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Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle.

ABSTRACT: Biomaterials, which can contain appropriate biomechanical and/or biochemical cues, are increasingly being investigated as potential scaffolds for tissue regeneration and/or repair for treating myocardial infarction, heart failure, and peripheral artery disease. Specifically, injectable hydrogels are touted for their minimally invasive delivery, ability to self-assemble in situ, and capacity to encourage host tissue regeneration. Here we present detailed methods for fabricating and characterizing decellularized injectable cardiac and skeletal muscle extracellular matrix (ECM) hydrogels. The ECM derived hydrogels have low cellular and DNA content, retain sulfated glycosaminoglycans and other extracellular matrix proteins such as collagen, gel at physiologic temperature and pH, and assume a nanofibrous architecture. These injectable hydrogels are amenable to minimally invasive, tissue specific biomaterial therapies for treating myocardial infarction and peripheral artery disease.

SUBMITTER: Ungerleider JL

PROVIDER: S-EPMC4526417 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle.

Ungerleider J L JL Johnson T D TD Rao N N Christman K L KL

Methods (San Diego, Calif.) 20150402

Biomaterials, which can contain appropriate biomechanical and/or biochemical cues, are increasingly being investigated as potential scaffolds for tissue regeneration and/or repair for treating myocardial infarction, heart failure, and peripheral artery disease. Specifically, injectable hydrogels are touted for their minimally invasive delivery, ability to self-assemble in situ, and capacity to encourage host tissue regeneration. Here we present detailed methods for fabricating and characterizing ...[more]

PMID: 25843605

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Project description:Biodegradable injectable hydrogels have been extensively studied and evaluated in various medical applications such as for bulking agents, drug delivery reservoirs, temporary barriers, adhesives, and cell delivery matrices. Where injectable hydrogels are intended to facilitate a healing response, it may be desirable to encourage rapid cellular infiltration into the hydrogel volume from the tissue surrounding the injection site. In this study, we developed a platform technique to rapidly form pores in a thermally responsive injectable hydrogel, poly(NIPAAm-co-VP-co-MAPLA) by using mannitol particles as porogens. In a rat hindlimb muscle injection model, hydrogels incorporating porosity had significantly accelerated cellular infiltration. To influence the inflammatory response to the injected hydrogel, enzymatically digested urinary bladder matrix (UBM) was mixed with the solubilized hydrogel. The presence of UBM was associated with greater polarization of the recruited macrophage population to the M2 phenotype, indicating a more constructive foreign body response. The hybrid hydrogel positively affected the wound healing outcomes of defects in rabbit adipose tissue with negligible inflammation and fibrosis, whereas scar formation and chronic inflammation were observed with autotransplantation and in saline injected groups. These results demonstrate the value of combining the effects of promoting cell infiltration and mediating the foreign body response for improved biomaterials options soft tissue defect filling applications. STATEMENT OF SIGNIFICANCE:Our objective was to develop a fabrication process to create porous injectable hydrogels incorporating decellularized tissue digest material. This new hydrogel material was expected to exhibit faster cellular infiltration and a greater extent of pro-M2 macrophage polarization compared to control groups not incorporating each of the functional components. Poly(NIPAAm-co-VP-co-MAPLA) was chosen as the representative thermoresponsive hydrogel, and mannitol particles and digested urinary bladder matrix (UBM) were selected as the porogen and the bioactive decellularized material components respectively. In rat hindlimb intramuscular injection models, this new hydrogel material induced more rapid cellular infiltration and a greater extent of M2 macrophage polarization compared to control groups not incorporating all of the functional components. The hybrid hydrogel positively affected the wound healing outcomes of defects in rabbit adipose tissue with negligible inflammation and fibrosis, whereas scar formation and chronic inflammation were observed with autotransplantation and in saline injected groups. The methodology of this report provides a straightforward and convenient mechanism to promote cell infiltration and mediate foreign body response in injectable hydrogels for soft tissue applications. We believe that the readership of Acta Biomaterialia will find the work of interest both for its specific results and general translatability of the findings.

Project description:The native extracellular matrix of cartilage contains entrapped growth factors as well as tissue-specific epitopes for cell-matrix interactions, which make it a potentially attractive biomaterial for cartilage tissue engineering. A limitation to this approach is that the native cartilage extracellular matrix possesses a pore size of only a few nanometers, which inhibits cellular infiltration. Efforts to increase the pore size of cartilage-derived matrix (CDM) scaffolds dramatically attenuate their mechanical properties, which makes them susceptible to cell-mediated contraction. In previous studies, we have demonstrated that collagen crosslinking techniques are capable of preventing cell-mediated contraction in CDM disks. In the current study, we investigated the effects of CDM concentration and pore architecture on the ability of CDM scaffolds to resist cell-mediated contraction. Increasing CDM concentration significantly increased scaffold mechanical properties, which played an important role in preventing contraction, and only the highest CDM concentration (11% w/w) was able to retain the original scaffold dimensions. However, the increase in CDM concentration led to a concomitant decrease in porosity and pore size. Generating a temperature gradient during the freezing process resulted in unidirectional freezing, which aligned the formation of ice crystals during the freezing process and in turn produced aligned pores in CDM scaffolds. These aligned pores increased the pore size of CDM scaffolds at all CDM concentrations, and greatly facilitated infiltration by mesenchymal stem cells (MSCs). These methods were used to fabricate of anatomically-relevant CDM hemispheres. CDM hemispheres with aligned pores supported uniform MSC infiltration and matrix deposition. Furthermore, these CDM hemispheres retained their original architecture and did not contract, warp, curl, or splay throughout the entire 28-day culture period. These findings demonstrate that given the appropriate fabrication parameters, CDM scaffolds are capable of maintaining complex structures that support MSC chondrogenesis.

Dataset Information

Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle.

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Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle.

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