Characteristics of collagen-rich ECM hydrogels and their

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Review

Characteristics of collagen-rich ECM hydrogels and their functionalization with PEG derivatives for enhanced biomedical applications: A review Magdalena Rangel-Argote, Jesús Alejandro Claudio Rizo, José Luis Mata-Mata, and Birzabith Mendoza-Novelo ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00282 • Publication Date (Web): 16 Oct 2018 Downloaded from http://pubs.acs.org on October 17, 2018

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ACS Applied Bio Materials

Characteristics of collagen-rich ECM hydrogels and their functionalization with PEG derivatives for enhanced biomedical applications: A review Magdalena Rangel-Argote,†,‡,ǁ Jesús A. Claudio-Rizo,§,ǁ José L. Mata-Mata,*,‡ and Birzabith Mendoza-Novelo*,†

†

Departamento de Ingenierías Química, Electrónica y Biomédica, DCI, Universidad de

Guanajuato, Loma del Bosque 103, 37150, León, GTO. México.

‡

Departamento de Química, DCNE, Universidad de Guanajuato, Noria alta s/n, 36050,

Guanajuato, GTO. México.

§

Facultad de Ciencias Químicas, Universidad Autónoma de Coahuila, Venustiano

Carranza s/n, 25280, Saltillo, COAH, México.

KEYWORDS: PEG derivatives, ECM hydrogels, hybrid hydrogels, collagen crosslinking

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ABSTRACT: The hydrogels of natural extracellular matrix (ECM) are excellent biomaterials with promising applications in the physiological manufacture of threedimensional (3D) constructs that replicate native tissue-like architectures and function as cargo-delivery, 3D bioprinting or injectable systems. ECM hydrogels retain the bioactivity to trigger key cellular processes in the tissue engineering and regenerative medicine (TERM) strategies. However, they lack suitable physicochemical properties which restricts their applications in vivo. This demand that mechanical and degradation properties of the ECM hydrogels must be balanced against biological properties. By incorporating poly(ethylene glycol) (PEG) into mammalian type I collagen-rich ECM substrates, this task can be accomplished. This review is focused on the use of PEG derivatives, widely used in formulations of pharmaceutical products or in synthesis of biomedical polyurethanes, as a strategy to modulate both physical and biological properties of natural ECM hydrogels. The processing-property relationship in decellularized ECM hydrogels, as well as the main results when used in TERM are discussed. A comparison of the characteristics of PEG-ECM hydrogels is provided in terms of the improvement of structure, mechanics and degradation behavior. Finally, the


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benefits of producing PEG-ECM hydrogels according to in vitro and in vivo performance in different proofs-of-concept of emergent biomedical technologies are overviewed.

INTRODUCTION

In general, it is accepted that bioactivity of a biomaterial and, consequently, its ability to participate in tissue regeneration processes are influenced by its mechanical, physicochemical and degradation properties. Biomaterials in hydrogel state can provide a highly swollen 3D environment like native tissues and allow the diffusion of nutrients and cell debris through the porous network.1,2 Depending on the origin, hydrogels can be natural (e.g., collagen,3,4 fibrin,5,6 elastin,7,8 chitosan,9,10 cellulose,11,12 alginate,13,14 hyaluronic acid15,16) or synthetic (e.g., poly(acrylic acid) (PAA),17 poly(ethylene glycol) (PEG),18,19

poly(vinyl

alcohol)

(PVA),20,21

polyacrylamide

(PAAm)22

and

polypeptides23,24). In general, the hydrogels are being studied in the reparation and assisted regeneration of a variety of tissues, such as nerve,25 cardiac,26 skin,27 cartilage,14,28 bone29 and vasculature.30


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The ECM is the non-cellular component in all tissues and organs that provides not only essential physical scaffolding for the cellular constituents but also initiates crucial biochemical and biomechanical cues, which are required for tissue morphogenesis, differentiation and homeostasis.31,32 This matrix is comprised of a variety of proteins and polysaccharides that are locally secreted and assembled into a network organized in close association with the surface of the cell that produced them,33 as outlined in Figure 1. Type I collagen is the main structural protein that functions as mechanical support and load bearing element in the ECM. Besides, it holds a role in the cell–matrix interactions as binder for other proteins (such as fibronectin, laminin) to promote essential cellular functions.34 The intact ECM can be processed by decellularization methodologies to remove cellular and nuclear components from tissues. Then, it can be hydrolyzed in acidic conditions to produce water-dispersed collagen molecules. Since collagen triple helix is retained in the hydrolysates, its polymerization (self-assembly) under physiological conditions (pH 7.0, 37 °C) produces an ECM gel. The hydrogels derived from decellularized ECM retain the biocompatibility related to their matrix components, but


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they lack suitable mechanical properties and a controlled degradation rate.35,36 Moreover, the use of animal ECM as a biomaterial is often associated with disadvantages that include potential immunogenicity and variability among source tissues.37 The modification of these biopolymers with synthetic polymers is a way to improve properties in the gel state. Consequently, the applications of these biohybrids could be more efficient and safer. PEG, a polymer of ethylene oxide repetitive units, is one of the most used synthetic polymers for the functionalization of peptides or proteins, in a so-called PEGylation process.38 PEG is the name of a family of hydrophilic polymers with applications in the surface modification,39 biofuncionalization38,40 drug delivery41, cell photoencapsulation42 and TERM.43 It is considered as a safe and non-toxic polymer.41 PEG has linear and branched (multiarm or star) structures, as shown in Figure 1. The end groups of a basic PEG molecules are hydroxyls, which can be derivatized into other functional groups, such as methyloxyl, carboxyl, amine, thiol, vinyl sulfone, azide, acetylene, and acrylate.44 The two functional end groups can be the same (symmetric) or different


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(asymmetric), which are versatile for the formation of hydrogels or for chemical conjugation with biomolecules.41,44,45 PEG-ECM hydrogels are attractive biomaterials because they provide a 3D template in an aqueous environment with biological activity due to the presence of ECM molecules.46–48. The techniques of biofabrication and the selection of PEG derivatives are also crucial to balance the physical and biological properties of hybrid hydrogels. Herein, we discuss the processing and main characteristics of the most studied natural ECMs in the gel state. Strategies focused on the activation of PEG molecules for their conjugation with the collagen molecule and evidence on the modulation of the gel characteristics are also discussed. By the end of the review, the perspectives of the enhancement of the properties and application of natural ECM hydrogels after the modification with PEG derivatives in the TERM context are discussed.


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Figure 1. Schematic representation of ECM and PEG molecules as precursors in the preparation of hybrid biomedical hydrogels. The variety of biomacromolecules that are locally secreted and assembled in close association with the surface of the cell that produced them is outlined (left). The linear and branched structures in PEG are also outlined (right).

PROCESSING–PROPERTY

RELATIONSHIP

IN

DECELLULARIZED

ECM

HYDROGELS


7


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The natural ECM provides of crucial biochemical and biomechanical cues for cells involved in the wound healing process.32,49 For this, composition and physical properties of ECM gels are essential to influence on cellular function. The preservation of the native composition and the demand-over modification are of paramount importance in the search of gels with enhanced properties and function. This aspect has led the assessment of several source tissues. Among them are rat tail tendon,50 bovine Achilles tendon,51 bovine pericardium,52 porcine intestinal submucosa,53 porcine bladder,54 fish skin55 and porcine skin.56 These ECM hydrogels have shown bioactivity and biocompatibility associated with their residual composition.31,52 Table 1 compares the changes in the residual composition of the ECM due to the decellularization and solubilization treatments. It follows that the residual composition in the ECM hydrolysates depends on the selected tissue. The decellularization process is intended to remove cellular materials from tissue to render the resultant ECM scaffold compatible with implantation in an immunocompetent host.35,57–59 Whereas, the solubilization of the acellular ECM must retains the type I collagen triple helix structure. This task is accomplished using diluted acid assisted with


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pepsin which is responsible for removing telopeptides which decrease the immunogenicity of collagen.31,35,60 The use of different tissues requires the use of decellularization and extraction methods that can impact differentially composition and properties of the resulting ECM gel. Table 2 compares several types of ECM hydrogels in terms of the tissue of origin, the biochemical composition, the processing conditions and the main results in TERM studies.


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Table 1. Effect of processing of several animal tissues on ECM composition ‘richness’. The alteration to the ECM composition is dependent upon the tissue of interest.

Biochemical residual composition after decellularization and Type of hydrolysis steps ECM

Collage n

Bovine bone Porcine cartilage Porcine esophagu s Porcine liver

I

GA

Lamini

Elasti

Fibronecti

Proteoglyca

G

n

n

n

ns

++

I and II

+++

I, III and V

+

+++

Growt h factors ++

++

Re f

61

62,6

+++

+++

+

+

+++

+++

+

64

++

++

65

3

I, III, IV, VI,

XI, ++

++

and XIX

Porcine

I, III, IV

dermis

and VII

Fish skin

I and II

Porcine

I, III, IV,

small

V

intestine

VII

++

+++

++

+++

++

++

+

+

+

+++

+++

+++

+++

+++

and +++

++

66,6 7

68

+++

35,5 2


10

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Bovine tendon

I

+++

+

+

52

I

+++

+

+

52

++

++

Achilles Rat tail Porcine urinary bladder

I, III and IV

+

++

++

+

35

The + symbol is associated with the relative number of components assessed in the ECM hydrolysates. The presence of higher + symbol means that higher quantity of biomolecule is presented. If the + symbol is not indicated, it means that the component was not detected in the assay.


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Table 2. Diverse ECMs employed in the design of biomedical hydrogels.

Source

of

ECM

Detected

Treatment characteristics

residual

components

ECM

Main role of the ECM hydrogel

Ref

Bone Decellularization: Bovine

chloroform:methanol, Solubilization:

trypsin/EDTA.

hydrochloric

acid,

pepsin.

Type

I

collagen;

GAG;

non- It induces in vivo bone formation

collagenous proteins and retained exhibiting cellular debris.

osteoinductivity

and

69,70

enhanced mineralization.

Cartilage Decellularization: trypsin, nucleases, Porcine

Triton X-100, peracetic acid:ethanol. Type I, II collagen; GAG; laminin It Solubilization:

hydrochloric

acid, and elastin.

stimulates

chondrogenesis

and

prevents angiogenesis.

63

pepsin. Esophagus Porcine (Mucosa/ Submucos

trypsin/EDTA, Type I, III and IV collagens; GAG; It enhances migration of esophageal stem cells and supports formation of 3D Triton X-100, sodium deoxycholate, laminin and elastin organoids. peracetic acid:ethanol. Solubilization: Decellularization:


12

64

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a)


acetic acid, pepsin.

Liver Decellularization: Porcine

trypsin/EDTA, Type I, III, IV, VI, XI and XIX It supports and anchorages for cells,

Triton X-100, sodium deoxycholic collagens, acid, peracetic acid, sodium dodecyl elastin;

fibronectin;

laminin; segregates

proteoglycans;

growth intercellular

sulfate. Solubilization: hydrochloric factors; heparin sulfate; biglycan induces acid, pepsin.

and tenascin.

tissue,

regulates

communication,

phenotypic

maturation

and

71

of

human fetal hepatocytes.

Skin Decellularization:

trypsin;

ethanol, Type I, III, IV and VII collagens;

Porcine

H2O2, Triton X-100/EDTA, peracetic elastin; fibronectin; laminin; GAG;

(dermis)

acid:ethanol.

Solubilization: growth factors (VEGF, FGF and

hydrochloric acid, pepsin. Decellularization: Fish

NaOH,

TGF-) and hyaluronic acid.

It

induces

myogenesis,

supports

myoblast fusion with less fibroblast

56,72

infiltration and gel contraction. It exhibits low immunogenicity and high

butyl

alcohol, acetic acid, centrifugation. Type I collagen. Solubilization: acetic acid, pepsin.

biodegradability,

while

facilitating

adhesion, spreading and proliferation of

73–75

epithelial cells.

Small intestine submucosa Porcine

Decellularization: ethanol, Triton X- Type I, III, IV, V and VII collagens; It repairs defects in abdominal wall,


13

53,76,7


100/EDTA, nucleases. Solubilization: GAG hydrochloric acid, pepsin.

(heparin,

heparin sulphate);

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hyaluronic

sulphate, fibronectin;

acid, diaphragm,

lower

chondroitin esophagus,

urinary

tract,

7

musculotendinous

laminin; structures and blood vessels.

elastin and growth factors (TGF-, b-FGF, VEGF). Tendon Bovine Achilles

Decellularization: ethanol, Triton X100/EDTA, nucleases. Solubilization: hydrochloric acid, pepsin.

Rat tail

Solubilization:

Type I collagen; GAG; laminin; stem fibronectin and proteoglycans.

cells

and

enhances

bone

regeneration by human adipose stromal

52

cells.

Decellularization: Triton/EDTA,

It induces osteogenic differentiation of

It facilitates repair of tendon tissue

ethanol, nucleases. Type I collagen; GAG; laminin; hydrochloric

acid, fibronectin and proteoglycans

pepsin.

without

exacerbating

inflammation

and

a

prolonged enhances

78,79

differentiation of the epidermis and dermis layers.

Urinary bladder Porcine (basement membrane)

Decellularization:

peracetic Type I, III, IV and VII collagens; It promotes myogenesis and acid/ethanol. Solubilization: elastin; GAG and growth factors reconstruction of laryngeal and hydrochloric acid, pepsin. (VEGF, FGF, EGF, TGF-, KGF, esophageal tissues, and acts in the


14

80,81

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HGF, PDGF, BMP).

treatment of urinary incontinence and as a myocardial patch.


15


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CROSSLINKING OF ECM HYDROGELS AND ITS EFFECT ON PROPERTIES

Replication of native ECM-like architectures in vitro is behind the motivation of the exploration of biohybrid hydrogels in TERM applications. ECM hydrogels exhibit biocompatibility and biodegradability, but they have poor mechanical properties and fast degradation, limiting their use as cargo delivery systems or long-term dressings, among others.82–84 The properties can be tailored by physical crosslinking (e. g., using freeze-drying cycles84–86 or forming interpenetrated networks (IPN) with other macromolecules86), and/or by chemical crosslinking (using

glutaraldehyde,82,87

genipin,85,88

carbodiimides,89

acrylates90

or

oligourethanes84). Typically, hydrogel formation is the result of self-assembly of the collagen that occurs simultaneously with crosslinking, or in a stepwise process, as outlined in Figure 2. These methodologies involve the formation of covalent bods between reactive groups of the collagen molecule, such as carboxylate (-COO-) and amine (-NH2), and reactive crosslinkers. As a consequence, delayed degradation, enhanced mechanical properties, and impaired antigen recognition

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have been achieved, but with poor modulation.83 Thus, the challenge still focuses on the development of efficient synthetic routes under physiological conditions to regulate the physicochemical properties of the gel without being detrimental to the biocompatibility of ECM biomaterials. PEG-based approaches that benefit from the aqueous miscibility of acid-solubilized ECM with PEG derivatives are promising methods to address this task.

Figure 2. Outline of the preparation of hybrid hydrogels based on hydrolyzed ECM and water-soluble crosslinkers. Aspect of (a) liquid precursors, (b) hydrogel and (c) sponge. Scheme of the gel formation by (I) simultaneous process and (II) stepwise process.



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PEG DERIVATIVES AS MODULATORS OF THE PROPERTIES OF THE ECM HYDROGELS

PEG, HO–(CH2CH2O)n–H, is a not toxic and not antigenic synthetic polymer, available with molecular weights from 200 to tens of thousands.91 PEG is on the FDA’s GRAS list, (compounds Generally Recognized as Safe) and has been approved by the FDA for internal consumption.91,92 PEG is considered as weakly immunogenic, a factor that has allowed the development of PEG–protein conjugates as drugs.41 The PEG solution in water is used in tissue culture media and for organ preservation,92 while in the gel state it is used for drug delivery and biomedical devices.93,94 PEG hydrogels with high mechanical strength and biodegradability are of special interest in the search for temporary devices in the repair of tendon or articular cartilage.95,96 PEG has also been used as scaffolding biomaterial for cells, due to its ability to be easily modified to create a variety of novel structures with different reactive groups and properties. Consequently, PEG has been combined with other


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polymers to produce hydrogels intended to engineer cartilage,95 bone97 and nerve,98 as well as to support key cellular and biophysiologic events of wound healing, such as vascularization

99

and cell differentiation.100 In this respect,

controlled synthesis of functionalized-PEG provides versatile agents for modifying bioactive natural polymers (e.g., chitosan, collagen, alginate) in order to balance the physicochemical and biological properties of biohybrid hydrogels. Functionalization of PEG. The physicochemical properties of the ECM hydrogels can be tuned by incorporating PEG molecules that bring various functionalities. Scheme 1 shows the diverse methodologies available to synthetize functionalizedPEG. The hydroxyl end groups in PEG, either linear or multiarm,101 have been modified with functionalities, including acrylate, methacrylate, aldehyde or isocyanate. Then, the conjugation of ECM proteins or peptide sequences with them renders a biohybrid gel network that combines properties.102 Modification of the ECM hydrogels with PEG-derivatives. Chart 1 illustrates the main chemical methodologies that use PEG derivatives for the modification of biopolymer through substituents ended in -NH2 or -COOH. The resulting hydrogels 19 ACS Paragon Plus Environment


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are potentially biodegradable and provide mechanical support and a swollen 3D environment to encapsulate cells or bioactive molecules.43 The concentration of PEG in biohybrid hydrogels seems to be important to improve their mechanics and degradation.92 Properties such as nontoxicity, nonimmunogenicity, and transport of nutrient and oxygen have been maintained after modification of the ECM hydrogels with PEG.27,47,103 The biofabrication of PEG-ECM hydrogels under mild conditions has resulted in suitable cell encapsulation techniques.44,104 Since PEG resists protein adsorption, cells can not bind directly to it.44,105 This makes it an attractive additive in ECM hydrogels to preserve the bioactivity of the biopolymers.36,47,106 The conjugation of functionalized-PEG with the residues in the ECM biopolymers, as mentioned previously, is influenced by the reaction conditions.107 It is reasonable that the different chemical techniques cause distinctive characteristics in the methods and the resulting materials. Table 3 shows the relevant aspects of the synthesis of PEG derivatives and their conjugation with ECM biopolymers (mainly type I collagen), as well as the advantages and disadvantages of the biofabrication methods. 20 ACS Paragon Plus Environment

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Scheme 1. Synthetic routes for the preparation of functionalized-PEG used in the design of biomedical hydrogels.



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Chart 1. Illustrative representation of several chemical methodologies based on PEG derivatives tested for the control of the properties of ECM hydrogels. The scheme shows the collagen structure with its N-ended reactive groups, and the chemical linkages formed with functionalized-PEG.


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Table 3. Main characteristics of functionalized-PEG and their uses in the design of biomedical ECM-based hydrogels.

Functionalized-

Main

steps

PEG

derivatization Mixing

in

in

PEG

and

(PEGDA)

in

with

K2CO3

hydrogel Advantages

inert of collagen network.

and within

collagen

into hydrogel.

aqueous/organic phases.

MgSO4,

the

Infiltration of PEGDA

extraction

Drying

biohybrid

in

Disadvantages

Ref

acryloyl

atmosphere. Washing

steps

trimethylamine/ Physical crosslinking

dichloromethane

PEG diacrylate

Main

formation

PEG

chloride

the

with

UVin of

hydrogel

enhanced

mechanical

and hydrolytic stability (that is dependent on and

the

exhibiting

time of UV irradiation),

anhydrous photopolymerization

precipitation

A

susceptibility

towards

enzymatic

UV irradiation induces formation

of

reactive

radicals, altered collagen structure, and a potential cytotoxicity.

46,108 ,

109

network- degradation.

diethyl ether and dried under infiltrated PEGDA. vacuum. PEGsuccinimidyl

Coupling of ended carboxylic Mixing PEG-NHS (0- An in-situ gelled Crosslinking is groups to the PEG molecule 30 %v) with collagen hydrogel exhibiting susceptible to moisture


110,11 1


ester

(PEG- Reaction

NHS)

with solution.

oxocarbonylsuccinimidyl chloride under mild conditions (30 min, at 25°C).

Mixing

dibutyraldehyde (PEG-DBA)

Heating (37°C, 18 h) for

the

hydrogel

formation.

with

butyryl

chloride

using

tissue- and

induces

altered

adhesion properties, as collagen structure and well as highly tunable changes

in

mechanics, swelling and morphology degradation properties.

the of

encapsulated cells. Crosslinking requires a

with of A hydrogel exhibiting post-treatment collagen and enhanced mechanical, sodium benzene as solvent and HCl cyanoborohydride with chitosan. optical and suturability as catalyzer in inert cytotoxic effects and properties, as well as Mixing biopolymers atmosphere. produces high permeability to glucose with PEG-DBA, EDC crosslinking index Evaporation of by-produced and albumin. and NHS. reducing porosity and ethanol and benzene. diffusion properties. diacetal

PEG-

PEG

enhanced

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Reaction

of

PEG

Mixing

solutions

hydrolyzed An in-situ gelled Gel formation is inhibited with hydrogel exhibiting with high concentrations oligourethane (30 tunable properties of oligourethanes, and its

112

with Mixing ECM

Polyurethane

aliphatic diisocyanates.

prepolymers

Blocking isocyanate groups %w) and neutralizing. depending on the cytocompatibility is also with sodium bisulfite. decreased. Heating (37°C for 2 chemical structure of


84,113

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h).

oligourethanes.

Activation Radical

polymerization

of

PEG multiarms triols, tetradiols or pentadiols. (-NHS, -DA)

Functionalization with amine reactive groups.

of

Crosslinking

induces

carboxylic groups in An injectable and in-situ altered surface collagen with gelled hydrogel chemistry, porosity and EDC/NHS. properties, exhibiting without the diffusion gel formation Reaction with amine need for an external while requires long incubation reactive 4S-PEG- (pH polymerization trigger. 5.5, 10 h, 37°C).

47,105 ,

114

times.

EDC: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; NHS: N-Hydroxysuccinimide; 4S-PEG: PEG ether tetrasuccinimidyl glutarate.



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CHARACTERISTICS AND APPLICATIONS OF THE PEG-ECM HYDROGELS Injectable systems containing cells. ECM biomaterials in the gel state that act as templates for cells and as injectable substrates require of adequate physicochemical properties, which are expected to be reached after their modification with PEG derivatives. In the search of gels for vascular tissue engineering, diacrylamide-PEGcollagen hydrogels exhibited hydrolytic stability and control in the susceptibility towards enzymatic degradation.42,115 The organization of endothelial cells within these hydrogels, after a photocrosslinking process, depended on the degree of crosslinking induced in the material. The coculture of endothelial cells and fibroblasts within these hydrogels produced enhanced capillary morphogenesis in vitro.42 Figure 3 illustrates examples of studies about ECM hydrogels modified with other PEG derivatives, including PEG-NHS and PEG-DBA. The effect of the modification on the microstructure and the behavior in vitro and in vivo is appreciated. Two multiarm PEGDA were employed to prepare hydrogels derived from decellularized myocardial matrix: i) crosslinking of the matrix proteins using a amine-


26

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reactive star-PEGDA, and ii) the radical photopolymerization of two different multiarmPEGDA.114 Both methods allowed the conjugation of PEG to the myocardial ECM, producing a network of nanofibers as the unmodified matrix does. The crosslinking agent and its molecular weights were associated with the fiber diameter in the gel. Hybrid hydrogels synthesized with star-PEGDA gelled after 30 min, like unmodified matrix gels, while the materials prepared by photopolymerization gelled in 4 min. The incorporation of PEGDA did not prevent the cell adhesion and migration through the hybrid matrix; offering the possibility of generating an injectable hydrogel that degrades more slowly in in vivo conditions. While the photopolymerization allowed 3D encapsulation of the cells. Multiarm PEG derivatives have been tested in the encapsulation of chondrocytes104 and nucleus pulposus cells.116 Chondrocytes were encapsulated and homogeneously dispersed in hydrogels based on collagen crosslinked with 4S-PEG. The cell survival, glycosaminoglycan production and expression of type II collagen increased with the culture time and suggested this injectable system is useful in minimally invasive treatment strategies for cartilage repair.104 In the search of injectable reservoir systems


27


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for intervertebral disc regeneration, a nucleus pulposus-carrier hydrogel comprised of type II collagen (porcine cartilage), hyaluronic acid and 4S-PEG with low cytotoxicity was developed. This hydrogel system was stable in culture and had the capacity to support cell growth, maintain type I collagen expression and preserve the nucleus pulposus cell morphology.

Figure 3. Representative applications of ECM-PEG hydrogels. a) General aspect and b) SEM-visualized microstructure of the hydrogels comprised of: I) non-crosslinked collagen (CHG), II) collagen crosslinked with 4S-PEG50, III) pure PEGDA, and IV)


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collagen crosslinked with PEGDA. (I) CHG showed a homogeneous network of regular fibrils, whereas (II) 4S-PEG50 showed few fibril-like structures as indicated by the white arrows. Red arrow in (IV) indicates a flat PEGDA structure surrounded by collagen fibrils, while the image inset (III and IV) shows the gel microstructure at 40,000x magnification. c) H&E analysis of implants comprised of I) collagen/chitosan crosslinked with PEG-DBA and EDC/NHS, and II) collagen crosslinked with PEG-DBA and EDC/NHS, after 120-day rat subcutaneous implantation. Cross-sectional view of the implants revealed that materials is surrounded by the host tissue. Radiographs of the defect site in the cranium of New Zealand rabbits obtained by X-ray examination after surgery for 4 (III) and 12 (IV) weeks using a PEG-PCL-PEG/collagen/ hydroxyapatite hydrogel (where PCL is polycaprolactone). d) Immunofluorescent staining of constructs cultured with wild-type endothelial cells for 14 days revealed capillary networks in (I) PEGDA/1%PEG and (II) PEGDA/2%PEG (red is CD31+ cells, green is actin, and blue are nuclei). Confocal micrographs of L929 fibroblastic cells grown on the (III) collagenPEG gels and (IV) collagen-PEG-NHS (nuclei in blue, F-actin in red). Panel a(I-II) and panel b(I-II) reproduced with permission from reference

117

copyright 2017 American


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Chemical Society. Panels a(III-IV) and b(III-IV) reproduced with permission from reference

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copyright 2015 Elsevier. Panel c(I-II) reproduced with permission from

reference

112

copyright 2008 Elsevier. Panel c(III-IV) reproduced with permission from

reference

97

copyright 2012 Elsevier. Panel d(I-II) reproduced with permission from

reference

42

copyright 2013 Elsevier. Panel d(III-IV) reproduced from reference

110

copyright 2012 Grace and Wah, under the attribution non-commercial, no derivative license.

Bone marrow mesenchymal stem cells (MSCs) were embedded in an injectable hydrogel based on thiolated collagen and triblock acrylate-containing oligo(acryloyl carbonate)-b-poly(ethylene

glycol)–oligo(acryloyl

carbonate)

(OAC-PEG-OAC)

copolymers.118 This hydrogel system, formed via a Michael-type addition reaction, was evaluated as an intramyocardial injection in an infarcted rat heart. The presence of polycarbonate in these bioactive hybrid hydrogels allowed a controllable hydrolytic degradation rate and non-acidic degradation products and provided improved mechanical properties. In part due to the multiple acryloyl functional groups allowing


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facile adjustment of the crosslinking density. On the other hand, the Michael-type addition hydrogels have been extensively explored for the in-situ formation of biodegradable hydrogels that they are formed quickly under physiological conditions without the aid of a catalyst and without generating any byproducts, fully circumventing potentially toxic contaminations. The loading of the bone marrow MSCs in biohybrid ECM hydrogels has reached preclinical studies in animals with positive effect on cardiac function after myocardial infarction, mainly through multiple paracrine effects. Biohybrid hydrogels have been used in bone tissue engineering. For this, injectable systems based on PEG-ECM hydrogels have been combined with other synthetic polymers and bioactive inorganic particles. A triblock PEG-PCL-PEG copolymer was mixed with collagen (from bovine tendon) and nano-hydroxyapatite to render a thermoresponsive hydrogel.97 The copolymer transitions from the liquid state to the gel state at temperatures close to those of the human body, along with the collagen. After injection in rabbit cranial defects, the bone healing was favorable after 20 weeks of implantation, which was associated with composition and biodegradability of the hydrogels.


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Fibrillogenesis in vitro of collagen is induced by increasing pH and temperature, followed by the chemical crosslinking step. The unreactive PEG chains have also proven to induce the collagen self-assembly; controlling the fiber size and mechanical properties.111 A method based on the protected isocyanate chemistry has been proposed as an alternative to properly induce simultaneously the self-assembly of type I collagen and its crosslinking by grafting molecules of water-soluble oligourethane.84 Gel formation rate and the network parameters such as fiber diameter, porosity, crosslinking degree, mechanics, swelling, in vitro degradation and cell proliferation, kept a direct relationship with the oligourethane concentration. This suggested hydrogels where the adjustment of the crosslinking degree offers advantages to control the materials structure and their properties. Controlled release systems containing bioactive cargos. Hydrogels based on PEGcollagen capable of delivering therapeutics in a controlled manner represent a platform for guiding tissue regeneration. In the design of biocomposite hydrogels combining structure and properties for loading and delivering of cargos with immunomodulatory activity, the incorporation of silica particles and dexamethasone inside oligourethane-


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collagen hydrogels was proposed,113,119 as schematized in Figure 4. In this approach, the molecular weight of oligourethanes, synthesized from PEG and hexamethylene (HDI), L-lysine (LDI), isophorone or trimethylhexamethylene diisocyanates, was determined by the chemical structure of the starting aliphatic diisocyanate. Consequently, the collagen gel formation and both the physicochemical characteristics and mechanics of the formed 3D network had a direct relation with the oligourethane molecular weight. The crosslinking of collagen with oligourethanes was compatible with the orthosilicate polycondensation depositing silica particles on the 3D network. Oligourethane based on LDI induced a high crosslinking degree, but also increased water uptake, susceptibility to degradation and cytocompatibility, contrary to the impact of HDI-based oligourethane. Since an enhanced secretion of the chemoattractant cytokines transforming growth factor-beta1 (TGF-β1) and monocyte chemoattractant protein-1 (MCP-1 or CCL-2) was registered in macrophages cultured on hydrogels crosslinked with LDI-based oligourethane, an immunomodulatory hydrogel was suggested.113

In

addition,

biocomposite

hydrogels

showed

local

release

of

dexamethasone at pH 7.4 and 37 °C in vitro.119 Consequently, the delivery of


33


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dexamethasone from biocomposites enhanced cell metabolic activity and TGF-β1 secretion by macrophages RAW264.7. The cell delivery represents another potential alternative to regulate the in vivo biological performance.

A biomaterial with PEG hydrogels containing entrapped

collagen type 1 (from rat tail) to support cell–matrix interactions and matrix metalloproteinase (MMP)-sensitive crosslinks to enable facile recovery of the encapsulated aggregates was developed.120 The platform was demonstrated with rat insulinoma cell line RIN-m5F and human embryonic stem cell (hESC) derived pancreatic progenitor cells, showing encapsulation and subsequent controlled release of single cells and aggregates without adversely affecting viability. MMP-sensitive PEG hydrogel containing collagen type I acted as a platform for hESC-derived pancreatic progenitors that maintains viable aggregates, aggregate size, and progenitor state and offers facile recovery of aggregates. It was suggested as a promising 3D culture platform for the survival, differentiation, and maturation of pancreatic progenitor cells into functional β-cells.


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Figure 4. Biocomposites hydrogels based on ECM, PEG and inorganic nanoparticles as promising biomaterials to modulate the biological response.

Modulating cellular behavior in 3D culture systems. Hydrogels composed of PEGcollagen have demonstrated the ability to modulate cellular phenotypes in a 3D microenvironment. In an unreactive system, PEG chains act as modulators of the collagen self-assembly (in vitro fibrillogenesis) though thermodynamic control.111 This methodology allowed controlled fiber size and mechanics of the collagen-derived hydrogels. Consequently, the hydrogels showed the ability to modulate the phenotype of encapsulated fibroblasts. The cell-instructive hydrogels have also been generated through reactive systems. The incorporation of PEG and PEG-NHS in collagen


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hydrogels to produce different structural characteristics allowed the stimulation of a range of cellular microenvironments.110 Again, PEG influenced the aggregation of the collagen fibrils producing larger fiber diameter, while the PEG-NHS acted as a crosslinking agent of the collagen fibrils and decreased the pore size of the gel. L929 fibroblasts cultured on the collagen-PEG hydrogels showed the highest levels of filamentous actin accompanied by an elongated morphology. In contrast, a round phenotype of fibroblasts seeded onto collagen-PEG-NHS hydrogels was reported. Radiation-induced crosslinking has been reported in a terpolymer hydrogel based on collagen, PEG and polyvinylpyrrolidone (PVP).121 A moderate dose of -irradiation and a low concentration of PVP–PEG increased the human fibroblast viability compared to the irradiated plain collagen. In addition, fibroblast proliferation and viability were observed in hybrid hydrogels comprised of collagen, PEG-dimethacrylate and HA.122 The morphology of the cells changed from spherical to flattened spread morphology with increasing concentrations of HA demonstrating clearly the migration of the cells for the formation of an interconnected cellular network. A relationship between the structure of the hybrid gel network and the behavior of the cells would be interesting to investigate.


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All together, these observations suggest a scarless wound healing, in which damaged skin tissue is restored in a regenerative manner,123 can be engineered with collagenPEG instructive hydrogels for the cells. The nerve cell behavior was also related to the differences in the mechanical properties of the collagen-PEG-DA hydrogels.105 The gel rigidity (storage modulus, G ') increased significantly with increasing PEG-DA concentration, while the addition of collagen reduced it. After controlling for gel mechanics, neurite expression by PC12 line cells and neurite extension of the chicks’ dorsal root ganglia were improved with hydrogels of lower stiffness. PEGDA photopolymerized with collagen mimetic peptide was used to encapsulate chondrocytes.106 After culture of these cells in collagenPEGDA, they were able to increases the production of glycosaminoglycan collagen, 87 and 103 %, respectively, as compared with the control PEG hydrogels. Corneal epithelial cells have been cultured in PEG-collagen IPN hydrogels for searching substitutes alternatives to the donor tissue in corneal transplants.124,125 First, human corneal epithelial cells were seeded into the IPN hydrogels formed by photocuring of poly(6-methacryloyl-α-D-galacto-pyranose) (pMG, a glycopolymer


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crosslinked by PEGDA) and type I collagen (porcine) crosslinked with EDC/NHS.125 The incorporation of pMG into collagen hydrogel increased the tensile strength and modulus and degradation resistance towards collagenase, as well as retained the optical characteristics, which were comparable to those of human corneas. Second, cells were cultured in a corneal substitute based on collagen-phosphorylcholine IPN hydrogels.124 In this case, porcine atelocollagen was crosslinked with EDC/NHS, and 2methacryloyloxyethyl phosphorylcholine (MPC) was crosslinked with PEGDA. This IPN hydrogel showed increased mechanical strength and resistance against collagenase digestion or UV degradation. In addition, the collagen–MPC hydrogels supported the attachment and proliferation of immortalized human corneal epithelial cells and promoted nerve growth and tissue (epithelium, stroma) regeneration in mini-pigs. The behavior of human MSCs within an IPN hydrogel based on collagen type I and PEGDA was reported.46 The encapsulation process maintained cell viability above 90%. The delay time between the formation of the cell-containing collagen hydrogel and the formation of the PEGDA-crosslinked network was reported as a key factor to allow cell propagation within the IPN hydrogels. The cell elongation was enabled in the IPN


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hydrogels, while resistance to cell-mediated matrix contraction and thromboresistance increased, relative to pure collagen hydrogels. Elongated MSCs within the collagenPEGDA IPN hydrogel progressed through the initial stages of smooth muscle cell differentiation when cultured in the presence of TGF-β3, a growth factor that can stimulate either chondrogenesis or smooth muscle cell formation depending on the local cell environment. Finally, Table 4 recaps a variety of cells and gels which are studied as 3D culture systems for modulating cellular behavior.


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Table 4. Examples of 3D culture systems that use ECM-PEG hydrogels.

Cells

Gels

Study

Ref

Endothelial cells Bovine type-I collagen

Investigate

and fibroblasts

ECM-PEGDA

constructs to support co-cultures.

Human

Rat tail

Support the initial stages of hMSC

mesenchymal stem cells

PC12 cells

Mouse fibroblasts

Immortalized human

progression

ECM-PEGDA

ability

toward

of

a

these

smooth

42

46

muscle cell lineage. Examine

Rat tail

how

concentrations

of

PEG gels influence the stiffness,

ECM-acryl-PEG-NHS

PC12 cell behavior and dorsal root

with the hydrogel formation.

Porcine

collagen

powder

(type-I

105

ganglia (DRG) neurite extension. Cell encapsulation simultaneously

ECM-PEG-NHS

corneal atelocollagen)

epithelial cells

the

100

Corneal implants

112

Viability and proliferation analysis

114

Cell viability in fibroblasts

121

ECM-PEG-DBAEDC/NHS

Fibroblasts

Myocardial matrix ECM-star-PEG-NHS Pepsinized

Human fibroblast

porcine

collagen ECM-PEG-PVP


40

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Dermal

Rat tail

fibroblasts

ECM-4S-PEG100 Liver,

Full-thickness skin equivalents for in

heart,

skeletal muscle Human liver cells

vitro testing

117

and Implementation in creating a viable

PEG and functional primary human liver (linear, 4-arm, and 8- construct in vitro. ECM-multiarm

126

arm)

Elastomeric materials for the treatment of defects in soft tissues. Robust and tough PEG-based hydrogels have been proposed as disposable biomedical devices, flexible sensors and actuators, or complex tissues structure-mimicking scaffolds.47,127,128 The photocrosslinking of PEG-lactide diacrylate (PEGLADA) in the presence of type I collagen resulted in a elastomeric and degradable hydrogel system.127 The mechanical properties of the hydrogels depended predominantly on the concentration of PEGLADA, whereas the degradation was strongly dependent on temperature. This behavior was associated with a balance of the molecular interactions that reinforce the fibrous structure of collagen. The crosslinking of collagen with multiarm PEG functionalized with succinimidyl ester reactive groups rendered a hydrogel with elastic moduli comparable


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to soft tissues including skin and non-fibrotic liver.47 In an approach to closely mimic the mechanical characteristics of the native cornea, the crosslinking of collagen/chitosan hydrogels with EDC/NHS and PEG-DBA simultaneously produced an increase in mechanical strength and elasticity.112 This was related to the formation of hybrid networks with both short- and long-range cross-linking agents. Scl2-2 (collagen-mimetic protein)-PEGDA hydrogels have been tested as templates to induce lumen endothelialization after implantation of small-diameter arterial graft prostheses. The adhesion, proliferation, spreading and function of both the endothelial progenitor cells and the human umbilical vein endothelial cells were supported observed in these hydrogels. 129 Bioinks for 3D bioprinting. Additive manufacturing, known as 3D printing, is a methodology that uses computer-aided design (CAD) software to produce physical models in 3D, which could be used as templates for biomedical applications. Generally, this process involves the creation of successive layers based on a mixture of polymers with the desired thermal and rheological behavior. The set of these polymeric layers generates the final shape of the template. In this regard, diverse formulations of


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polymers, whether natural or synthetic, have been studied to improve their applications in 3D bioprinting, i. e., the manufacture of constructs containing cells.130–133 The incorporation of pericardial hydrolyzed ECM (including collagen, fibronectin, and glycosaminoglycans) into PEGDA hydrogels formed a 3D-printable and degradable hydrogel with significantly distinct modulus depending on concentration of either component. Rat bone marrow derived macrophages developed an M2 phenotype in response to low amounts of pericardial ECM in culture.133 The structural integrity and fracture toughness of fibroblast-laden hydrogels was achieved by bioprinting of PEGDA and gelatin.134 Varying the volume ratios of gelatin methacrylate-to-PEG-dimethacrylate, the behavior (cell viability, spreading) of human periodontal ligament stem cells were found to be depended on the ECM composition.132 The 3D stereolithographic technology was employed to yield a layer-by-layer UV polymerizable rapid prototyping system, which is proposed as multi-material cantilevers composed of PEGDA and acrylic-PEG-collagen mixtures.135 The incorporation of acrylic-PEG-collagen into PEGDA-based materials enhanced adhesion, spreading and organization of cells without altering the ability to vary the elastic modulus through the molecular weight of


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PEGDA. Cardiomyocytes derived from neonatal rats were seeded on the cantilevers. These cantilevers were used as a sensor to measure the contractile forces of cardiomyocyte cell sheets, and as an early prototype for the design of cell-based biohybrid actuators. These observations suggest that PEG-ECM materials should be considered as potential bioink for 3D bioprinting, expanding the standardization of the manufacturing process and biological evaluation.

PERSPECTIVES AND CONCLUSIONS

Currently, diverse reactive forms of functionalized-PEG have been synthesized and coupled with the reactive groups of the wide variety of ECM-components. As mentioned above, direct relationships of the incorporation of PEG derivatives with the physicochemical and biological properties of the hybrid hydrogels have been established. Incorporated either by physical or chemical processes, PEG derivatives accelerate the gelation rate of type I collagen (majority ECM's protein), modifying the structural parameters and surface chemistry of the natural ECM gel network. It is


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important to consider that the efficiency of these approaches improves when the components of the native ECM are conserved because they are responsible for a suitable biological response. Since the mechanics and degradation of a hydrogel are associated with the response of cells to them, the modification of the collagen-rich ECM gel network with PEG derivatives is an attractive route to obtain biomaterials with tailored characteristics and feasible manufacturing. Moreover, this modification could support the enrichment of hybrid ECM hydrogel with therapeutic cargoes such as cells, drugs or nanoparticles, which is already envisaged as a strategy to enhance the bioactivity and control of the 3D cellular microenvironment. As a final comment, the increasing applications of decellularized ECM hydrogels, and the adequate conjugation with PEG derivatives to further improve the properties represents a promising area of research for the generation of customized biomedical hydrogels. AUTHOR INFORMATION

Corresponding Author


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E-mail: [email protected] (B.M.N.) and E-mail: [email protected]

*

(J.L.M.M.).

Author Contributions ǁ

M.R.A. and J.A.C.R. contributed equally.

Funding Sources Mexico's National Council of Science and Technology (CONACYT): grant PDCPN_2015/1310. ACKNOWLEDGMENT This work was supported by a doctoral scholarship from CONACYT to M.R.A and the grant PDCPN_2015/1310.

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Characteristics of collagen-rich ECM hydrogels and their

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