Tag Archive | Rotator Cuff

Surgery for Rotator Cuff Tears: The Better of Two Goods

We’re all familiar with the phrase “lesser of two evils,” but I’m an optimist and prefer the phrase “better of two goods.” In the October 2, 2019 issue of JBJS, Ramme et al. compare surgical versus nonsurgical treatment of full-thickness rotator cuff tears. Both cohorts had improved outcomes relative to baseline, but surgical management was the better of two goods.

The authors retrospectively analyzed a prospective cohort of adult patients with full-thickness rotator cuff tears who had elected either surgical or nonsurgical treatment. Ramme et al. utilized propensity score matching to pair up patients in each group according to factors thought to influence outcome, such as age, sex, tear size, chronicity, muscle atrophy, and the Functional Comorbidity Index. This matched-pair analysis is a valiant attempt to eliminate bias that is inherent in retrospective analyses, and this study design also mimics the real-world scenario of shared decision making between physician and patient.

The 2-year follow-up analysis of 107 propensity score-matched patients revealed that both groups improved in 4 patient-reported functional outcomes and pain compared to their baseline measures before treatment. However, the final outcome measurements and magnitude of improvement were statistically greater in the surgical management group (p <0.001).

This study will help shoulder surgeons have more meaningful discussions with their patients about treatment options for full-thickness rotator cuff tears. We know that with proper treatment—either surgical or nonsurgical—patients can expect improvement in pain and function. However, patients who elect surgical management may have the potential for even greater outcomes, and that definitely sounds like the “better of two goods.”

Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media

Glycation and Rotator Cuff Degeneration

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Advanced glycation end products (AGEs) form through a nonenzymatic process by which reducing sugars undergo Maillard rearrangement with amino acids. During rearrangement, the carbonyl group of the sugar reacts with the amino group of the amino acid, producing N-substituted glycosylamine and water.

During cooking, glycation occurs at 140° to 165° C (280° to 330° F), resulting in the browning of foods such as bread and French fries. This nonenzymatic reaction also occurs at human body temperature over decades. AGE formation can decrease the viscoelasticity and tensile strength of human tissue, resulting in increased mechanical stiffness that affects bone, ligaments, cartilage, and menisci. In cartilage, the excessive accumulation of AGEs leads to a more brittle matrix that is susceptible to fatigue and failure. AGEs also contribute to the etiology of several diabetic complications, including adhesive capsulitis of the shoulder.

Rotator cuff degeneration and tears become more common with age. Accumulated mechanical loads and anatomic variation play a large role. The role of AGEs in rotator cuff degeneration and tears has been suspected, but the exact mechanisms remain in question. Investigators recently showed that AGEs have detrimental effects on human rotator cuff-derived cells in vitro and on intact rat infraspinatus tendons ex vivo.1

In Vitro Findings
Rotator cuff-derived cells were obtained from 12 torn cuff edges during supraspinatus tendon repairs in patients with an average age 64.8 years. The cells were cultured in (1) regular medium with 500 μg/mL AGEs (high-AGE group), (2) regular medium with 100 μg/mL AGEs (low-AGE group), and (3) regular medium alone (control group). Cell viability was significantly suppressed in the high-AGE group relative to the control group. Vascular endothelial growth factor secretion was significantly greater in the high- and low-AGE groups than in the control group. Immunofluorescence stain demonstrated enhancement of hypoxia-inducible factor-1α, reactive oxygen species expressions, and cell apoptosis in the high- and low-AGE groups compared with the control group.

Ex Vivo Findings
Four upper limbs with intact rotator cuff tendons were harvested from 10-week old rats and cultured in regular medium or regular medium with 500 μg/mL AGEs. Mechanical testing showed significantly higher tensile strength in the control group than in the AGE group.

These results beg the question as to whether reduction of AGEs might delay or prevent rotator cuff senescence-related degeneration.

Reference

  1. Mifune Y, Inui A, Muto T, Nishimoto H, Kataoka T, Kurosawa T, Yamaura K, Mukohara S, Niikura T, Kokubu T, Kuroda R. Influence of advanced glycation end products on rotator cuff. J Shoulder Elbow Surg. 2019 Aug;28(8):1490-1496. doi: 10.1016/j.jse.2019.01.022. Epub 2019 Apr 10. PMID: 30981546

Assessing Fatty Infiltration in Rotator Cuff Tears: MRI vs Ultrasound

In the setting of rotator cuff injuries, higher degrees of fatty infiltration into cuff muscles are positively correlated with higher repair failure rates and worse clinical outcomes. MRI continues to be the gold standard imaging modality for evaluating fatty infiltration of the rotator cuff, but ultrasound represents another viable modality for that assessment—at considerably lower cost. Such is the conclusion of Tenbrunsel et al. in a recent issue of JBJS Reviews.

The authors reviewed 32 studies that investigated imaging modalities used to assess fatty infiltration and fatty atrophy. They found that grading fatty infiltration using ultrasound correlated well with grading using MRI. However, the authors identified difficulties distinguishing severe from moderate fatty infiltration on ultrasound, but they added that discerning mild from moderate fatty infiltration is more important clinically. Tenbrunsel et al. also mention sonoelastography, which measures tissue elasticity and can also be used to help determine the severity of fatty atrophy of the rotator cuff.

Overall, the trade-off between MRI and ultrasound comes down to higher precision with the former and lower cost with the latter.

For more information about JBJS Reviewswatch this video featuring JBJS Editor-in-Chief Dr. Marc Swiontkowski.

What’s New in Sports Medicine 2019

Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.

This month, Albert Gee, MD, a co-author of the April 17, 2019 “What’s New in Sports Medicine,” selected the five most clinically compelling findings from among the 30 noteworthy studies summarized in the article.

Anterior Cruciate Ligament (ACL) Reconstruction

–Norwegian researchers randomized 120 patients to undergo either single-bundle or double-bundle ACL reconstruction and followed them for 2 years.1 They found no difference between the 2 techniques in any patient-reported outcome, knee laxity measurements, or activity levels. These results, along with the preponderance of evidence from other comparative trials over the last 5 years, strongly suggest that routine use of 2 bundles to primarily reconstruct a torn ACL adds no clinical benefit over a well-positioned single-bundle reconstruction.

Knee Cartilage Repair

–A randomized study compared long-term patient outcomes after knee cartilage repair using microfracture versus mosaicplasty.2 Included patients had 1 or 2 focal femoral lesions measuring between 2 and 6 cm2. Better outcomes after a minimum of 15 years of follow-up were found in the mosaicplasty group. Although there were only 20 patients in each arm, the Lysholm-score differences between the groups were both clinically important and statistically significant. More patients in the mosaicplasty group than in the microfracture group said they would have the surgery again, knowing their 15-year outcome.

Rotator Cuff

–UK researchers randomized 313 patients with ≥3 months of subacromial pain and an intact rotator cuff who had completed a nonoperative program of physical therapy and injection to 1 of 3 groups: arthroscopic subacromial decompression, diagnostic arthroscopy (“sham” surgery), or no intervention.3 At 6 months and 1 year, all groups demonstrated statistically significant and clinically important improvement, but patient-reported outcome scores were significantly better in both surgical groups compared with the no-treatment group. The data suggest that patients such as these improve over time, regardless of management, but that surgical decompression  may offer a slight benefit over nonoperative management because of the placebo effect.

–A randomized controlled trial investigated the effect of a formal preoperative education program (2-minute video plus handout)4 about postoperative narcotic use, side effects, dependence risk, and addiction potential among >130 patients undergoing arthroscopic rotator cuff repair surgery. The education group consumed 33% less narcotic medication at 6 weeks and 42% less at 12 weeks compared with the control group. Among the more than one-quarter of the patients who had used opioids prior to surgery, those randomized to the education group were 6.8 times more likely than controls to discontinue narcotic use during the study period.

Hip Arthroscopy

–A randomized controlled trial of >300 patients compared hip arthroscopy and “best conservative care” for treating femoroacetabular impingement (FAI).5 Only 8% of patients crossed over from conservative care to the surgical group. The mean adjusted difference in iHOT-33 scores at 1 year was 6.8, in favor of hip arthroscopy. However, adverse events were more frequent in the arthroscopy cohort, and a within-trial economic evaluation suggested that hip arthroscopy was not cost-effective compared with conservative care during the 1-year trial period.

References

  1. Aga C, Risberg MA, Fagerland MW, Johansen S, Trøan I, Heir S, Engebretsen L. No difference in the KOOS Quality of Life Subscore between anatomic double-bundle and anatomic single-bundle anterior cruciate ligament reconstruction of the knee: a prospective randomized controlled trial with 2 years’ follow-up. Am J Sports Med.2018 Aug;46(10):2341-54. Epub 2018 Jul 18.
  2. Solheim E, Hegna J, Strand T, Harlem T, Inderhaug E. Randomized study of long-term (15-17 years) outcome after microfracture versus mosaicplasty in knee articular cartilage defects. Am J Sports Med.2018 Mar;46(4):826-31. Epub 2017 Dec 18.
  3. Beard DJ, Rees JL, Cook JA, Rombach I, Cooper C, Merritt N, Shirkey BA, Donovan JL, Gwilym S, Savulescu J,Moser J, Gray A, Jepson M, Tracey I, Judge A, Wartolowska K, Carr AJ; CSAW Study Group. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial. Lancet. 2018 Jan 27;391(10118):329-38. Epub 2017 Nov 20.
  4. Syed UAM, Aleem AW, Wowkanech C, Weekes D, Freedman M, Tjoumakaris F, Abboud JA, Austin LS. Neer Award 2018: the effect of preoperative education on opioid consumption in patients undergoing arthroscopic rotator cuff repair: a prospective, randomized clinical trial. J Shoulder Elbow Surg.2018 Jun;27(6):962-7. Epub 2018 Mar 26.
  5. Griffin DR, Dickenson EJ, Wall PDH, Achana F, Donovan JL, Griffin J, Hobson R, Hutchinson CE, Jepson M,Parsons NR, Petrou S, Realpe A, Smith J, Foster NE; FASHIoN Study Group. Hip arthroscopy versus best conservative care for the treatment of femoroacetabular impingement syndrome (UK FASHIoN): a multicentre randomised controlled trial. Lancet. 2018 Jun 2;391(10136):2225-35. Epub 2018 Jun 1.

March 2019 Article Exchange with JOSPT

In 2015, JBJS launched an “article exchange” collaboration with the Journal of Orthopaedic & Sports Physical Therapy (JOSPT) to support multidisciplinary integration, continuity of care, and excellent patient outcomes in orthopaedics and sports medicine.

During the month of March 2019, JBJS and OrthoBuzz readers will have open access to the JOSPT article titled “The Impact of Decreased Scapulothoracic Upward Rotation on Subacromial Proximities.”

In this shoulder kinematics study of 40 people classified as having high or low scapulothoracic upward rotation, contact between the coracoacromial arch and rotator cuff tendon occurred in 45% of participants. The relatively low prevalence of contact suggests that subacromial rotator cuff compression may be less common than traditionally presumed.

What We Owe our Patients—Continuous Improvement

It has been said that a surgeon’s skill and judgment account for between 80% and 90% of a patient’s outcome. (I believe this is true for both surgical and nonsurgical treatments.) Throw in a physician’s ability to listen and clearly communicate with patients, and I am sure we are approaching that 90% mark. That means that when we conduct randomized trials comparing two types of knee prostheses or fracture-fixation constructs, we are, in essence, scrutinizing only about 10% of the patient-outcome equation. 

So how do we best evaluate the 90% of the outcome equation that is physician-dependent? With the advent of “bundled” episodes of care, the orthopaedic community has emphasized the need for risk-adjustment in evaluating surgeon performance. Clearly, there are certain patients who are at higher risk for worse outcomes than others, such as those with diabetes, nicotine abuse, advanced age, and less social support.

In the December 19. 2018 issue of The Journal, Thigpen et al. report on patient outcomes 6 months after arthroscopic rotator cuff repair in 995 patients treated by 34 surgeons. The authors evaluated patient-reported outcomes from all surgeons using both unadjusted and adjusted ASES change scores. The adjusted scores took into account about a dozen baseline patient characteristics, including symptom severity, functional and mental scores, medical comorbidities, and Workers’ Compensation status. Relative to performance rankings based on unadjusted data, risk adjustment significantly altered the rankings for 91% of the surgeons.  According to the authors, these findings “underpin the importance of risk-adjustment approaches to accurately report surgeon performance.”

But what is of even greater interest to me is that risk adjustment led to positive increases in patient outcomes for some surgeons, while decreasing outcomes for other surgeons. Some of these outcome differences likely reflect each surgeon’s patient-selection biases, but in the words of the authors, the numbers strongly suggest “that there is a meaningful, distinguishable difference in patient outcomes between surgeons.”

What should we do with this data? In my opinion, surgeons in the lower 80%  of the list, at least, ought to be engaging with the surgeons who demonstrated the highest adjusted performance scores to understand what is helping them obtain outcomes that are superior to everyone else’s. We owe it to our patients to understand what our personal outcomes are for at least the most common conditions we treat. I believe it borders on unethical behavior to quote patients outcome data of a procedure from the peer-reviewed literature when we have no idea how our personal results compare. Orthopaedic surgeons need to be more active in lobbying our groups and health systems to support best practices for clinical outcome data collection and reporting so we can, in turn, improve our care by adopting the best practices of the surgeons with the best outcomes.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

What’s New in Orthopaedic Rehabilitation 2018

Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.

This month, Nitin Jain, MD, MSPH, a co-author of the November 21, 2018 Specialty Update on Orthopaedic Rehabilitation, summarized the most clinically compelling findings from among the more than 40 noteworthy studies summarized in the article.

Acute Pain Management

–A randomized double-blind study comparing 4 two-way combinations of analgesics (three of which contained an opioid medication)1 in emergency-department patients experiencing acute extremity pain found no significant between-group differences in mean pain scores at 1 and 2 hours after medication administration.

Total Hip Arthroplasty

–A randomized clinical trial of >100 patients who underwent unilateral total hip arthroplasty found no significant differences in functional outcomes between a group that participated after surgery in a self-directed home exercise program and a group that participated in a standardized physical therapy program.

Concussion

–An assessment of brain tissue from 202 American football players2 whose organs were donated for neuropathological evaluation found that 87% had evidence of chronic traumatic encephalopathy (CTE). Analysis of brain tissue from former NFL players in the cohort showed that nearly all had severe CTE.

Rotator Cuff Tears

–A study following the natural progression of full-thickness, asymptomatic, degenerative rotator cuff tears found that patients with fatty muscle degeneration were more likely to experience tear-size progression than those without fatty infiltration.

Low Back Pain

–A study consolidating data from 3 separate randomized trials attempted to evaluate the efficacy of radiofrequency (RF) neurotomy for treating a heterogeneous collection of diagnoses that commonly result in low back pain.3 No significant or clinically important differences were found when the RF procedure was compared with a standardized exercise program. The number needed to treat for all 3 arms of the study ranged from 4 to 8, with a median of 5. Some have called into question the methods of this study, particularly the diagnostic criteria used for patient inclusion and the potential inaccuracy of lumping together heterogeneous diagnoses.

References

  1. Chang AK, Bijur PE, Esses D, Barnaby DP, Baer J. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
  2. Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML,Solomon TM, Nowinski CJ, McHale L, Cormier KA, Kubilus CA, Martin BM, Murphy L, Baugh CM, Montenigro PH, Chaisson CE, Tripodis Y, Kowall NW, Weuve J, McClean MD, Cantu RC,Goldstein LE, Katz DI, Stern RA, Stein TD, McKee AC. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA. 2017 Jul 25;318(4):360-70.
  3. Juch JNS, Maas ET, Ostelo RWJG, Groeneweg JG, Kallewaard JW, Koes BW, Verhagen AP, van Dongen JM, Huygen FJPM, van Tulder MW. Effect of radiofrequency denervation on pain intensity among patients with chronic low back pain: the Mint randomized clinical trials. JAMA. 2017;318(1):68-81.

What’s New in Shoulder and Elbow Surgery 2018

Shoulder & elbowEvery month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.

This month, Robert Tashjian, MD, co-author of the October 17, 2018 Specialty Update on shoulder and elbow surgery, selected the most clinically compelling findings from among the 36 studies summarized in the Specialty Update.

Progression of Primary Osteoarthritis
–A study evaluating the relationship between glenoid erosion patterns and rotator cuff muscle fatty infiltration found that fatty infiltration was associated with B3 glenoids, increased pathologic glenoid retroversion, and increased joint-line medialization. The authors recommend close observation of patients with B-type glenoids, as the progression of glenoid erosion is more likely in B-type than A-type glenoids.

Perioperative Pain Management
–In a randomized controlled trial of perioperative pain management in patients undergoing primary shoulder arthroplasty, narcotic consumption during the first 24 postoperative hours was similar between a group that received interscalene brachial plexus blockade and a group that received intraoperative soft-tissue infiltration of liposomal bupivacaine. The interscalene group had lower VAS pain scores at 0 and 8 hours postoperatively; both groups had similar VAS pain scores at 16 hours; and the soft-tissue infiltration group had lower pain scores at 24 hours postoperatively.

Rotator Cuff
–In a reevaluation of patients with nonoperatively treated chronic, symptomatic full-thickness rotator cuff tears that had become asymptomatic at 3 months, researchers found that at a minimum of 5 years, 75% of the patients remained asymptomatic.1 The Constant scores in the group that remained asymptomatic were equivalent at 5 years to those who initially underwent surgical repair. While these findings suggest that nonoperative treatment can yield clinical success at 5 years, the authors caution that “individuals with substantial tear progression or the development of atrophy will likely have a worse clinical result.”

–A recent study of the progression of fatty muscle degeneration in asymptomatic shoulders with degenerative full-thickness rotator cuff tears found that larger tears at baseline had greater fatty degeneration, and that tears with fatty degeneration were more likely to enlarge over time. Median time from tear enlargement to fatty degeneration was 1 year. Because the rapid progression of muscle degeneration seems to occur with increasing tear size, such patients should be closely monitored if treated nonoperatively.

Shoulder Instability in Athletes
–An evaluation of outcomes among 73 athletes who had undergone Latarjet procedures found that, after a mean follow-up of 52 months, ASES scores averaged 93. However, only 49% of the athletes returned to their preoperative sport level; 14% decreased their activity level in the same sport; and 12% changed sports altogether. While the Latarjet can help stabilize shoulders in athletes, the likelihood is high that the athlete won’t return to the same level in the same sport after the procedure.

Reference

  1. Boorman RS, More KD, Hollinshead RM, Wiley JP, Mohtadi NG, Lo IKY, Brett KR. What happens to patients when we do not repair their cuff tears? Five-year rotator cuff quality-of-life index outcomes following nonoperative treatment of patients with full-thickness rotator cuff tears. J Shoulder Elbow Surg. 2018 Mar;27(3):444-8.

JBJS 100: Massive Rotator Cuff Tears, Continuous Passive Motion

JBJS 100Under one name or another, The Journal of Bone & Joint Surgery has published quality orthopaedic content spanning three centuries. In 1919, our publication was called the Journal of Orthopaedic Surgery, and the first volume of that journal was Volume 1 of what we know today as JBJS.

Thus, the 24 issues we turn out in 2018 will constitute our 100th volume. To help celebrate this milestone, throughout the year we will be spotlighting 100 of the most influential JBJS articles on OrthoBuzz, making the original content openly accessible for a limited time.

Unlike the scientific rigor of Journal content, the selection of this list was not entirely scientific. About half we picked from “JBJS Classics,” which were chosen previously by current and past JBJS Editors-in-Chief and Deputy Editors. We also selected JBJS articles that have been cited more than 1,000 times in other publications, according to Google Scholar search results. Finally, we considered “activity” on the Web of Science and The Journal’s websites.

We hope you enjoy and benefit from reading these groundbreaking articles from JBJS, as we mark our 100th volume. Here are two more:

The Outcome and Repair Integrity of Completely Arthroscopically Repaired Large and Massive Rotator Cuff Tears
L M Galatz, C M Ball, S A Teefey, W D Middleton, K Yamaguchi: JBJS, 2004 February; 86 (2): 219
In one of the earliest studies to investigate the relationship between the anatomic integrity of arthroscopic rotator cuff repair and clinical outcome, these authors found that the rate of recurrent defects was high but that at 12 months after surgery, patients experienced excellent pain relief and functional improvement. However, at the 2-year follow-up, the clinical results had deteriorated substantially. Investigations into the relationship between cuff-repair integrity and clinical outcomes are ongoing.

The Biological Effect of Continuous Passive Motion on the Healing of Full-thickness Defects in Articular Cartilage: An Experimental Investigation in the Rabbit
R B Salter, D F Simmonds, B W Malcolm, E J Rumble, D Macmichael, N D Clements: JBJS, 1980 January; 62 (8): 1232
In this paper, Salter and colleagues hypothesized that “continuous passive motion [CPM] of a synovial joint in vivo would have a beneficial biological effect on the healing of full-thickness defects in articular cartilage.” They found that CPM stimulated more rapid and complete cartilage restoration than either immobilization or intermittent active motion, and since then CPM has been commonly used in humans after cartilage repair. However, CPM’s actual efficacy in people—after cartilage repair or total knee arthroplasty—remains controversial.

JBJS 100: Shoulder Impingement and Distraction Osteogenesis

JBJS 100Under one name or another, The Journal of Bone & Joint Surgery has published quality orthopaedic content spanning three centuries. In 1919, our publication was called the Journal of Orthopaedic Surgery, and the first volume of that journal was Volume 1 of what we know today as JBJS.

Thus, the 24 issues we turn out in 2018 will constitute our 100th volume. To help celebrate this milestone, throughout the year we will be spotlighting 100 of the most influential JBJS articles on OrthoBuzz, making the original content openly accessible for a limited time.

Unlike the scientific rigor of Journal content, the selection of this list was not entirely scientific. About half we picked from “JBJS Classics,” which were chosen previously by current and past JBJS Editors-in-Chief and Deputy Editors. We also selected JBJS articles that have been cited more than 1,000 times in other publications, according to Google Scholar search results. Finally, we considered “activity” on the Web of Science and The Journal’s websites.

We hope you enjoy and benefit from reading these groundbreaking articles from JBJS, as we mark our 100th volume. Here are two more:

Anterior Acromioplasty for Chronic Impingement Syndrome in the Shoulder
C S Neer: JBJS, 1972 January; 54 (1): 41
For many years after its publication, this 1972 JBJS article changed the treatment approach for patients with shoulder disability. But more recently, arthroscopy and magnetic resonance imaging arthrography have identified other painful non-impingement shoulder conditions. Consequently, the liberal use of acromioplasty to treat “impingement” is being replaced by a trend toward making an anatomic diagnosis, such as a partial or complete rotator cuff tear, and performing aggressive rehabilitation prior to corrective surgery.

Use of the Ilizarov Technique for Treatment of Non-union of the Tibia Associated with Infection
G K Dendrinos, S Kontos, E Lyritsis: JBJS, 1995 June; 77 (6): 835
This case series described a technique of bone transport with bridging achieved by distraction osteogenesis. The defects averaged 6 cm, the mean duration of treatment was 10 months, and the mean time to union was 6 months. More recent research has focused on augmenting the osteogenic potential of tissues in the distraction gap with substances such as bone morphogenetic protein, platelet-rich plasma, and mesenchymal stem cells.