Cartilage Repair Using Composites of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronic Acid Hydrogel in a Minipig Model

Abstract

The cartilage regeneration potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with a hyaluronic acid (HA) hydrogel composite has shown remarkable results in rat and rabbit models. The purpose of the present study was to confirm the consistent regenerative potential in a pig model using three different cell lines. A full-thickness chondral injury was intentionally created in the trochlear groove of each knee in 6 minipigs. Three weeks later, an osteochondral defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm-wide and 5-mm-deep reaming. A mixture (1.5 ml) of hUCB-MSCs (0.5 3 10 7 cells per milliliter) and 4% HA hydrogel composite was then transplanted into the defect on the right knee. Each cell line was used in two minipigs. The osteochondral defect created in the same manner on the left knee was untreated to act as the control. At 12 weeks postoperatively, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. The cellular characteristics (e.g., cellular proliferation and chondrogenic differentiation capacity) of the hUCB-MSCs influenced the degree of cartilage regeneration potential. This evidence of consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1044-1051 SIGNIFICANCETo date, several studies have investigated the chondrogenic potential of human umbilical cord bloodderived mesenchymal stem cells (hUCB-MSCs); however, the preclinical studies are still limited in numbers with various results. In parallel, in the past several years, the cartilage regeneration potential of hUCB-MSCs with a hyaluronic acid (HA) hydrogel composite have been investigated and remarkable results in rat and rabbit models have been attained. (These experimental results are currently in preparation for publication.) Before applying the cartilage regeneration technique in a human clinical trial, it seemed necessary to confirm the consistent result in a larger animal model. At 12 weeks postoperatively, the minipigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. This evidence of consistent cartilage regeneration with composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future.

Development of kartogenin-conjugated chitosan–hyaluronic acid hydrogel for nucleus pulposus regeneration

“…21 Chitosan is structurally analogous to GAGs, and HA is a major component of the ECM in the NP. 10,12,14 Hydroxyl groups in HA can cross-link with amino groups in CS. CS when combined with glycerol phosphate and HA can undergo a sol-gel transition at 37°C by covalent crosslinking.…”

“…HA has been used broadly for osteoarthritis treatment, 11 as an intra-articular injective material, and has been proven to support cell proliferation and maintain the chondrogenic phenotype. 12 It has been demonstrated that HA-based hydrogels can direct recovery or replacement of the endogenous NP for NP tissue engineering and cellular therapies. 13 Another suitable candidate for cartilage and NP tissue repair is chitosan.…”

Cartilage repair techniques in the knee: stem cell therapies

“…Jung showed that enhancement of cartilage repair with the use of collagen type I/III membrane significantly improves the repair tissue quality in minipigs [37]. In addition, use of allogenic MSC and xenoimplantation of human umbilical cord bloodderived MSC were tested in this animal model, showing induction of cartilage healing by those cell types [42,44]. Efficacy of MSC/scaffold constructs have been shown in other large animals such as sheep, horse, and goats [45][46][47][48][49].…”

“…Among those, a (mini)pig model has been most frequently employed in previous studies [37][38][39][40][41][42][43][44]. Various cell types and materials were tested in the studies.…”

“…With the intent of evaluation with models that is more relevant to clinical condition in humans, large animals such as pig and sheep have been used as experimental subjects [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]. Among those, a (mini)pig model has been most frequently employed in previous studies [37][38][39][40][41][42][43][44].…”