Current progress of self‑healing polymers for medical applications in tissue engineering

Purpose: Self-healing polymers can repair damage and recover functionality, potentially extending the lifetime and safety of biomedical devices. Although self-healing hydrogels have been reviewed previously, papers focused specifically on their use in tissue engineering are scarce. This review summarizes fabrication methods, polymers, biomedical examples, and recent progress in self-healing polymers for tissue engineering.

Hypothesis: This is a review article and does not test a single formal hypothesis. Its central premise is that rational selection of natural and synthetic polymers, combined with covalent or non-covalent crosslinking strategies, can produce self-healing hydrogels with suitable mechanical, biological, and drug-release properties for bone, cartilage, skin, neural tissue engineering, and drug delivery.

Aims: Describe fabrication methods of self-healing hydrogels and the polymers employed. - Summarize natural and synthetic polymers used for self-healing biomedical hydrogels. - Provide examples of hydrogels intended for biomedical purposes and discuss key functional properties. - Highlight the most recent progress in utilizing self-healing polymers in tissue engineering.

Delivery system: System type: Self-healing hydrogels. - Natural polymers: Chitosan, xanthan gum, alginate, gelatin, guar gum; also bean gum, gellan gum, carrageenan. - Synthetic polymers: Polyacrylamide, poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), Pluronic F127. - Crosslinking strategies: - Covalent: Imine/Schiff base, disulfide, acylhydrazone, boronate ester, Diels–Alder, reversible radical reactions. - Non-covalent: Hydrogen bonding, π–π stacking, ionic interactions, zwitterionic interactions, metal–ligand coordination, host–guest interactions. - Payloads / bioactive components: Drugs (DOX, chlorhexidine, bFGF, colistin), silver nanoparticles, cells (endothelial progenitor cells, neural stem cells, chondrocytes, myoblasts), exosomes, growth factors. - Applications: Bone, cartilage, skin/wound healing, brain/CNS, and controlled drug release.

Approach: Review of recent literature covering in vitro and in vivo studies. In vivo models include mice, rats, rabbits, and zebrafish. Disease/tissue contexts include cranial bone defects, articular cartilage defects, burn wounds, bacterial infection, CNS injury, and cancer drug release. No new primary experiments, group sizes, or doses are reported.

Key methods: Mechanical/self-healing characterization: Rheology (storage modulus G′, loss modulus G″), tensile and compression tests, self-healing efficiency, injectability, shear-thinning, recovery time. - Physicochemical characterization: Swelling, degradation, gelation time, morphology. - Biological characterization: Cell viability, proliferation, migration, differentiation, antibacterial assays, histology, in vivo tissue regeneration. - Drug release: Cumulative release profiles under physiological or stimulus conditions.

Key results: Acylhydrazone-crosslinked nanocomposite hydrogel: self-healing efficiency 97.5%; nearly 100% cell viability. - P(BAL-co-DMSA) hydrogel: self-healing within ~5 s in air and underwater; stretchability ~4500%; complete degradation 100% in 5 h at 60 °C. - Xanthan gum/silk fibroin hydrogel: 93% recovery in 120 s; injectable and drug-release capable. - PVA hydrogel: autonomous self-healing via freezing–thawing; 35 wt% polymer; healed gel stretched to ~100% extension. - Bone: silk fibroin-based hydrogel promoted angiogenesis at 8 weeks post-implantation; self-healing conductive polyurethane increased osteogenic gene expression (RUNX2, COL1, OCN) by 21 days. - Cartilage: DN agar/PVA hydrogel self-healed after 10 min and retained ~67% tensile strength; hyaluronic acid/furylamine DN hydrogel showed 8-fold higher adhesive strength than control. - Skin: acylhydrazone hydrogel recovered ~95% of original G′ after high strain; CEC-TPH/PEG-DA hydrogel self-healed after 6 h; chitosan/bacterial cellulose hydrogel self-healed within 10 min. - Brain: CEC–OSA hydrogel had G′ 77–1900 Pa, supported neural stem cell proliferation/differentiation, and improved zebrafish cerebellum injury recovery 3 times higher than untreated controls. - Drug release: sequential release system delivered chlorhexidine rapidly and bFGF in a sustained manner; photo-degradable hydrogel released DOX under UV irradiation.

Interpretation: Self-healing hydrogels are promising for tissue engineering because they are injectable, adhesive, structurally modifiable, and capable of loading therapeutic substances. They show potential for bone, cartilage, skin, and neural tissue restoration and for drug delivery. However, clinical translation still requires extensive in vivo testing of biodegradability, biocompatibility, immunogenicity, and biological effects. Multi-drug release at different rates and predictive in vivo release modeling remain major challenges. A multidisciplinary approach combining chemistry, medicine, and engineering is needed to achieve efficient and safe self-healing hydrogels.

Limitations: This is a review, not a primary study; no new experimental data or meta-analysis. - Most reported systems remain preclinical; clinical data are lacking. - Long-term biodegradability, biocompatibility, and immunogenicity are unresolved. - Degradation rate is critical: too-fast degradation may prevent therapeutic objectives. - Controlled release of two or more distinct compounds at different rates is an extraordinary challenge. - Theoretical modeling of in vivo drug release is underdeveloped. - Extensive in vivo animal testing is still needed before human clinical trials.