A Meta-analysis of Tissue Engineered Skin Improved Wound Closure in Diabetic Foot Ulcers_Chinese Journal of Evidence-Based Medicine

Authors：

TENG YongJun ^1,2 , WANG Jinwen ¹ , WANG Yanjiong ³ , YANG Kehu ² , YAN Xiang ¹ , TIAN Jinhui ² , MA Bin ² , WANG Jianmin ¹ ,  LI Youping ^2,4

1. The First Hospital of Lanzhou University, Lanzhou 730000, China2. Evidence Based Medicine Center of Lanzhou University, Lanzhou 730000, China3. Military Hospital of Gansu Provincial Armed Police, Lanzhou 730000, China4. Chinese Cochrane Center, Chengdu, 610041 Sichuan, China;

Corresponding author：

LI Youping, Email: yzmylab@hotmail.com

Keywords：

Diabetic foot ulcer; Tissue-engineered skin; Living-skin equivalent; Meta-analysis

DOI：

10.7507/1672-2531.20090106

Video：

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Objective 　To systematically analyze the randomized controlled trials that compare tissue-engineered skin (TES) with conventional treatment for chronic diabetic foot ulcer (DFU) in terms of effectiveness and utilization.
Methods 　We searched the electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, CBMWeb, CNKI, and VIP) in order to compare the efficiency and safety between TES and conventional treatment (CT) in the patients with DFU. In addition, we manually searched reference lists from original studies and review articles.
Results 　Seven trials were included, which were all randomized controlled trials and had a duration of DFU over 6 weeks. There were 880 participants that met inclusion criteria in all studies, and all patients underwent pre-treatment procedures and were treated by TES (human skin equivalents, living skin equivalents or bioengineered skin, such as Graftskin, Dermagraft and Graftjacket) for 12 weeks. All trials had two groups: the treatment group and the control group, but the two trials divided the treatment groups into 3 different dosages and 2 different ulcer allocation subgroups, respectively. Meta-analysis results showed significant differences in the rate of complete wound closure (P lt;0.0001, 95%CI 0.08 to 0.20) and in the occurrence of complications and severe adverse events (P=0.008, 95%CI – 0.06 to – 0.01) between TES treated patients and conventionally treated patients.
Conclusion 　The review shows TES improves completed closure of DFU compared with CT, and it is more effective in reducing side effects.

Citation： TENG YongJun,WANG Jinwen,WANG Yanjiong,YANG Kehu,YAN Xiang,TIAN Jinhui,MA Bin,WANG Jianmin,LI Youping. A Meta-analysis of Tissue Engineered Skin Improved Wound Closure in Diabetic Foot Ulcers. Chinese Journal of Evidence-Based Medicine, 2009, 09(5): 584-592. doi: 10.7507/1672-2531.20090106 Copy

1.	neuropathic ulcer of the foot. A pilot, randomized, double-blind, placebo-controlled study. Diabetes Care, 1995, 18(1): 64-69.
2.	noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial. Diabetes Care, 2003, 26(10): 2853-2859.
3.	Thanh L, Dinh AV. Treatment of diabetic ulcers. Dermatologic Therapy, 2006, 19: 348-355.
4.	Edward JB, Jessie HA, Karin MN, et al. Prediction of Diabetic Foot Ulcer Occurrence Using Commonly Available Clinical Information. Diabetes Care, 2006, 29: 1202-1207.
5.	Sanders LJ. Diabetes mellitus. Prevention of amputation. J Am Podiatr Med Assoc, 1994, 84(7): 322-328.
6.	Managing foot ulcers in patients with diabetes. Drug and Therapeutics Bulletin, 2002, 40(2): 11-14.
7.	Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders: a clinical practice guideline (2006 revision). Journal of Foot and Ankle Surgery, 2006, 45(5): SUPPL. (S1-S66).
8.	Consensus development conference of diabetic foot wound care. Diabetes Care, 1999, 22: 1354-1360.
9.	Eaglstein WH, Iriondo M, Laszlo K. A composite skin substitute (graftskin) for surgical wounds. A clinical experience. Dermatol Surg, 1995, 21: 839-943.
10.	Advanced Tissue Sciences and Smith & Nephew present Dermagraft data. Ostomy Wound Manage, 1997, 43(4): 77-78, 80.
11.	Martin BR, Sangalang M, Wu S, et al. Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience. International Wound Journal, 2003, 2(2): 161-165.
12.	Gentzkow GD, Scott DI, Kenneth SH. Use of Dermagraft, a Cultured Human Dermis, to Treat Diabetic Foot Ulcers. Diabetes Care, 1996, 19: 350-354.
13.	Richard JL, Parer RC, Daures JP, et al. Effect of topical basic fibroblast growth factor on the healing of chronic diabetic.
14.	Veves AF, Armstrong V, Sabolinski DG, et al. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care, 2001, 24(2): 290-295.
15.	Elisabeth HH, David KC, Georgette NS, et al. Obtaining Quality Real-world Treatment Data for Economic Models: Methodology and Results of a Wound Care Medical Abstraction Study. www. valuemedics.com/ispor-dfu.pdf, 2003.
16.	Lazareth I. Local care and medical treatment for ischemic diabetic ulcers. Journal des Maladies Vasculaires, 2002, 27(3): 157-163.
17.	American Diabetes Association: Foot care in patients with diabetes mellitus (Position Statement). Diabetes Care, 1996, 19 (Suppl. 1): S23-S24.
18.	Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials, 1996, 17(1): 1-12.
19.	Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Jama, 1995, 273(5): 408-412.
20.	Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med, 2002, 21: 1539-1558.
21.	Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. In: Cochrane Library. 2006.
22.	Petitti DB. Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis. New York: Oxford University Press, 2000(94-118).
23.	Caravaggi C, De Giglio R, Pritelli C, et al. HYAFF 11-based autologous dermal and epidermal grafts in the treatment of.
24.	Jason R, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg, 2002, 41(5): 291-299.
25.	Richard AP, Howard E, Jeffrey LJ, et al. A Human Dermal Replacement for the Treatment of Diabetic Foot Ulcers. Wounds, 1997, 1(9): 175-183.
26.	Marston WA, Hanft J, Norwood P, et al. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care, 2003, 26(6): 1701-1705.
27.	Sams HH, Chen J, King LE. Graftskin treatment of difficult to heal diabetic foot ulcers: one center’s experience. Dermatol Surg, 2002, 28(8): 698-703.
28.	Eaglstein WH, Alvarez OM, Auletta M. Acute excisional wounds treated with a tissue-engineered skin (Apligraf). Dermatol Surg, 1999, 25: 195-201.
29.	Greenhalgh DG. Wound healing and diabetes mellitus. Clinics in Plastic Surgery, 2003, 30(1): 37-45.
30.	Brem H, Sheehan P, Boulton AJ. Protocol for treatment of diabetic foot ulcers. American Journal of Surgery, 2004, 187(5): SUPPL. 1 (1S-10S).
31.	Metcalfe AD, Ferguson MW. Harnessing wound healing and regeneration for tissue engineering. Biochemical Society Transactions, 2005, 33(2): 413-417.
32.	Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen, 2006, 14(6): 680-692.
33.	American Diabetes Association: Consensus Development Conference on Diabetic Foot Wound Care (Consensus Development Conference Report). Diabetes Care, 1999, 22: 1354-1360.
34.	Gregory SS, Gary SR, Vincent F, et al. Wound bed preparation: a systematic approach to wound management. Wound Repair and Regeneration, 2003, 11: 1-28.
35.	William JJ, Patricia P, Keith GH. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev, 2004, 20(S1): S78-S89.
36.	Rathur HM, Boulton AJM. The diabetic foot. Clinics in Dermatology, 2007, 25(1): 109-120.
37.	Katz I, Harlan A, Miranda PB, et al. A randomized trial of two irremovable off-loading devies in mangement of plantar neuropathic diabetic foot ulcers. Diabetes Care, 2005, 28: 555-559.
38.	Hartsell H, Brand R, Frantz R, et al. The effects of total contact casting materials on plantar pressures. Foot Ankle International, 2004, 25: 73-78.
39.	Birke JA, Pavich MA, Patout CA, et al. Comparison of forefoot ulcer healing using alternative off-loading methods in patients with diabetes mellitus. Adv Skin Wound Care, 2002, 15: 210-215.
40.	Schaper NC, Prompers LM, Huijberts MSP. Treatment of diabetic foot ulcers. Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry, 2007, 7(1): 95-104.
41.	Newton DJ, Khan F, Belch JJF, et al. Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy. Journal of Foot and Ankle Surgery, 2002, 41(4): 233-237.
42.	Lorenzi G, Crippa M, Rossi G, et al. Open and endovascular revascularization combined with regenerative dermal skin graft in the treatment of ischemic ulcers. Italian Journal of Vascular and Endovascular Surgery, 2005, 12(2): 61-64.
43.	Allenet B, Pare?e F, Lebrun T, et al. Cost-effectiveness modeling of Dermagraft? for the treatment of diabetic foot ulcers the French context. Diabetes and Metabolism, 2000, 26(2): 125-132.
44.	Dalla PL, Cogo A, Deanesi W, et al. Using hyaluronic acid derivatives and cultured autologous fibroblasts and keratinocytes in a lower limb wound in a patient with diabetes: a case report. Ostomy Wound Manage, 2002, 48(9): 46-49.
45.	Saap LJ, Donohue K, Falanga V. Clinical classification of bioengineered skin use and its correlation with healing of diabetic and venous ulcers. Dermatologic Surgery, 2004, 30(8): 1095-1100.
46.	Loveland LJ, McClure LP, Page JC, et al. Living skin equivalents. Lower Extremity, 1996, 3(4): 231-236.
47.	Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs, 1997, 21(11): 1203-1210.
48.	Ercem A. Current and investigative uses of Graftskin (Apligraf﹫) in wound care introduction. Wounds, 2000, 12(5): 4A-11A.
49.	Sabolinski ML, Alvarez O, Auletta M, et al. Cultured skin as a ’smart material’ for healing wounds: experience in venous ulcers. Biomaterials, 1996, 17(3): 311-320.
50.	Hu S, Kirsner RS, Falanga V, et al. Evaluation of Apligraf persistence and basement membrane restoration in donor site wounds: a pilot study. Wound Repair Regen, 2006, 14(4): 427-433.
51.	Curran MP, Plosker GL. Bilayered bioengineered skin substitute (Apligraf?): A review of its use in the treatment of venous leg ulcers and diabetic foot ulcers. BioDrugs, 2002, 16(6): 439-455.
52.	Redekop WK, McDonnell J, Verboom P, et al. The Cost Effectiveness of Apligraf? Treatment of Diabetic Foot Ulcers. Pharmaco Economics, 2003, 21(16): 1171-1183.

1. neuropathic ulcer of the foot. A pilot, randomized, double-blind, placebo-controlled study. Diabetes Care, 1995, 18(1): 64-69.
2. noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial. Diabetes Care, 2003, 26(10): 2853-2859.
3. Thanh L, Dinh AV. Treatment of diabetic ulcers. Dermatologic Therapy, 2006, 19: 348-355.
4. Edward JB, Jessie HA, Karin MN, et al. Prediction of Diabetic Foot Ulcer Occurrence Using Commonly Available Clinical Information. Diabetes Care, 2006, 29: 1202-1207.
5. Sanders LJ. Diabetes mellitus. Prevention of amputation. J Am Podiatr Med Assoc, 1994, 84(7): 322-328.
6. Managing foot ulcers in patients with diabetes. Drug and Therapeutics Bulletin, 2002, 40(2): 11-14.
7. Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders: a clinical practice guideline (2006 revision). Journal of Foot and Ankle Surgery, 2006, 45(5): SUPPL. (S1-S66).
8. Consensus development conference of diabetic foot wound care. Diabetes Care, 1999, 22: 1354-1360.
9. Eaglstein WH, Iriondo M, Laszlo K. A composite skin substitute (graftskin) for surgical wounds. A clinical experience. Dermatol Surg, 1995, 21: 839-943.
10. Advanced Tissue Sciences and Smith & Nephew present Dermagraft data. Ostomy Wound Manage, 1997, 43(4): 77-78, 80.
11. Martin BR, Sangalang M, Wu S, et al. Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience. International Wound Journal, 2003, 2(2): 161-165.
12. Gentzkow GD, Scott DI, Kenneth SH. Use of Dermagraft, a Cultured Human Dermis, to Treat Diabetic Foot Ulcers. Diabetes Care, 1996, 19: 350-354.
13. Richard JL, Parer RC, Daures JP, et al. Effect of topical basic fibroblast growth factor on the healing of chronic diabetic.
14. Veves AF, Armstrong V, Sabolinski DG, et al. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care, 2001, 24(2): 290-295.
15. Elisabeth HH, David KC, Georgette NS, et al. Obtaining Quality Real-world Treatment Data for Economic Models: Methodology and Results of a Wound Care Medical Abstraction Study. www. valuemedics.com/ispor-dfu.pdf, 2003.
16. Lazareth I. Local care and medical treatment for ischemic diabetic ulcers. Journal des Maladies Vasculaires, 2002, 27(3): 157-163.
17. American Diabetes Association: Foot care in patients with diabetes mellitus (Position Statement). Diabetes Care, 1996, 19 (Suppl. 1): S23-S24.
18. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials, 1996, 17(1): 1-12.
19. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Jama, 1995, 273(5): 408-412.
20. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med, 2002, 21: 1539-1558.
21. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. In: Cochrane Library. 2006.
22. Petitti DB. Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis. New York: Oxford University Press, 2000(94-118).
23. Caravaggi C, De Giglio R, Pritelli C, et al. HYAFF 11-based autologous dermal and epidermal grafts in the treatment of.
24. Jason R, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg, 2002, 41(5): 291-299.
25. Richard AP, Howard E, Jeffrey LJ, et al. A Human Dermal Replacement for the Treatment of Diabetic Foot Ulcers. Wounds, 1997, 1(9): 175-183.
26. Marston WA, Hanft J, Norwood P, et al. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care, 2003, 26(6): 1701-1705.
27. Sams HH, Chen J, King LE. Graftskin treatment of difficult to heal diabetic foot ulcers: one center’s experience. Dermatol Surg, 2002, 28(8): 698-703.
28. Eaglstein WH, Alvarez OM, Auletta M. Acute excisional wounds treated with a tissue-engineered skin (Apligraf). Dermatol Surg, 1999, 25: 195-201.
29. Greenhalgh DG. Wound healing and diabetes mellitus. Clinics in Plastic Surgery, 2003, 30(1): 37-45.
30. Brem H, Sheehan P, Boulton AJ. Protocol for treatment of diabetic foot ulcers. American Journal of Surgery, 2004, 187(5): SUPPL. 1 (1S-10S).
31. Metcalfe AD, Ferguson MW. Harnessing wound healing and regeneration for tissue engineering. Biochemical Society Transactions, 2005, 33(2): 413-417.
32. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen, 2006, 14(6): 680-692.
33. American Diabetes Association: Consensus Development Conference on Diabetic Foot Wound Care (Consensus Development Conference Report). Diabetes Care, 1999, 22: 1354-1360.
34. Gregory SS, Gary SR, Vincent F, et al. Wound bed preparation: a systematic approach to wound management. Wound Repair and Regeneration, 2003, 11: 1-28.
35. William JJ, Patricia P, Keith GH. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev, 2004, 20(S1): S78-S89.
36. Rathur HM, Boulton AJM. The diabetic foot. Clinics in Dermatology, 2007, 25(1): 109-120.
37. Katz I, Harlan A, Miranda PB, et al. A randomized trial of two irremovable off-loading devies in mangement of plantar neuropathic diabetic foot ulcers. Diabetes Care, 2005, 28: 555-559.
38. Hartsell H, Brand R, Frantz R, et al. The effects of total contact casting materials on plantar pressures. Foot Ankle International, 2004, 25: 73-78.
39. Birke JA, Pavich MA, Patout CA, et al. Comparison of forefoot ulcer healing using alternative off-loading methods in patients with diabetes mellitus. Adv Skin Wound Care, 2002, 15: 210-215.
40. Schaper NC, Prompers LM, Huijberts MSP. Treatment of diabetic foot ulcers. Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry, 2007, 7(1): 95-104.
41. Newton DJ, Khan F, Belch JJF, et al. Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy. Journal of Foot and Ankle Surgery, 2002, 41(4): 233-237.
42. Lorenzi G, Crippa M, Rossi G, et al. Open and endovascular revascularization combined with regenerative dermal skin graft in the treatment of ischemic ulcers. Italian Journal of Vascular and Endovascular Surgery, 2005, 12(2): 61-64.
43. Allenet B, Pare?e F, Lebrun T, et al. Cost-effectiveness modeling of Dermagraft? for the treatment of diabetic foot ulcers the French context. Diabetes and Metabolism, 2000, 26(2): 125-132.
44. Dalla PL, Cogo A, Deanesi W, et al. Using hyaluronic acid derivatives and cultured autologous fibroblasts and keratinocytes in a lower limb wound in a patient with diabetes: a case report. Ostomy Wound Manage, 2002, 48(9): 46-49.
45. Saap LJ, Donohue K, Falanga V. Clinical classification of bioengineered skin use and its correlation with healing of diabetic and venous ulcers. Dermatologic Surgery, 2004, 30(8): 1095-1100.
46. Loveland LJ, McClure LP, Page JC, et al. Living skin equivalents. Lower Extremity, 1996, 3(4): 231-236.
47. Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs, 1997, 21(11): 1203-1210.
48. Ercem A. Current and investigative uses of Graftskin (Apligraf﹫) in wound care introduction. Wounds, 2000, 12(5): 4A-11A.
49. Sabolinski ML, Alvarez O, Auletta M, et al. Cultured skin as a ’smart material’ for healing wounds: experience in venous ulcers. Biomaterials, 1996, 17(3): 311-320.
50. Hu S, Kirsner RS, Falanga V, et al. Evaluation of Apligraf persistence and basement membrane restoration in donor site wounds: a pilot study. Wound Repair Regen, 2006, 14(4): 427-433.
51. Curran MP, Plosker GL. Bilayered bioengineered skin substitute (Apligraf?): A review of its use in the treatment of venous leg ulcers and diabetic foot ulcers. BioDrugs, 2002, 16(6): 439-455.
52. Redekop WK, McDonnell J, Verboom P, et al. The Cost Effectiveness of Apligraf? Treatment of Diabetic Foot Ulcers. Pharmaco Economics, 2003, 21(16): 1171-1183.

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A Meta-analysis of Tissue Engineered Skin Improved Wound Closure in Diabetic Foot Ulcers

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