ear Readers: Wound exudate is a perennial challenge to professionals and caregivers. It may also provide clues to wound vitality and may play a role in healing or wound deterioration. Clinically it has been shown to contain natural growth factors that trigger cell proliferation1 and enzymes that autolytically debride necrotic tissue and fibrin2. This Evidence Corner focuses on a versatile family of exudate components, called matrix metalloproteinases (MMPs). They are natural proteolytic enzymes deemed essential to tissue regeneration and remodeling3. At least one topically applied MMP inhibitor was reported to delay healing4. Conversely, high serum ratios of one matrix metalloproteinase, MMP-9 to TIMP-1, a tissue inhibitor of matrix metalloproteinase, are reportedly associated with pressure ulcer deterioration5, and thus may either signal or cause tissue damage. The two recent articles described below explore tissue healing responses when MMPs are inhibited giving us a view of emerging evidence for diverse roles of MMPs and their inhibitors in wound healing.
MMP Inhibitor Improves Gingival Healing after Access Flap Surgery
Reference: Gapski R, Barr JL, Sarment DP, et al. J Periodontol 2004;75(3):441–52.
Rationale: MMP inhibitors used as adjunctive therapy to periodontal scaling and root planing have been shown to promote new attachment of gum to bone in patients with periodontal disease. Would they work similarly in conjunction with periodontal access flap surgery in patients with severe chronic periodontal disease?
Objective: Explore the effect of systemic MMP inhibitor low-dose doxycycline (LDD) versus placebo combined with periodontal access flap surgery (AFS) on modulation of periodontal wound repair in patients with severe chronic periodontitis.
Methods: A randomized, placebo-controlled, double-masked trial evaluated the clinical, biochemical and microbial measures of periodontal disease response to AFS followed by six months of oral therapy with LDD (20mg capsules of doxycycline hyclate b.i.d.) or placebo capsules (placebo capsules b.i.d.) in 12 patients with severe chronic periodontitis in each group. Clinical gum attachment levels, probing depth, bleeding on probing, a radioimmunoassay for gingival crevicular fluid ICTP, a marker for bone resorption, and microbial DNA analysis of presence and levels of 40 bacterial species were measured at baseline and 3, 6, 9, and 12 months after surgery.
Results: The 10 patients completing the protocol with AFS + LDD had significantly reduced bleeding on probing while taking LDD as compared to the 11 patients receiving AFS + Placebo. No other MMP inhibitor-associated differences were statistically significant except that patients with the greatest clinical deterioration on enrollment (> 6 mm probe depths) experienced more probe depth reduction in response to
AFS + LDD than in response to AFS + Placebo. While ICTP, the bone resorption marker appeared slightly depressed in AFS + LDD patients compared to AFS + Placebo patients, substantial ICTP rebounds occurred when LDD was withdrawn. No statistically significant differences in bacterial species or levels were found between LDD and placebo groups on any pathogen tested.
Conclusions: LDD in combination with access flap surgery may improve the healing response to gingival surgery as measured by reduced probe depth in patients with severe chronic periodontal disease and by reduced bleeding on probing. These effects were not mediated by antimicrobial activity of LDD.
MMP Inhibitor Reduces Scarring
Reference: Wong TL, Mead AL, Khaw PT. Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery. Invest Ophthalmol Vis Sci 2003;44:1097–103.
Rationale: Long-term success after glaucoma filtration surgery requires post-surgical healing and survival of the surgically created bleb, with minimal scarring to facilitate aqueous flow from the anterior chamber into the subconjunctival space reducing anterior chamber depth. Use of cell proliferation inhibitors like 5-fluorouracil and mitomycin-C to reduce scarring have been associated with inappropriate bleb healing with potentially blinding complications. Synthetic MMP inhibitors reduce tissue damage in pseudomonas-induced corneal ulceration and other ocular proliferative disease models and inhibit many fibroblast-mediated healing and scarring functions, even at low concentrations deemed non-cytotoxic. Therefore it was reasoned that they may ameliorate scarring after glaucoma filtration surgery.
Objective: A prospective, randomized, masked-observer, pre-clinical study explored the effect of subconjunctival ilomastat, an MMP-inhibitor, on an aggressive subconjunctival scarring model in rabbits, to assess its potential safety and tolerance in vivo.
Methods: Immediately after experiencing filtration surgery of the left eye simulating glaucoma surgery, New Zealand rabbits were given 0.1 ml subconjuctival injections of either 100mM ilomastat dissolved in DMSO or phosphate-buffered saline (PBS) with the same volume of vehicle. Injections were repeated daily through the ninth post-surgical day, the most dynamic period of wound repair and remodeling for this wound model. Operated eyes of 11 rabbits each receiving ilomastat or vehicle were compared with unoperated eyes by slit examination at Days 7, 10, 14, 17, 21, 24, and 28 after surgery. Clinical evaluations included intraocular pressure and anterior chamber depth, as well as bleb appearance, size, height and surrounding vascularity. Operated and nonoperated contralateral eyes were also rated histologically for conjunctival appearance and epithelial toxicity in the same 11 rabbits per treatment group 28 days after surgery plus six rabbits per group at 7, 14, and 21 days after surgery.
Results: Bleb failure was experienced by all 11 eyes (100%) treated with vehicle as compared to three eyes (27%) treated with ilomastat. Ilomastat-treated eyes also experienced longer bleb survival (p<0.001). From post-surgical Day 10 forward, anterior chamber depth reduction remained greater (p=0.002) and bleb area remained larger (p< 0.001) for ilomastat-treated eyes than for vehicle-treated eyes. Intraocular pressure remained normal significantly longer in the ilomastat-treated eyes. Histologically, from Day 14 onward the affected areas of ilomastat-treated eyes were less cellular, with less scar tissue, less new extracellular matrix development and reduced myofibroblast populations as compared to corresponding areas of vehicle-treated eyes.
Conclusions: While a better delivery system would be needed to make ilomastat treatment clinically practical, treatment of simulated rabbit eye glaucoma filtration surgery sites with this MMP inhibitor reduced scarring, intraocular pressure and anterior chamber depth as compared to vehicle control and was well-tolerated in this pre-clinical model.
Clinical Perspective
MMPs appear to play many roles in wound repair, potentially as complex as those of growth factors or molecules in the inflammatory cascade. These pilot findings suggest that limiting excessive MMPs may moderate healing and scarring in two very different wound situations: periodontal deterioration and ocular scarring. Further research is needed to define these tissue responses and the dosage and delivery systems needed to produce them consistently. Given the essential involvement of MMPs in repair, their inhibition may apply only in situations where MMPs are known to be excessive, with dosage carefully designed to normalize certain MMP levels, not destroy them. Further research is needed to explore the amount and type of tissue destruction associated with excess MMPs, and the conditions in which it occurs. Further research is also needed to define the sensitivity, specificity and positive and negative predictive value of any single MMP (or MMP/TIMP ratio) as a tool for diagnosis or prediction of chronic or acute wound risk of deterioration or non-healing. While this research progresses, clinicians can continue to heal chronic wounds consistently by accurately diagnosing and addressing each patient's primary cause of tissue deterioration, such as pressure, trauma, impaired circulation, nutritional deficiency etc., removing necrotic tissue and providing an appropriately moist environment for healing to progress. These principles remain to be widely used in current practice6. They may seem pedestrian compared to the wonders in store for future wound care professionals to use, yet, consistently applied, they provide sterling chronic wound care
outcomes7–9. |
References
1. Madden M, Nolan E, Finkelstein JL, et al. Comparison of an occlusive and a semi-occlusive dressing and the effect of the wound exudate upon keratinocyte proliferation. J Trauma 1989;29(7):924–30.
2. Mulder G, Jones R, Cederholm-Williams S, et al. Fibrin cuff lysis in chronic venous ulcers treated with a hydrocolloid dressing. Int J Dermatol 1993;32(4):304–6.
3. Agren MS, Mirastschijsku U, Karlsmark T, Saarialho-Kere UK. Topical synthetic inhibitor of matrix metalloproteinases delays epidermal regeneration of human wounds. Exp Dermatol 2001;10(5):337–48.
4. Dasu MR, Spies M, Barrow RE, Herndon DN. Matrix metalloproteinases and their tissue inhibitors in severely burned children. Wound Repair Regen 2003;11(3):177–80.
5. Ladwig GP, Robson MC, Liu R, et al. Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen 2002;10(1):26–37.
6. van Rijswijk L. Moist dressings: Bridging the gap between research and practice. Adv Skin Wound Care 2004;17(5):254–5.
7. Kerstein MD, Gemmen E, vanRijswijk L, et al. Cost and cost effectiveness of venous and pressure ulcer protocols of care. Disease Management and Health Outcomes 2001;9(11):651–6.
8. Bolton L, McNees P, van Rijswijk L, et al. Wound healing outcomes using standardized care J WOCN 2004;31(3):65–71.
9. Ohura T, Sanada H, Mino Y. Clinical activity-based cost effectiveness of traditional versus modern wound management in clients with pressure ulcers. Wounds 2004;16(5):157–63.
|
