Introduction

Joint preservation has been an area of intense research in recent years.^1-4 Arthroplasty is an option only for certain joints in the event of symptomatic osteoarthritis, with modest evidence to date.⁵ However, the younger patients may also be better suited to delaying joint replacement surgeries to negate the possibility of multiple joint revision surgeries in their lifetime.⁶ To preserve the joint, modern strategies have arrived at the use of biologics, exosomes, as well as osteotomies.

Content

Biologics can be offered as intra-articular injections to directly facilitate the osteochondral repair.^1-4 Notably, biologics can be categorised into three broad categories: 1) extracellular matrices, 2) growth factors, and 3) stem cells. Extracellular matrices such as hyaluronic acid restore viscoelasticity and can act as a tissue network promoting cell interaction.⁴ Growth factors such as platelet-rich plasma can stimulate cellular migration, cellular proliferation, and matrix deposition.⁷ Stem cells are pluripotent and have the potential to differentiate into the desired tissue required for the damaged osteochondral construct.⁸ The mechanisms of these classical biologics are theoretically favourable for osteochondral repair. However, its supporting clinical evidence has remained limited as a whole to date.^1-4 There may be several reasons for this: 1) the optimal facilitation of osteochondral repair is of a multipronged synergistic approach of a combination of extracellular matrices with growth factors as well as possibly stem cells, 2) cellular therapies may incite immunogenic responses, and 3) pluripotent cells may generate inappropriate cell types.

Exosomes are 50 to 200 nm small extracellular vesicles most often extracted from mesenchymal stem cells.^9,10 These vesicles can carry proteins, membrane lipids, and miRNA that can be instrumental for osteochondral repair. In in vitro and animal studies to date, the postulated mechanism of exosomes for osteochondral repair has included immunomodulation, anti-apoptosis, proliferation, cellular migration, and matrix synthesis.¹⁰ Exosomes pose a breath of fresh air for osteochondral repair because of their inherent ability as a vesicle. Therefore, they can potentially allow selective loading of the favoured cytokines or scaffolding. In addition, exosome therapy negates the cellular aspect to only possess the key component for osteochondral repair and may dismiss the inflammatory effects otherwise possible in whole cellular therapy constructs.¹⁰ As exosomes are no longer associated with their stem cell construct, pluripotency is negated as well as the possibility to generate inappropriate cell types. In preclinical studies to date, exosomes appear efficacious in the regeneration of both the cartilage and subchondral bone.¹¹ However, the evidence of this for clinical models has yet to be affirmed.

The optimal administration protocol for biologics and in particular, exosomes is key for prime clinical application. Besides classical biologics, exosome concentration and volume employed for osteochondral repair have been largely variable in the literature to date.¹¹ This is especially concerning because of the possibility of a dose-response relationship.¹² The lack of preclinical and clinical studies coupled with the heterogeneity of outcomes reported has hindered further investigation of this matter to date. Specifically, regarding exosome research, the translatability of the current preclinical studies for clinical applications has also been an area of debate. Future studies must determine the bioavailability/biodistribution of biologics/exosomes.

Osteotomies can also offer to alter the biomechanics in the malaligned joint to offload stress points and therefore, alleviate pain and provide an improved environment for osteochondral repair. To date, surgical alignment correction has been mainly employed for knee osteoarthritis (high tibial osteotomy) and ankle osteoarthritis (low tibial osteotomy), both with favourable outcomes.^13,14 During surgery, the observation of degenerated cartilage has prompted adjuvant strategies to further aid osteochondral repair. Mesenchymal stem cells augmentation is of such, where its addition has demonstrated modestly improved functional outcomes compared to high tibial osteotomies alone.¹⁵

There has been a continuous stream of joint preservation research. However, due to the limitations inherent in classical biologics, pronounced by the limited evidence across the various joints to date, exosome therapy may be the future direction for the biological facilitation of osteochondral repair.¹⁰ The use of exosomes for osteochondral repair has been currently limited to preclinical models, with the transition to clinical models a necessity for safe clinical application. These studies must also aid in verifying the efficacy, optimal treatment protocol (exosome source, concentration, volume, number, and frequency of injections), and side effect profiles. Nonetheless, tibial osteotomies appear a safe and effective joint preserving strategy.

References

1. Bennell KL, Hunter DJ, Paterson KL. Platelet-rich plasma for the management of hip and knee osteoarthritis. Curr Rheumatol Rep. 2017;19(5):24. doi: 10.1007/s11926-017-0652-x.

2. Delanois RE, Etcheson JI, Sodhi N, Henn RF 3rd, Gwam CU, George NE, et al. Biologic therapies for the treatment of knee osteoarthritis. J Arthroplasty. 2019;34(4):801-813. doi: 10.1016/j.arth.2018.12.001.

3. Le ADK, Enweze L, DeBaun MR, Dragoo JL. Current clinical recommendations for use of platelet-rich plasma. Curr Rev Musculoskelet Med. 2018;11(4):624-634. doi: 10.1007/s12178-018-9527-7.

4. Witteveen AG, Hofstad CJ, Kerkhoffs GM. Hyaluronic acid and other conservative treatment options for osteoarthritis of the ankle. Cochrane Database Syst Rev. 2015;(10):CD010643. doi: 10.1002/14651858.CD010643.pub2.

5. Gademan MG, Hofstede SN, Vliet Vlieland TP, Nelissen RG, Marang-van de Mheen PJ. Indication criteria for total hip or knee arthroplasty in osteoarthritis: a state-of-the-science overview. BMC Musculoskelet Disord. 2016;17(1):463. doi: 10.1186/s12891-016-1325-z.

6. Losina E, Katz JN. Total knee arthroplasty on the rise in younger patients: are we sure that past performance will guarantee future success? Arthritis Rheum. 2012;64(2):339-341. doi: 10.1002/art.33371.

7. Arnoczky SP, Sheibani-Rad S. The basic science of platelet-rich plasma (PRP): what clinicians need to know. Sports Med Arthrosc Rev. 2013;21(4):180-185. doi: 10.1097/JSA.0b013e3182999712.

8. Humphreys PA, Mancini FE, Ferreira MJS, Woods S, Ogene L, Kimber SJ. Developmental principles informing human pluripotent stem cell differentiation to cartilage and bone. Semin Cell Dev Biol. 2021:S1084-9521(21)00306-2. doi: 10.1016/j.semcdb.2021.11.024.

9. Maehara M, Toyoda E, Takahashi T, Watanabe M, Sato M. Potential of exosomes for diagnosis and treatment of joint disease: towards a point-of-care therapy for osteoarthritis of the knee. Int J Mol Sci. 2021;22(5):2666. doi: 10.3390/ijms22052666.

10. Toh WS, Lai RC, Hui JHP, Lim SK. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin Cell Dev Biol. 2017;67:56-64. doi: 10.1016/j.semcdb.2016.11.008.

11. Tan SSH, Tjio CKE, Wong JRY, Wong KL, Chew JRJ, Hui JHP, et al. Mesenchymal stem cell exosomes for cartilage regeneration: a systematic review of preclinical in vivo studies. Tissue Eng Part B Rev. 2021;27(1):1-13. doi: 10.1089/ten.TEB.2019.0326.

12. Zhou Q, Cai Y, Jiang Y, Lin X. Exosomes in osteoarthritis and cartilage injury: advanced development and potential therapeutic strategies. Int J Biol Sci. 2020;16(11):1811-1820. doi: 10.7150/ijbs.41637.

13. Santoso MB, Wu L. Unicompartmental knee arthroplasty, is it superior to high tibial osteotomy in treating unicompartmental osteoarthritis? A meta-analysis and systemic review. J Orthop Surg Res. 2017;12(1):50. doi: 10.1186/s13018-017-0552-9.

14. Aujla RS, Perianayagam G, Siddiqui BM, Divall P, Bhatia M. Distal tibial osteotomy for varus ankle arthritis: A meta-analysis and systematic review. J Arthrosc Jt Surg. 2021;8(3):238-245

15. Tan SHS, Kwan YT, Neo WJ, Chong JY, Kuek TYJ, See JZF, et al. Outcomes of high tibial osteotomy with versus without mesenchymal stem cell augmentation: a systematic review and meta-analysis. Orthop J Sports Med. 2021;9(6):23259671211014840. doi: 10.1177/23259671211014840.

Acknowledgments

None