An Injectable Engineered Cartilage Gel Improves Intervertebral Disc Repair in a Rat Nucleotomy Model.

Lower back pain is a major problem caused by intervertebral disc degeneration. A common surgical procedure is lumbar partial discectomy (excision of the herniated disc causing nerve root compression), which results in further disc degeneration, severe lower back pain, and disability after discectomy. Thus, the development of disc regenerative therapies for patients who require lumbar partial discectomy is crucial. Here, we investigated the effectiveness of an engineered cartilage gel utilizing human fetal cartilage-derived progenitor cells (hFCPCs) on intervertebral disc repair in a rat tail nucleotomy model. Eight-week-old female Sprague-Dawley rats were randomized into three groups to undergo intradiscal injection of (1) cartilage gel, (2) hFCPCs, or (3) decellularized extracellular matrix (ECM) (n = 10/each group). The treatment materials were injected immediately after nucleotomy of the coccygeal discs. The coccygeal discs were removed six weeks after implantation for radiologic and histological analysis. Implantation of the cartilage gel promoted degenerative disc repair compared to hFCPCs or hFCPC-derived ECM by increasing the cellularity and matrix integrity, promoting reconstruction of nucleus pulposus, restoring disc hydration, and downregulating inflammatory cytokines and pain. Our results demonstrate that cartilage gel has higher therapeutic potential than its cellular or ECM component alone, and support further translation to large animal models and human subjects.

Mesenchymal Stem Cells and Exosomes: A Novel Therapeutic Approach for Corneal Diseases.

The cornea, with its delicate structure, is vulnerable to damage from physical, chemical, and genetic factors. Corneal transplantation, including penetrating and lamellar keratoplasties, can restore the functions of the cornea in cases of severe damage. However, the process of corneal transplantation presents considerable obstacles, including a shortage of available donors, the risk of severe graft rejection, and potentially life-threatening complications. Over the past few decades, mesenchymal stem cell (MSC) therapy has become a novel alternative approach to corneal regeneration. Numerous studies have demonstrated the potential of MSCs to differentiate into different corneal cell types, such as keratocytes, epithelial cells, and endothelial cells. MSCs are considered a suitable candidate for corneal regeneration because of their promising therapeutic perspective and beneficial properties. MSCs compromise unique immunomodulation, anti-angiogenesis, and anti-inflammatory properties and secrete various growth factors, thus promoting corneal reconstruction. These effects in corneal engineering are mediated by MSCs differentiating into different lineages and paracrine action via exosomes. Early studies have proven the roles of MSC-derived exosomes in corneal regeneration by reducing inflammation, inhibiting neovascularization, and angiogenesis, and by promoting cell proliferation. This review highlights the contribution of MSCs and MSC-derived exosomes, their current usage status to overcome corneal disease, and their potential to restore different corneal layers as novel therapeutic agents. It also discusses feasible future possibilities, applications, challenges, and opportunities for future research in this field.

Mesenchymal Stem Cell-Derived Exosomes and Intervertebral Disc Regeneration: Review.

Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration in the composition of the extracellular matrix, excessive oxidative stress, and inflammation in the intervertebral disc. Pharmacological and surgical interventions are considered a boon for the treatment of IVDD, but the effectiveness of those strategies is limited. Mesenchymal stem cells (MSCs) have recently emerged as a possible promising regenerative therapy for IVDD due to their paracrine effect, restoration of the degenerated cells, and capacity for differentiation into disc cells. Recent investigations have shown that the pleiotropic effect of MSCs is not related to differentiation capacity but is mediated by the secretion of soluble paracrine factors. Early studies have demonstrated that MSC-derived exosomes have therapeutic potential for treating IVDD by promoting cell proliferation, tissue regeneration, modulation of the inflammatory response, and reduced apoptosis. This paper highlights the current state of MSC-derived exosomes in the field of treatment of IVDD with further possible future developments, applications, and challenges.

Genetic Therapy for Intervertebral Disc Degeneration.

Intervertebral disc (IVD) degeneration can cause chronic lower back pain (LBP), leading to disability. Despite significant advances in the treatment of discogenic LBP, the limitations of current treatments have sparked interest in biological approaches, including growth factor and stem cell injection, as new treatment options for patients with chronic LBP due to IVD degeneration (IVDD). Gene therapy represents exciting new possibilities for IVDD treatment, but treatment is still in its infancy. Literature searches were conducted using PubMed and Google Scholar to provide an overview of the principles and current state of gene therapy for IVDD. Gene transfer to degenerated disc cells in vitro and in animal models is reviewed. In addition, this review describes the use of gene silencing by RNA interference (RNAi) and gene editing by the clustered regularly interspaced short palindromic repeats (CRISPR) system, as well as the mammalian target of rapamycin (mTOR) signaling in vitro and in animal models. Significant technological advances in recent years have opened the door to a new generation of intradiscal gene therapy for the treatment of chronic discogenic LBP.

Effect of Topical Programmed Death-Ligand1 on Corneal Epithelium in Dry Eye Mouse.

Dry eye disease (DED) is a growing health concern that impacts millions of individuals every year, and is associated with corneal injury, excessive oxidative stress and inflammation. Current therapeutic strategies, including artificial tears and anti-inflammatory agents, are unable to achieve a permanent clinical cure due to their temporary nature or adverse side effects. Therefore, here, we investigated the effectiveness of the topical administration of programmed death-ligand 1 (PD-L1) in the mouse model of DED. The model was generated in C57BL/6 mice by excising the extra orbital lacrimal gland and causing desiccation stress with scopolamine injections. Subsequently, either phosphate-buffered saline (3 µL/eye) or PD-L1 (0.5 µg/mL) was topically administered for 10 days. Tear volume was evaluated with phenol red thread, and corneal fluorescein staining was observed to quantify the corneal epithelial defect. Corneas were collected for histological analysis, and the expression levels of inflammatory signaling proteins such as CD4, CD3e, IL-17, IL-1ß, pIkB-α, pNF-kB and pERK1/2 were assessed through immunofluorescence and Western blot techniques. Our results demonstrate that desiccating stress-induced corneal epithelial defect and tear secretion were significantly improved by topical PD-L1 and could reduce corneal CD4+ T cell infiltration, inflammation and apoptosis in a DED mouse model by downregulating IL-17 production and ERK1/2-NFkB pathways.

Effect of Exposure to Particulate Matter on the Ocular Surface in an Experimental Allergic Eye Disease Mouse Model.

In response to the escalating concern over the effect of environmental factors on ocular health, this study aimed to investigate the impact of air pollution-associated particulate matter (PM) on ocular allergy and inflammation. C57BL/6 mice were sensitized with ovalbumin (OVA) topically and aluminum hydroxide via intraperitoneal injection. Two weeks later, the mice were challenged with OVA and exposed to PM. Three groups-naive, OVA, and OVA-sensitized with PM exposure (OVA + PM) groups-were induced to an Allergic Eye disease (AED) model. Parameters including clinical signs, histological changes, inflammatory cell infiltration, serum OVA-specific immunoglobulins E (IgE) levels, mast cells degranulation, cellular apoptosis and T-cell cytokines were studied. The results demonstrate that exposure with PM significantly exacerbates ocular allergy, evidenced by increased eye-lid edema, mast cell degranulation, inflammatory cytokines (IL-4, IL-5 and TNF-α), cell proliferation (Ki67), and serum IgE, polymorphonuclear leukocytes (PMN), and apoptosis and reduced goblet cells. These findings elucidate the detrimental impact of PM exposure on exacerbating the severity of AED. Noticeably, diminished goblet cells highlight disruptions in ocular surface integrity, while increased PMN infiltration with an elevated production of IgE signifies a systemic allergic response with inflammation. In conclusion, this study not only scientifically substantiates the association between air pollution, specifically PM, and ocular health, but also underscores the urgency for further exploration and targeted interventions to mitigate the detrimental effects of environmental pollutants on ocular surfaces.

Development of a Nanohybrid Peptide Hydrogel for Enhanced Intervertebral Disc Repair and Regeneration.

Effective therapeutic approaches to overcome the heterogeneous pro-inflammatory and inhibitory extracellular matrix (ECM) microenvironment are urgently needed to achieve robust structural and functional repair of severely wounded fibrocartilaginous tissues. Herein we developed a dynamic and multifunctional nanohybrid peptide hydrogel (NHPH) through hierarchical self-assembly of peptide amphiphile modified with biodegradable two-dimensional nanomaterials with enzyme-like functions. NHPH is not only injectable, biocompatible, and biodegradable but also therapeutic by catalyzing the scavenging of pro-inflammatory reactive oxygen species and promoting ECM remodeling. In addition, our NHPH method facilitated the structural and functional recovery of the intervertebral disc (IVD) after severe injuries by delivering pro-regenerative cytokines in a sustained manner, effectively suppressing immune responses and eventually restoring the regenerative microenvironment of the ECM. In parallel, the NHPH-enhanced nucleus pulposus cell differentiation and pain reduction in a rat nucleotomy model further validated the therapeutic potential of NHPH. Collectively, our advanced nanoscaffold technology will provide an alternative approach for the effective treatment of IVD degeneration as well as other fibrocartilaginous tissue injuries.

Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold.

Degeneration of fibrocartilaginous tissues is often associated with complex pro-inflammatory factors. These include reactive oxygen species (ROS), cell-free nucleic acids (cf-NAs), and epigenetic changes in immune cells. To effectively control this complex inflammatory signaling, it developed an all-in-one nanoscaffold-based 3D porous hybrid protein (3D-PHP) self-therapeutic strategy for treating intervertebral disc (IVD) degeneration. The 3D-PHP nanoscaffold is synthesized by introducing a novel nanomaterial-templated protein assembly (NTPA) strategy. 3D-PHP nanoscaffolds that avoid covalent modification of proteins demonstrate inflammatory stimuli-responsive drug release, disc-mimetic stiffness, and excellent biodegradability. Enzyme-like 2D nanosheets incorporated into nanoscaffolds further enabled robust scavenging of ROS and cf-NAs, reducing inflammation and enhancing the survival of disc cells under inflammatory stress in vitro. Implantation of 3D-PHP nanoscaffolds loaded with bromodomain extraterminal inhibitor (BETi) into a rat nucleotomy disc injury model effectively suppressed inflammation in vivo, thus promoting restoration of the extracellular matrix (ECM). The resulting regeneration of disc tissue facilitated long-term pain reduction. Therefore, self-therapeutic and epigenetic modulator-encapsulated hybrid protein nanoscaffold shows great promise as a novel approach to restore dysregulated inflammatory signaling and treat degenerative fibrocartilaginous diseases, including disc injuries, providing hope and relief to patients worldwide.

Current Advances in Regenerative Strategies for Dry Eye Diseases: A Comprehensive Review.

Dry eye disease (DED) is an emerging health issue affecting millions of individuals annually. Ocular surface disorders, such as DED, are characterized by inflammation triggered by various factors. This condition can lead to tear deficiencies, resulting in the desiccation of the ocular surface, corneal ulceration/perforation, increased susceptibility to infections, and a higher risk of severe visual impairment and blindness. Currently, the clinical management of DED primarily relies on supportive and palliative measures, including the frequent and lifelong use of different lubricating agents. While some advancements like punctal plugs, non-steroidal anti-inflammatory drugs, and salivary gland autografts have been attempted, they have shown limited effectiveness. Recently, there have been promising developments in the treatment of DED, including biomaterials such as nano-systems, hydrogels, and contact lenses for drug delivery, cell-based therapies, biological approaches, and tissue-based regenerative therapy. This article specifically explores the different strategies reported so far for treating DED. The aim is to discuss their potential as long-term cures for DED while also considering the factors that limit their feasibility and effectiveness. These advancements offer hope for more effective and sustainable treatment options in the future.