Injectable, porous, and cell-responsive gelatin cryogels

Koshy, Sandeep T.; Ferrante, Thomas; Lewin, Sarah A.; Mooney, David J.

doi:10.1016/j.biomaterials.2013.11.044

Cited by 279 publications

(249 citation statements)

References 31 publications

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“…Ionically crosslinked samples fragmented significantly after 1 month in vivo, resulting in cell infiltration, whereas the click alginate hydrogels remained intact during the 2 month study and were highly resistant to cell infiltration. In tissue engineering applications where cell trafficking within the hydrogel is desirable, click alginate hydrogels could be processed using existing techniques to introduce microscale porosity to the hydrogels [50,51]. Alternatively, click alginate polymers could be crosslinked using tetrazine or norbornene-modified matrix metalloproteinase-degradable peptide sequences to allow cell-mediated degradation [29,52].…”

Section: Discussionmentioning

confidence: 99%

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

et al. 2015

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Abstract:Alginate hydrogels are well-characterized, biologically inert materials that are used in many biomedical applications for the delivery of drugs, proteins, and cells. Unfortunately, canonical covalently crosslinked alginate hydrogels are formed using chemical strategies that can be biologically harmful due to their lack of chemoselectivity. In this work we introduce tetrazine and norbornene groups to alginate polymer chains and subsequently form covalently crosslinked click alginate hydrogels capable of encapsulating cells without damaging them. The rapid, bioorthogonal, and specific click reaction is irreversible and allows for easy incorporation of cells with high post-encapsulation viability. The swelling and mechanical properties of the click alginate hydrogel can be tuned via the total polymer concentration and the stoichiometric ratio of the complementary click functional groups. The click alginate hydrogel can be modified after gelation to display cell adhesion peptides for 2D cell culture using thiol-ene chemistry.Furthermore, click alginate hydrogels are minimally inflammatory, maintain structural integrity over several months, and reject cell infiltration when injected subcutaneously in mice. Click alginate hydrogels combine the numerous benefits of alginate hydrogels with powerful bioorthogonal click chemistry for use in tissue engineering applications involving the stable encapsulation or delivery of cells or bioactive molecules.

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Section: Discussionmentioning

confidence: 99%

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

et al. 2015

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“…Cryogel-based cell delivery has also been developed by Mooney and colleagues (21,22), who fabricated shape-memory millimeter-scale cryogels realizing s.c. injection of a single-cell-loaded cryogel each time through a 16-gauge needle. In the present study, we developed biodegradable microscale gelatin cryogels (GMs) enabling injection of 150 GMs per mouse using clinically used setting (i.e., 23-gauge needles) for cell therapy and proved the superior therapeutic efficacy of the 3D injectable microniches by priming seeded cells within the GMs.…”

Section: Discussionmentioning

confidence: 99%

Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

134

143

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The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproducible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strategies are therefore in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biodegradable gelatin microcryogels (GMs). The microniches are constituted by in vitro priming human adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell-cell interactions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, survival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based therapy. In particular, 3D microniche-based therapy with 10 5 hMSCs realized better ischemic limb salvage than treatment with 10 6 freeinjected hMSCs, the minimum dosage with therapeutic effects for treating CLI in literature. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy for treating CLI with the lowest cell dosage in mouse models. This study offers a widely applicable cell delivery platform technology to boost the healing power of cell regenerative therapy.C ell-based regenerative therapy holds great promise for repair and restoration of damaged tissues or organs with numerous clinical trials and preclinical animal testing reported for treating complex diseases (1). Common route of cell administration for clinical cell therapy is based on either systematic administration (e.g., i.v. infusion), relying on cells homing to the lesion sites (2), or direct injection of cells into the damaged tissues (3). However, therapeutic benefits of the administered cells are still limited and sometimes irreproducible due to cell loss and cell death (4). Taking cell therapy for ischemic heart diseases as an example, only ∼5% of mesenchymal stem cells (MSCs) survived after being transplanted into an infarcted porcine heart (5). Mechanical damage during injection, high rate of cell loss and leakage to surrounding tissues, cell death due to lack of appropriate cell-cell and cell-matrix interactions in the ischemic and inflammatory lesion tissues could all contribute to poor cell retention, survival, functionality, and reproducibility of the treatment (6, 7).A rational solution to enhance the therapeutic efficacy and reproducibility of cell therapy is to administer a large dose of cells to ensure sufficient number of functional cells ...

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“…21 Gelatinmethacrylamide (GelMA), modification of gelatin with unsaturated methacrylate groups, can be copolymerized to form hydrogel via light or chemical initiators under mild conditions with low cytotoxicity. [21][22][23] Growth factors play a key role in the regeneration of damaged tissues by stimulating cellular activities such as cell migration, proliferation, and differentiation. However, growth factors, released directly without protection, will be quickly degraded and deactivated by enzymes and other physicalchemical effectors in vivo and in vitro.…”

Section: Zhuang Et Almentioning

confidence: 99%

Gelatin-methacrylamide gel loaded with microspheres to deliver GDNF in bilayer collagen conduit promoting sciatic nerve growth

Zhuang¹,

Bu²,

Liu³

et al. 2016

IJN

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In this study, we fabricated glial cell-line derived neurotrophic factor (GDNF)-loaded microspheres, then seeded the microspheres in gelatin-methacrylamide hydrogel, which was finally integrated with the commercial bilayer collagen membrane (Bio-Gide ® ). The novel composite of nerve conduit was employed to bridge a 10 mm long sciatic nerve defect in a rat. GDNF-loaded gelatin microspheres had a smooth surface with an average diameter of 3.9±1.8 μm. Scanning electron microscopy showed that microspheres were uniformly distributed in both the GelMA gel and the layered structure. Using enzyme-linked immunosorbent assay, in vitro release studies (pH 7.4) of GDNF from microspheres exhibited an initial burst release during the first 3 days (18.0%±1.3%), and then, a prolonged-release profile extended to 32 days. However, in an acidic condition (pH 2.5), the initial release percentage of GDNF was up to 91.2%±0.9% within 4 hours and the cumulative release percentage of GDNF was 99.2%±0.2% at 48 hours. Then the composite conduct was implanted in a 10 mm critical defect gap of sciatic nerve in a rat. We found that the nerve was regenerated in both conduit and autograft (AG) groups. A combination of electrophysiological assessment and histomorphometry analysis of regenerated nerves showed that axonal regeneration and functional recovery in collagen tube filled with GDNF-loaded microspheres (GM + CT) group were similar to AG group ( P >0.05). Most myelinated nerves were matured and arranged densely with a uniform structure of myelin in a neat pattern along the long axis in the AG and GM + CT groups, however, regenerated nerve was absent in the BLANK group, left the 10 mm gap empty after resection, and the nerve fiber exhibited a disordered arrangement in the collagen tube group. These results indicated that the hybrid system of bilayer collagen conduit and GDNF-loaded gelatin microspheres combined with gelatin-methacrylamide hydrogels could serve as a new biodegradable artificial nerve guide for nerve tissue engineering.

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Injectable, porous, and cell-responsive gelatin cryogels

Cited by 279 publications

References 31 publications

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

Gelatin-methacrylamide gel loaded with microspheres to deliver GDNF in bilayer collagen conduit promoting sciatic nerve growth

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