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Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial

Saw KY, Anz A, Jee CSY, Merican S, Ching-Soong Ng R, Roohi SA, et al.

Arthroscopy, 2013 Apr;29(4):684-94.
PMID: 23380230 DOI: 10.1016/j.arthro.2012.12.008

PURPOSE: The purpose of this study was to compare histologic and magnetic resonance imaging (MRI) evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intra-articular injections of hyaluronic acid (HA) with and without peripheral blood stem cells (PBSC).
METHODS: Fifty patients aged 18 to 50 years with International Cartilage Repair Society (ICRS) grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients each were randomized to the control (HA) and the intervention (PBSC + HA) groups. Both groups received 5 weekly injections commencing 1 week after surgery. Three additional injections of either HA or PBSC + HA were given at weekly intervals 6 months after surgery. Subjective IKDC scores and MRI scans were obtained preoperatively and postoperatively at serial visits. We performed second-look arthroscopy and biopsy at 18 months on 16 patients in each group. We graded biopsy specimens using 14 components of the International Cartilage Repair Society Visual Assessment Scale II (ICRS II) and a total score was obtained. MRI scans at 18 months were assessed with a morphologic scoring system.
RESULTS: The total ICRS II histologic scores for the control group averaged 957 and they averaged 1,066 for the intervention group (P = .022). On evaluation of the MRI morphologic scores, the control group averaged 8.5 and the intervention group averaged 9.9 (P = .013). The mean 24-month IKDC scores for the control and intervention groups were 71.1 and 74.8, respectively (P = .844). One patient was lost to follow-up. There were no notable adverse events.
CONCLUSIONS: After arthroscopic subchondral drilling into grade 3 and 4 chondral lesions, postoperative intra-articular injections of autologous PBSC in combination with HA resulted in an improvement of the quality of articular cartilage repair over the same treatment without PBSC, as shown by histologic and MRI evaluation.
LEVEL OF EVIDENCE: Level II, randomized controlled trial (RCT).

Matched MeSH terms: Hyaluronic Acid/administration & dosage*
Fulltext Randomized controlled trial comparing efficacy of conventional and new single larger dose of intra-articular viscosupplementation in management of knee osteoarthritis

Suppan VKL, Wei CY, Siong TC, Mei TM, Chern WB, Nanta Kumar VK, et al.

J Orthop Surg (Hong Kong), 2017 9 28;25(3):2309499017731627.
PMID: 28946838 DOI: 10.1177/2309499017731627

BACKGROUND: Intra-articular hyaluronic acid (HA) injection is used in management of knee, hand and hip osteoarthritis. While HA injection is included in the list of evaluated therapies, its efficacy and optimum dosing still have no consensus. This study was conducted to explore the possibility of using single injection HA to increase patient convenience while maintaining the therapeutic efficacy.

METHODS: We present a prospective, open label, non-blinded, randomized controlled trial performed in accordance with guidelines in principles of good clinical practice. Block randomization was done for patients to receive either single 5 ml GO-ON injection or the conventional three injections of 2.5 ml GO-ON at weekly interval. Baseline Western Ontario McMaster University Osteoarthritis (WOMAC) scores were evaluated and recorded. All subjects were re-evaluated at 3 months and the WOMAC score recorded again as primary end points. Data analyses were performed with IBM SPSS Statistics for Windows software (version 21.0, IBM Corp, Armonk, New York, USA).

RESULTS: In the cohort of 127 patients, 33 were males and 94 females. The mean age was 59.1 years (standard deviation (SD) = 7.25) in single injection arm and 60.1 years (SD = 7.72) in triple injection arm. The two groups were recorded to have no significant difference in age ( p = 0.46) and Kellgren-Lawrence radiological grade ( p = 0.694). There was significant increase in the WOMAC scores from the baseline (pre-injection) to that recorded 3 months after injection ( p < 0.001) in patients of both groups. However, there was no statistically significant difference noticed in this clinical improvement between the two arms ( p = 0.889).

CONCLUSION: The study shows single 5 ml dose regime comparing well with conventional three doses of 2.5 ml of intra-articular GO-ON HA injected at weekly intervals and confirms good efficacy, tolerability and safety of single larger dose of GO-ON knee intra-articular injection.

Matched MeSH terms: Hyaluronic Acid/administration & dosage*
Fulltext Effect of intra-articular hyaluronic injection on postural stability and risk of fall in patients with bilateral knee osteoarthritis

Khalaj N, Abu Osman NA, Mokhtar AH, George J, Abas WA

ScientificWorldJournal, 2014;2014:815184.
PMID: 25136689 DOI: 10.1155/2014/815184

Knee osteoarthritis is a common cause of disability which influences the quality of life. It is associated with impaired knee joint proprioception, which affects postural stability. Postural stability is critical for mobility and physical activities. Different types of treatment including nonsurgical and surgical are used for knee osteoarthritis. Hyaluronic acid injection is a nonsurgical popular treatment used worldwide. The aim of this study was to demonstrate the effect of hyaluronic acid injections on postural stability in individuals with bilateral knee osteoarthritis. Fifty patients aged between 50 and 70 years with mild and moderate bilateral knee osteoarthritis participated in our study. They were categorized into treatment (n = 25) and control (n = 25) groups. The treatment group received five weekly hyaluronic acid injections for both knees, whereas the control group did not receive any treatment. Postural stability and fall risk were assessed using the Biodex Stability System and clinical "Timed Up and Go" test. All the participants completed the study. The treatment group showed significant decrease in postural stability and fall risk scores after five hyaluronic acid injections. In contrast, the control group showed significant increase. This study illustrated that five intra-articular hyaluronic acid injections could significantly improve postural stability and fall risk in bilateral knee osteoarthritis patients. This trial is registered with: NCT02063373.

Matched MeSH terms: Hyaluronic Acid/administration & dosage*
Hyaluronic acid decorated tacrolimus-loaded nanoparticles: Efficient approach to maximize dermal targeting and anti-dermatitis efficacy

Zhuo F, Abourehab MAS, Hussain Z

Carbohydr Polym, 2018 Oct 01;197:478-489.
PMID: 30007638 DOI: 10.1016/j.carbpol.2018.06.023

Nano-delivery systems have gained remarkable recognition for targeted delivery of therapeutic payload, reduced off-target effects, and improved biopharmaceutical profiles of drugs. Therefore, we aimed to fabricate polymeric nanoparticles (NPs) to deliver tacrolimus (TCS) to deeper layers of the skin in order to alleviate its systemic toxicity and improved therapeutic efficacy against atopic dermatitis (AD). To further optimize the targeting efficiency, TCS-loaded NPs were coated with hyaluronic acid (HA). Following the various physicochemical optimizations, the prepared HA-TCS-CS-NPs were tested for in vitro drug release kinetics, drug permeation across the stratum corneum, percentage of drug retained in the epidermis and dermis, and anti-AD efficacy. Results revealed that HA-TCS-CS-NPs exhibit sustained release profile, promising drug permeation ability, improved skin retention, and pronounced anti-AD efficacy. Conclusively, we anticipated that HA-based modification of TCS-CS-NPs could be a promising therapeutic approach for rationalized management of AD, particularly in children as well as in adults having steroid phobia.

Matched MeSH terms: Hyaluronic Acid/administration & dosage
Fulltext One-year follow-up of efficacy and cost of repeated doses versus single larger dose of intra-articular hyaluronic acid for knee osteoarthritis

Suppan VKL, Tew MM, Wong BC, Chan HK, Chew YW, Tan CS, et al.

J Orthop Surg (Hong Kong), 2020 3 5;28(1):2309499019895029.
PMID: 32129141 DOI: 10.1177/2309499019895029

PURPOSE: A recent 3-month randomized, open-label controlled trial found that the intra-articular hyaluronic acid injection (GO-ON®) given as a single dose of 5 mL is as effective and safe as three repeated doses of 2.5 mL in patients with knee osteoarthritis. However, the information on the long-term efficacy and economic implications of the single-dose regimen is still limited. Hence, this follow-up study was designed to compare the effectiveness and costs of the two regimens 12 months following the treatment.
METHODS: All the 127 patients, who received either three repeated doses (n = 64) or a single dose (n = 63) of GO-ON in the previous trial, were followed up in month 12 following the treatment. The effectiveness of both the regimens was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the mean WOMAC scores were compared with those recorded at the baseline and in month 3. Additionally, the total treatment costs of the two regimens, taking account of both direct and indirect costs, were computed and compared.
RESULTS: A total of 125 patients (98.4%) completed the assessment. Despite the reduction of the overall mean WOMAC score from 39.24 to 19.93 (p < 0.001) in the first 3 months following the treatment with GO-ON, no further changes were observed up to month 12 (p > 0.95). In the meantime, the two regimens did not differ in the mean WOMAC scores (p = 0.749) and in the subscale scores for pain (p = 0.970), stiffness (p = 0.526), and physical functioning (p = 0.667) in month 12. The cost for single-dose injection was found to be approximately 30% lower compared to the repeated doses.
CONCLUSION: These findings indicate that the single larger dose of GO-ON is as effective as the repeated doses over 12 months, and yet the total treatment cost is lowered.

Matched MeSH terms: Hyaluronic Acid/administration & dosage*
Articular cartilage regeneration with autologous marrow aspirate and hyaluronic Acid: an experimental study in a goat model

Saw KY, Hussin P, Loke SC, Azam M, Chen HC, Tay YG, et al.

Arthroscopy, 2009 Dec;25(12):1391-400.
PMID: 19962065 DOI: 10.1016/j.arthro.2009.07.011

PURPOSE: The purpose of the study was to determine whether postoperative intra-articular injections of autologous marrow aspirate (MA) and hyaluronic acid (HA) after subchondral drilling resulted in better cartilage repair as assessed histologically by Gill scoring.
METHODS: In a goat model we created a 4-mm full-thickness articular cartilage defect in the stifle joint (equivalent to 1.6 cm in the human knee) and conducted subchondral drilling. The animals were divided into 3 groups: group A (control), no injections; group B (HA), weekly injection of 1 mL of sodium hyaluronate for 3 weeks; and group C (HA + MA), similar to group B but with 2 mL of autologous MA in addition to HA. MA was obtained by bone marrow aspiration, centrifuged, and divided into aliquots for cryopreservation. Fifteen animals were equally divided between the groups and sacrificed 24 weeks after surgery, when the joint was harvested, examined macroscopically and histologically.
RESULTS: Of the 15 animals, 2 from group A had died of non-surgery-related complications and 1 from group C was excluded because of a joint infection. In group A the repair constituted mainly scar tissue, whereas in group B there was less scar tissue, with small amounts of proteoglycan and type II collagen at the osteochondral junction. In contrast, repair cartilage from group C animals showed almost complete coverage of the defect with evidence of hyaline cartilage regeneration. Histology assessed by Gill scoring was significantly better in group C with 1-way analysis of variance yielding an F statistic of 10.611 with a P value of .004, which was highly significant.
CONCLUSIONS: Postoperative intra-articular injections of autologous MA in combination with HA after subchondral drilling resulted in better cartilage repair as assessed histologically by Gill scoring in a goat model.
CLINICAL RELEVANCE: After arthroscopic subchondral drilling, this novel technique may result in better articular cartilage regeneration.

Matched MeSH terms: Hyaluronic Acid/administration & dosage*
High tibial osteotomy in combination with chondrogenesis after stem cell therapy: a histologic report of 8 cases

Saw KY, Anz A, Jee CS, Ng RC, Mohtarrudin N, Ragavanaidu K

Arthroscopy, 2015 Oct;31(10):1909-20.
PMID: 26008951 DOI: 10.1016/j.arthro.2015.03.038

PURPOSE: To histologically evaluate the quality of articular cartilage regeneration from the medial compartment after arthroscopic subchondral drilling followed by postoperative intra-articular injections of autologous peripheral blood stem cells (PBSCs) and hyaluronic acid with concomitant medial open-wedge high tibial osteotomy (HTO) in patients with varus deformity of the knee joint.
METHODS: Eight patients with varus deformity of the knee joint underwent arthroscopic subchondral drilling of International Cartilage Repair Society (ICRS) grade 4 bone-on-bone lesions of the medial compartment with concomitant HTO. These patients were part of a larger pilot study in which 18 patients underwent the same procedure. PBSCs were harvested and cryopreserved preoperatively. At 1 week after surgery, 8 mL of PBSCs was mixed with 2 mL of hyaluronic acid and injected intra-articularly into the knee joint; this was repeated once a week for 5 consecutive weeks. Three additional intra-articular injections were administered weekly at intervals of 6, 12, and 18 months postoperatively. Informed consent was obtained at the time of hardware removal for opportunistic second-look arthroscopy and chondral biopsy. Biopsy specimens were stained with H&E, safranin O, and immunohistochemical staining for type I and II collagen. Specimens were graded using the 14 components of the ICRS Visual Assessment Scale II, and a total score was obtained.
RESULTS: Second-look arthroscopy showed satisfactory healing of the regenerated cartilage. Histologic analysis showed significant amounts of proteoglycan and type II collagen. The total ICRS Visual Assessment Scale II histologic scores comparing the regenerated articular cartilage (mean, 1,274) with normal articular cartilage (mean, 1,340) indicated that the repair cartilage score approached 95% of the normal articular cartilage score. There were no infections, delayed unions, or nonunions.
CONCLUSIONS: Chondrogenesis with stem cells in combination with medial open-wedge HTO for varus deformity correction of the knee joint regenerates cartilage that closely resembles the native articular cartilage.
LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Matched MeSH terms: Hyaluronic Acid/administration & dosage
Curcumin-laden hyaluronic acid-co-Pullulan-based biomaterials as a potential platform to synergistically enhance the diabetic wound repair

Shah SA, Sohail M, Minhas MU, Khan S, Hussain Z, Mahmood A, et al.

Int J Biol Macromol, 2021 Aug 31;185:350-368.
PMID: 34171251 DOI: 10.1016/j.ijbiomac.2021.06.119

Injectable hydrogel with multifunctional tunable properties comprising biocompatibility, anti-oxidative, anti-bacterial, and/or anti-infection are highly preferred to efficiently promote diabetic wound repair and its development remains a challenge. In this study, we report hyaluronic acid and Pullulan-based injectable hydrogel loaded with curcumin that could potentiate reepithelization, increase angiogenesis, and collagen deposition at wound microenvironment to endorse healing cascade compared to other treatment groups. The physical interaction and self-assembly of hyaluronic acid-Pullulan-grafted-pluronic F127 injectable hydrogel were confirmed using nuclear magnetic resonance (1H NMR) and Fourier transformed infrared spectroscopy (FT-IR), and cytocompatibility was confirmed by fibroblast viability assay. The CUR-laden hyaluronic acid-Pullulan-g-F127 injectable hydrogel promptly undergoes a sol-gel transition and has proved to potentiate wound healing in a streptozotocin-induced diabetic rat model by promoting 93% of wound closure compared to other groups having 35%, 38%, and 62%. The comparative in vivo study and histological examination was conducted which demonstrated an expeditious recovery rate by significantly reducing the wound healing days i.e. 35 days in a control group, 33 days in the CUR suspension group, 21 days in unloaded injectable, and 13 days was observed in CUR loaded hydrogel group. Furthermore, we suggest that the injectable hydrogel laden with CUR showed a prompt wound healing potential by increasing the cell proliferation and serves as a drug delivery platform for sustained and targeted delivery of hydrophobic moieties.

Matched MeSH terms: Hyaluronic Acid/administration & dosage*
Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology

Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K, Jee CS, et al.

Arthroscopy, 2011 Apr;27(4):493-506.
PMID: 21334844 DOI: 10.1016/j.arthro.2010.11.054

PURPOSE: The purpose of this study was to evaluate the quality of articular cartilage regeneration after arthroscopic subchondral drilling followed by postoperative intraarticular injections of autologous peripheral blood progenitor cells (PBPCs) in combination with hyaluronic acid (HA).
METHODS: Five patients underwent second-look arthroscopy with chondral core biopsy. These 5 patients are part of a larger pilot study in which 180 patients with International Cartilage Repair Society grade III and IV lesions of the knee joint underwent arthroscopic subchondral drilling followed by postoperative intra-articular injections. Continuous passive motion was used on the operated knee 2 hours per day for 4 weeks. Partial weight bearing was observed for the first 6 to 8 weeks. Autologous PBPCs were harvested 1 week after surgery. One week after surgery, 8 mL of the harvested PBPCs in combination with 2 mL of HA was injected intra-articularly into the operated knee. The remaining PBPCs were divided into vials and cryopreserved. A total of 5 weekly intra-articular injections were given.
RESULTS: Second-look arthroscopy confirmed articular cartilage regeneration, and histologic sections showed features of hyaline cartilage. Apart from the minimal discomfort of PBPC harvesting and localized pain associated with the intra-articular injections, there were no other notable adverse reactions.
CONCLUSIONS: Articular hyaline cartilage regeneration is possible with arthroscopic subchondral drilling followed by postoperative intraarticular injections of autologous PBPCs in combination with HA.
LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Matched MeSH terms: Hyaluronic Acid/administration & dosage