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.
Chapter 4
Nitric Oxide: The Overlooked Molecule in Patient Care
Nathan S. Bryan, Ph.D.
Texas Therapeutics Institute, The University of Texas
Health Science Center at Houston
ABSTRACT
Although often overlooked, nitric oxide (NO) is one of the most important signaling molecules in the body. It is involved in virtually every organ system, and is responsible for modulating an astonishing variety of effects. Thus, it is no surprise to learn that a host of diseases or conditions may be caused or affected by the body’s dysregulation of NO production/signaling. Maintaining NO homeostasis is critical for optimal health and disease prevention, and developing diagnostics and therapeutics to accomplish this will have a profound effect on public health. The aim of this paper is to introduce the reader to the importance of NO, and the age-dependent decline in NO production and its consequences, NO diagnostics and therapeutic strategies for maintaining NO homeostasis will also be considered.
INTRODUCTION
Chronic diseases including heart disease, diabetes, Alzheimer’s, and cancer account for 61% of deaths worldwide. Almost 45 % of these deaths occur prematurely before the age of 70. Fortunately though, most of these deaths are preventable by diet and lifestyle modification. The common factor causal for these chronic diseases may be insufficient nitric oxide (NO). Science has now shown that certain diets and moderate exercise can restore NO and positively affect these chronic diseases. The discovery in the 1980’s of the mammalian biosynthesis of NO and its roles in the immune1,2 cardiovascular3,5 and nervous6 systems established a startling new paradigm in the history of cellular signaling mechanisms. In fact, the discovery of NO was so profound that a Nobel Prize was awarded in 1998 to the 3 US scientists responsible for its discovery.
NO is one of the most important signaling molecules in the body, and is involved in virtually every organ system where it is responsible for modulating an astonishing variety of effects. NO has been shown to be involved in and affect every biological system in humans.