The Use of Biologics for Hip Preservation

Abstract

Purpose of Review

A wide array of nonoperative modalities to treat hip pain are aimed at restoring and maintaining the structural and physiologic characteristics of the joint. The purpose of this review is to describe the current understanding of biologics in hip pathology by providing an evidence-based overview of treatment modalities available for orthopedic surgeons.

Recent Findings

The use of biologics as a primary treatment or adjunct to traditional management has shown encouraging results for the treatment of hip pain. Studies have demonstrated safety with minimal complications when using platelet rich plasma, hyaluronic acid, or stem cells to treat hip pain caused by osteoarthritis, femoroacetabular impingement syndrome, tendinopathy, or osteonecrosis of the femoral head. Several studies have been able to demonstrate meaningful clinical results that can improve treatment standards for hip pain; however, more work must be performed to better delineate the appropriate protocols, indications, and limitations of each modality.

Summary

Recent advances have inspired renewed interest in biologics for patients with hip pain. We present a concise review of platelet rich plasma, hyaluronic acid, stem cells, and matrix metalloprotease inhibitors and their applicability to hip preservation surgery.

Introduction

With an annual incidence of 37 per 1000 people, hip pain is a widely prevalent, debilitating issue. [1] The causes of hip pain are multifactorial and can be related to both intrinsic and extrinsic factors. Intrinsically, intra-articular causes of hip pain include labral tears, chondral injury, ligamentous tears, and synovitis. [2] These mechanical insults to the hip result in the release of proinflammatory cytokines such as Interlukin-6 (IL-6) and tumor necrosis factor alpha (TNF- α), which are detected by the richly innervated hip [3]. In order to effectively manage the root cause of pain it is important to gain an understanding of therapies which ideally maximize healing and reduce inflammation in the hip joint. A wide array of operative and nonoperative modalities are available to treat hip pain aimed at restoring and maintaining appropriate structural and physiologic characteristics of the joint. [4]

Several recent advances have inspired renewed interest in biologics for patients with hip pain. [5, 6] Of interest in the hip joint, is the use of platelet rich plasma (PRP), hyaluronic acid (HA), stem cells, and matrix metalloprotease (MMP) inhibitors. PRP is a concentrate plasma with a supra-physiologic platelet count that aids in healing through the release of various growth factors and cytokines. [7] HA is a naturally occurring glycosaminoglycan which is believed to impact the function of synovial fluid and protect articular cartilage. [8] Stem cells are undifferentiated cells with osteogenic and chondrogenic abilities that rapidly replicate and produce osteoblasts and chondrocytes. [9] MMP inhibitors are tissue inhibitors that inhibit the function of matrix proteolytic enzymes that degrade extracellular matrix. [10] The purpose of this review is to describe the current knowledge of biologics in hip pathology by providing an evidence-based overview of treatment modalities available for orthopedic surgeons and provide insight into which treatment modalities require further investigation.

Pathomorphology of the Hip Joint

A number of pathoanatomical processes have been found to contribute to hip pain and premature OA in patients. Of these conditions, acetabular dysplasia, femoroacetabular impingement (FAI) and aberrations to proximal femoral alignment (e.g. excess anteversions, inclination, or retroversion) encompass a significant portion. [11] Biologics have been investigated as a means to improve the management of pain for each process.

Acetabular dysplasia is due to a congenital inability of the acetabulum to offer sufficient coverage of the femoral head which leads to aberrant reactive forces across the articular cartilage, producing joint microinstability. Over time, acetabular dysplasia often leads to bony impingement, capsular attenuation and degenerative joint disease associated with labral hypertrophy and degeneration. [12–14] FAI is caused by aberrant morphology of the proximal femur and/or acetabulum, which leads to a pathologic impingement during motion. [15] This interplay causes injury to surrounding structures such as the chondral surface and labrum resulting in pain in adjacent body segments. On the femoral side, aberrations in proximal femur morphology such as excess anteversion, inclination and/or retroversion in the femoral neck, are thought to lead to chronic pain and functional impairment. [16, 17] Moreover, there is an association between atraumatic anterior hip microinstability and proximal femoral anteversion, as well as anterior impingement secondary to femoral retroversion. [16, 18] On the acetabular side, excessive acetabular wall protrusions result in a deepened acetabular socket. This morphological variant can produce a pincer type FAI due to the compression of the labrum between the femoral neck and acetabular rim, resulting in severe pain. [19] Understanding the pathophysiology and premature osteoarthritic changes in patients is critical when critically evaluating biologic treatment options.

Platelet-Rich Plasma

Platelet rich plasma is a concentrated plasma with a supra-physiologic platelet count. Normal plasma has a platelet concentration of roughly 1.5–4.5 × 10⁵/μL; PRP contains at least a fourfold increase in platelet concentration. [20] Platelets play a critical role in healing by releasing vital growth factors and cytokines (Table 1) that are thought to stimulate mitogenesis of mesenchymal stem cells, which are responsible for enhancing bone repair and tissue angiogenesis. [21, 22] The final composition of PRP, however, is highly variable and dependent on the centrifugation technique and concomitant activation factors. [23] Activation leads to immediate release of growth factors from the alpha-granules of platelets and cleavage of fibrinogen to fibrin allowing platelets to undergo the clotting process. [24] Platelet activation and promotion of clotting prevents the breakdown of tissue barriers. [25] Activation can be achieved by adding autologous thrombin or calcium chloride. Theoretically, calcium activates platelets via the intrinsic coagulation pathway which is reliant on calcium as a cofactor to convert prothrombin to thrombin; activation via autologous thrombin directly stimulate platelet activation through G protein coupled receptors. [26, 27] Another variable in the preparation of PRP is presence or absence of leukocytes. Buffy coat-based preparation systems produce leukocyte-rich PRP while plasma-based preparation systems typically yield leukocyte-poor PRP. The majority of leukocytes are neutrophils, which are pro-inflammatory. Therefore, leukocyte-rich PRP is pro-inflammatory while leukocyte-poor preparations are considered anti-inflammatory. [24, 28] Studies have illustrated many potential benefits of having leukocytes present in PRP solutions including the immune and antibacterial properties of leukocytes as well as improved wound healing through inflammatory signaling and release of growth factors. [29, 30]

Table 1.

Growth Factors Found in Platelet-Rich Plasma

Name	Abbreviation	Physiologic Role
Epidermal Growth Factor	EGF	Stimulates proliferation and differentiation of epithelial cells, promotes the release of cytokines by mesenchymal and epithelial cells.
Fibroblast Growth Factor	FGF	Stimulates the development of chondrocytes, mesenchymal cells, and osteoblasts
Insulin-like Growth Factor	IGF	Stimulates the synthesis of collagen. Stimulates cellular growth and differentiation in bone, vasculature, and other tissue.
Platelet Derived Growth Factor	PDGF	Stimulates the synthesis of collagen, chemotaxis of fibroblasts, and activation of macrophages.
Transforming Growth Factor ß	TGF-ß	Promotes angiogenesis, type I collagen synthesis, and inhibits bone resorption via inhibition of osteoclasts
Vascular Endothelial Growth Factor	VEGF	Promotes angiogenesis, promotes proliferation of epithelia cells, increases vessel permeability, and promotes the chemotaxis of PMN and macrophages.

Due to wide variation in PRP preparation, two classification systems have been proposed. [29, 31] In the classification system described by Mishra and colleagues there are 4 types of PRP, type 1 has no activation agent and is leukocyte rich, type 2 is activated and leukocyte rich, type 3 has no activation and is leukocyte poor, and type 4 is activated and leukocyte poor. [31] The PAW classification system described by DeLong et al. consists of 3 parameters: platelet concentration, activation, and white blood cells (Table 2). PRP usage in the hip has been described in operative and non-operative treatment of tendinopathies, FAI, and OA (Table 3).

Table 2.

Platelet Rich Plasma Classification System

Mirsha et al. Classification
Type	White Blood Cells	Activation
1	Increased over baseline	No
2	Increased over baseline	Yes
3	Minimal or None	No
4	Minimal or None	Yes
	A: >5x platelets
	B: <5x platelets
PAW Classification
Platelet Concentration
P1	below baseline
P2	baseline – 750,00 platelet/μl
P3	750,000 - 1,250,000 platelet/μl
P4	over 1,250,000 platelet/μl
White blood Cells
A	Total WBC above baseline
B	Total WBC below baseline
α	Neutrophils above baseline
β	Neutrophils below baseline
Activated Denoted by X
Abbreviation; WBC, white blood cells.

Table 3.

Overview of Clinical Outcomes in Prospective Literature on Platelet-Rich Plasma

Study	Level of Evidence	Type of Platelet-Rich Plasma	Pathology	Experimental Group	Control Group	Outcome
Battaglia et al. (2013)	–	Leukocyte-poor, Activated	Hip OA	50 Patients (PRP)	50 Patients (HA)	mHHS, VAS
Dallari et al. (2016)	I	Leukocyte-poor, Activated	Hip OA	44 Patients (PRP)	36 Patients (HA)	VAS, WOMAC, mHHS
Fitzpatrick et al. (2018)	I	Leukocyte-rich, non-activated	Gluteal tendinopathy	40 Patients (PRP)	40 Patients (Corticosteroids)	mHHS, MCID
Fitzpatrick et al. (2019)	I	Leukocyte-rich, non-activated	Gluteal tendinopathy	65 Patients (PRP)	13 Patients (PRP)	mHHS
Hamid et al. (2014)	II	Leukocyte-rich, Activated	Hamstring Tendinopathies	14 Patients (Rehabilitation + PRP)	14 Patients (Rehabilitation)	RTP, BPI-SF, Hamstring strength
LaFrance et al. (2015)	I	Leukocyte-rich	Operative Management of FAI	20 Patients (PRP)	15 Patients (Normal Saline	NAHS, mHHS, HOS-ADL, HOS-Sport
Rafols et al. (2015)	II	Leukocyte-rich, Activated	Operative Management of FAI	30 Patients (PRP)	27 (No PRP)	mHHS, VAS, MRI
Redmond et al. (2014)	II	Leukocyte-poor	Operative Management of FAI	91 Patients (PRP)	180 Patients (bupivacaine)	HOS-ALD, mHHS, HOS-Sport, NAHS, VAS
Sante et al. (2016)	–	Leukocyte-poor	Hip OA	21 Patients (PRP)	22 Patients (HA)	VAS, WOMAC
Thompson et al. (2019)	I	Leukocyte-rich	Trochanteric Pain Syndrome	24 Patients (PRP)	24 Patients (Saline)	BPI, Likert Scale, Medication use, Health professional consultation rate

Abbreviations: OA, osteoarthritis; PRP, platelet-rich plasma; HA, hyaluronic acid; mHHS, modified Harris Hip Score; VAS, visual analog pain score; MCID, minimal clinical important difference; RTP, return to play; BPI-SF, Brief Pain Inventory Short Form; NAHS, Non-Arthritic Hip Score; HOS-ADL, Hip Outcome Score - Activity of Daily Living; HOS-Sport, Hip Outcome Score - Sport Specific subscale; iHOT-33, International Hip Outcome Tool - 33; MRI, magnetic resonance imaging; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Several investigations have evaluated conservative management of chronic tendinopathies with PRP. A randomized control trial (RCT) by Hamid et al. assessed the efficacy of PRP injections in athletes with grade 2a hamstring muscle injuries; fourteen patients underwent PRP injections with rehabilitation and fourteen patients underwent rehabilitation alone. [32] The PRP formulation used was classified as P4-x-A, according to PAW. Hamid et al. found that patients administered PRP returned to play faster than those treated with rehabilitation, although this did not reach significance (26.7 ± 7 days vs. 42.5 ± 20.6 days; p = 0.20). The PRP cohort did have significantly lower pain severity scores as measured via Brief Pain Inventory – Short Form (BPI-SF) (b = −0.390; standard error [SE], 60.142; 95% CI, −0.67 to −0.11;P = .007). A Level I RCT study by Fitzpatrick et al. investigated pain and function in forty patients after a single injection of PRP in the management of gluteal tendinopathy compared to forty patients after a single injection of corticosteroids. [33••] A leukocyte rich PRP preparation was used. Patients treated with PRP had significantly improved mean modified Harris Hip (mHHS) at 12 weeks compared to the corticosteroid group (74.05 ± 13.92 vs. 67.13 ± 16.04; p = 0.048). A higher portion of patients undergoing PRP treatment reported symptomatic improvement compared to corticosteroids; however, significance was not reached (64.1% vs. 45.9%, p = 0.11). [34] In a follow-up study of the same patients, Fitzpatrick et al. evaluated mHHS and found the PRP cohort experienced further improvements compared to the corticosteroid group at a long-term follow-up of 24 weeks (77.60 ± 11.88 vs. 65.72 ± 15.28; P = 0.0003). [35••] Thompson et al. evaluated 24 patients undergoing PRP therapy for the management of greater trochanteric pain syndrome and assessed the efficacy of PRP (leukocyte rich, non-activated) versus placebo (normal saline) in pain control. [36•] At 12 month follow-up investigators found no significant difference in BPI pain scores between cohorts at any point. (At 12 months 95%CI, −0.79 to 0.93; p = 0.87).

Several studies evaluated using PRP to treat FAI. Redmond et al. performed a prospective study of intraoperative PRP (leukocyte-poor) vs. bupivacaine during hip arthroscopy for labral tears. [37] At 3 months post-operatively, there were no significant difference in pain scores between the groups. At 2 year follow-up, the PRP group had significantly higher VAS pain scores compared to controls (3.4 vs. 2.5; p = 0.005). There was no significant difference in Hip Outcome Score – Activity of Daily Living (HOS – ALD) score, Hip Outcome Score – Sport Specific Subscale (HOS-S), or Non-Arthritic Hip Score (NAHS) between either group at any time point. Similarly, Rafols et al. conducted a RCT comparing 30 patients undergoing intra-articular PRP versus 27 controls who received no additional therapy following arthroscopic hip surgery for FAI with 24-month follow-up. [38] The study endpoints included pain score, mHHS, and MRI at 24 months post-operatively. PRP used was activated and leukocyte rich. The PRP group reported significantly less pain 48 h post-operatively compared to the controls (3.04 ± 4.0 vs. 5.28 ± 6.0; P < 0.05). There was no difference in mHHS scores between the groups at any time. Notably, upon MRI evaluation 6 months post-operatively, the PRP group had significantly fewer joint effusions (21.1% vs. 36.7%; p < 0.05). In assessing the effect of PRP on clinical outcomes following arthroscopic labral repair and femoral neck osteoplasty, LaFrance et al. performed a study comparing intraoperative PRP (leukocyte rich) injections to normal saline. [39] Investigators found no significant differences in Non-Arthritic Hip Score, mHHS, HOS between the cohorts at 1, 3, 6, and 12 month follow-up.

Several studies have investigated PRP as a nonoperative modality in managing pain in hip OA. Battaglia et al. performed a study comparing treatment of hip OA with PRP to HA; mHHS and VAS were assessed at 12 months. [40] PRP preparation used was activated with calcium chloride and leukocyte poor. Patients received 3 intraaarticular ultrasound guided injections at 2 week intervals. There was no clinically significant difference in mHHS (mean, 95% CI, 65.73 (60.60–70.86) vs. 72.55 (67.42–77.65)) and VAS scores (mean, 95% CI, 4.75 (4.08–5.43) vs. 4.59 (3.92–5.26)) 12 months following treatment between the PRP group or HA group. This suggested PRP is not superior to HA in patients with symptomatic hip OA at 12 months follow up. Sante et al. perform a RCT of 21 patients undergoing intraarticular PRP versus 21 patients undergoing intraarticular HA in the treatment of hip osteoarthritis. [41] The PRP formulation used was leukocyte poor with no mention of activation factor. They found that at 4 weeks post treatment, the PRP group had significantly lower VAS pain scores when compared to the HA group (4.73 ± 3.4 vs. 5.27 ± 1.6; p < 0.01). At 16 weeks post treatment patients in the HA group exhibited significantly lower VAS pain scores than the patients in the PRP group (3.63 ± 2.1 vs. 6.36 ± 2.1; p < 0.01). Dallari et al. also conducted a RCT examining intraarticular injections of PRP vs. HA in patients with hip OA. [42] This study had 12 months follow up following treatment and consisted of 3 cohorts; a PRP group with 44 patients, a HA group with 36 patients, and a PRP + HA group with 31 patients. The formulation of PRP use was leukocyte poor and activated with calcium chloride. The patients administered PRP had the lowest VAS scores at all time points (p < 0.05).

Currently, there are no guidelines for the best practice for hip PRP usage. There is significant heterogeneity in the current literature regarding optimal composition and quality of growth factors and cytokines present in the different PRP preparations; in fact many studies do not mention PRP in the context of any specific classification or preparation motif. Consequently, results are neither reproducible nor generalizable across different PRP formulations. Current evidence does not support the universal usage of PRP for hip preservation. Treatment of hip tendinopathies have the strongest evidence of PRP as an effective treatment modality, while PRP for the management of OA and as an adjunct to the surgical management of FAI requires further investigation. Orthopedic surgeons must be mindful of the inconsistent and inconclusive literature regarding using PRP in their clinical practice.

Hyaluronic Acid (HA)

Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan comprised of alternating D-glucuronic acid and N-acetyl-D-glucosamine units, which is thought to portend lubricating, viscoelastic, and anti-inflammatory properties. [43] HA is found in many human tissues, including synovial fluid, vitreous body, dermis, epidermis, thoracic lymph, serum, urine, and connective tissue. [44] The short half-life of native HA has led researchers to crosslink HA to different chemical substrates to prolong the efficacious properties and desired traits. [45, 46] Viscosupplementation (VS) with hyaluronic acid was popularized after studies demonstrated that the ability of synovial fluid to protect articular cartilage becomes significantly impaired due to decreased HA molecular weight and concentration because of a resulting reduction in the viscosity of the joint’s synovial fluid. [47] HA has been investigated as a treatment modality for hip pain specifically in the setting of OA and FAI (Table 4).

Table 4.

Overview of Clinical Outcomes in Prospective Literature on Hyaluronic Acid

Study	Type of Study	HA Injection	Pathology	Experimental Group (HA)	Control Group	Outcome
Milgore et al. (2020)	Retrospective analysis	Single injection HYMOVIS ONE	OA	198	–	Lequense Index, NSAID days/month, VAS
Pogliacomi et al. (2018)	Case series	Single injection high MW HA	OA	226	–	WOMAC, HHS
Milgore et al. (2009)	RCT	Two injections, one per month Hyalubrix	OA	20	Mepivacaine 20	Lequense Index, NSAID days/month
Ye et al. (2018)	Meta-analysis of RCTs	Single or double injection various forms of HA	OA	148	PRP 155	VAS, HHS, WOMAC
Brander et al. (2019)	Double blind RCT	Single injection hylan G-F	OA	182	Saline 175	PTGA, WOMAC
Lee et al. (2016)	Double blind RCT cross-over	1 injection; 2 if cross-over	FAI	14 HA first	16 TA first	VAS, HOOS

Abbreviations: HA, hyaluronic acid; RCT, randomized controlled trial; OA, osteoarthritis; VAS, visual analog score; HHS, Harris Hip Score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; PTGA, Patient Global-Self Assessment; JSN, joint space narrowing; TA, triamcinolone acetate; HOOS, Hip Disability and Osteoarthritis Outcome Score; MWs, molecular weights

HA has been studied most extensively for the treatment of OA in the hip. Milgore et al. conducted a multicenter, retrospective analysis of single HA injection involving 198 patients with hip OA (90.9% KL grade II or III) and demonstrated significantly improved pain and function scores according to VAS (5.3 ± 1.9 vs 6.4 ± 2.2; p = 0.004) and Lequesne Index (7.6 ± 2.4 vs 11.5 ± 4.6; p = 0.008) as well as lower NSAID consumption at 6 months (12.8 ± 3.2 days/month, p = 0.007) and 12 months (9.5 ± 2.1 days/month, p = 0.009) post injection compared to baseline. [48] A case series from Pogliacomi et al. investigated the effectiveness of a single intraarticular injection of high molecular weight HA to treat hip OA (Kellgren-Lawrence [KL] grades 1–3). [49•] The authors used HHS and WOMAC outcome scores to evaluate patient response. HSS scores were significantly improved at 3 months (70.2 ± 1.6, p < 0.001), 6 months (75.1 ± 1.5, p < 0.001), and 12 months (72.5 ± 1.7, p < 0.001) post-injection compared to baseline (57.4 ± 1.7). Similarly, WOMAC scores significantly improved at 3 months (52.9 ± 1.8, p < 0.001), 6 months (48.1 ± 1.8, p < 0.001), 12 months (50.3 ± 2.0, p < 0.001) post-injection compared to baseline (62.2 ± 2.0). Additionally, the study substratified treatment response by KL classification and revealed grade II OA had the greatest response to HA from baseline to 3 months according to WOMAC and maintained the comparatively greater response at 6 and 12 months. These studies demonstrated HA can be effective as single-agent treatment in restoring function to patients with hip OA and suggests the effect is maximal in patients with moderate OA.

Comparative studies investigating HA against other treatment modalities have produced mixed results. Milgliore et al. performed a RCT comparing 22 patients injected with HA to 20 patients injected with mepivacaine in patients with hip OA. [50] Using the Lequense index to evaluate outcomes, patients treated with HA had significant improvement compared to the mepivacaine cohort from baseline (7.09 ± 3.78 vs 7.75 ± 4.15; p = 0.30) to 3 months (5.15 ± 5.15 vs 6.53 ± 4.33; p < 0.001) and 6 months (3.94 ± 2.58 vs 6.41 ± 4.14; p < 0.05). Similar to the previous study, patients treated with HA showed significant reduction in NSAID usage at 3 months (2.1 ± 0.4 days/month vs 5.5 ± 3.0 days/month; p < 0.001) and 6 months (1.5 ± 0.5 days/month vs 2.3 ± 1.0 days/month; p < 0.001) compared to the mepivacaine cohort. The authors felt HA injections are an effective treatment for patients with hip OA based on the Lequense index. In a meta-analysis of RCTs comparing 155 patients undergoing PRP versus 148 patients undergoing HA for patients with hip OA (KL grades 1–4), [51••] Ye et al. found that intraarticular PRP demonstrated statistically significant lower VAS scores at 2 months compared to HA (WMD = −0.376, 95% CI: −0.614 to −0.138, p = 0.002); however, there was no significant difference at 6 months (WMD = −0.141, 95% CI: −0.401 to 0.119, p = 0.289) and 12 months (WMD = −0.083, 95% CI: −0.343 to 0.117, p = 0.534). Additionally, there was no difference in HHS (WMD = 0.706, 95% CI: −6.333 to 7.745, p = 0.844) and WOMAC (WMD = −3.134, 95% CI: −6.624 to 0.356, p = 0.078) at 12 months. Again, seeking to understand the comparative effectiveness of HA, Brander et al. performed a multicenter, double-blind RCT with 357 patients who had painful hip OA comparing a single 6-mL HA injection to a single 6-mL placebo saline injection. [52••] The analysis demonstrated significant improvement in both the HA and saline cohorts according to the WOMAC-A1 (−2.19 ± 0.16, p = <0.0001; −2.26 ± 0.17, p = <0.0001), WOMAC-C (−2.05 ± 0.16, p = <0.0001; −2.11 ± 0.16 p = <0.0001), and Patient Global Self-Assessment, PTGA, (−2.00 ± 0.16, p = <0.0001; −2.06 ± 0.17, p = <0.0001). However, there was no statistical difference between the placebo saline and HA group WOMAC-A1 (p = 0.7462), WOMAC-C (p = 0.7894), and PTGA (p = 0.7977). The results of this study were unable to demonstrate a beneficial effect from HA treatment compared to saline placebo in the treatment of hip OA. These studies demonstrate that, when compared to other therapeutic agents, the patient-derived benefit from HA, as well as floor/ceiling effects still must be elucidated.

HA is also being investigated as a modality to treat FAI-related pain by attempting to prevent progression to OA and delay surgical intervention through improved function. [53] In a randomized, double-blind, cross-over investigation comparing 16 patients first injected with triamcinolone acetate and 14 patients first injected with HA for the treatment of FAI, Lee et al. found no significant difference in VAS score reduction (VAS: 3.7 vs 3.7; p = 0.943). [54] However, HOOS demonstrated significant difference in mean improvement for the HA group compared to the triamincolone group (13.8 vs −2.2; p = 0.031). Therefore, the authors concluded that HA is effective at improving function, but not pain when compared to triamcinolone to treat FAI.

In summary, despite an excellent safety profile [55], limited literature yields a lack of robust data in support of HA treating hip pain compared to other treatment modalities. Orthopedic surgeons must be aware there are no official guidelines regarding HA in the hip; therefore, additional research is warranted to identify appropriate clinical indications and future guidelines for HA usage in the hip.

Stem Cells

Stem cells are undifferentiated cells with the ability to rapidly replicate and mature into cells that release desired growth factors and regulators. [56, 57] The characteristics of stem cells beneficial to hip pathology include self-renewal, clonality, and potency. Mesenchymal stem cells (MSCs) are the most frequently used stem cell product to treat OA, FAI, and ONFH (Table 5) due to their ability to differentiate into tissues of interest (osteoblasts, chondrocytes, and adipocytes) and their commercial availability.

Table 5.

Overview of Clinical Outcomes in Prospective Literature on Mesenchymal Stem-Cells

Study	Type of Study	Type of MSCs	Pathology	Experimental Group	Control Group	Outcome
Dall’Oca et al. (2019)	Cohort	Adipose	OA	6	–	VAS, HHS, WOMAC
Rivera et al. (2019)	Case control	Bone marrow concentrate	FAI	40	40	VAS, mHHS, iHOT-33
Wang et al. (2019)	Meta-analysis	Bone	ONFH	275	265	THA, WOMAC, HHS, volume of post-operative necrotic zone

Abbreviations: RCT, randomized controlled trial; ONFH, osteonecrosis of the femoral head; OA, osteoarthritis; FIAS, femoroacetabular impingement syndrome; THA, total hip arthroplasty; VAS, visual analog score; HHS, Harris Hip Score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; mHHS, modified Harris Hip Score; iHOT-33, International Hip Outcome Tool - 33

MSCs can be procured from many anatomic locations; however, the location of extraction has a significant influence on the cells’ ability to differentiate. [58] MSCs acquired from adipose tissue demonstrate inferior chondrogenic capability when compared to bone-marrow derived MSCs. [59] Murata et al. examined the native MSCs in the hip joint for patients with FAI and OA to determine viability and usage potential. They discovered patients with OA had greater colony numbers of MSCs with greater osteogenic and adipogenic potential but decreased viability and less chondrogenic and proliferative potential when compared to patients with FAI; consequently, MSCs from patients with FAI exhibited better potential for stem cell therapy regarding the treatment of OA compared to patients who are already diagnosed with OA. [60]

One difficulty with stem cell treatment is the complexity harvesting and preparing the cells. The process for harvesting bone marrow-derived MSCs includes the following: bone marrow aspiration, gradient centrifugation, mononuclear cells (MNCs) separation, seeding MNCs in culture plate, selecting adherent cells by exchanging culture medium every 2 to 3 days, and finally, expanding to confluency over 7 to 10 days. [61, 62] It has been demonstrated that an increased local load of stem cells can lead to better patient outcomes; [59] however, in order to endorse an optimal concentration or load of cells injected correlating to an outcome, further investigation is required.

Dall’Oca et al. performed a cohort study of 6 patients evaluating adipose derived MSC treatment in early-stage hip OA. [63•] At 6 months post-operatively, significant improvements were recorded in the patients HHS (67.2 ± 3.4 to 84.6 ± 6.3; p < 0.0001), WOMAC (19.8 ± 3.4 to 36.3 ± 4.7; p < 0.0001), and VAS scores (4.6 ± 0.8 to 1.5 ± 0.5; p < 0.0001). No patients worsened or suffered any significant complications during the study. Rivera et al. conducted a case control study comparing forty patients undergoing bone marrow concentrate combined with hip arthroscopic intervention to treat FAI as compared to forty patients undergoing arthroscopic intervention alone. [64] When compared to the control group, the BMC cohort demonstrated significant pain reduction at 12 and 24 months according to VAS and improvement in function at 12 and 24 months post-operative as measured by mHHS and iHOT-22 (0.033; 0.024). While this is a small study, it demonstrated potential for improved outcomes when MSCs are used as an adjunct to arthroscopy of the hip for the treatment of OA.

To evaluate therapy options for surgical core decompression to treat ONFH, Wang et al. conducted a meta-analysis and found 14 RCTs comparing 265 patients undergoing isolated surgical core decompression to 275 patients undergoing bone marrow-derived MSC instilled into the core tract after decompression. [65•] Compared with core decompression alone, the MSC group demonstrated significant decrease in VAS score at 6 months (WMD = −7.08, 95% CI: [−10.68, −3.49]; P = 0.001), 12 months (WMD = −7.28, 95% CI: [−10.16, −4.39]; P = 0.000), and 24 months (WMD = −7.93, 95% CI: [−14.99, −0.87]; P = 0.028) and a decrease in the number of hips undergoing total hip arthroplasty (RR = 0.39, 95% CI: [0.19, 0.78]; P = 0.007), WOMAC score (WMD = −10.56, 95% CI: [−15.84, −5.28]; P = 0.001), and volume of post-operative necrotic zone (WMD = −0.05, 95% CI: [−0.08, −0.02]; P = 0.001). The authors concluded MSC combined with core decompression provided better pain relief and can delay the collapse of the femoral head more effectively compared to isolated surgical core decompression.

It is worth noting there are no official guidelines outlining best use practices for stem cells in orthopedic procedures. Using MSCs adjunctively to treat ONFH has supporting evidence in the literature. Although studies demonstrate benefit from using MSCs in FAI and OA, additional high quality research needs to be performed to more accurately assess efficacy. Surgeons utilizing stem cells to treat hip pain must be knowledgeable regarding different stem cell modalities and a lack of definitive evidence in some cause of hip pain, notably OA and FAI.

Matrix Metalloproteases

Matrix metalloproteases (MMPs) are a collection of enzymes that can break down extracellular matrix protein. [66] Tissue inhibitors of metalloproteinases (TIMPs) are proteins that regulate MMP activity. [67] MMPs are vital for maintaining equilibrium in various tissues, but overexpression of specific MMPs have been implicated in various orthoapedic disease states, including OA and FAI. [68] Specifically, an increased expression of MMP-1 and MMP-2 and a decreased expression of TIMP-1 have been reported in degenerated labral tissues in patients with FAI. [69]

Studies have examined the effectiveness of MMP inhibitors in treating patellar or achilles tendinopathies as well as rheumatoid arthritis and OA in the knee. [70–72] While some surgeons have advocated for the use of MMP inhibitors for hip pathology, the literature lacks investigation of these drugs for hip pathologies. With demonstrated benefits in other joints, further research into the potential effectiveness of MMP inhibitors in the hip is warranted.

Conclusion

The use of biologics as a primary treatment or adjunct to traditional management has shown encouraging results for the treatment of hip pain. Studies have demonstrated safety with minimal complications when using platelet rich plasma, hyaluronic acid, or stem cells to treat hip pain caused by osteoarthritis, femoroacetabular impingement syndrome, tendinopathy, or osteonecrosis of the femoral head. Several studies have been able to demonstrate meaningful clinical results that can improve treatment standards for hip pain; however, additional studies, specifically large randomized controlled ones must be performed to better define the appropriate protocols, indications, and limitations of each treatment modality.

Compliance with Ethical Standards

Kelechi R. Okoroha reports potential conflicts of interest from the following companies: Arthrex (grand and education), Smith & Nephew (education, travel, lodging), Pinnacle (education), Medwest Associates (education), Wright Medical Technology (travel and lodging), Stryker Corporation (travel and lodging).

Toufic R. Jildeh, Muhammad J. Abbas, and Patrick Buckley declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.