Injectable human tendon extracellular matrix via isopropanol-assisted delipidation and mild decellularization for tendon regeneration.

Tendon injuries remain a major clinical challenge due to their limited intrinsic healing capacity and the shortcomings of current treatment options. Extracellular matrix (ECM)-based approaches are promising; however, most clinically available injectable ECMs are xenogeneic, raising concerns about immunogenicity, pathogen transmission, and limited durability. Human-derived injectable ECMs have recently gained attention, yet conventional solubilization-based preparations often disrupt native architecture and compromise biological function. Here, we present an injectable decellularized human tendon (DHT) produced by a dual-step isopropanol (IPA)-assisted delipidation combined with mild decellularization. This process effectively removed lipids and cells while preserving ultrastructure, collagen organization, and key growth factors, with no cytotoxic residues detected. Notably, instead of chemical solubilization, injectability was achieved by micropulverization and hydration, enabling minimally invasive delivery while retaining structural integrity and native ECM cues. In vitro studies demonstrated that injectable DHT supported the viability and proliferation of human tenocytes and promoted tenogenic differentiation of human adipose-derived stem cells. In a rat Achilles tendon injury model, injectable DHT significantly enhanced ECM remodeling, neovascularization, and functional tendon regeneration compared with human acellular dermal matrix and porcine collagen controls. For the first time, this study demonstrates that an IPA-assisted, mildly decellularized, and mechanically processed human tendon ECM can be formulated into an injectable while preserving its native architecture and bioactivity. To our knowledge, this study presents one of the first injectable, human tendon-derived ECM formulations specifically designed as a flowable, tissue-specific therapeutic platform for tendon regeneration, and systematically evaluated for its biological performance both in vitro and in vivo.