Cartilage regeneration in OA

OA is a debilitating health problem common in elderly patient populations worldwide. Painful OA lowers quality of life by limiting the normal daily activities of patients [16, 17]. Current existing medical treatments aim to remedy symptoms only. Commonly prescribed treatments include non-steroidal anti-inflammatory drugs (NSAIDs), steroids, hyaluronic acids (HAs), and physical therapy. However, MSCs, in the form of autologous adipose SVF or culture expanded form, are an alternative therapy that can potentially treat the underlying cause of OA by regenerating cartilage.

One of the major drawbacks of applying autologous adipose SVF in orthopedic conditions is the lack of availability of randomized controlled studies. Most, if not all, literature available with regard to the human application of autologous adipose SVF are either in the format of case reports or cohort studies. Due to such constraints, despite the successful results reported by these articles, it is not yet readily accepted as a mainstream medical treatment.

In 2011, for the first time, Pak reported a case series of treating patients with OA of the knees with autologous adipose SVF and regenerating cartilage-like tissue [11]. Pak obtained autologous adipose SVF from digesting about 100 g of adipose tissue with collagenase and going through the centrifugation-dilution washing cycle as described by Zuk et al. [8, 9]. This autologous adipose SVF, with platelet rich plasma (PRP) and HA, was then injected percutaneously into the knee joints of two patients. After 3 months, the visual analog score (VAS) for pain, functional rating index (FRI), and range of motion (ROM) of the patients were assessed and shown to be improved along with MRI evidence of cartilage regeneration [11]. The inclusion criteria and exclusion criteria were listed as follows: Inclusion criteria: (i) chronic or degenerative joint disease causing significant functional disability and/or pain; (ii) the failure of conservative treatments; and (iii) an unwillingness to proceed with surgical intervention. Exclusion criteria: (i) active inflammatory or connective tissue disease thought to impact pain condition (i.e., lupus, rheumatoid arthritis, and fibromyalgia); (ii) active non-corrected endocrine disorder that might impact pain condition (i.e., hypothyroidism and diabetes); (iii) active neurologic disorder that might impact pain condition (i.e., peripheral neuropathy and multiple sclerosis); (iv) pulmonary and cardiac disease uncontrolled with medication usage; (v) history of active neoplasm within the past 5 years; (vi) blood disorders documented by abnormal complete blood count (CBC) within 3 months including severe anemia, thrombocytopenia, leukocytosis and/or leukopenenia; and (vii) medical conditions precluding the injection procedures.

Subsequently in 2013, Pak et al. reported a retrospective cohort study involving 91 patients with various orthopedic conditions [18]. Between the period of 2009 and 2010, Pak et al. treated 91 patients with OA of the knees, OA of the hips, and osteonecrosis of the femoral heads with percutaneous injections of autologous adipose SVFs along with autologous PRPs and HAs. The study reported the average efficacy of the regenerative treatment to be 65% at 3 months without any serious side effects and without any development of tumors. Some of the side effects reported were swelling and tendonitis [18].

In 2016, Pak et al. published a case series reporting that addition of autologous adipose ECM along with the SVF may also be effective when used together with autologous PRP and HA [19]. As in other reports, Pak et al. obtained autologous adipose SVF from digesting 100 g of adipose tissue with a collagenase. However, this time, unlike other reports, they added autologous adipose tissue-derived ECM, extracted by using an adipose tissue homogenizer, into the mixture of autologous adipose SVF, along with autologous PRP and HA. The mixture was injected into the knees of three patients with OA of the knees. Three months after treatment, all three patients’ symptoms, measured using FRI, ROM, and VAS pain score, improved. In addition, comparison of pre-treatment and post-treatment MRI data of all three patients demonstrated cartilage-like tissue regeneration [19].

In 2012, Koh and Choi also reported a retrospective cohort study treating 25 OA patients with autologous adipose SVF with autologous PRP [20]. This group obtained autologous adipose SVF from digesting only 19 g of adipose tissue extracted from the knee fat pad. Koh et al. also used the centrifugation-dilution method described by Zuk et al. [8, 9]. As performed by Pak et al., these adipose SVFs with autologous PRP was percutaneously injected into the knees of 25 patients with OA after performing arthroscopic debridement and lavage. The article states that the mean Lysholm knee scoring scales, Tegner activity level scales, and VAS scores improved significantly in the treated group compared to the control group. No imaging studies were carried out. No major side effects were reported [20].

In 2013, Koh et al. reported a case series involving 18 patients with OA of the knees receiving autologous adipose SVF obtained from digesting only 9 g of adipose tissue from the knee fat pad [21]. The autologous adipose SVF with autologous PRP were percutaneously injected into knees of 18 patients after arthroscopic debridement and lavage. After a few months, the patients were evaluated with Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scores, Lysholm knee scoring scales, and VAS scores and MRI studies. The patients improved on all criteria, including the cartilage whole-organ MRI scores. No serious complications were reported [21].

In 2014, Koh et al. reported a case series involving second-look arthroscopy results in 35 patients with knee OA treated with autologous adipose SVF [22]. In this report, Koh et al. incorporated arthroscopic guidance when injecting the knees with adipose SVF. Initially, the patients underwent arthroscopic examinations with debridement and lavage. Afterward, autologous adipose SVF with autologous PRP were injected under arthroscopic guidance. Only about 23 g of adipose tissue was used. About 12.7 months after treatment, second-look arthroscopy was performed. The results showed that the mean International Knee Documentation Committee (IKDC) and Tegner activity level scales significantly improved, but 76% of the patients had abnormal repair tissue observed during arthroscopy [22].

In another study reported by Koh et al. in 2014, the clinical results and second-look arthroscopy findings were compared between an autologous adipose SVF/PRP injection group and a PRP-only group [23]. This study involved 44 patients undergoing open-wedge high tibial osteotomies (HTO). This time, autologous adipose SVF were obtained from 120 g of adipose tissue from the patients’ buttocks. Afterward, the autologous adipose SVFs were injected with autologous PRP in 23 patients under arthroscopic guidance and the other 21 patients were injected with autologous PRP alone under arthroscopic guidance. After 24 months of the treatment, the results showed that the autologous adipose SVF/PRP group showed significantly greater improvement than the PRP-only group, as measured by VAS for pain, Knee injury Osteoarthritis Outcome Score (KOOS) subscales for pain and symptoms, and second-look arthroscopic evaluation. Arthroscopic exams showed fibrocartilage regeneration in 50% of the adipose SVF/PRP group versus 10% in the PRP-only group. However, the Lysholm score was similarly improved in both groups [23].

Later in 2015, Koh et al. reported another case series involving second-look arthroscopy results of 30 patients with OA of the knees treated with autologous adipose SVF obtained from 120 g of adipose tissue from the patients’ buttocks [24]. The autologous adipose SVF was injected with PRP under arthroscopic guidance. Of the 30 patients, 16 patients underwent second look arthroscopies about 25 months after the initial treatment. Of the 16 patients, 10 patients (63%) had improved cartilage, 4 patients (25%) had maintained the cartilage, but 2 patients (12%) failed in healing cartilage defects. The study reported that all patients showed significant improvement in OA outcome scores (KOOS), VAS pain scale, and Lysholm score [24].

In another study, Kim et al. compared the efficacy of autologous adipose SVF alone to that of autologous adipose SVF with fibrin glue [25]. The fibrin glue was used as a scaffold for stem cells to attach. This study involved 54 patients with knee OA. Autologous adipose SVF was obtained from digesting 120 g of adipose tissue with collagenase. Of the 54 patients, 37 patients were treated with autologous adipose SVF only and the other 17 patients were injected with autologous adipose SVF with fibrin glue. After about 28 months, the mean IKDC score and Tegner activity level scale in both groups were compared and had improved significantly; the improvement was comparable in both groups. However, in second-look arthroscopies, International Cartilage Repair Society (ICRS) scores were better in the adipose SV with fibrin glue group [25].

In 2014, Bui et al. reported a case series involving 21 patients with OA of the knees [26]. The patients were treated with autologous adipose SVF with PRP. The adipose SVF was obtained from digesting 50–100 ml of lipoaspirates originating from the abdomen. Then, the autologous adipose SVF with autologous PRP was injected percutaneously into the diseased knees. After 8.5 months of treatment, all 21 patients showed improved VAS pain score and the Lysholm score. There was also a significant increase in the thickness of the cartilage, as depicted on the MRIs [26].

In early 2015, Michalek et al. reported a multi-center case-control study involving 1114 patients with OA of the knees and hips from four different countries (USA, Czech Republic, Slovakia, and Lithuania) [27]. These patients were percutaneously injected with autologous adipose SVF and followed for average 17 months. No serious side effects were reported and no incidents of cancer were reported. The clinical effects, measured on the basis of pain, non-steroid analgesic usage, limping, extent of joint movement, and stiffness, all improved. At 12 months after treatment, 63% of all patients reported approximately 75% symptom improvement and 91% of all patients reported approximately 50% of symptom improvement [27].

In 2016, Fodor et al., another group in the USA, reported clinical improvement of 8 knee OA patients treated with autologous adipose SVF obtained by digesting 150–250 ml of lipoaspirates [28]. All patients attained full activity with decreased knee pain. WOMAC scores, VAS pain scale score, ROM, and timed up-and-go (TUG) results all improved. The improvement in WOMAC scores and VAS scores were maintained at 1 year. Comparing preoperative MRI to 3-months postoperative MRI showed no detectable structural differences. No major side effects were observed [28].

Chondromalacia patellae (CMP)

CMP is a knee joint disorder defined by cartilaginous softening of patellar bone cartilage and may cause patellofemoral pain syndrome (PFPS), which is characterized by anterior knee pain (AKP) along with malalignment of the tibio-patello-femoral joint [29, 30]. CMP can be diagnosed with MRI along with clinical history and physical examination [29, 30]. Currently, only symptomatic treatment is available. As in OA, commonly prescribed treatments include NSAIDs and physical therapy. Thus, CMP poses a major therapeutic challenge. However, as a few recent studies have shown the possibility of cartilage recovery using MSCs [31], the combination of autologous adipose SVF with correction of alignment may be a novel approach to treating CMP.

In 2013, Pak et al. reported a case series involving three patients with CMP of the knees [32]. Pak et al. treated these patients with autologous adipose SVF using 100 g of adipose tissue obtained from the abdomen of the patients. The adipose SVF was injected percutaneously with PRP and HA. After 3 months of treatment, the patients’ symptoms improved in terms of VAS pain scale, FRI, and ROM. The study also showed positive regeneration of hyaline cartilage at the patellofemoral joints of all three patients between pre- and post-treatment MRIs [32].

Meniscus tear

The meniscus is a fibrocartilaginous disk that functions to transfer weight, absolve shock to the knee, and to protect the hyaline cartilage at the knee joint [33]. With knee injuries, the meniscus may be damaged causing it to be torn. Such meniscus tears are initially treated conservatively with NSAIDs and physical therapy [34, 35]. If conservative treatment fails, an arthroscopic meniscectomy is traditionally performed. However, arthroscopic meniscectomy, either full or partial, is associated with early onset of OA of the knees [36]. Thus, potential cartilage regeneration with MSCs, or autologous adipose SVF, may offer a major therapeutic breakthrough.

In 2014, Pak et al. reported that autologous adipose SVF may be effective in treating meniscus tears [37]. This case report involved one patient treated with autologous adipose SVF obtained from digesting approximately 40 g of packed adipose tissue with collagenase. Afterward, the autologous adipose SVF was injected with PRP and HA. After 3 months of treatment, the patient’s symptoms, measured with VAS scores for pain, FRI, and physical therapy ROM, had improved. In addition, probable regeneration of the meniscus cartilage was documented by pre- and post-treatment MRIs [37].