Aldehyde‐Amine Chemistry Enables Modulated Biosealants with Tissue‐Specific Adhesion

Soft-tissue surgical sealants provide an ideal material class for assessment of tissue–material interactions. Sealant adhesion can be rigorously quantified through a series of functional assays that supplement characterizations of tissue reactivity and material fate. A collection of experimental techniques can be exploited to elucidate mechanistic aspects of tissue–material interactions with general implications, extending beyond the immediate scope of adhesive materials. Moreover, though sealants are routinely used in clinical procedures, active questions and limitations force physicians to choose between extremes of adhesion strength and biocompatibility. [1] Common cyanoacrylate derivatives adhere strongly to tissue, but their vigorous and uncontrolled tissue crosslinking along with the release of toxic degradation by-products dramatically impedes healing and regeneration processes. [2] The polymerization of alkylcyanoacrylates occurs via anionic and zwitterionic polymerizations in the presence of weak bases such as alcohols, water, and amino acids encountered in living tissues. [3] Cyanoacrylates with short side alkyl chains (methyl or ethyl) rapidly degrade to form cyanoacetate and formaldehyde, characterized by acute and chronic inflammation. The longer alkyl chains degrade slower, resulting in more limited accumulation of toxic byproducts that may be effectively eliminated by tissues. Histotoxicity depends on the vascularity of tissues, being greater in well-vascularized soft tissues. [4] Fibrin glues represent the opposite polar extreme along the spectrum of sealants [4] eliciting a mild tissue response, but with relatively non-specific and minimally adhesive tissue interaction. [5–7] Though these and all sealants rely on intimate tissue–material interactions for functional adhesion, target-tissue properties have been largely ignored in material design. Instead, one general formulation is proposed for application to the full range of soft tissues across diverse clinical applications. [8–13] Here, we demonstrate that aldehyde-mediated adhesion to tissue strongly depends on target-tissue type and state, and propose a rational approach for the engineering of application-specific surgical sealants. Copolymeric hydrogels featuring aminated star polyethylene glycolandhigh-molecular-weight dextranaldehyde(PEG:dextran) possess a series of physico-chemical properties that can be modified to create a family of materials with tunable tissue adhesion. [14–17] The two polymer constituents of PEG:dextran were prepared as minimally viscous aqueous solutions and consistently polymerized through injection from a dual chamber syringe equipped with a mixing tip. [15,16] The cohesive integrity of PEG:dextran is derived from imine bonds that form through a Schiff base reaction between amines and aldehydes. [14–17] When crosslinked on soft-tissue surfaces, aldehydes not consumed in bulk network formation form analogous bonds with tissue amines to achieve adhesion. Aldehydes in excess of what is required for cohesion or adhesion can induce tissue toxicity. [18] Consequently, material aldehyde density is the key design parameter for informative evaluation of tissue-material adhesion and tissue response. We designed and evaluated a series of PEG:dextran formulations featuring low (8.8%, abbreviated L-PD), medium (14.0%, abbreviated M-PD), and high (20.0%, abbreviated H-PD) levels of dextran aldehyde solid content. Additional design parameters, including dextran molecular weight (10 kDa) and oxidation state (50%), and PEG amine solid content (25%) were identical among formulations, and selected to provide stable and bioreactive networks for evaluation of adhesive