**3. Biomaterials/MSC-based composites for osteoarthritis management**

Biomaterials of different categories and characteristics have attracted great concerns of investigators in the field of MSC-based regenerative medicine, and thus allow the utilization of unique scaffolds to promote the expansion of MSCs and facilitate their differentiation into appropriate lineages [24, 44]. Biomaterials with highly biocompatible properties are adequate to act as splendid scaffolds for cell attachment and supply preferable microenvironment for the maintenance, differentiation, and biofunction of the encapsulated MSCs, which collectively benefit the *in situ* tissue engineering and translational medicine [45–47]. To date, a series of biomaterials with discrete advantages and disadvantages have been developed and combined with MSCs for regenerative purposes such as the highly biocompatible natural (e.g., collagen, chitosan) and synthetic (e.g., poly-ethyleneglycol, polycaprolactone) biomaterials [44, 46].

### **3.1 Hydrogel/MSC-based scaffolds for OA management**

Hydrogels are splendid biomaterials with unique physical and chemical properties for both soft and hard tissue engineering and regenerative medicine, which largely attributes to the feasibility of orchestrating the critical properties (e.g., elasticity, water content, bioactivity, mechanical stiffness, degradation) rationally and conveniently [48–50]. For decades, hydrogels alone or in combination with appropriate biomaterials have been extensively investigated in various osteoarticular disorders such as OA and meniscus injury [51–53]. For example, our groups recently reported the reinforced efficacy upon OA rabbits by hyaluronic acid (HA) hydrogel and PSC-MSCs composite (HA/PSC-MSCs) compared to those with HA hydrogel or PSC-MSCs alone [24]. Instead, Chung and colleagues systematically compared the efficacy by implanting various hydrogels/UC-MSCs composites in rats such as alginate, chitosan, pluronic, hyaluronic acid (HA), and verified that HA/hUC-MSCs composites rather than relative hydrogels resulted in preferable cartilage repair and achieved collagen organization pattern and cellular arrangements much similar to the adjacent uninjured articular cartilage [54].

Recently, Yang and colleagues further reported the utilization of an injectable and biocompatible Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel for OA treatment, which was found with considerable improvement by controlling the release of MSC-derived small extracellular vesicles (MSC-sEVs) [55]. Similarly, Heirani-Tabasi et al. confirmed the enhanced chondrogenic differentiation capacity of adipose-derived MSCs (AD-MSCs) after incubation with an injectable chitosanhyaluronic acid (CS-HA) hydrogel [56]. Additionally, Tang et al. demonstrated that sEVs derived from umbilical cord MSCs (UC-MSC-sEVs) revealed comparable therapeutic effects for OA but with upregulated proteins mostly involved in extracellular matrix (ECM) organization, immune effector process, PI3K-AKT and Rap1 signaling pathways [57]. Collectively, MSCs or derivatives (e.g., exosomes, sEVs) in combination with injectable hydrogels have attracted considerable attention in OA management for their advantaged chondrogenic differentiation capacity [51, 56, 58].

#### **3.2 Hydroxyapatite (HAP)/MSCs scaffolds for OA management**

State-of-the-art renewals have also highlighted the combination of HAP-based biomaterials with MSCs for OA administration and bone regeneration. For instance, Ji and colleagues recently took advantage of a novel hybrid scaffold composed of nanohydroxyapatite (nHA)/poly ε-caprolactone (PCL) and thermosensitive hydroxypropyl chitin hydrogel (HPCH) for bone defect repair via a mechanism of enhancing vascularization and osteogenesis of encapsulated MSCs [59].

Instead, Shimomura et al. took advantage of a scaffold-free tissue-engineered construct (TEC) and a HAP artificial bone for the treatment of a rabbit osteochondral defect model, and found that osteochondral defects treated with the synovial MSCderived TEC and HAP composite revealed more rapid and efficient subchondral bone repair coupled with cartilaginous tissues as well as good tissue integration to adjacent host cartilage. Moreover, the combined MSC-based implants significantly accelerated postoperative rehabilitation and sustained the longer-term durability of repaired osteochondral lesions in patients with OA [5]. Similarly, with the aid of bone marrowderived MSCs (BM-MSCs) and an interconnected porous hydroxyapatite ceramic (IP-CHA), the large osteochondral defect of the knee in a 21-year-old man was effectively alleviated, and cartilage-like regeneration and bone formation were

observed as well [12]. Additionally, we recently also reported the preferable outcomes of OA by conducting multidimensional optimization of MSC-based formulation in combination with the advantageous HA/PG biomaterials, which showed evaluated therapeutic efficacy over HA alone in ameliorating osteoarthritis progression [60, 61].
