Macroporous polymeric scaffolds as 3D cell niches for tissue regeneration

May 23, 2019

Macroporous polymeric scaffolds as 3D cell niches for tissue regeneration

Technology description

Many tissues in human body are characterized by aligned morphology including muscle, tendon, nerve and blood vessels etc. Recreating such aligned structures is crucial for restoring the functions of these tissues upon tissue loss during disease processes or traumatic events. As such, there is a critical need for methods that allow guiding aligned cell organization and tissue formation, which remains lacking. In this invention, we describe a novel method that allows fabrication of macroporous tissue engineering scaffold with aligned topographical cues for guiding cell alignment and tissue formation in 3D. Such aligned macroporous polymeric scaffolds exhibit great tensile strength, support homogeneous cell encapsulation in 3D, and guide cell organization as well as new extracellular matrix deposition in an alignment manner.

Researchers in the Yang Lab at Stanford have created a new platform for engineering tissue with improved properties and non-invasive injection delivery. Specifically, they have created a microribbon (μRB) hydrogel scaffold which, unlike other hydrogels, forms macropores. These macropores allow cellular migration, matrix deposition, nutrient flow, and integration with endogenous vasculature. The μRB scaffold has tunable properties such as stiffness, biochemical coating, and macropore size. Further, unlike other macroporous scaffolds, the μRB system supports direct cell encapsulation, provides a cell friendly environment, and can be delivered through a non-invasive injection. These features of the uRB system enable the ex vivo creation of a wide variety of tissue grafts with improved biomechanical properties such as load bearing, tensile strength, linear alignment for contractile strength.

Stage of Research:In vivo proof of concept in mouse models of cranial graft and fat graft (see "Supporting Data for figures"). Numerous in vitro PoC studies.

Supporting Data

μRB-based scaffolds enhanced stem cell survival and proliferation in vivo compared to conventional hydrogels after being transplanted in a mouse critical size cranial defect model:(A) Transplanted scaffolds in the cranial defect. (B–E) BLI on days 1 and 7. The red end of the color scale indicates higher signal (in radiance unit, p/sec/cm^3/sr). (F) BLI imaging showed μRB scaffolds led to significantly higher cell survival at day 1 than in conventional hydrogels (p=.002). μRBs enabled cell proliferation up to three-fold after 7 days, whereas the cell number in HG controls remained low; (G) μRB scaffolds led to consistently higher number of transplanted stem cells than conventional hydrogels throughout 6 weeks (p<0.05), with the greatest difference observed within the first 2 weeks. n = 4 per group, error-bars: standard deviations.

Microribbon scaffold leads to greater mineralized bone repair than hydrogel:Analyzed microCT imaging data showed cell-laden μRBs led to faster and greater mineralized bone repair than conventional hydrogels in a critical sized mouse cranial defect over 6 weeks. Percent of bone healing was normalized to the defect size at day 1. n=4 per group, error-bars: standard deviations.

μRB scaffold, but not hydrogel, creates more linearly aligned muscle tissue:(A,B) Immunostaining of myosin heavy chain (MHC), a marker of contractile smooth muscle cell phenotype in both aligned μRB scaffolds (top row) and gelatin–MA hydrogels. (A) Day 7, (B) day 21 (green: smooth muscle myosin heavy chain, blue: nuclei, scale bar: 100 lm). (C, D) Immunostaining of newly deposited extracellular matrix protein at day 21. (C) Red: collagen I, blue: nuclei, scale bar: 100 lm. (D) Green: collagen IV, blue: nuclei, scale bar: 100 μm.

Long term tensile strength of μRB scaffold:(A,B) A photograph of aligned μRB scaffold (A) before uniaxial tension test and (B) at maximum tensile strain (200%). (C) Tensile stress–strain curve of aligned μRB scaffold. (D) Calculated tensile modulus from stress-strain curve (*p < 0.05).

All figures adapted from:
Han, Li-Hsin, et al. "Microribbon-based hydrogels accelerate stem cell-based bone regeneration in a mouse critical-size cranial defect model."Journal of biomedical materials research. Part A104.6 (2016): 1321.
Lee, Soah, et al. "Aligned microribbon-like hydrogels for guiding three-dimensional smooth muscle tissue regeneration."Journal of biomedical materials research. Part A104.5 (2016): 1064.

Application area

Bone graft (in vivo PoC, see 'Supporting Data') Linearly aligned smooth muscle formation for graft (see ''Supporting Data') Fat grafts for plastic surgery (In vivo PoC data available upon CDA) Cartilage graft (In vivo PoC data available upon CDA) Research tool for 3D in vitro disease modeling, tissue modeling, expansion of stem cells.

Advantages

Compared with injectible systems:greater celullarity, survival, as cells and nutrients are better able to migrate through macropores. Better formation of and integration with host vasculature.Compared with other macroporous scaffolds:cell friendly, can be formed simultaneously with cells rather than needing to be preformed with harsh solvents and heat. More homogeneous distribution throughout scaffold leads to higher cell number and survival. No invasive procedure required to deliver to patients.

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More information

Institution

Stanford University

Keywords:

urb system enable

vitro poc studies

greatest difference observed

myosin heavy chain

uniaxial tension test

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