Collagen Biografts for Tunable Drug Delivery

Functional tissue regeneration requires careful merger of optimal biograft material with drug delivery technology. Type I collagen, the predominant and major structural component of the extracellular matrix represents an ideal natural polymer candidate for such integrated tissue engineering and local molecular delivery strategies. Despite several advantages over other materials including biological signaling capacities, proteolytic biodegradability, low immunogenicity, and collagen-based biomaterials have found a very limited commercialization and clinical application. There is a scope to overcome the disadvantages that obstruct the potential of collagen as a multifunctional delivery platform for soft tissue reconstruction and be able to precisely and predictably control its microstructure, mechanical properties, and proteolytic degradability.

The tunability of collagen at a fibrillar and molecular level, along with its proteolytic degradability, can offer a great potential to create multifunctional soft tissue grafts capable of spatiotemporal molecular delivery. However, conventional collagen implants with minimal or no crosslinking provide little control over tunability without having exogenously cross-linked and/or chemically treated. Without these modifications, conventional collagen formulations degrade rapidly, without allowing for the host tissue to deposit its own ECM (Liang HC, Chang Y, Hsu CK, Lee MH, Sung HW, Biomaterials 25:3541–3552, 2004). Therefore, there is a need to regulate collagen microstructure as well as the degradation (Perez-Puyana V, Romero A, Guerrero A, J Biomed Mater Res Part A 104:1462–1468, 2016) in a way that preserves collagen properties and provides desired molecular release kinetics. When designing a drug delivery system, it is important to quantify molecular release kinetics, analyze the empirical model of molecular release, and elucidate the mechanisms involved in the release process (Siegel RA, Rathbone MJ, Fundamentals and applications of controlled release drug delivery. Springer US, Boston, 2012).

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.

Poor vascularization is a hallmark of chronic wounds such as diabetic foot ulcers. Vascularization can be improved through the use of growth factors (GFs) such as VEGF, delivered using collagen-based materials. However, the GFs are delicate to handle, costly to use, and must be administered in the correct dosages for the safety of the patient. One of the problems currently is the poor ability of collagen constructs to become vascularized within a reasonable time. This calls for the design of collagen-based drug delivery systems that allows for controlled, precise, sustained, and localized release of GFs. Affinity-based retention strategy binding VEGF to heparin and heparin to collagen has the potential to offer controlled release of VEGF through collagen while retaining the collagen fibril’s physiologically relevant self-assembly properties. Heparin and VEGF quantity should be carefully chosen to not affect VEGF or collagen biological activity and physical properties. The therapeutic vascularization potential of collagen-based systems can be tested on the Chorioallantoic membrane (CAM) model because of its simplicity, inexpensiveness, and suitability for large-scale screening.