Bioengineered scaffolds for modulation of immune system and the uses thereof

1 . A composition for modulating the immune system in a subject, comprising:

a porous scaffold comprising a click-hydrogel or a click-cryogel, wherein the porous scaffold comprises macropores having a diameter greater than about 20 μm;

a growth factor comprising a bone morphogenetic protein-2 (BMP-2) present at between about 1 ng to about 1000 ng per scaffold or at about 0.03 ng/mm 3 to about 350 ng/mm 3 by volume of scaffold, and in an amount effective for inducing formation of a tissue or an organ within the scaffold and recruiting a cell into the scaffold; and

a differentiation factor comprising a Delta-like 4 (DLL-4) that induces the differentiation of the recruited cell into a T cell progenitor cell, wherein the T cell progenitor cell is capable of differentiating to a T cell.

2 . The composition of claim 1 , wherein the scaffold comprises a click hydrogel.

3 . The composition of claim 1 , wherein the scaffold comprises a polymer or co-polymer selected from the group consisting of polylactic acid, polyglycolic acid, PLGA, alginate or an alginate derivative, gelatin, collagen, agarose, hyaluronic acid, poly(lysine), polyhydroxybutyrate, poly-epsilon-caprolactone, polyphosphazines, poly(vinyl alcohol), poly(alkylene oxide), poly(ethylene oxide), poly(allylamine), poly(acrylate), poly(4-aminomethylstyrene), pluronic polyol, polyoxamer, poly(uronic acid), poly(anhydride), poly(vinylpyrrolidone), and any combination thereof.

4 . The composition of claim 1 , wherein:

(i) the scaffold comprises a polymer or co-polymer selected from the group consisting of alginate, alginate derivative, and the combination thereof; and/or

(ii) the scaffold comprises a polymer or co-polymer selected from the group consisting of hyaluronic acid, hyaluronic acid derivative, and the combination thereof.

5 . The composition of claim 1 , wherein:

(i) the scaffold comprises pores having a diameter between about 20 μm and 100 μm;

(ii) the scaffold comprises a macropore, optionally wherein the macropore has a diameter between about 50 μm and 80 μm, and/or

(iii) the scaffold comprises macropores of different sizes.

6 . The composition of claim 1 , wherein the scaffold is injectable.

7 . The composition of claim 1 , wherein:

(i) the scaffold comprises methacrylated alginate (MA-alginate);

(ii) the scaffold comprises a hyaluronic acid or a hyaluronic acid-derivative;

(iii) the click-hydrogel or click cryogel comprises a click-alginate, a click-gelatin, or a click-hyaluronic acid; and/or

(iv) the scaffold comprises hydroxyapatite.

8 . The composition of claim 1 , wherein the scaffold comprises porogen hydrogel microbeads and a bulk hydrogel, wherein the porogen hydrogel microbeads degrade at least 10% faster than the bulk hydrogel polymer scaffold following administration of the scaffold into a subject and/or wherein the porogen hydrogel microbeads comprise oxidized alginate.

9 . The composition of claim 1 , wherein:

(i) the cell is a stem cell;

(ii) the cell is a progenitor cell;

(iii) the cell is a stromal cell; or

(iv) the cell is a hematopoietic stem cell.

10 . The composition of claim 1 , wherein:

(i) the tissue or the organ comprises a bone tissue or a hematopoietic tissue;

(ii) the tissue or the organ is formed about 7-21 days after the composition is administered to the subject; and/or

(iii) the tissue or the organ is formed about 14 days after the composition is administered to the subject.

11 . The composition of claim 1 , wherein:

the growth factor retains its bioactivity for at least twelve days after the growth factor is incorporated into the scaffold.

12 . The composition of claim 1 , wherein the T cell comprises a cell selected from the group consisting of a CD4+ T cell, a CD8+ T cell, a regulatory T cell (Treg), and any combination thereof, or wherein the T cell comprises a Treg.

13 . The composition of claim 1 , wherein:

(i) the differentiation factor is covalently linked to the scaffold;

(ii) the differentiation factor is covalently linked to the scaffold utilizing click chemistry;

(iii) the differentiation factor is covalently linked to the scaffold utilizing N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) chemistry, NHS and dicyclohexylcarbodiimide (DCC) chemistry, avidin-biotin reaction, azide and dibenzocycloocytne chemistry, tetrazine and transcyclooctene chemistry, tetrazine and norbornene chemistry, or di-sulfide chemistry; and/or

(iv) the differentiation factor retains its bioactivity for at least about three months after the differentiation factor is incorporated to the scaffold.

14 . The composition of claim 1 , wherein:

(i) the recruited cell is a transplanted cell;

(ii) the recruited cell is not a transplanted cell;

(iii) the recruited cell is autologous;

(iv) the recruited cell is allogeneic; or

(v) the recruited cell is xenogeneic.

15 . The composition of claim 1 , wherein the differentiated cell is capable of migrating out of the scaffold, and/or wherein the differentiated cell is capable of homing to a tissue in a subject after the composition is administered to the subject.

16 . The composition of claim 1 , further comprising a homing factor that is capable of promoting the recruitment of the cell to the scaffold.

17 . The composition of claim 16 , wherein the homing factor comprises a stromal cell derived factor.

18 . A method of modulating the immune system, reducing immune over-reactivity, increasing donor chimerism, and/or promoting balanced reconstitution of T cells of a human having a compromised immune system, comprising administering to the human a composition comprising:

a porous scaffold comprising a click-hydrogel or a click-cryogel;

a growth factor comprising a bone morphogenetic protein-2 (BMP-2) present in an amount effective for inducing formation of a tissue or an organ within the scaffold and recruiting a cell into the scaffold; and

a differentiation factor comprising a Delta-like 4 (DLL-4) that induces the differentiation of the recruited cell into a T cell progenitor cell,

thereby modulating the immune system of the human,

wherein the human has a compromised immune system due to immunosenescence, congenital immunodeficiency, or acquired immunodeficiency.

19 . A syringe comprising:

a needle;

a reservoir that comprises the composition of claim 1 ; and

a plunger.

20 . A kit comprising:

the composition of claim 1 ; and

instructions to administer the composition.