems have resulted only in marginal improvement in care. Newly developed innovations in wound care are discussed as are future directions for research.

INTRODUCTION

Thermal Injuries

Advances in the treatment of serious burns have been achieved by centralizing treatment in “burn units” where multiple specialties including surgery, infectious disease, and critical care medicine have contributed to improvement in survival. This has been achieved by more effective management of the hypermetabolic state, infection control and nutrition. As a result of increased survival from serious burns, more patients are left with the sequelae of the resultant cutaneous and psychological scars.

The fibroblastic reaction to a thermal injury includes increased levels of inflammatory cytokines including interleukin-4 (IL-4), which increases several weeks after injury and continues for several months. In this stage of disordered healing there is increased collagen formation and decreased collagenolysis resulting in the formation of a hypertrophic scar.

Lasers have been used in the treatment of these hypertrophic scars with varying degrees of success. The SOFT™ method was developed to address the issue of the heterogeneity of the thickness of such scars. With this approach each region of a scar is treated with a fractional ablative laser at a depth sufficient to penetrate the scar.¹ This both reduces the volume of the scar tissue and creates channels that may allow resident and circulating stem cells to gain access to the scar and help normalize the structure of the tissue. Early case studies have established the credibility of this concept and further improvement of efficacy can be achieved by defining the optimal:

•Density of treatment to the area (pitch);

•Quantity of thermal effect (in addition to the ablative effect);

•Timing of the treatment in relation to the burn.²

Other areas of potential research include optimizing nutrition, low-level light therapy (LLT), and the use of growth factors (including platelet rich plasma) and adult mesenchymal stem cells to modify abnormal tissue generation.

Chronic Wounds

In 2007, 5.7 million patients were treated for chronic wounds at a direct cost of $20 billion.³ Failure of wounds to heal can result in aesthetic issues, pain, decreased mobility, amputation, and decreased quality of life.

Wound healing in diabetic patients is especially problematic. This is secondary to:

•Large and small vessel vascular disease resulting in decreased profusion;

•Neuropathy – diabetic patients are more likely to become injured (and re-injured);

•Dysfunction of white blood cells;

•Glycation – resulting in increased susceptibility to free radical injury.

The microbiology of chronic wounds is also problematic. These wounds are often populated by multiple organisms living in a “biofilm”. Bacteria coexisting in a biofilm are organized in a 3-dimensional structure, are able to react to the environment, to communicate, and to act in concert to overcome the limitations of nutrients, low oxygen tension, and host defenses.^4,5

TREATMENT OF CHRONIC WOUNDS

Conventional Treatment

Conventional treatment of chronic wounds includes:

•Treating the underlying condition (revascularization, improving insulin receptor sensitivity);

•Avoiding re-injury (therapeutic footwear);

•Debridement (scalpel, curette, biological);

•Dressings impregnated with iodine or silver;

•Antibiotics

•Hyperbaric oxygen (HBO₂).

The conventional wisdom regarding HBO₂ is that it improves the physiologic state of hypoxic hypoperfused tissue. Recently, it has been proposed that the therapeutic effect is based on oxidative stress that activates intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS are signaling molecules that stimulate the production of cytokines and growth factors which lead to increased angiogenesis.^6,7

The treatment outlined above, often delivered in the setting of a specialized multidisciplinary wound care center, has resulted in improvement in the care of patients with chronic wounds although challenges remain.8

Innovative Treatments

Vacuum Assisted Closure (VAC)

Negative pressure wound therapy has been employed successfully to treat non-healing wounds and is thought to remove exudates, harmful cytokines, and bacteria, thus disrupting the adaptive mechanisms of the biofilm.⁹

Growth Factors

Platelet derived growth factor (PDGF) is believed to stimulate angiogenesis via a paracrine mechanism. A recombinant PDGF has been synthesized and incorporated into a topical product (becaplermin) that has shown a 14% improvement in wound healing of diabetic ulcers at 20 weeks. Enhancement of this effect may be achieved by incorporating growth factor into nanofibrous scaffolds or by a gene delivery system. For gene delivery, human PDGF-B gene is inserted into an adenovirus vector and the virus is applied to the wound. Fibroblasts, endothelial cells, and inflammatory cells that migrate into the wound from surrounding tissue become transfected and then manufacture PDGF.^10,11

Mesenchymal Stem Cells

Adult mesenchymal stem cells can differentiate into fibroblasts and keratinocytes. They also modulate immune response and stimulate angiogenesis by paracrine signaling (release of growth factors such as PDGF, epidermal growth factor, transforming growth factor-β, vascular endothelial growth factor, keratinocyte growth factor, and fibroblast growth factor-2).¹² This approach can potentially overcome barriers preventing healing in a chronic wound. These barriers include both a loss of resident stem cells and growth factors and prevention of the influx of remote stem cells which are limited by fibrin cuffs surrounding the wound and poor local perfusion.

Adult mesenchymal stem cells can be harvested from autologous adipose tissue (ADSC) and are used in several applications in orthopedic, cosmetic, and regenerative medicine. This approach has been used in the treatment of traumatic lower extremity ulcers improving healing in 10 weeks from 87.4% +/- 4.4% to 97.8% +/- 1.5% over hyalauronic acid alone.¹³ Studies are now ongoing for the treatment of critical limb ischemia with encouraging preliminary results.

FUTURE PROSPECTS

Improvements in tissue harvesting and laboratory processing are ongoing and currently able to produce approximately 3-4 times as many platelets (and growth factors) and 20 times the number of stromal vascular fraction (SVF) cells (including ADSCs) as were reported in Cervelli’s study above.¹³ Studies to evaluate the hypothesis that increased growth factors and ADSCs would result in improved healing are planned.

REFERENCES

1.Bowen R. An objective approach to ablative fractional treatment of scars (SOFT). Lasers Surg Med. 2009; supplement 21:91.

2.Bowen R. A novel approach to ablative fractional treatment of mature thermal burn scars. J Drugs Dermatol. 2010;9:389-92.

3.Branski LK,Gauglitz GG, Hendon DN, Jeschke MG. A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2009;35:171-180.

4.Parsek MR, Greenberg EP. Sociomicrobiology: the connections between quorum sensing and biofilms. Trends Microbiol. 2005;13:27-33.

5.deBeer D, Stoodley P, Roe F, Lewandowski Z. Effects of biofilm structures on oxygen distribution and mass transport. Biotechnol Bioeng. 2004;43:1131-1138.

6.Maulik N. Redox signaling of angiogenesis. Antioxid Redox Signal. 2002;4:805-815.

7.Ushio-Fukai M, Alexander R. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem. 2004;264:85-97.

8.Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2004;2:CD004123.

9.Armstrong DG, Lavery LA; Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet. 2005;366:1704-1710.

10.Tyrone JW, Mogford JE, Chandler LA, et al. Collagen-embedded platelet-derived growth factor DNA plasmid promotes wound healing in a dermal ulcer model. J Surg Res. 2000;93:230-236.

11.Wei G, Jin Q, Giannobile WV, Ma PX. Nano-fibrous scaffold for controlled delivery of recombinant human PDGF-BB. J Control Release. 2006;112:103-110.

12.Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells. 2007;25:2896-2902.

13.Cervelli V, Gentile P, De Angelis B, et al. Application of enhanced stromal vascular fraction and fat grafting mixed with PRP in post-traumatic lower extremity ulcers. Stem Cell Res. 2011;6:103-111.

ABOUT THE AUTHOR

Dr. Robert Bowen is an Internal Medicine and Pulmonary specialist, Board Certified in Cosmetic Laser Surgery by the American Board of Laser Surgery. He is a Fellow of the American Society of Laser Medicine and Surgery and has published research articles on laser medicine. Dr. Bowen is a Diplomate of the American Board of Anti-Aging Medicine and a graduate of the Aesthetic Medicine Fellowship.