**3.1 Hydrogels/MSCs scaffolds for wound healing**

Wound healings are regulated by series of events with overlapping phases, which represent an intractable issue in clinical practice [83, 84]. State-of-the-art renewal has indicated the prospective applications of hydrogel in combination with MSCs or MSC-derived exosomes in skin wound healing, and in particular, the recurrent and refractory cutaneous types (**Table 1**) [83, 85]. Of them, chronic refractory wounds are disorders attribute to multifactorial comorbidity with characteristics of inflammation and impaired vascular networks, which eventually result in unfavorable prognosis due to the lack of effective treatments [36, 86]. Recently, Yang and the colleagues topically applied UC-MSC-derived exosomes encapsulated into the thermosensitive PF-127 hydrogel (hydrogel/MSC-exo) and demonstrated that hydrogel/MSC-exo scaffold significantly upregulated expression of multiple cytokines (e.g., VEGF and TGFβ-1), enhanced regeneration of granulation tissue and accelerated wound closure

#### *Hydrogels - From Tradition to Innovative Platforms with Multiple Applications*

**Figure 1.** *Illustration of hydrogel/MSC-based cytotherapy for tissue engineering.*

rate in a streptozotocin-induced diabetic rat model, which was further verified by another study in a streptozotocin-induced diabetic model with hydrogel/AD-MSC composite [33, 36]. Marusina et al. and Xin et al. reported the influence of tunable bio-inert poly (ethylene glycol)-based hydrogels and microporous annealed particle hydrogels on MSCs and the optimization of cell-degradable hydrogels/MSCs delivery for wound re-epithelialization [81, 87]. Zhang et al. took advantage of the bioluminescence imaging (BLI) technology and further demonstrated the therapeutic effects of prostaglandin E2 (PGE2) and chitosan (CS) hydrogel (PGE2 + CS hydrogel) in a murine wound healing model via modulating the M1 and M2 paradigms of macrophage activation [88]. Meanwhile, a full sheet consisting of A-MSCs on thermoresponsive polymers have been considered as advantaged skin substitute for the management of burn wounds [89]. Collectively, these studies suggested that hydrogel-based MSC/MSC-exo therapy represent a novel therapeutic approach for refractory cutaneous regeneration of chronic wounds.

#### **3.2 Hydrogels/MSCs scaffolds for osteoarticular diseases**

Despite the dramatic progress in bone reconstruction, the osteoarticular diseases and bone regeneration in clinical practices are still challenging [82]. Hydrogels have been extensively investigated in numerous osteoarticular diseases (e.g., osteoarthritis) and bone regeneration (e.g., craniofacial bone tissue) largely attribute to the high cell compatibility [34]. For example, Ji et al. recently combined MSCs with a newly synthesized hybrid scaffold consisting of thermosensitive hydroxypropyl chitin hydrogel (HPCH) and 3D-printed nano-hydroxyapatite (nHA)/poly

#### *Mesenchymal Stem/Stromal Cells and Hydrogel Scaffolds for Tissue Engineering DOI: http://dx.doi.org/10.5772/intechopen.101793*

(ε-caprolactone) (PCL) for bone regeneration. Strikingly, they found the vascularization and osteogenesis and immunomodulation of encapsulated MSCs as well as cytokine secretion of macrophages were collectively orchestrated in bone defect mice model [35].

Osteoarthritis (OA) is recognized as the most prevalent chronic joint disease, which increases in prevalence with age and resultant in functional loss or decline in quality of life, and in particular, act as a major socioeconomic cost worldwide and a leading musculoskeletal cause of impaired mobility in individuals over 65-year-old [90, 91]. Despite joint replacement is an effective strategy for symptomatic end-stage disease, yet most of the functional outcomes are poor and the lifespans of prostheses are largely limited [91, 92]. Current studies have shown that MSC-based cytotherapy are promising for osteoarticular disease administration. For example, Portron et al. and Merceron et al. found that the *in vivo* chondrogenic potential of AD-MSCs encapsulated in a cellulose-based self-setting hydrogel (Si-HPMC) preconditioned by hypoxia (5% oxygen) was significantly enhanced compare to that in the control (20% oxygen) group, which was confirmed by subcutaneous transplantation of AD-MSCs with an injectable hydrogel in rabbits [93, 94]. Very recently, our group also found that the application of hyaluronic acid (HA) hydrogel/PSC-MSCs and HA hydrogel/ hydroxyapatite/UC-MSC (HA/HAP/UC-MSC) composite with reinforced efficacy upon OA rabbits and mice, respectively (**Table 1**) [11]. It's noteworthy that Chung and their colleagues have systematically explored and detailed dissected the efficacy of articular cartilage repair *in vivo* by combining UC-MSCs with various hydrogels such as alginate, pluronic, HA, and chitosan. They finally concluded that HA hydrogel/UC-MSC composites resulted in preferable cartilage repair and collagen organization pattern, which were similar to adjacent uninjured articular cartilage [95]. Additionally, the gingival MSC-laden photocrosslinkable hydrogels were also confirmed with preferable biocompatibility, biodegradability, and osteoconductivity for craniofacial bone tissue engineering in rat peri-implantitis model as well [34]. Taken together, the biodegradable and biocompatible hydrogels can serve as advantaged scaffolds and supply structural integrity for cellular organization and morphogenic guidance of hydrogel scaffold-laden MSCs [88].

#### **3.3 Hydrogels/MSCs scaffolds for reproductive diseases**

Premature ovarian failure (POF) is a refractory disorder with declined fertility in females [96, 97]. In 2019, Yang and their colleagues took advantage of collagen scaffold loaded with UC-MSCs (collagen/UC-MSCs) and verified the efficacy in POF mice via increasing estrogen (E2) and ovarian volume, and promoting granulosa cell proliferation and ovarian angiogenesis [96]. Similarly, Ding et al. reported the rescue of E2 concentrations and activation of follicles in the dormant ovaries of premature ovarian failure (POF) patients with long history of infertility after transplantation of collagen/UC-MSC scaffold (**Table 1**) [38].

As to premature ovarian insufficiency (POI), an intractable endocrine disease that severely restricts the reproductive and physiological function of females and resultant in menopausal symptoms, a series of literatures have suggested the ameliorative effect of hydrogel/MSC composite or hydrogel/MSC-derived microvesicles/secretomes via facilitating angiogenesis, enhancing granulosa cell generation and steroidogenesis, and accelerating follicular regeneration [98–101]. Notably, Li et al. have summarized the current renewal of the therapeutic effects and molecular mechanisms of MSC-based cytotherapy in both preclinical research and clinical trials [102].

#### **3.4 Hydrogels/MSCs scaffolds for vascular diseases**

Peripheral arterial diseases (PAD) are severe medical conditions, which are characterized by blood vascular blockage and low limb Doppler signals and commonly associated with hind-limb ischemia or critical limb ischemia (CLI) [103]. For decades, we and other investigators have primarily suggested the therapeutic of MSCs or MSCderived exosomes in hind limb ischemia models by alleviating the severity, promoting angiogenesis, and enhancing immunomodulation [9, 104, 105]. In recently years, a certain number of outstanding researchers turned to injectable hydrogels such as self-assembled Nap-GFFYK-Thiol hydrogel, nitric oxide-releasing hydrogels, and the novel hydrogel composed of pooled platelet lysate (PL) to enhance the efficacy of MSCs or derivations upon peripheral artery diseases (PADs) [37, 106–108]. For example, Lee et al. found that fucoidan was adequate to improve the bioactivity and vasculogenic potential of MSCs in hind limb ischemia murine with chronic kidney disease (CKD) whereas Nammian et al. further compared the variations of efficacy between BM-MSCs and AD-MSCs for CLI [109, 110]. Notably, Ding and their colleagues systematically dissected an injectable nanocomposite hydrogel consisting of chitosan, gelatin, β-glycerophosphate and Arg-Gly-Asp (RGD) peptide for potential applications of facilitating vascularization and tissue engineering [111]. Collectively, the aforementioned studies suggest that hydrogel/MSC-based composites occupy a greater angiogenic potential over single hydrogel- or MSC-based treatment for PADs.

#### **3.5 Hydrogels/MSCs scaffolds for digestive diseases**

Gastroparesis is characterized by pyloric dysfunction, vomiting, severe nausea, delayed gastric emptying and impaired fundamental structures, which is related with consume of enteric neurons and interstitial cells of Cajal [112]. Meanwhile, stem cell therapy has also been extensively explored in inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn's disease (CD) in both preclinical studies and clinical trials [113–115]. State-of-the-art updates have indicated the mitigatory effects of MSCs in gastrointestinal diseases such as acute ulcerative colitis and perianal CD [8, 10, 68, 116]. For example, we recently reported the spatio-temporal metabolokinetics and efficacy of placenta-derived MSCs (P-MSCs) on intractable CD with enterocutaneous fistula in mice via simultaneously accelerating neovascularization and downregulating reactive oxygen species (ROS) [8]. Interestingly, Joddar et al. conducted delivery of the MSC-alginate/gelatin/poly-l-lysine hydrogel atop stomach grafts facing the luminal side, and confirmed the significant advance towards the entire tissueengineered "microgels" or "gastric patch" [112]. Of note, the therapeutic effects of MSCs via systemic administration are still contradictory largely due to the localization in the lungs, which is confirmed by the outcomes of two clinical trials with BM-MSC transplantation [117, 118]. Therefore, the local administration of hydrogel/MSC or hydrogel/ MSC-exosomes are promising alternatives for resolving refractory digestive diseases.

### **4. Conclusions**

Tissue engineering is an inveterate and promising area in the field of regenerative medicine, which also has long-lasting limitations in engineering and regenerating tissues. MSCs of different origins are splendid "seeds" for the efficient administration of various refractory and recurrent diseases. As mentioned above, MSCs as well as the
