History of regenerative medicine in the field of orthopedics

Older past

Research and clinical application pertaining to regenerative medicine may be recent; however, its presence and importance were well known even in ancient times as they knew that when noxious stimuli are applied to injured tissue, it can induce healing. This fact has been traceable to 500 BC in Rome. Hot needle therapy was a common form of treatment for soldiers with joint dislocations.^[6] In the 20^th century, prolotherapy became quite common. It is a procedure where hyperosmolar substances were injected into damaged tissue to induce healing. Hippocrates identified that cartilage damage was associated with severe morbidity. Hence, multiple techniques were attempted to heal this damaged cartilage. Some such procedures were bloodletting, Roman baths, medicinal herbs consumption, and acupuncture.^[7]Non-operative treatment was practiced even in the 1930s. A general surgeon from Philadelphia used sclerosing agents to treat a thumb injury and later the treatment of painful hypermobile joints with little success.^[8]

Recent past

The regenerative medical treatment for the knee osteoarthritis (OA) and articular cartilage injuries of the joints has been tried in the last century. A timeline for various landmark therapies is shown in [Figure 1].

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Figure 1:

Timeline of evolution of the treatment of symptomatic cartilage lesions.

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In the 1940s, the treatment for OA was conservative until it was Magnuson who described extensive debridement and removal of loose degenerated particles of cartilage, synovium, and osteophytes from the knee, thus inducing a healing response.^[9] This procedure was popular for many years until it was replaced with formal arthroplasty. Hackett et al. (1956) laid the foundation for prolotherapy.^[10,11]According to his theory, peripheral joints which were painful were a result of axial instability and referred neural input with loss of muscular and ligamentous control. He used this novel technique for the treatment of arthritic joints. Pridie (1959) was working relentlessly in the United Kingdom. He expanded on the previous work of Magnuson and presented a technique of closely spaced multiple drilling of knee arthritic articular cartilage defects to promote a regenerative response. He could not show his clinical outcomes at long-term follow-up at this time.^[12] However, it was Insall (1974) who performed this procedure for 60 patients and achieved excellent results in selected patients.^[13]Microfracture (MFx) was initially discovered only to treat cartilage loss which was a full thickness in nature, unlike Pridie drilling was more for the treatment of arthritis.^[14] The initial technique was described in 1984; however, the clinical results showing its usefulness in the long term were reported in 2003, by Steadman et al. much later with average 11-year follow-up.^[15] Following these results, many researchers were interested in this technique which leads to various studies. It was concluded that the size and location of the lesion were important in the prognosis of the disease. The smaller lesions located on the femoral condyles and trochlea showed superior results with this method of treatment. However, larger and multifocal lesions and those located on patellar sites still did not show reproducible superior outcomes and thus presented a treatment dilemma. Mosaicplasty was a newer technique discovered and popularized by Hangody and Füles.^[16] In 2004, he published his results in 831 patients. According to this study, he achieved excellent results for 92% (femoral), 87% (tibial), and 79% (patellar) lesions. It is a procedure where cartilage (osteochondral plug) is harvested from the healthy non-weight-bearing donor site and transported to the debrided and prepared recipient site. Only 3% of patients in his study showed mild donor site morbidity.

Autologous chondrocyte implantation (ACI) was another new technique which was developed by Brittberg et al.^[17] This technique involved the culture of articular chondrocytes in a laboratory for 3–6 weeks. These cells were then reimplanted onto the prepared lesion site. There are four generations of this technique. In the first generation, ACI cells used to be injected below a periosteal patch so that they were contained. However, this went into disrepute due to its complications of patch dislodgement and hypertrophy. The second- and third- generation ACI used biodegradable polymers as delivery systems. The fourth-generation ACI technique is essentially gel based and specifically used culture-expanded bone marrow- derived cells that demonstrated excellent short-term safety and efficacy to autologous chondrocytes for focal cartilage lesions.^[18]

Caplan also known as the father of mesenchymal stem cell coined the term ‘‘MSC”.^[19] Later, marrow stimulation procedures such as MFx and/or drilling were combined with the application of various sources of stem cells such as concentrated bone marrow aspirate (BMAC), adipose- stromal vascular fraction (A-SVF), culture expanded-adipose derived stem cells, and peripheral blood stem cells. These were found to be successful in short- to mid-term follow-up. However, long-term follow-up with large sample sizes was still needed to alter the clinical practice.

Over the years, medical advances and quest to find the greatest advantages with minimally invasive procedures gave birth to the age of regenerative injection therapy (RIT). Linetsky^[20] coined the term regenerative injection therapy or RIT. He expanded on the work already done by Gedney, Hackett, and Hem- wall and considered injecting various agents that induce a biological response, such as sodium bicarbonate/calcium gluconate, hyaluronic acid (HA),^[21]dextrose, BMAC, PRP, nano or micronized fat, A-SVF, and culture-expanded MSCs both allogeneic and autologous from a multitude of sources.^[22-25] The volume and quality of studies are on a steep rise and hence helping scientists all over the world to study the application of cells and if these are safe and efficacious. Demineralized bone matrix has been known for its osteoinductive properties and clinical applications for more than 5 decades.^[26] Bone morphogenetic protein 2 and 7 were the active ingredients that were found to be clinically useful. These have already been cloned in the 1980s; however, they were approved for clinical use only in the 2000s. Despite having known the benefits of using stem cells for regeneration, progress in this field for clinical use has been slow. There is still a lack of efficient guidelines and ethical clearance to use these in clinical work. As the researchers have studied more about inflammation and its mediators in detail, PRP injections have come into extensive as a method to regenerate tissue.^[27] Platelets carry inflammatory mediators which are critical for the healing process; hence, injecting a higher than the physiologic concentration of platelets could induce tissue regeneration. This was first tried as early as the 1970s. These platelets were similarly used in 1987 for an open heart surgery performed in italy. This became popular during the 1990s, for oral and maxillofacial surgeries. Many other fields were exploring this exciting technology of regeneration. Surgeons tried this to improve flap survival and bone healing. More recently, it is vastly being used for the treatment of sports injuries such as lateral epicondylitis, muscle ruptures, ACL tears, and heel pathologies.^[28]