Emerging Implications for Extracellular Matrix-Based Technologies in Vascularized Composite Allotransplantation

Abstract

Despite recent progress in vascularized composite allotransplantation (VCA), limitations including complex, high dose immunosuppression regimens, lifelong risk of toxicity from immunosuppressants, acute and most critically chronic graft rejection, and suboptimal nerve regeneration remain particularly challenging obstacles restricting clinical progress. When properly configured, customized, and implemented, biomaterials derived from the extracellular matrix (ECM) retain bioactive molecules and immunomodulatory properties that can promote stem cell migration, proliferation and differentiation, and constructive functional tissue remodeling. The present paper reviews the emerging implications of ECM-based technologies in VCA, including local immunomodulation, tissue repair, nerve regeneration, minimally invasive graft targeted drug delivery, stem cell transplantation, and other donor graft manipulation.

Figure 1

Limitations associated with VCA: Limitations and complications currently associated with VCA include (a) the lifelong need for high dose, multidrug immunosuppressive medications, (b) acute (and chronic) VCA rejection, and (c) side effects and toxicity of antirejection therapies. Patient noncompliance is the main cause of graft loss. Tac: tacrolimus, MMF: Mycophenolate mofetil, Rapa: Rapamycin, St: Steroid, and Top: topical.

Figure 2

Implantable devices for drug localized delivery. Minimally invasive implantation of drug eluting biomaterials offers advantages over oral drug regimens including localized drug delivery, minimizing or eliminating systemic side effects, and overcoming the barrier of patient noncompliance. (a) Graft implanted biomaterials release active drugs or prodrugs in controlled fashion upon in vivo degradation directly into the local tissue microenvironment. (b) Pharmacokinetic profiles of oral medication versus. (c) Implantable drug eluting materials. Additional advantages include reduced dosing, frequency and duration of dosing, favorable drug kinetics and maintenance of pharmacologic agents within the therapeutic window limiting systemic exposure.

Figure 3

Extracellular matrix-derived biomaterials: Materials derived from the ECM via decellularization of native tissues possess a number of beneficial properties that together promote constructive tissue remodeling. ECM-derived biomaterials can modulate wound healing mechanisms including angiogenesis and the immune system and facilitate important cellular processes such as cell migration, proliferation, and differentiation.

Figure 4

Biomaterial-mediated tissue repair: The biomaterial-host interaction is a complex process composed of multiples stages. Following implantation, the surface of the material is covered with blood and plasma protein through a process known as the Vroman effect. In conjunction with hemostasis, the Vroman effect facilitates the formation of a temporary fibrin-rich matrix that mediates the interaction between native tissues and the implanted construct. This temporary matrix also facilitates cellular access into the material. The innate immune system is activated and a neutrophil accumulation at the periphery of the implant becomes histologically apparent within minutes to hours of implantation. In the following days, this neutrophil accumulation is gradually replaced by a macrophage infiltrate that facilitates scaffold degradation and matricryptic peptide release. The macrophage infiltrate then transitions from an M1 proinflammatory phenotype into an M2 proremodeling phenotype. Signaling molecules produced by the innate immune system and scaffold degradation products act synergistically to recruit stem/progenitor cells from nearby tissues and the bone marrow. Together this heterogeneous cell population known as the constructive cell infiltrate is responsible for further scaffold degradation, neomatrix deposition, and constructive functional tissue remodeling.

Figure 5

Minimally invasive delivery of ECM-based hydrogels. (a) ECM-derived hydrogels can be manufactured via enzymatic digestion of powdered ECM in an acidic 1 mg/mL pepsin solution. Gelation is induced by neutralizing the pH and salt concentration with 0.1 N NaOH solution followed by warming to 37°C. (b) ECM-derived hydrogels exist in a liquid phase at 25°C and therefore can be delivered minimally invasively via injection. Once in situ, hydrogels reach thermal equilibrium with the surrounding tissue and polymerize spontaneously at 37°C. Their degradation profile and biocompatible properties make ECM-derived hydrogels potential candidates for drug delivery applications.