Hepatocyte Spheroid‐Laden Self‐Healing Hydrogel Containing Decellularized Liver Matrix and Tannic Acid: A Potential Treatment for Metabolic‐Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT

Metabolic‐dysfunction‐associated steatotic liver disease (MASLD) affects approximately 38% of the global population. The present study evaluated the therapeutic efficacy of a hepatocyte spheroid‐laden composite hydrogel comprising a chitosan–phenol self‐healing hydrogel (CPDP), decellularized liver matrix (DLM), and tannic acid (TA), assessing its effects in both in vitro and in vivo rat models of MASLD. This design combined the rapid gelation, self‐healing ability, and injectability of CPDP, the antioxidant properties of TA, the high biocompatibility of DLM and the ability of hepatocyte spheroids to mimic the liver microenvironment and maintain hepatic function. Our results demonstrated that the composite self‐healing hydrogel incorporating TA (0.1 wt%) and DLM (0.002 wt%) laden further with hepatocyte spheroids (“TA‐CDS”) exhibited significant therapeutic effects, including reductions in body weight, liver weight, and liver‐to‐body‐weight ratio in MASLD rats. After 2 weeks of treatment, TA‐CDS markedly improved hepatic function and lipid metabolism, as evidenced by favorable changes in serum biochemical parameters, including liver enzymes and lipid profiles. This study underscores the short‐term therapeutic efficacy of the hepatocyte spheroid‐laden composite self‐healing hydrogel for MASLD therapy. Further studies are warranted to evaluate its long‐term safety, degradation behavior, tissue response, and therapeutic efficacy before clinical translation.