Table 2 Summary of scaffolds for MSC delivery in diabetic wound healing

Hydrogel scaffold

Collagen type I

Mouse BM-MSCs and AD-MSCs

STZ-induced diabetic C57BL/6 mouse

Murine BM-MSCs and AD-MSCs are equivalent at enhancing wound healing

MSC treatment improve wound healing by increasing VEGF-A expression, cellular proliferation, endothelial cell density, numbers of macrophages and smooth muscle cells and upregulating Notch signalling

Guo et al. [57]

Hydrogel scaffold

Collagen type I

Mouse BM-MSCs

STZ-induced diabetic C57BL/6 mouse

Transplantation of rolled scaffolds containing BM-MSC increased wound healing, cellular proliferation and capillary density as well as increased number of macrophages, fibroblasts and smooth muscle cells

Scaffolds in a rolled formation, were hypoxia, induced MSC secrete VEGF

Assi et al. [56]

Hydrogel scaffold

PEGDA and gelatin

Mouse AD-MSCs

db/db diabetic mouse

AD-MSC embedded hydrogel significantly accelerated diabetic wound healing

Hydrogel-mediated delivery of AD-MSCs accelerated wound closure by supressing infiltration of inflammatory cells (macrophages and T cells) and enhancing neovascularization

Dong et al. [59]

Hydrogel scaffold

N-isopropylacrylamide and poly (amidoamine)

Mouse BM-MSCs

db/db diabetic mouse

Promoted granulation tissue formation, angiogenesis, ECM secretion, wound contraction, and re-epithelialization

Hydrogel promoted BM-MSC secretion of TGFβ-1 and bFGF, inhibited pro-inflammatory M1 macrophage expression

Chen et al. [60]

Hydrogel scaffold

Pluronic F-127

Rat AD-MSCs

STZ-induced diabetic Sprague Dawley rat

AD-MSC-hydrogel enhanced angiogenesis and cell proliferation at the wound site, accelerated wound closure

Upregulated expression of VEGF and TGFβ-1 play a key role in matrix deposition, cellular migration and wound healing

Kaisang et al. [62]

Hydrogel scaffold

Silk fibroin, chitosan

Rat AD-MSCs

STZ-induced diabetic Sprague Dawley rat

Wound closure rate increased. Neovascularization improved

AD-MSCs engrafted in hydrogel scaffold promoted the secretion level of EGF, TGF-β, VEGF in the diabetic wound bed

Wu et al. [63]

Hydrogel scaffold

POLY(β-aminoester)-tetraaniline, HA, gelatin, laccase

AD-MSCs (unknown species)

STZ-induced diabetic Sprague Dawley rat

AD-MSC encapsulated hydrogel enhanced vascular regeneration and immunoregulation in diabetic wound bed, promoted the reconstruction of blood vessels, hair follicles and dermal collagen matrix

AD-MSCs encapsulated in hydrogel exhibited upregulated expression of HIF-1a and connexin 43

Jin et al. [66]

Hydrogel scaffold

HA and PEGDA

AD-MSCs (species unknown)

STZ-induced diabetic Sprague Dawley rat

Improved diabetic wound healing process, enhanced angiogenesis and re-epithelialization

Hydrogel maintained the stemness and secretion abilities of AD-MSCs

Xu et al. [67]

Hydrogel scaffold

Chitosan and HA

Rat BM-MSCs

STZ-induced diabetic Sprague Dawley rat

Promoted granulation tissue formation, collagen deposition, cell proliferation, neovascularization and enhanced diabetic wound healing

The secretion of growth factors (TGF-β1, VEGF and bFGF) from BM-MSCs were increased, hydrogel regulated the inflammatory environment via modulating the macrophages polarization

Bai et al. [64]

Hydrogel scaffold

Chitosan, polyvinyl alcohol, S-nitroso-N-acetylpenicillamine (SNAP)

Rabbit BM-MSCs

Alloxan-induced diabetic rabbit

SNAP-loaded hydrogel combined with BM-MSC significantly improved wound healing rate, re-epithelialization and collagen deposition

The gene-expression of VEGF and SDF-1a were significantly upregulated in wounds treated with BM-MSCs embedded in Nitric-oxide-releasing hydrogels

Ahmed et al. [65]

Hydrogel scaffold

HA

Human AD-MSCs

db/db diabetic mouse

AD-MSC promoted wound closure and accelerated epithelialization

Stem cell markers (NANOG, OCT3/4, SOX-2 and SSEA-3) were up-regulated in AD-MSC microgel

Feng et al. [68]

Hydrogel scaffold

Gellan gum and HA

Human AD-MSCs

STZ-induced diabetic CD1-ICR mouse

AD-MSCs treatment resulted in re-epithelialization, thicker and more differentiated epidermis on wound bed

AD-MSCs treatment improve wound healing via modulating the inflammatory response during proliferative phase of wound healing to promote a successful neovascularization

Da silva et al. [70]

Hydrogel scaffold

Decellularized adipose matrix

Human AD-MSCs

KK/Upj-Ay/J mouse (Diabetic mouse)

Accelerated wound closure and increased neovascularization

Decellularized adipose matrix supported hAD-MSCs survival and proliferation, enhanced paracrine activity and increased secretion of HGF

Chen et al. [71]

Hydrogel scaffold

HyStem®-HP hydrogel

VEGFA hyper secreted human BM-MSCs

db/db diabetic mouse

Improved wound healing rate in wounds treated with VEGFA hyper secreted hBM-MSCs

N/A

Srifa et al. [72]

Hydrogel scaffold

PEGDA, 1-vinyl-2-pyrrolidinone, eosin Y

Rat ISCs and human BM-MSCs

db/db diabetic mouse

ISC:MSC combination group accelerate diabetic wound healing almost 3 times faster than control group (14 vs. ~ 40 days), without intermediate scab or scar

Co-encapsulation of ISC and BM-MSC in hydrogel improved wound healing by secreting insulin, VEGF, and TGFβ-1. The viability and function of MSC improved due to activation of the PI3K-Akt/PKB pathway

Aijaz et al. [73]

Sponge scaffold

Collagen type I

Rabbit BM-MSCs

Alloxan-induced diabetic rabbit

Collagen BM-MSC treatment promoted wound closure and angiogenesis in diabetic rabbit ulcer

Increased total length of blood vessels with enhanced neovascularization in collagen BM-MSC group

O’Loughlin et al. [79]

Sponge scaffold

Collagen, chitosan

Rat BM-MSCs

STZ-induced diabetic Wistar rat

BM-MSC treatment accelerated wound closure in diabetic rat

Hypoxia pre-treated BM-MSC increased the expression of HIF-1a, VEGF, and PDGF, promoted wound closure via reducing inflammation and enhancing angiogenesis in diabetic wound bed

Tong et al. [80]

Sponge scaffold

Chitosan, collagen, nanostructured lipid carriers, simvastatin

Rat epidermal MSCs

STZ-induced diabetic Wistar rat

Increased wound closure rate, promoted vascularization, enhanced viability and proliferation of stem cells

Sponge scaffolds provide a microenvironment suitable for cell proliferation, molecules transmission, and a controlled release of simvastatin

Örgül et al. [82]

Sponge scaffold

Chitosan and polyurethane

Rat AD-MSCs

STZ-induced diabetic Sprague Dawley rat

MSC-scaffold bio-complex and acupuncture treatment improved wound closure (90.34 ± 2.3%), completely re-epithelialized in 8 days

The combined treatment of MSC-scaffold bio-complex and acupuncture on wounds produced synergistic immunomodulatory effects via activating C3a and C5a, up-regulating the secretion of cytokines SDF-1 and TGF β-1, and downregulating proinflammatory cytokines TNF-α and IL-1β

Chen et al. [83]

Sponge scaffold

Curcumin, chitosan, alginate, EGF

Mouse BM-MSCs

STZ-induced diabetic Sprague Dawley rat

BM-MSCs delivered by Curcumin-EGF scaffold significantly improved wound closure by increasing granulation tissue formation, collagen deposition and angiogenesis

The scaffold enhanced BM-MSC viability and expression of transcription factors associated with the maintenance of pluripotency and self-renewal (OCT3⁄4, SOX2, and Nanog)

Mohanty et al. [84]

Fibrous scaffold

Polycaprolactone, pluronic-F-127, gelatin

Mouse BM-MSCs

TALLYHO type 2 diabetic mouse

BM-MSC engraftment enhanced granulation tissue formation, promoted angiogenesis and collagen deposition in diabetic wound site

The BM-MSC engraftment inhibited the formation of M1-type macrophages and expression of pro-inflammatory cytokines (IL-6, TNF-α), promoted formation of M2-type macrophages and expression of anti-inflammatory cytokines (IL-4, IL-10) in the diabetic wound

Chen et al. [92]

Fibrous scaffold

Polylactic acid, silk and collagen

Human BM-MSCs

STZ-induced C57BL/6 J diabetic mouse

HO-1-overexpressing human BM-MSCs-scaffold complex significantly promote angiogenesis and wound healing

Over-expression of HO-1 promoted the proliferation and paracrine (e.g. VEGF) activity of BM-MSC via Akt signalling pathway

Hou et al. [93]

Fibrous scaffold

Polylactic acid, silk and collagen

Human BM-MSCs

STZ-induced C57BL/6 J diabetic mouse

Wound healed prominently, more blood vessel formation

Brain-derived neurotrophic factor activated MSCs differentiate into endothelial cells and accelerated wound healing

He et al. [94]

Fibrous scaffold

Aloe vera, polycaprolactone

Human UC-MSCs

db/db diabetic mouse

Diabetic wounds showed rapid wound closure, re-epithelialization and increased number of sebaceous glands and hair follicles

After treatment, the wounds showed positive keratinocyte markers (cytokeratin, involucrin, filaggrin) and increased expression of ICAM-1, TIMP-1, and VEGF-A

Tam et al. [95]

Fibrous scaffold

Silk fibroin

Human AD-MSCs

db/db diabetic mouse

Both AD-MSCs-SF and decellularized AD-MSCs-SF significantly enhanced wound closure, completing the process in around 10 days as compared to 15–17 days in control group

SF bind angiogenic factors (bFGF and TGF-β) produced by AD-MSCs; AD-MSCs-SF stimulate hUVECs migration through release of VEGF; Enhanced ECM deposition, angiogenesis and immunomodulation; Down-regulated inflammatory gene expression (Mif and Il6st)

Navone et al. [96]

Decellularized graft

Cadaveric skins of human donors

Rat AD-MSCs

STZ-induced diabetic Sprague Dawley rat

AD-MSCs-scaffold treatment significantly enhanced wound closure and epithelialization

AD-MSCS secreted angiogenic growth factors (VEGF, HGF, TGFβ and bFGF) resulting in accelerated wound healing

Nie et al. [111]

Decellularized graft

IRC mouse skin

Mouse BM-MSCs

Diabetic ICR mouse

BM-MSC-decellularized graft increased angiogenesis and reepithelialisation on diabetic wound bed

BM-MSCs-scaffold treatment enhanced synthesis of collagen type I during wound healing, increased epidermal thickness and vessel density

Chu et al. [98]

Decellularized graft

IRC mouse skin

Mouse BM-MSCs

STZ-induced IRC mouse

Induced robust vascularization and collagen deposition and rapid re-epithelialization

Scaffolds provide a microenvironment for cell attachment, migration and proliferation

Fu et al. [112]

Decellularized graft

Porcine skin, collagen, and chitosan

Human UC-MSCs

STZ-induced diabetic Sprague Dawley rat

UC-MSC delivered by decellularized graft significantly improved wound healing

Therapeutic effect of UC-MSCs on diabetic wound significantly enhanced by the activation of Wnt signalling pathway

Han et al. [113]