An In Situ Gelling Drug Delivery System for Improved Recovery after Spinal Cord Injury

Liu, Dongfei; Jiang, Tao; Cai, Wei; Chen, Jian; Zhang, Hongbo; Hietala, Sami; Santos, Hélder A.; Yin, Guoyong; Fan, Jin

doi:10.1002/adhm.201600055

Cited by 34 publications

(34 citation statements)

References 60 publications

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“…For instance, a hydrogel incorporating poloxamer-407/188 polymer and monosialoganglio-side (GM1-hydrogel) was found be effective in preventing cell apoptosis and glial scar formation in rabbit spinal cord injuries (SCI) [60]. Recently, our group prepared a thermosensitive GFs hydrogel system for delivering single GFs directly to the lesion area of damaged nerves [26], which consists of poloxamer 407 and heparin through a poly-condensation reaction.…”

Section: Discussionmentioning

confidence: 99%

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

et al. 2018

Biomaterials

199

140

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Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p<0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.

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Section: Discussionmentioning

confidence: 99%

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

et al. 2018

Biomaterials

199

140

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“…15,30 In a typical experiment, HP hydrogel exhibited a liquid state in low temperature. After it was locally administered in vivo, a three-dimensional network structure was formed which sustained the drug releasing from the HP hydrogel.…”

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confidence: 99%

Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

Zhang¹,

Xia²,

Xu³

et al. 2017

IJN

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Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E 2 ) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat’s endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E 2 -HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E 2 -HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E 2 -HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E 2 -HP hydrogel showed a prolonged release of E 2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E 2 -HP hydrogel group. We also demonstrated that E 2 -HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E 2 into the injured endometrium. Therapeutic strategies targeting ER stress using E 2 -HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions.

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“…However, maintaining the retention and stability of exosomes over time and resist of microenvironment variation in vivo after transplantation is a significant barrio to enhance the therapeutic efficacy in the clinical application of MSC-derived secreta [56,57]. Tan et al [58] demonstrated that therapeutic molecules such as neurotrophin (BDNF) could be effectively encapsulated and delivered to the target tissue of SCI in a sustained manner with retained biological activity via biomaterials, reducing undesirable biological side effects in non-target regions.…”

Section: Secretome Of Mscs and Suppression Of Neuroinflammationmentioning

confidence: 99%

Biomaterial-supported MSCs transplantation enhances cell-cell communication for spinal cord injury

Wang

yang

2020

Preprint

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The spinal cord is part of the central nervous system (CNS) and serves to connect the brain to the peripheral nervous system and peripheral tissues. The cell types that primarily comprise the spinal cord are neurons and several categories of glia, including astrocytes, oligodendrocytes, and microglia. Ependymal cells and small populations of endogenous stem cells, such as oligodendrocyte progenitor cells, also reside in the spinal cord [1]. Neurons are interconnected in circuits; those that process cutaneous sensory input are mainly located in the dorsal spinal cord, while those involved in proprioception and motor control are predominately located in the ventral spinal cord [2]. Due to the importance of the spinal cord, neurodegenerative disorders and traumatic injuries affecting the spinal cord will lead to motor deficits and loss of sensory inputs. Spinal cord injury (SCI), resulting in paraplegia and tetraplegia as a result of deleterious interconnected mechanisms encompassed by the primary and secondary injury, represents a heterogeneously behavioral and cognitive deficit that remains incurable. Following SCI, various barriers containing the neuroinflammation, neural tissue defect (neurons, microglia, astrocytes, and oligodendrocytes), cavity formation, loss of neuronal circuitry and function must be overcame[3]. Notably, the pro -inflammatory and anti-inflammatory effect s of cell-cell communication networks play critical roles in homeostatic, driving the pathophysiologic and consequent cognitive outcomes. In the spinal cord, astrocytes, oligodendrocytes and microglia are involved in not only development but also pathology. Glial cells play dual roles (negative vs. positive effects) in these processes. After SCI, detrimental effects usually dominate and significantly retard functional recovery, and curbing these effects is critical for promoting neurological improvement. Indeed, residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (macrophages and neutrophils), activated by SCI, give rise to full-blown inflammatory cascades. These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit[4]. Given the various multifaceted obstacles in SCI treatment, a combinatorial therapy of cell transplantation and biomaterial implantation may be addressed in detail here. For the sake of preserving damaged tissue integrity and providing physical support and trophic supply for axon regeneration, MSCs transplantation has come to the front stage in therapy for SCI with the constant progress of stem cell engineering [5]. MSCs transplantation promotes scaffold integration and regenerative growth potential. Integrating into the implanted scaffold, MSCs influences implant integration by improving the healing process[6]. Conversely, biomaterial scaffolds offer MSCs with a sheltered microenvironment from the surrounding pathological changes, in addition to bridging connection spinal cord stump and offering physical and directional support for axonal regeneration. Besides, Biomaterial scaffolds mimic the extracellular matrix to suppress immune responses. Here, we review the advances in combinatorial biomaterial scaffolds and MSCs transplantation approach that targets certain aspects of various intercellular communications in the pathologic process following SCI. Finally, the challenges of biomaterial-supported MSCs transplantation and its future direction for neuronal regeneration will be presented.

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An In Situ Gelling Drug Delivery System for Improved Recovery after Spinal Cord Injury

Cited by 34 publications

References 60 publications

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

Biomaterial-supported MSCs transplantation enhances cell-cell communication for spinal cord injury

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An In Situ Gelling Drug Delivery System for Improved Recovery after Spinal Cord Injury

Cited by 34 publications

References 60 publications

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17&beta;-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

Biomaterial-supported MSCs transplantation enhances cell-cell communication for spinal cord injury

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Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model