Polysaccharide-Based Injectable Hydrogels with Fast Gelation and Self-Strengthening Mechanical Kinetics for Oral Tissue Regeneration.

Oral defects lead to a series of function disorders, severely threatening the patients' health. Although injectable hydrogels are widely studied in tissue regeneration, their mechanical performance is usually stationary after implant, without further self-adaption toward the microenvironment. Herein, an injectable hydrogel with programmed mechanical kinetics of instant gelation and gradual self-strengthening along with outstanding biodegradation ability is developed. The fast gelation is realized through rapid Schiff base reaction between biodegradable chitosan and aldehyde-modified sodium hyaluronate, while self-strengthening is achieved via slow reaction between redundant amino groups on chitosan and epoxy-modified hydroxyapatite. The resultant hydrogel also possesses multiple functions including (1) bio-adhesion, (2) self-healing, (3) bactericidal, (4) hemostasis, and (5) X-ray in situ imaging, which can be effectively used for oral jaw repair. We believe that the strategy illustrated here will provide new insights into dynamic mechanical regulation of injectable hydrogels and promote their application in tissue regeneration.

Scar Tissue-Targeting Polymer Micelle for Spinal Cord Injury Treatment.

Spinal cord injury (SCI) is a devastating disorder, leading to permanent motor and sensory deficit. Despite recent advances in neurosciences, the treatment efficacy on SCI patients remains unsatisfactory, mainly due to the poor accumulation, short retention, and lack of controlled release of therapeutics in lesion tissue. Herein, an injured spinal cord targeting prodrug polymer micelle is built. An esterase-responsive bond is used to link apocynin (APO) monomer, because of the enhanced esterase activity found in microglia cells after activation, which ensures a controlled degradation of APO prodrug (Allyloxypolyethyleneglycol-b-poly [2-(((4-acetyl-2-methoxyphenoxy)carbonyl)oxy)ethyl methacrylate], APEG-PAPO or PAPO) by activated microglia cells. A scar tissue-homing peptide (cysteine-alanine-glutamine-lysine, CAQK) is introduced to the PAPO to endow the polymer micelle the lesion tissue-targeting ability. As a result, this CAQK-modified prodrug micelle (cPAM) exhibits an improved accumulation and prolonged retention in lesion tissue compared to the control micelle. The cPAM also leads to superior tissue protection and sustained motor function recovery than the control groups in a mouse model of SCI. In conclusion, the cPAM induces an effective treatment of SCI by the lesion tissue specific delivery of the prodrug polymer via its robust scar binding effect, making the scar tissue a drug releasing platform for sustained treatment of SCI.

An injectable recombinant human milk fat globule-epidermal growth factor 8-loaded copolymer system for spinal cord injury reduces inflammation through NF-κB and neuronal cell death.

Spinal cord injury (SCI) is a common disease and a major cause of paralysis, carrying much burden around the world. Despite the progress made with growth factors therapy, the response rate of acute SCI treatment still remains unsatisfactory, due largely to complex and severe inflammatory reactions. Herein, we prepare a MFG-E8-loaded copolymer system-based anti-inflammation therapy for SCI treatment. It is shown that the MFG-E8-loaded copolymer system can decrease pro-inflammatory cytokine expression and neuron death. In a rat model of crush-caused SCI, the copolymer system shows significant therapeutic efficacy by ameliorating inflammation, decreasing fibrotic scar, promoting myelin regeneration and suppressing overall SCI severity.

Swelling-Mediated Mechanical Stimulation Regulates Differentiation of Adipose-Derived Mesenchymal Stem Cells for Intervertebral Disc Repair Using Injectable UCST Microgels.

Mechanical stimulation is an effective approach for controlling stem cell differentiation in tissue engineering. However, its realization in in vivo tissue repair remains challenging since this type of stimulation can hardly be applied to injectable seeding systems. Here, it is presented that swelling of injectable microgels can be transformed to in situ mechanical stimulation via stretching the cells adhered on their surface. Poly(acrylamide-co-acrylic acid) microgels with the upper critical solution temperature property are fabricated using inverse emulsion polymerization and further coated with polydopamine to increase cell adhesion. Adipose-derived mesenchymal stem cells (ADSCs) adhered on the microgels can be omnidirectionally stretched along with the responsive swelling of the microgels, which upregulate TRPV4 and Piezo1 channel proteins and enhance nucleus pulposus (NP)-like differentiation of ADSCs. In vivo experiments reveal that the disc height and extracellular matrix content of NP are promoted after the implantation with the microgels. The findings indicate that swelling-induced mechanical stimulation has great potential for regulating stem cell differentiation during intervertebral disc repair.

Sustained release of GDF5 from a designed coacervate attenuates disc degeneration in a rat model.

Low back pain is often caused by intervertebral disc degeneration, which is characterized by nucleus pulposus (NP) and extracellular matrix (ECM) degeneration. Human adipose-derived stem cells (hADSCs) induced by growth and differentiation factor-5 (GDF5) can differentiate into an NP-like phenotype. Although stem cell-based therapy with prolonged exposure to growth factors is regarded as a promising treatment, the efficacy of this approach in attenuating the disc degeneration process is limited by the short lifespan of growth factors. In our study, a unique growth factor delivery vehicle composed of heparin and the synthetic polycation poly(ethylene argininylaspartate diglyceride) (PEAD) was used to sustain GDF5 release. The results showed that sustained release of GDF5 by the PEAD:heparin delivery system promoted hADSC differentiation to an NP-like phenotype in vitro. After injection of the PEAD:heparin:GDF5 delivery platform and hADSCs into intervertebral spaces of coccygeal (Co) vertebrae Co7/Co8 and Co8/Co9 of the rat, the disc height, water content, and structure of the NPs decreased more slowly than other treatment groups. This new strategy may be used as an alternative treatment for attenuating intervertebral disc degeneration with hADSCs without the need for gene therapy. STATEMENT OF SIGNIFICANCE: Low back pain is often caused by intervertebral disc degeneration, which is characterized by nucleus pulposus (NP) and extracellular matrix (ECM) degeneration. Human adipose-derived stem cells (hADSCs) induced by growth and differentiation factor-5 (GDF-5) can differentiate into an NP-like phenotype. Although stem cell-based therapy with prolonged exposure to growth factor is regarded as a promising treatment, the efficacy of this approach in the disc regeneration process is limited by the short life of growth factors. In our study, a unique growth factor delivery vehicle comprised of heparin and the synthetic polycation poly(ethylene argininylaspartate diglyceride) (PEAD) was used to sustain the release of GDF-5. Numerous groups have explored IDD regeneration methods in vitro and in vivo. Our study differs in that GDF5 was incorporated into a vehicle through charge attraction and exhibited a sustained release profile. Moreover, GDF-5 seeded coacervate combined with hADSC injection could be a minimally invasive approach for tissue engineering that is suitable for clinical application. We investigated the stimulatory effects of our GDF-5 seeded coacervate on the differentiation of ADSCs in vitro and the reparative effect of the delivery system on degenerated NP in vivo.