Porous, resorbable biomaterials can serve as temporary scaffolds that support cell infiltration, tissue formation, and remodeling of nonhealing skin wounds. Synthetic biomaterials are less expensive to manufacture than biologic dressings and can achieve a broader range of physiochemical properties, but opportunities remain to tailor these materials for ideal host immune and regenerative responses. Polyesters are a well-established class of synthetic biomaterials; however, acidic degradation products released by their hydrolysis can cause poorly controlled autocatalytic degradation. Here, we systemically explored reactive oxygen species (ROS)–degradable polythioketal (PTK) urethane (UR) foams with varied hydrophilicity for skin wound healing. The most hydrophilic PTK-UR variant, with seven ethylene glycol (EG7) repeats flanking each side of a thioketal bond, exhibited the highest ROS reactivity and promoted optimal tissue infiltration, extracellular matrix (ECM) deposition, and reepithelialization in porcine skin wounds. EG7 induced lower foreign body response, greater recruitment of regenerative immune cell populations, and resolution of type 1 inflammation compared to more hydrophobic PTK-UR scaffolds. Porcine wounds treated with EG7 PTK-UR foams had greater ECM production, vascularization, and resolution of proinflammatory immune cells compared to polyester UR foam–based NovoSorb Biodegradable Temporizing Matrix (BTM)–treated wounds and greater early vascular perfusion and similar wound resurfacing relative to clinical gold standard Integra Bilayer Wound Matrix (BWM). In a porcine ischemic flap excisional wound model, EG7 PTK-UR treatment led to higher wound healing scores driven by lower inflammation and higher reepithelialization compared to NovoSorb BTM. PTK-UR foams warrant further investigation as synthetic biomaterials for wound healing applications.

Significance: Clinical healing by secondary intention frequently occurs in skin that is firmly anchored to underlying (human) connective tissue. Small animals (rodents) are extensively utilized to model human cutaneous wound healing, but they heal by wound contraction, a process that is limited in the human and confounds quantitative and qualitative evaluation of experimental wound repair. Recent Advances: To alleviate wound contraction in loose-skinned species, practical solutions include choosing anatomical sites with firmly attached dermis and subcutis (e.g., rabbit ear) or performing mechanical fixation of the skin by using one of a number of devices or splints. In each case, the wound volume remains relatively constant, allowing the histomorphometric or biomolecular quantification of the cellular response under well-controlled, experimental conditions. In addition, the defined aperture of the splinted wound allows the placement of a variety of materials, including scaffolds, cells, and biologically active formulations into the wound site in an effort to potentiate the healing response and abrogate scarring. In contrast, production of larger experimental wounds or the deliberate distraction of wound margins can be used to model a hypertrophic response. Critical Issues: Device design parameters should consider ease of application, durability, and lack of interference with the normal influx of local and circulating cells to the wound site. Future Directions: Improved methods of securing flexible splints would provide a more efficient experimental platform. These devices could also incorporate optical or electronic sensors that report both the mechanical and physiological status of the healing.