Chronic wounds fail to heal due to an imbalance between extracellular matrix (ECM) deposition and degradation, impaired cell recruitment, and lack of essential neovascularization (Demidova-Rice TN, Durham JT, Herman IM, Adv Wound Care 1:17–22, 2012). Normal healing of acute wounds represents a multistep process beginning with hemostasis and inflammation during the acute stages of healing, followed by phases of robust cellular proliferation, ECM deposition, matrix remodeling, and ultimately scar formation (Gurtner GC, Werner S, Barrandon Y, Longaker MT, Wound Repair Regen 453:314–321, Singer AJ, Clark RAF, N Engl J Med 341:738–746, 1999). However, in chronic wounds, the dynamic spatiotemporal interaction between endothelial cells, angiogenesis factors, and surrounding ECM proteins is impaired (Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M, Wound Repair Regen 22:569–578, 2014), causing the wound to be in a permanent inflammatory state (Wild T, Rahbarnia A, Kellner M, Sobotka L, Eberlein T, Nutrition 26:862–866, 2010) and display increased proteolytic activity contributed by excessive production of matrix metalloproteinases (MMPs) (Rayment EA, Upton Z, Shooter GK, Br J Dermatol 158:951–961, 2008, Yager DR, Nwomeh BC, Wound Repair Regen 7:433–441, 1999). MMPs in turn break down components of the ECM and inhibit growth factors that are essential for tissue synthesis and regeneration (Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY, Diab Med 25:419–426, 2008). Therefore, promoting recreation of the natural type I collagen fibril scaffold while fostering rapid and functional neovascularization and tissue regeneration at the wound site is pivotal to the restoration of healing of chronic wounds. While many advanced wound dressings and skin substitutes have been introduced in the wound care market during the last decades (Yazdanpanah L, Nasiri M, Adarvishi S, World J Diabet 6:37–53, 2015, Vyas KS, Vasconez HC, Healthcare 2:356–400, 2014, Hrabchak C, Flynn L, Woodhouse KA, Expert Rev Med Devices 3:373–385, 2006, Bello YM, Falabella AF, Eaglstein WH, Am J Clin Dermatol 2:305–313, 2001, Kamel RA, Ong JF, Eriksson E, Junker JPE, Caterson EJ, J Am Coll Surg 217:533–555, 2013, Biedermann T, Boettcher-Haberzeth S, Reichmann E, Eur J Pediatr Surg, 23:375–382, 2013, Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, Landsman AS, Lavery LA, Moore JC, Schuberth JM, Wukich DK, Andersen C, Vanore JV, J Foot Ankle Surg 45:S1–S66, 2006, Moura LIF, Dias AMA, Carvalho E, de Sousa HC, Acta Biomater 9:7093–7114, 2013), no general satisfactory clinical solution has been achieved to date (Moura LIF, Dias AMA, Carvalho E, de Sousa HC, Acta Biomater 9:7093–7114, 2013, Briquez PS, Hubbell JA, Martino MM, Adv Wound Care 4:479–489, 2015) because of undesirable outcomes of these products, including inflammation-mediated healing leading to scar formation rather than tissue regeneration, slow neovascularization, and cellularization, and a need for multiple applications that adds to patient discomfort, pain, and healthcare cost. Tunable drug delivery devices made from collagen can overcome these problems through the improved design of multifunctional biografts.
